Grading the Overall Quality of Evidence
The quality of the overall body of evidence was then determined on the basis of the quality grades for all outcomes of interest, taking into account explicit judgments about the relative importance of each outcome. The resulting 4 final categories for the quality of overall evidence were: “A,” “B,” “C,” or “D” (Table 6).
This category was designed to allow the WG to issue advice on topics not explicitly addressed in the systematic review. The current guideline is notable in that many clinically important topics in living donation are not ethically or practically amenable to randomized controlled study designs and have not been not addressed in controlled observational studies. Thus, many recommendations were generated on topics deemed important for the care of living donors that were not addressed by eligible studies in the systematic evidence review. These recommendations were developed using other literature and WG consensus, and are therefore ‘ungraded.’
As a result, very few of the guideline recommendations were rated for strength of the recommendation and quality of the evidence. This is not to say that there was no evidence for such “ungraded” guideline recommendations, but the WG and ERT only graded recommendations that were included as part of the ERT’s systematic review and fulfilled the a priori search inclusion criteria. The WG felt that such “good practice statements” were necessary to address important aspects of donor care, and their preponderance may be attributed to numerous reasons as stated in Table 7.11 When the WG determined that there was evidence for a recommendation that was outside the scope of the ERT review, this was indicated in the rationale for that recommendation. It is also important to note that when recommendations from other KDIGO WGs were modified for the purpose of this guideline, the prior grading was provided in the rationale but the adapted recommendations were not graded so as to limit grading only to statements derived from the de novo systematic review performed for this guideline.
Developing the Recommendations
Draft recommendation statements were developed by the WG cochairs and WG members with input from all WG members. The health risks and benefits associated with each recommendation were considered when formulating the guideline, as well as information on patient preferences when available. Recommendation statements were revised in a multi-step process during teleconferences and 2 face-to-facemeetings, as well as in subsequent emails. All WG members provided feedback on initial and final drafts of the recommendations.
Format for Recommendations
Each chapter contains one or more specific recommendations. When pertinent evidence was available in the systematic review, the strength of recommendation is indicated as level 1 or level 2 and the quality of the supporting evidence is shown as A, B, C, or D. When the ERT search parameters did not identify evidence from eligible studies pertinent to a recommendation, the statement is ungraded. In all cases, recommendation statements and grades (if applicable) are followed by rationale text summarizing the key points of the evidence base and the judgments supporting the recommendations. Research recommendations for future work to help resolve current uncertainties are also outlined at the conclusion of each chapter.
Limitations of Systematic Review Approach
Although the literature searches were intended to be comprehensive, they were not exhaustive. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. However, any important studies known to domain experts that were missed by the electronic literature searches were added to retrieved articles and reviewed by the WG.
Review of Guideline Development Process
Several tools and checklists have been developed to assess the quality of the methodological process for systematic review and guideline development. These include the Appraisal of Guidelines for Research and Evaluation (AGREE 2) criteria,12 the Conference on Guideline Standardization (COGS) checklist,13 and the Institute of Medicine’s recent Standards for Systematic Reviews14 and Clinical Practice Guidelines We Can Trust.15Table 8 displays the criteria which correspond to the COGS checklist and how each one is addressed in this guideline.
Public Comment and Revision
A draft of the guideline was distributed for open public review in November 2015. The guideline was revised into final form by WG cochairs and members. A point-by-point response to all public comments is available online (Supplemental Appendix E, SDC,http://links.lww.com/TP/B433). All WG members approved the final version of the guideline.
CHAPTER 1: GOALS OF EVALUATION, FRAMEWORK FOR DECISION-MAKING, AND ROLES AND RESPONSIBILITIES
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 1 and therefore the following recommendations are “Not Graded.”
Goals and Principles of Evaluation
- 1.1: The donor candidate’s willingness to donate a kidney voluntarily without undue pressure should be verified.
- 1.2: The benefits and risks of kidney donation should be assessed for each donor candidate.
- 1.3: The decision to accept or exclude a donor candidate should follow transplant program policies.
- 1.4: Donor candidate decision-making should be facilitated through education and counseling on individualized risks and benefits, methods to minimize risks, and the need for postdonation follow-up.
- 1.5: For an accepted donor candidate, a plan for donation care and follow-up should be formulated to minimize risks of donation.
- 1.6: For an excluded donor candidate, a plan for any needed care and support should be formulated.
Framework for Decision-Making
- 1.7: The donor candidate, the intended recipient, and the transplant program must all agree with the decision to proceed with donation in concordance with transplant program policies and informed consent.
- 1.8: Transplant program policies must be defensible based on current understanding of the risks and benefits of kidney donation, and should apply to all donor candidates evaluated at the center.
- 1.9: Each transplant program should establish policies describing psychosocial criteria that are acceptable for donation, including any program constraints on acceptable relationships between the donor candidate and the intended recipient.
- 1.10: All donor candidates should be evaluated using the same criteria, regardless of whether donation is directed towards a designated recipient.
- 1.11: Each transplant program should establish policies describing medical criteria that are acceptable for donation, addressing when possible, numeric thresholds for short-term and long-term postdonation risks above which the transplant program will not proceed with donation. Risks should be expressed as absolute rather than relative risks.
- 1.12: When possible, transplant programs should provide each donor candidate with individualized quantitative estimates of short-term and long-term risks from donation, including recognition of associated uncertainty, in a manner that is easily understood by donor candidates.
- 1.13: Transplant programs should evaluate donor candidate risks in comparison to predetermined thresholds for acceptance. If a donor candidate’s postdonation risk is above the transplant program’s acceptable risk threshold, the risk is not acceptable for donation. If a donor candidate’s postdonation risk is below the transplant program’s acceptable risk threshold, the candidate makes the decision whether or not to proceed with donation.
- 1.14: If a donor candidate is not acceptable, the transplant program should explain the reason for nonacceptance to the donor candidate.
- 1.15: Transplant programs should protect donor candidate’s privacy regarding the evaluation, including all considerations in the decision to donate or not.
Roles and Responsibilities
- 1.16: A multidisciplinary transplant program team knowledgeable in kidney donation and transplantation should evaluate, care for, and formulate a plan for donor care including long-term follow-up.
- 1.17: Transplant programs should minimize conflict of interest by providing at least one key team member not involved in the care or evaluation of the intended recipient who evaluates the donor candidate and participates in the determination of donor acceptance.
- 1.18: Transplant programs should conduct as efficient a donor evaluation as possible, meeting the needs of donor candidates, intended recipients and transplant programs.
Goals and Principles of Donor Evaluation
Evaluation of candidates for living kidney donation requires balancing ethical principles of autonomy, beneficence, nonmaleficence, voluntarism and justice.16 Determining acceptability or nonacceptability of donor candidates requires an assessment of their potential risks and anticipated benefits of donation, independent of intended recipient issues. Donation must be voluntary (autonomous), and the motivation for donation must be altruistic – to satisfy a well-considered desire to help another person. There must be protection from undue pressure or coercion at every step in the evaluation and donation process, including the option to confidentially withdraw from the evaluation or to decline to donate at any time with the full support of the transplant program.17 In addition to these ethical principles, protection of patient privacy must be ensured. However, information regarding donor lifestyle, exposures or medical history that increase the risk for transmission of disease may need to be disclosed to the intended recipient for donation and transplantation to proceed; donor candidates should be given the opportunity to withdraw if they do not consent to sharing relevant personal health information in such circumstances.
Preservation of donor candidate autonomy and minimization of short-term and long-term risks are high priorities in the practice of living donation. The transplant program has the responsibility to disclose anticipated risks and benefits to the donor candidate and intended recipient, tailored when possible for the characteristics of each donor candidate.18 The donor candidate must have adequate time to make an informed decision and must accept the need for long-term follow-up. The transplant program must offer support for decision-making through education and the informed consent process, and has a responsibility to confirm that the donor candidate understands the likely risks and benefits of donation. The transplant program makes the final determination of acceptance of the donor candidate, based on the program’s policies. The transplant program must have a mechanism for resolving disagreement among team members regarding acceptability of donor candidates that avoids conflicts of interest.
A Quantitative Framework for Equitable Decision Making
There will always be risks to living kidney donation. A central objective of donor candidate evaluation and selection is to minimize risks of short-term and long-term adverse outcomes after donation, and to ensure the risks are acceptable. Consistent, transparent and defensible decision-making to accept or decline a living kidney donor candidate has been limited by the lack of an evidence-based means to provide individualized, quantitative estimates of postdonation risk. Prior living kidney donor guidelines describe postdonation risk in relation to single predonation characteristics assessed in isolation, and generally agree on the single predonation characteristics that are associated with higher risks of poor postdonation outcomes. However, prior guidelines often differ on the recommended specific threshold for a characteristic that should be used to accept or decline living donor candidates, and are unclear about how values above or below the threshold alter the risk of postdonation outcomes. There have been several calls to improve the current status quo, and to support better shared decision making between donor candidates and their transplant professionals.16,19-21
An important advance is quantification of the combined impact of all of a donor candidate’s predonation demographic (eg, age, sex, and race) and health characteristics at the time of evaluation (eg, kidney function, blood pressure [BP], body mass index [BMI], and so on) on the risk of serious adverse outcomes after donation. Serious postdonation adverse outcomes can be surgical, medical or psychosocial, and may occur during the perinephrectomy period, in a fixed period of long-term follow-up (eg, 15 years after donation), or for the remaining lifespan of the donor.
As described within this overall framework, a transplant program can use various methods to establish its threshold for acceptable outcomes after kidney donation. For example, if a transplant program decides a lifetime postdonation risk of kidney failure of up to 5% is acceptable, and if a candidate’s projected risk is estimated to be above this threshold, the program should decline this candidate as a donor. Donor candidate autonomy does not overrule medical judgment and transplant professionals are ethically justified to decline a donor candidate when they believe the risk of poor postdonation outcomes is too high.22 A poor outcome can have a very negative impact on the donor, on their recipient, and on public opinions about living donation.
Each transplant program should strive to develop and communicate a quantitative threshold of “acceptable risk” for each serious postdonation adverse outcome it wishes to avoid. Thresholds should be both evidence-based and consensus-based, and there are various sources of evidence and processes by which consensus can be achieved. Once established, a threshold should be applied consistently and transparently for all donor candidates evaluated by a program (unless subsequently revised). When a donor candidate’s estimated risk is below the acceptable risk threshold, the transplant program should accept a donor candidate, and it should be the candidate’s decision whether or not to proceed with living kidney donation after being informed of the risks. When a candidate’s estimated risk is above the acceptable threshold, the transplant program is justified in declining the candidate and can ground its decision in a quantitative framework (Figure 3).
During the development of this guideline we have advanced concepts and analyses to support this framework and approach. Here we discuss certain serious adverse outcomes and their amenability to quantitative risk estimation. We focus particularly on the postdonation development of kidney failure requiring dialysis or transplantation because it is a central outcome of a donor candidate’s long-term risk. Finally, we describe the path for future work necessary to strengthen this framework, which includes the need for additional data.
The incidence of perioperative death after living kidney donation is low. The 90-day all-cause mortality in a recent United States (US) study of 80 347 donors was reported to be approximately 1 in 3000 (0.03%) based on 25 deaths.23 Similar rates have also been reported in other studies.24,25 Given the low incidence of perioperative mortality, estimates for predonation characteristics that alter the risk of perioperative death are imprecise. For example, in this same study,23 a predonation history of hypertension was associated with a 1 in 270 risk of 90-day mortality. However, this estimate was based only on 2 observed deaths, and the estimate would have substantially changed if 1 more or less death was observed; the 95% CI for the estimate was also wide, ranging from 1 in 75 to 1 in 2220. Thus, even if a transplant program defines an acceptable risk threshold for perinephrectomy mortality (for example, an incidence less than 1 in 1000), it will be difficult at this time to reliably determine a given donor candidate’s estimated risk of this outcome according to their profile of predonation characteristics.
With respect to perioperative complications, the ERT identified 2 systematic reviews that examined perinephrectomy outcomes in relation to demographic and health characteristics of accepted donors. The ERT rated the quality of this evidence as very low (Evidence Report Tables 6 and 7, SDC,http://links.lww.com/TP/B434). In one review, a group of selected older donors (mean age, 66 years; range, 60 to 85 years at donation) did not differ statistically from a group of younger donors in their operative time, intraoperative blood loss, and length of hospital stay.26 In both reviews, groups of selected obese donors (mean BMI of 34.5 kg/m2; range 32-39 kg/m2) did not differ statistically from groups of nonobese donors in their rates of perioperative complications, operative time, blood loss and length of hospital stay.26,27
Since then a large US study examined predonation characteristics associated with a higher risk of donor nephrectomy-related complications (as assessed through administrative data rather than adjudication, using a composite outcome of digestive, respiratory, procedural, urinary, hemorrhage, infectious or cardiac complications).28 In this study, where each donor candidate characteristic was considered by itself (rather than as a combination of characteristics), complication rates were higher in men versus women (9.6% vs 7.2%); among African Americans (10.4%) and whites (8.7%) compared with other racial groups (6.3%); among donors without private insurance (8.5%) compared with those who had private insurance (7.3%); and among donors with hypertension (17.7%) compared with those without hypertension (7.9%).
A subsequent study integrated national US donor registry data from 2008 to 2012 with administrative records from a consortium of 98 academic hospitals and found that 16.8% of donors experienced a diagnosis or procedure for a perinephrectomy complication, most commonly gastrointestinal (4.4%), bleeding (3.0%), respiratory (2.5%), and surgical/anesthesia-related injuries (2.4%).29 Major complications, defined as Clavien severity level 4 or 5, were identified in 2.5% of donors. After adjustment for demographic, clinical (including comorbidities), procedure, and center factors, compared with white donors, African Americans had significantly higher risks (P < 0.05) of experiencing any complication (18.2% vs 15.5%) and of experiencing major complications (3.7% vs 2.2%). Other significant correlates of major complications included obesity, predonation blood disorders, psychiatric conditions, and robotic nephrectomy, while greater annual hospital volume predicted lower risk.
As future data become available, it may become possible for transplant programs to estimate the risk of well-defined, serious perioperative complications according to a donor candidate’s individual profile of baseline characteristics, and to compare these estimates to a threshold of acceptable risk to inform donor acceptance decisions.
Donating a kidney is a decision with lifetime implications for the donor. While there are many outcomes to consider after kidney donation, a central outcome directly related to having one kidney removed is the long-term risk of developing kidney failure requiring dialysis or transplantation, commonly referred to as ESKD. Donor candidates often have a good understanding of the health effects of kidney failure, as their reason to donate is to treat the kidney failure of their intended recipient. For these reasons, we have grounded a quantitative framework for medical evaluation and acceptance of donor candidates on the long-term risk of postdonation kidney failure.
Each donor candidate has a long-term risk (cumulative incidence) of developing kidney failure that is influenced by the combination of risks conferred by their demographic and health characteristics at the time of evaluation plus risk attributable to donation (Figure 4). Demographic characteristics include age, sex, and race. Health characteristics include glomerular filtration rate (GFR), albuminuria, BMI, BP, diabetes status, smoking history, family history of kidney disease, and other factors. The risk attributable to donation may also vary according to demographic and health characteristics. Minimizing the lifetime risk of kidney failure in accepted donors is important to safeguard the practice, regardless of the degree to which it can be established that donation contributed to the risk of kidney failure.
Challenges to determining the postdonation lifetime risk of kidney failure based on current studies include limitations of study follow-up (the largest studies followed most donors for less than 2 decades rather than for their lifetime).30 The risk of kidney failure after donation is nonlinear, and is expected to be higher later (≥10 years) than earlier (<10 years) after donation.31 When the WG was convened, 2 recent studies reported that the risk of kidney failure is higher in donors compared with risk among nondonors with similar baseline demographics. The ERT assessed the quality of evidence from these 2 studies as moderate (Table 2 of Slinin et al3).30,32 Available data suggest that the average donation-attributable risk of kidney failure is approximately 27 per 10 000 (0.3%) at 15 years,30 but there is substantial uncertainty in the estimate, and there are not sufficient data to project lifetime donation-attributable risk. Furthermore, the extent to which donation-attributable risk varies according to individual health characteristics is not known,33,34 although available evidence suggests there is higher donation-attributable risks in some subgroups, such African Americans compared with white donors.30
Existing large population-based studies can help estimate the long-term risk of treated kidney failure in the absence of donation, based on a candidate’s predonation health characteristics. Furthermore, if the risk of kidney failure attributable to donation becomes more precisely understood in relation to an individual’s profile of baseline characteristics, then demographic-related, health status related, and donation-attributable risks can be aggregated to project individualized estimates of long-terms risks of postdonation kidney failure.
To help advance this paradigm, we enlisted the help of the CKD-Prognosis Consortium (CKD-PC) to develop a tool to project the 15-year and lifetime incidence of kidney failure in the absence of donation based on demographic and health characteristics at the time of evaluation in low-risk persons from large population cohorts. CKD-PC is a research group composed of investigators who analyze large cohort data and perform collaborative meta-analyses. The methods and results of these analyses are reviewed briefly here and presented in expanded form in a separate publication.7 To project the estimated long-term incidence of kidney failure among persons who do not donate a kidney according to 10 demographic and health characteristics, risk associations were derived from a meta-analysis of 7 general population cohorts. Relative risks were calibrated to the population-level annual incidence of ESKD in the United States, derived from actual ESKD incidence and mortality data collected by the US Renal Data System and overall mortality data from the US Census.35 Fifteen-year projections were compared with the observed risk among 52 998 living kidney donors in the United States. For estimation of relative risks related to health characteristics, a total of 4 933 314 participants from 7 cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics similar to those of age-matched kidney donors, the 15-year projections of ESKD risk in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of lower eGFR, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESKD was highest among persons in the youngest age group, particularly among young black persons. The 15-year observed postdonation risks among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in healthy persons in the absence of donation, according to sex and race.
This study has important limitations.36 First, the projections were calibrated to historical incidence rates of ESKD from US population data. Annual incidence was derived with the use of life-table methods, which assume a constant age-, sex-, and race-specific incidence of ESKD over periods of decades and a static population substructure. Second, information on certain health characteristics of interest was not available, including heritable and environmental factors. The estimates reflect population averages for unmeasured characteristics. Donor candidates with a family history of kidney disease (especially younger candidates with such history) would be expected to have a higher risk of ESKD than projected. Third, the relative risk estimates were based on low-risk cohorts followed for a median of 4 to 16 years, based on an assumption of proportional hazards and after testing for nonproportionality. The analysis does not include untreated low GFR as an outcome, a condition that is more common among older persons, nor did it assess the risk of other outcomes, such as hypertension or preeclampsia, that have been linked to kidney donation. Finally, the analysis did not estimate the age at which ESKD would be expected develop in a donor candidate or the duration of ESKD before death.
The resulting risk models were incorporated into an online risk prediction tool for 15-year and lifetime ESKD risk (http://www.transplantmodels.com/esrdrisk/). Although the risk tool was developed specifically for the United States, the methods used may be adapted to other countries with the availability of local data sources. The WG endorses use of the online tool as the foundation for a new evaluation framework centered on simultaneous consideration of multiple demographic and health characteristics to predict long-term risk of an important outcome, while recognizing limitations in precision of risk estimates and uncertainty in donation-attributable risk. These models should be refined through further research to improve the precision and generalizability of predonation risk estimates and to incorporate estimates of indivdualized risk attributable to donation.
We endorse a quantitative framework for donor candidate evaluation and acceptance centered on lifetime risk of postdonation kidney failure (Table 9). For example, if a transplant program sets the acceptable lifetime postdonation ESKD risk threshold at 5%, and assumes a donation-attributable RR of 3.5 to 5.3 according to sex and race, then the acceptable predonation lifetime ESKD risk threshold would be approximately 1.0-1.5. This strategy enables decision-making based on a more comprehensive and integrated assessment of risk factors than is currently practiced, but application of the currently available online tool at this time requires clinician insight and interpretation.37 Currently, there remains uncertainty in lifetime risk estimates, particularly for younger donor candidates, donors from developing countries, and ethnicities other than black or white race. At this time, transplant programs and donor candidates may consider other factors in their acceptance criteria for living kidney donation in addition to quantitative risk estimates. We see this work as starting point, and advocate strongly for continued efforts to improve the precision, tailoring and generalizability of predonation and postdonation risk estimates. Quantifying donation-attributable risk according to predonation demographic and health profile is a leading priority for future research, and we will update the online tool once estimates are available.
In summary, we advocate for a quantitative paradigm wherein transplant programs accept or decline donor candidates using the strongest evidence-based criteria currently available to simultaneously consider a profile of risk factors (demographic and health characteristics at evaluation and risk attributable to donation) and support consistent, transparent and defensible decisions. Ongoing efforts are needed to strengthen and advance this paradigm, including incorporation of data from cohorts observed for longer periods of time (ideally over the lifetime) and from diverse countries; estimation of risks related to genetic and familial factors; and quantification of donation-attributable risks according to multiple predonation health characteristics. The scope of the current guideline is focused on donor safety, and excludes consideration of recipient outcomes based on donor characteristics. However, we appreciate that a donor candidate’s profile of predonation characteristics may also have important impacts on posttransplant recipient outcomes, and that topic also warrants future consideration.
Roles and Responsibilities
Transplant programs bear the primary responsibility for evaluation, care and follow up of living kidney donor candidates and donors. The main responsibilities of the transplant program are to establish and maintain policies and a team of professionals to provide care according to policies. However, many other entities share in these responsibilities (Table 10). The decision to donate should be regarded as a shared responsibility between the donor candidate, the donor candidate’s primary physician, and the transplant program. Transplant programs and the organizations that regulate transplant practice should:
- Evaluate and disclose risks to the best of currently available knowledge
- Respect the donor candidate’s autonomy, including autonomy to take risk, within a program’s/regulators’ upper bound of acceptable risk
- Embrace a long-term relationship with the donor, because some risks are uncertain or evolving
- Strengthen and refine estimates of long-term projected predonation and postdonation risks of kidney failure, including incorporation of data from cohorts observed for longer periods of time (ideally over the lifetime), from different countries and regions, and estimates of risk related to familial, genetic (eg, apolipoprotein L1 [APOL1]), and other factors (eg, birth weight).
- Engage in consensus-building activities among transplant professionals, donors and recipients to help establish uniform threshold of unacceptable risk. Strategies that may help inform consensus include:
- ○ Estimate the long-term risk of kidney failure among previously accepted donors, such as those captured in large national databases.
- ○ Estimate long-term risk of kidney failure based on donor acceptance criteria specified in prior guidelines.
- ○ Evaluate implications of racial variation in long-term risk of kidney failure exceeding possible thresholds for acceptable risk on opportunities for living donation. Develop strategies to promote equitable access to kidney transplantation without placing certain donors at unacceptable risk.
- Determine the best methods of communicating individualized risks to donor candidates and their intended recipients so that the information is understood and supports patient decision-making.
- Explore application of individualized risk estimates to guide predonation support and counseling (eg, target predonation BMI levels) to minimize the risk of adverse postdonation outcomes.
- Develop tools to predict risks of adverse short- and long-term psychosocial outcomes and a broader spectrum of medical outcomes according to predonation characteristics.
CHAPTER 2: INFORMED CONSENT
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 2 and therefore the following recommendations are “Not Graded.”
Process of Informed Consent
- 2.1: Informed consent for donation should be obtained from the donor candidate in the absence of the intended recipient, family members and other persons who could influence the donation decision.
Capacity for Decision Making
- 2.2: The donor candidate’s capacity to provide informed consent (ie, ability to understand the risks, benefits and consequences of donation) should be confirmed before proceeding with evaluation and donation.
- 2.3: Substitute decision makers should not be used on behalf of a donor candidate who lacks the capacity to provide informed consent (eg, children or those who are mentally challenged), except under extraordinary circumstances and only after ethical and legal review.
Content of Disclosure
- 2.4: Protocols should be followed to provide each donor candidate with information on:
- The processes of evaluation, donor acceptance, and follow-up
- The types of information that may be discovered during the evaluation, and what the transplant program will do with such information
- Individualized risks, benefits and expected outcomes of the donor evaluation, donation, and postdonation health, including a discussion of the uncertainty in some outcomes
- Treatment alternatives available to transplant candidates, and average expected outcomes
- How personal health information will be handled
- Availability of transplant program personnel for support
Comprehension of Disclosed Information
- 2.5: The donor candidate’s understanding of the relevant information on the risks and benefits of donation should be confirmed before proceeding with donation.
- 2.6: Donor candidates should have adequate time to consider information relevant to deciding whether they wish to donate or not.
- 2.7: A donor candidate’s decision to withdraw at any stage of the evaluation process should be respected and supported in a manner that protects confidentiality.
- 2.8: A donor candidate who decides not to donate and has difficulty communicating that decision to the intended recipient should be assisted with this communication by the transplant program.
Obtaining informed consent to be evaluated as a living kidney donor candidate, and informed consent to undergo living kidney donation, are processes rather than a discreet event. The transplant program has a responsibility to establish that the donor candidate is capable of understanding the relevant information (capacity), is adequately informed of the likely risks and benefits of the donation, and of the alternative treatment options available to the recipient (disclosure), understands this information (understanding), and is acting voluntarily (voluntarism). This chapter provides recommendations to ensure satisfaction of the informed consent requirements for the living kidney donor candidate. The reader should also refer to chapter 1 for related discussions on the framework for decision-making and chapter 18 on the ethical, legal, and policy framework of living donation. Details of specific donation-related surgical, medical, and psychosocial risks are provided in other chapters (3-17) of the guideline.
Process of Informed Consent
Transplant programs must establish a defensible process to ensure that the requirements of informed consent are met.18,38-41 To date, donor candidate informed consent processes have been shown to vary widely across transplant programs worldwide, with discrepancies noted in standards, consistency and implementation.39,40,42-45 It has been recommended that the informed consent structure and process be the same for donor candidates regardless of relationship (or lack thereof for nondirected donation) between the donor candidate and their intended recipient.39,46,47
Transplant programs must assure a donor candidate is acting voluntarily and not yielding to pressure or coercion. It is best if evaluations of the donor candidate and the intended recipient are performed by separate teams to mitigate potential conflict of interest. A recommendation that the donor candidate be evaluated by a team that is independent of the evaluation of the intended recipient is also recommended in several past guidelines.47-51 The process of informed consent with a living kidney donor candidate should include discussions with a healthcare professional skilled and knowledgeable in organ donation and in evaluating a person’s comprehension of the information. In the United States, to minimize conflict of interest, living donor recovery hospitals must designate and provide each donor candidate with an Independent Living Donor Advocate who is independent of the intended recipient’s evaluation and the decision to transplant the intended recipient. This person seeks to ensure that the rights of the donor candidate are protected, that all the requirements of informed consent are met, and that the donation decision is made voluntarily.51 Other countries may use other strategies such as an external review of planned donations to ensure that independence, advocacy for the donor’s rights, and voluntarism are respected.52 While avoidance of conflict of interest is a central principle, it also remains important that healthcare professionals in the teams evaluating the donor candidate and intended recipient work together to ensure effective communication and coordination of the donation and transplant processes. For example, it would be inefficient to fully evaluate a donor candidate if their intended recipient does not meet eligibility criteria for transplantation.
Capacity for Decision Making
The transplant team has a duty to confirm that the donor candidate has the capacity to provide informed consent, and is able to communicate their decisions based on accurate comprehension of the information disclosed to them.2,18 Local laws and guidelines should be followed regarding minimum age criteria to become a living kidney donor.53 For example, prior guidelines indicate that persons who are younger than 18 years or who lack the mental capacity to provide informed consent should not become living kidney donors with the assistance of substitute decision-makers, and that donation in such a setting only be considered in highly exceptional circumstances (eg, young parent to child) after ethical and legal review.18,38,47,48,51,54,55
Content of Disclosure
Transplant programs must have a process to communicate relevant information to donor candidates that enables informed decision making.18 Some prior guidelines have suggested use of a standardized checklist to ensure that all items are disclosed.50 For US programs, the Organ Procurement and Transplantation Network (OPTN) has developed an informed consent checklist for programs to support compliance with policy requirements56 and a patient resource (English and Spanish translations) to explain the process in lay language for donor candidates.57
The donor candidate needs to be informed from the onset of what is involved in the donor evaluation, including the required assessments and anticipated timelines. In general, education about the process and potential outcomes of living donation should be introduced in a manner conducive to learning and understanding. Prior guidelines and policy statements have recommended that discussions be provided in a language that enables meaningful dialogue between the donor candidate and transplant program staff, using communication strategies and materials that are culturally sensitive.47,49 The information should also be presented in a sympathetic environment, using simple language, allowing time for questions, with information that is appropriate to a candidate’s understanding and experience, at a pace determined by their needs.49 Repetition of key information, and use of approaches that foster adult learning, are prudent.58 The information to be disclosed to the donor candidate is described in many prior guidelines and policy statements.47,48,51,54,59 Some regulations require minimum content elements that must be disclosed in the informed consent process,51 and these requirements should be respected when locally applicable. The donor candidate must also provide consent for some tests performed during the evaluation, such as consent to receive intravenous contrast for renal imaging. In this guideline, we present a list of the content of recommended disclosures during the donor candidate evaluation, considering these prior guidelines and policies (Table 11). Candidates should also be reminded that they can only donate a kidney as a living person once, even though they may know someone else who may need a kidney transplant in the future.
Treatment alternatives available to transplant candidates (in general terms, not with specific recipient medical information) should be disclosed to the donor candidate (Table 11). Donor candidates who are biologically incompatible with an intended recipient should be informed of the availability desensitization protocols and kidney paired donation (KPD), and the considerations related to pursuit of these treatment options. Logistics, outcomes and risks specific to KPD and planned incompatible transplantation are discussed in chapter 3 of this guideline. Participation in KPD and incompatible transplantation requires specific informed consent, and minimum content elements may be specified by paired donation programs.60,61 The transplant program should inform the donor candidate of policies regarding confidentiality and anonymity in KPD and nondirected donation, and should ensure donor acceptance of these policies before donation.62 Some programs now permit biologically compatible pairs to participate in KPD; when this option is discussed, donor candidates who are biologically compatible with their intended recipient should voluntarily decide whether or not to pursue this option.63-65
Participating in donor evaluation includes risks of discovery. These risks include possible discovery of a health condition that requires referral for further care, discovery of a health condition that could affect the donor candidate’s insurability or cost of insurance, or discovery of an infectious disease for which there is a reporting requirement to public health authorities. Transplant programs should establish policies for managing such discoveries, and share these policies with the donor candidate as part of the informed consent process for evaluation. Testing a donor candidate and intended recipient in a family for the purpose of assessing immune compatibility may identify misattributed biological relationships as an incidental finding. For example, misattributed paternity is estimated to occur in approximately 1 to 3% of father-child living kidney donor-recipient pairs, or approximately 0.25% to 0.5% of all living kidney donation evaluations.66 Transplant programs should establish a policy on how or whether this information is disclosed.67,68
The donor candidate should be informed of donation-related surgical, medical, and psychosocial outcomes and risks as provided in other chapters of this guideline, individualized whenever possible for donor characteristics, and including the uncertainty of estimates. As described in chapter 1, 90-day all-cause mortality after donation in a US study of 80 347 donors (1994-2009) based on registry data and national death records was approximately 1 in 3000 (0.03%).23 Similar rates have also been reported in other studies.24,25 Given the low incidence of perinephrectomy mortality, estimates for predonation characteristics that alter the risk of perioperative death are imprecise.
The donor candidate should be informed of anticipated recipient outcomes associated with living donor transplantation (such as 1-year, 5-year and median recipient graft and patient survival), and with available treatment alternatives including deceased kidney donor transplantation and different types of dialysis. US policy requires that donor candidates are provided with current national and program-specific 1-year transplant recipient patient and allograft survival statistics, and that donor candidates are also informed that any transplant candidate may have risk factors for increased likelihood of adverse outcomes (including graft failure, complications, mortality) that exceed local or national averages.51
Many regions have legislation that protects the confidentiality of personal health information, and the same protections apply to information collected during the donor candidate evaluation. The donor candidate should know that their personal health information will only be disclosed to their intended recipient or other parties if they provide permission to do so. The donor candidate should also know that it is likely they will be asked for permission to disclose certain personal health information to their intended recipient so that the intended recipient can provide informed consent for the transplant to occur.69,70 For example, in directed donation, while a donor candidate may wish to keep their act of donor evaluation initially confidential, if the transplant program does not permit anonymous directed donation, or if the intended recipient does not wish to proceed with anonymous directed donation, there may be a need for the donor candidate to provide permission for their identity to be disclosed to the intended recipient so that the intended recipient can make an informed decision about proceeding with the transplant. Similarly, donor candidates and intended recipients need to provide permission to make each other aware whether they are biologically compatible or not. During the donor evaluation process, it may be recognized that a donor candidate has additional health information that could impact the transplant outcome. For example, despite negative serological testing, a donor candidate may have a higher risk of specific infectious diseases based on his/her behavioral history. Some jurisdictions require standardized behavioral screening71 during the evaluation and consent from the donor candidate to inform the intended recipient of behavior associated with increased risk of certain infections, so that the intended recipient can provide informed consent for the transplant to proceed.51 Before donation the transplant program should also inform the donor candidate of requirements to share certain personal health information with the recipient after donation, such as in the rare circumstance where soon after transplant (ie, within 1-2 years) it is discovered the donor has evidence of a serious infectious disease or malignancy.51
It is possible that the intended recipient has health information that could impact transplant outcomes, and which the transplant team believes could affect the donor candidate’s decision making. For example, some donor candidates may want to know if the recipient lost a previously transplanted kidney due to medication nonadherence.72 Knowledge of a genetic kidney disease in an intended recipient may be important for the evaluation and care of a genetically related donor candidate. As for the health information of donor candidates, personal health information collected during the transplant candidate’s evaluation is protected under privacy law, and can only be shared with permission of the intended recipient. Prior guidelines, such as those of the British Transplantation Society and policy of the US OPTN, recommend disclosure of relevant information about the intended recipient to the donor candidate if the intended recipient has given consent48,51; the British Transplantation Society also recommends that donation and transplant not proceed unless the relevant information is shared.48 The criteria for relevant information beyond the determination that the intended recipient is approved as a suitable transplant candidate by their evaluation team are currently undefined. Ongoing efforts are warranted to develop standardized criteria for the identification and disclosure of recipient risk factors for adverse transplant outcomes that may be relevant to donor decision making, and when donation and transplant should not proceed in the absence of disclosure, weighing considerations of privacy law, ethics, and the concerns of donor and recipient candidates (see Research Recommendations).
Donor candidates should be informed of transplant program resources and personnel available to offer support. Such support can include psychological support in the setting of a poor recipient outcome after transplantation or donor complications, or financial reimbursement programs for out-of-pocket expenses incurred during the evaluation and donation process. The donor candidate should understand what is required of them after donation, including the likely timing and financial impacts of donation-related recommended lifelong healthcare. The donor candidate should also understand how this care will be provided after donation, and the transplant program’s policy for providing any healthcare (and what types of healthcare) after donation. In the US transplant programs are required to collect and report follow-up data on donors for 2 years after donation.73
In nearly all places in the world it is a crime to knowingly acquire or obtain any human organ for valuable consideration (ie, for anything of value such as money or property). Some prior guidelines recommend the donor candidate sign a statement attesting that they are not donating a kidney for monetary gain46,74; in the United States, such attestation is required for donation to proceed.51 The donor candidate should understand the withdrawal process from evaluation, and their right to withdraw at any time before donation with the full support of the transplant program (described further below in this guideline chapter). Finally, while transplant programs respect the autonomy of a donor candidate to proceed with donation based on their preferences, needs and values, programs remain ethically justified to decline a donor candidate who does not meet their eligibility criteria for donation (ie, when the donation is deemed to incur unacceptable risks).22 A donor candidate should understand the transplant program makes the final determination of whether the donor candidate is eligible for donation or not based on the results of their evaluation. If the donor candidate does not meet the transplant program’s criteria for donation, the program should inform the donor candidate of the decision and reason. Being told they do not meet a transplant program’s acceptance criteria is distressing for some donor candidates.75 The donor candidate should be informed how the transplant program will support them if they do not meet criteria for donation. Such support may include assistance in communicating the decision to the intended recipient; ongoing follow-up communication with the evaluation team; counseling related to the outcome of the evaluation; alternative ways of helping the intended recipient; and the possibility of referral to another program for a second opinion if the donor candidate does not accept the noneligibility decision.
Comprehension of Disclosed Information
Donor candidates should have adequate time to consider the information they are provided during the evaluation process, as this is required for informed consent. The duration of adequate time is not well defined, and may vary according to donor characteristics. Some, but not all transplant programs, require all donor candidates to exercise a minimal period for this adequate consideration, referred to as a ‘cooling-off’ period.44
In current routine care, an assessment of a donor candidate’s knowledge and comprehension of the possible outcomes of donation is typically done through discussions with healthcare professionals. Optimal methods to assess understanding in living donor candidates are not well defined,39,58 but general techniques for comprehension assessment may include use of “teach-back,” in which patients are asked to "teach back" what they have learned during their visit.76 An instrument for assessing comprehension during informed consent for living liver donation has been pilot tested,77 and provides a model for developing similar instruments for comprehension assessment in living kidney donor candidates. It is common for many donor candidates to voice no concerns during the evaluation process about the donation, as they are using an emotional rather than deliberative decision-making process. Some donors have an exaggerated sense of the true benefit of donation to their intended recipient, while others underappreciate the amount of postoperative physical pain they may experience or the time needed to fully recover after surgery.78
The Voluntary Nature of Kidney Donation
Voluntarism is established when a transplant program ensures the donor candidate is free from undue pressure or coercion in deciding whether or not to donate.79 Voluntarism should be respected by all members of the transplant team; as discussed above, additional safeguards may include use of Independent Living Donor Advocates or external reviews of planned donations.51,52 Special groups such as prisoners have unique considerations.80 Interviewing the donor candidate without the intended recipient, family members and other persons who could influence the donation decision is important in the assessment of voluntarism. Trust is maintained when the transplant program assures a donor candidate that their participation in evaluation and personal health information is confidential, to be shared with the intended recipient only with their approval. This enables the donor candidate to speak openly about their health and donation choices.
For the purposes of donor candidacy, ‘not deciding’ about donation should be considered the same as ‘deciding not to’ proceed, as may occur in cases of ambivalent donor candidates who have not decided to proceed, but who also have not elected to formally withdraw from the donation process.39
Transplant programs should support donor candidates who decide to withdraw from the evaluation process or decline to donate in a way that is respectful and confidential.81 So-called ‘medical alibis,’ provision of a false medical reason to justify unsuitability as a living donor, are discouraged as untruthful statements may undermine trust in the transplant program and the patient/physician relationship.81 Thiessen et al recommend that all donor candidates be offered a general statement regarding ‘unsuitability to donate’ at any time; there is controversy about whether the transplant program should assist the donor candidate with wording that includes factual medical findings which may or may not preclude donation (such as mildly elevated BP or risk factors for metabolic syndrome).82 Understandably, a donor candidate who decides not to donate may have difficulty communicating this decision to the intended recipient or others; in such circumstances the transplant program should assist with this communication, which may involve communication through the recipient evaluation team to the transplant candidate.
- Determine the best methods to achieve informed consent from living kidney donor candidates, including what methods are most useful to impart information including risks and outcomes and what methods are most useful to assess comprehension.42
- Through focus groups and/or surveys, develop standardized criteria for circumstances under which intended recipients should be asked for permission to disclose certain personal health information to the living kidney donor candidate (such as loss of a prior graft due to medication nonadherence), so that donor candidates can make an informed decision about whether to proceed with donation or not.
- ○ Develop standardized criteria for when donation and transplant should not proceed in the absence of disclosure, weighing considerations of privacy law, ethics, and the concerns of donor and recipient candidates.
- Perform postdonation surveys to measure donors’ assessments of the quality of standardized informed consent processes, including if the information provided before donation met the donor’s needs and prepared them for the donation.83
- Compare experiences of donors who donated before and after the implementation of country-specific regulations for better informed consent processes for the practice of living donation.
- Evaluate appropriate circumstances for and approaches to substitute decision making and use of surrogate consent, including definition of the necessary supporting ethical framework for particular scenarios.
- Develop ethically-grounded, practical strategies to consider and manage evaluation of living kidney donor candidates identified by the intended recipient or their representatives through mass advertising and social media.84
CHAPTER 3: COMPATIBILITY TESTING, INCOMPATIBLE TRANSPLANTATION, AND PAIRED DONATION
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 3 and therefore the following recommendations are “Not Graded.”
- 3.1: Donor ABO blood typing should be performed twice before donation to reduce the risk of unintended blood type incompatible transplantation.
- 3.2: Donor blood group A subtype testing should be performed when donation is planned to recipients with anti-A antibodies.
- 3.3: Human leukocyte antigen (HLA) typing for major histocompatibility complex (MHC) Class I (A, B, C) and Class II (DP, DQ, DR) should be performed in donor candidates and their intended recipients, and donor-specific anti-HLA antibodies should be assessed in intended recipients.
- 3.4: Donor candidates who are ABO blood group or HLA incompatible with their intended recipient should be informed of availability, risks, and benefits of treatment options, including kidney paired donation and incompatibility management strategies.
- 3.5: If a donor candidate and their intended recipient are blood type or crossmatch incompatible, transplantation should be performed only with an effective incompatibility management strategy.
- 3.6: Nondirected donor candidates should be informed of availability, risks and benefits of participating in kidney paired donation.
Evaluation: Blood Type and Histocompatibility Testing
ABO blood typing should be performed in living donor candidates before donation, including routine duplicate testing, to reduce the risk of unintended blood type-incompatible transplantation. Unintended ABO-incompatible (ABOi) transplantation should be avoidable with ABO typing of the donor and the recipient; however, human errors have led to cases of accidental ABOi organ transplantation in contemporary practice.85 ABO-subtype testing should be performed when donation is planned to recipients with anti-A antibodies.86 Human leukocyte antigen (HLA) typing for major histocompatibility complex (MHC) class I (A, B, C) and class II (DP, DQ, DR) should be obtained in living donor candidates for recipient candidates with anti-HLA antibodies, as part of the assessment of compatibility during preoperative planning; there is an association between the presence of HLA-C and/or HLA-DP and DQ and a higher incidence of graft rejection.87,88 While recipient care is out of the scope of this guideline, it is important to emphasize that recipient candidates should undergo antidonor antibody examinations, including complement-dependent cytotoxicity or flow cytometry crossmatching and Luminex (Bio-Rad Laboratories, Inc., Hercules, CA) assays to determine the history of sensitization,89 and this testing should be current before proceeding with donor nephrectomy and living donor transplantation.
Counseling Regarding Transplant Options and Expected Outcomes
Biological incompatibility remains a significant barrier to living donor kidney transplantation. Estimates based on blood group prevalence in the United States suggest that more than 35% of willing, healthy potential living donors are blood group incompatible with their intended recipients.90 Options for transplant candidates whose only willing, healthy donor is ABO or HLA incompatible include: KPD, planned incompatible transplantation (with preconditioning/desensitization treatment of the intended recipient as needed), attempting to find a different living donor, or waiting for a compatible deceased donor organ.91-93 While evaluation and management of the transplant recipient is not within the scope of this project, outcomes of recipients after various forms of transplant or waiting are relevant to living kidney donor candidate education. Perspectives of risk and benefit for counseling of the intended recipient and donor candidate include outcomes after compatible versus incompatible transplantation, outcomes after incompatible transplantation versus dialysis, and the likelihood of transplantation with options including KPD programs. Donor candidates who are ABO or HLA incompatible with their intended recipient should be informed of expected patient and graft survival for KPD and incompatible transplantation, as compared with compatible living donor transplantation and deceased donor transplantation, as well as expected patient survival on dialysis, based on best available information.
Kidney Paired Donation
KPD has emerged as a successful approach to address ABO blood group and HLA incompatibilities for those who have a willing, but incompatible living donor candidate. The fastest growing modality for living donor transplantation is KPD, rising from 2 cases in 2000 to approximately 700 cases reported to the US OPTN in 2013.94 In 2004, the Netherlands instituted a paired exchange system in all their transplant centers, which may explain the recent increase in living kidney donation in that country.95
Donor candidates who are ABO or HLA incompatible with their intended recipient should be informed of the availability of KPD, and the considerations related to pursuit of this treatment option. Participation in KPD requires KPD program-specific informed consent60,61 (Please see also chapter 2: Informed Consent for details). The transplant program should inform the donor candidate of policies regarding confidentiality and anonymity in KPD and nondirected donation, and should ensure donor acceptance of these policies before donation.62 Some programs now permit biologically compatible pairs to participate in KPD; when this option is discussed, donor candidates who are biologically compatible with their intended recipient should voluntarily decide whether or not to pursue this option.63-65
Donor candidates participating in KPD should be informed of the risks and benefits of kidney transport, possible organ redirection due to unforeseen circumstances, the inability to provide information on the ultimate recipient of their organ, as well as nonexchange donation options.60 Living donors participating in exchanges should have the option to travel to the recipient center; however, experience from countries with well-developed KPD programs suggests that transport of living donor kidneys can be accomplished safely without adversely impacting transplant outcomes, obviating the need for donor travel. In a survey of 30 US programs transporting 56 living donor kidneys (2007-2010), the creatinine nadir was less than 2.0 mg/dL (<177 μmol/L) in all recipients but one, and there were no cases of delayed graft function as defined by the need for dialysis in the first week.96 Continued feasible and safe transport of living donor kidneys in the United States has been reported.97
Nondirected donors (donor without an identified recipient) have the unique potential to expand the donor pool through chains of kidney exchanges.98 Nondirected donor candidates should be informed of opportunities for donating into a chain or KPD program, if available.
Participation in KPD should be considered preferable to incompatible transplantation if participation is deemed to have “reasonable” likelihood of yielding a compatible or lower-immunologic risk match for the donor candidate’s intended recipient. Despite the expansion of KPD, blood group O candidates continue to have much lower rates of success on KPD lists than their non–O counterparts, particularly in circumstances of broad HLA sensitization.86 Thus, for some transplant candidates, incompatible transplantation may offer their best option for transplantation without prolonged waiting times.
Blood Type-Incompatible Living Donor Transplantation
While incompatible transplantation without preconditioning/desensitization treatment of the recipient may lead to hyperacute rejection and allograft loss, predetermined incompatibility management protocols have been developed in recent decades. In 1987, successful ABOi living donor transplantation was introduced in Japan using pretransplant antibody depletion, to expand access to transplantation in the absence of legal recognition of brain death.99-101 Since that time, ABOi transplantation evolved into routine practice and constituted nearly 14% of living donor transplant procedures performed in Japan in 2011.
Recipient and donor candidates interested in ABOi living donor transplantation should be informed of possible complications and expected outcomes. US studies have reported higher rates of perioperative complications including hemorrhage, infections, and early graft loss compared with ABO-compatible (ABOc) transplantation.91,102 In contrast, some European and Asian studies have found no increases in early or longer-term complications after ABOi transplantation,103-106 possibly reflecting differences in preconditioning management protocols. Even in the US experience, after an early reduction in graft survival relative to blood ABOc living donor kidney transplant recipients,91 the average long-term graft survival in ABOi living donor transplant recipients is not inferior to, and often exceeds, that of ABOc deceased donor transplant recipients.91,107 In the United States, recipients of ABOi living donor kidney transplants also appear to incur higher costs of care before, during, and after transplant, although these costs increases are offset by avoiding long-term dialysis and its associated morbidity and costs.108
HLA-Incompatible Living Donor Transplantation
HLA-incompatible transplantation remains the most difficult hurdle in achieving successful transplant outcomes. Flow cytometry crossmatching + or Luminex +/complement dependent cytotoxicity- incompatibility may be acceptable with management including B-cell-depleting treatments (eg, anti-CD 20 antibody, rituximab) and/or splenectomy and/or intravenous immunoglobulin, but increased risk of early rejection remains, requiring additional immunosuppression and attendant risks to the recipient. Nonetheless, while allograft survival after HLA-incompatible living donor kidney transplantation is inferior to compatible transplantation, incompatible transplantation after desensitization may offer a substantial survival benefit compared with dialysis or waiting for a deceased donor kidney; however, there are few high-quality studies testing this hypothesis. A recent study compared 1025 recipients of HLA-incompatible living donor kidney transplants at 22 US medical centers with matched controls who remained on waiting lists or waited and received a transplant from a compatible deceased donor. After 8 years, 76.5% of those who received an incompatible living donor transplant were still alive, compared with 62.9% who remained on the waiting list or received a deceased donor transplant and only 43.9% who remained on the waiting list but were never transplanted.109 HLA-incompatible transplantation does confer additional costs compared with compatible transplantation, but may be cost-effective compared with dialysis; formal cost effectiveness evaluations are needed.110
What Prior Guidelines Recommend
In contrast with our recommendations, the European Renal Best Practice (ERBP) guideline for kidney donor and recipient evaluation recommends performing HLA-DQ, HLA-DP and HLA-C typing of the donor only when the intended recipient has HLA antibodies against those antigens.50 The ERBP does not recommend routine typing for MHC Class I-related chain-A and other non-HLA antigens in either recipient or donor. Similar to our recommendations, the ERBP recommends establishing programs to select a donor towards whom the recipient does not produce antibodies through KPD, and recommends transplanting patients with donor-specific antibodies only if this cannot be accomplished by KPD.50 Details of testing and clinical management associated with HLA and non-HLA antibodies in transplantation are out of the scope of the current guideline, but consensus-based recommendations from a 2012 Transplantation Society work group are available.89
In 2012, the American Society of Transplantation (AST)/American Society of Transplant Surgeons (ASTS) held a consensus conference directed at overcoming barriers to the adoption of KPD that produced recommendations related to KPD donor evaluation and care, guidelines for KPD histocompatibility testing, and recommended policies to overcoming geographic barriers to KPD.60
- Define mediators of clinical outcomes and optimal management of ABO and HLA incompatible living donor transplantation to support donor and recipient selection, understanding of transplant utility and informed consent, including:
- ○ Standardized, controlled comparisons of preconditioning/desensitization and posttransplant immunosuppressive protocols for incompatible transplantation
- ○ Elucidation of the mechanisms of antibody production and long-term impact on the allograft
- Develop a long-term, appropriately powered RCT to compare the outcomes and cost effectiveness of options for highly sensitized candidates including participation in KPD with varying waiting times versus living donor transplantation after various desensitization protocols.
CHAPTER 4: PREOPERATIVE EVALUATION AND MANAGEMENT
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 4 and therefore the following recommendations are “Not Graded.”
- 4.1: Donor candidates should receive guideline-based evaluation and management used for other noncardiac surgeries to minimize risks of perioperative complications, including a detailed history and examination to assess risks for cardiac, pulmonary, bleeding, anesthesia-related and other perioperative complications.
- 4.2: Donor candidates who smoke should be advised to quit at least 4 weeks before donation to reduce their risk of perioperative complications, and commit to lifelong abstinence to prevent long-term complications.
The goals of the general preoperative evaluation are to assess a donor candidate’s risk of perioperative complications according to their profile of predonation characteristics assessed through a careful medical history, physical examination and testing; to determine if this risk is acceptable to proceed with donation; and to counsel the donor candidate on how to minimize their risk of perioperative complications (eg, stop smoking, lose weight if obese). The donor then receives care during the perioperative period to minimize their risk of complications, so that they can return to their level of presurgical function as quickly as possible. Recommendations on how to achieve these outcomes with good preoperative evaluation and management are sparse in prior living kidney donor guidelines, other than a description of elements of the detailed history required before donation (eg, prior surgeries, anesthesia-related reactions and bleeding disorders).51 Associations of donation-specific surgical techniques with perioperative outcomes are described elsewhere (see chapter 17).
Risks of Perinephrectomy Complications
Living kidney donor nephrectomy is an elective surgical procedure that carries a low risk for complications as compared with other types of surgical procedures. As described in chapter 1, the 90-day all-cause mortality in a US study of integrated donor registry data and national death records (80 347 donors, 1994-2009) was approximately 1 in 3000 (0.03%) based on 25 deaths.23 Similar rates have also been reported in other studies.24,25 Given the low incidence of perioperative mortality, estimates for predonation characteristics that alter the risk of perioperative death are imprecise.
A US study recently described the incidence of perioperative complications in a large sample of living kidney donors from 1998 to 2010.28 Outcomes were assessed through administrative data, using a composite outcome of digestive, respiratory, procedural, urinary, hemorrhage, infectious or cardiac complications. The incidence of perioperative complications was 7.9% and decreased from 1998 to 2010 (from 10.1% to 7.6%). Limitations of this study include the lack of confirmation of donor status through patient level-linkages to the national registry, and use of weighting schemes to draw inferences for a “represented” sample of all US donors based on a stratified sample of 20% of acute care hospitalizations. A subsequent study integrated national US donor registry data as a source of verified living donor status with administrative records from a consortium of 98 academic hospitals (2008 to 2012, n = 14 964), and found that 16.8% of donors experienced any perioperative complication, most commonly gastrointestinal (4.4%), bleeding (3.0%), respiratory (2.5%), and surgical/anesthesia-related injuries (2.4%).29 Major complications, defined as Clavien grading system for surgical complications level 4 or 5,111 affected 2.5% of donors. The limitations of administrative database studies, including possible coding biases, highlight the need for prospective collection of granular clinical data on living donor perioperative outcomes. A Norwegian registry-based study of 1022 living kidney donations performed between 1997 and 2008 recorded 30 (2.9%) major complications and 184 (18%) minor complications by Clavien grading.112
Readmission after surgery is commonly used as a measure of care quality and healthcare utilization. A recent study examined postnephrectomy readmission using integrated US living donor registry data, records from a nationwide pharmacy claims warehouse, and administrative records from an academic hospital consortium (N = 14 959 donors, 2008-2012).113 Overall, 2.9% of donors were readmitted to hospital within 90 days of donation. 11.3% donors filled 1 or greater opioid prescription in the year before donation, and those with the highest level predonation opioid use were more than twice as likely as nonusers to be readmitted within 90 days postdonation (6.8% vs 2.6%; adjusted odds ratio [OR]; 95% lower CI [OR] 95% upper CI1.742.493.58). Adjusted readmission risk was also significantly (P < 0.05) higher for women (adjusted OR = 1.25), African Americans (adjusted OR = 1.45), spouses (adjusted OR = 1.42), exchange participants (adjusted OR = 1.46), uninsured donors (adjusted OR = 1.40), donors with predonation eGFR <60 mL/min per 1.73 m2 (adjusted OR = 2.68), donors with predonation pulmonary disease (adjusted OR = 1.54), and after robotic nephrectomy (adjusted OR = 1.68). Continued efforts to identify and prevent modifiable causes of postoperative complications in all donors are warranted to maximize safety of the donation procedure.
Readers are encouraged to refer to chapter 17 for discussion of acceptable surgical approaches to donor nephrectomy and anticipated outcomes. As discussed in the Framework for this guideline (chapter 1), the transplant program team should provide the donor candidate with individualized quantitative estimates of short-term and long-term risks from kidney donation to the extent possible, including recognition of associated uncertainty, in a manner that is easily understood by donor candidates.
Preoperative and Perioperative Management to Minimize the Risk of Perinephrectomy Complications
Guidelines for evaluation and management before noncardiac surgery in the general population have been thoroughly reviewed and summarized.114 There is no evidence to suggest that additional preoperative testing beyond guideline-based evaluation and management strategies used for other noncardiac surgeries results in a reduced incidence of perioperative complications in kidney donors.
Some transplant programs routinely perform preoperative noninvasive cardiac testing in older living kidney donor candidates (eg, stress electrocardiogram, nuclear stress test), but this practice is not supported by existing evidence. Recent US guidelines for the general population do not recommend cardiac testing for those undergoing noncardiac surgery with no active symptoms of heart disease who have reasonable functional capacity (defined as at least 4 metabolic energy equivalents, which represents the ability to walk 2 blocks on ground level or carry 2 bags of groceries up one flight of stairs without symptoms).115 Outside the context of perioperative evaluation, other guidelines recommended against noninvasive cardiac testing for asymptomatic coronary artery disease, or conclude that there is insufficient evidence to warrant such testing.116
Recent guidelines on the assessment of bleeding risk before surgery or invasive procedures describe the following117: (i) Routine coagulation screening before surgery to predict postoperative bleeding in unselected patients is not recommended; (ii) bleeding history assessment should include details of a family history of bleeding, previous excessive posttraumatic or postsurgical bleeding, and current use of antithrombotic drugs; (iii) if the bleeding history is negative, no further coagulation testing is indicated; (iv) comprehensive coagulation testing is warranted if the bleeding history is positive. Although evidence in the context of donor nephrectomy is lacking, current OPTN policy for living donor evaluation in the United States requires assessment of bleeding and clotting disorders in the medical history, and performance of coagulation testing,51 and other prior living donor evaluation guidelines have recommended blood coagulation testing.54,118
In a recent multicenter randomized trial of 10 010 patients undergoing noncardiac surgery, the use of aspirin before surgery and throughout the early postsurgical period had no significant effect on the risk of death or nonfatal myocardial infarction but increased the risk of major bleeding.119 The trial authors recommend aspirin not be started before surgery, and for those chronically taking aspirin to hold it at least 3 days before surgery.
Recent guidelines for the prevention of perioperative venous thromboembolism (ie, deep vein thrombosis and pulmonary embolism) describe the use of a risk score (Rogers or Caprini score) to determine which of early ambulation, mechanical prophylaxis or perioperative unfractionated heparin (or low-molecular-weight heparin) is warranted to reduce risk.120 Factors associated with a higher risk of perioperative venous thromboembolism include older age, obesity, and the use of oral contraceptive or hormone replacement therapy. Many donors will be at low risk (<2%) of perioperative venous thromboembolism, and some guidelines suggest early ambulation is all that is required in individuals at low risk of such events.
Guidelines to reduce the risk of perioperative pulmonary complications recommend a careful assessment of risk factors for postoperative pulmonary complications (conditions such as chronic obstructive pulmonary disease or congestive heart failure which will be absent in almost all donors).121 Preoperative spirometry and chest radiography are not recommended as routine tests to predict the risk for postoperative pulmonary complications. Patients at higher risk for postoperative pulmonary complications may benefit from deep breathing exercises or incentive spirometry, or selective use of a nasogastric tube (as needed for postoperative nausea or vomiting, inability to tolerate oral intake, or symptomatic abdominal distention). The utility and difficulties of the preoperative evaluation for the potential identification of obstructive sleep apnea is described elsewhere.122
There have been 6 RCTs that enrolled smokers (ranging from 47 to 213 patients) to receive a smoking cessation intervention or not before surgery (procedures other than donor nephrectomy)123 and found that smoking cessation reduced the risk of perioperative complications.
- Develop contemporary estimates of 5.10, the risk of perinephrectomy complications according to an individualized profile of predonation characteristics, accounting for changes in baseline comorbidity burdens.
- Assess the predictive value of novel risk factors for perioperative complications and readmission after donor nephrectomy, including use of opioids and other pharmaceuticals.113
- Perform RCTs to formally assess the efficacy of evaluation and perioperative management techniques to minimize the risk of perioperative complications after living donor nephrectomy.
CHAPTER 5: PREDONATION KIDNEY FUNCTION
Except in the case of Recommendation 5.10, the ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 5 and therefore the following recommendations are “Not Graded.” Some of the recommendations extrapolated from the 2012 KDIGO CKD Guideline (Section 1.4.3)124 were not part of the ERT review for this guideline and as such they are also “Not Graded.”
- 5.1: Donor kidney function should be expressed as glomerular filtration rate (GFR) and not as serum creatinine concentration.
- 5.2: Donor GFR should be expressed in mL/min per 1.73 m2 rather than mL/min.
- 5.3: Donor glomerular filtration rate (GFR) should be estimated from serum creatinine (eGFRcr) for initial assessment, following recommendations from the KDIGO 2012 CKD guideline.
- 5.4: Donor GFR should be confirmed using one or more of the following measurements, depending on availability:
- Measured GFR (mGFR) using an exogenous filtration marker, preferably urinary or plasma clearance of inulin, urinary or plasma clearance of iothalamate, urinary or plasma clearance of 51Cr-EDTA, urinary or plasma clearance of iohexol, or urinary clearance of 99mTc-DTPA
- Measured creatinine clearance (mCrCl)
- Estimated GFR from the combination of serum creatinine and cystatin C (eGFRcr-cys) following recommendations from the KDIGO 2012 CKD guideline
- Repeat estimated GFR from serum creatinine (eGFRcr)
- 5.5: If there are parenchymal, vascular or urological abnormalities or asymmetry of kidney size on renal imaging, single kidney GFR should be assessed using radionuclides or contrast agents that are excreted by glomerular filtration (eg, 99mTc-DTPA).
- 5.6: GFR of 90 mL/min per 1.73 m2 or greater should be considered an acceptable level of kidney function for donation.
- 5.7: The decision to approve donor candidates with GFR 60 to 89 mL/min per 1.73 m2 should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
- 5.8: Donor candidates with GFR less than 60 mL/min per 1.73 m2 should not donate.
- 5.9: When asymmetry in GFR, parenchymal abnormalities, vascular abnormalities, or urological abnormalities are present but do not preclude donation, the more severely affected kidney should be used for donation.
- 5.10: We suggest that donor candidates be informed that the future risk of developing kidney failure necessitating treatment with dialysis or transplantation is slightly higher because of donation; however, average absolute risk in the 15 years following donation remains low. (2C)
- The goals of the evaluation of kidney function in living donor candidates are to:
- Provide accurate assessment of level of GFR and prediction of long-term risk of ESKD (in the absence of and after donation) based on level of predonation GFR and other factors.
- Allow identification and exclusion of donor candidates whose postdonation risks are expected to exceed the acceptable risk threshold established by the transplant program.
- Provide counseling regarding level of risk for donor candidates whose long-term risks for ESKD are expected to be below the acceptable risk established by the transplant program.
- Provide counseling regarding the need for follow-up of decreased GFR after donation.
For this section, recommendations related to measurement of kidney function are based on physiological principles and recommendations for general clinical practice from the KDIGO 2012 CKD guideline.124 These recommendations were based on a systematic review of the literature, which included some studies of donors before and after kidney donation.125 There is no evidence to suggest that living kidney donor candidates or kidney donors differ from other populations regarding these recommendations.
Box 1. Key recommendations from the KDIGO 2012 CKD guideline regarding GFR estimation.124
- We recommend using serum creatinine and a GFR estimating equation for initial assessment (Recommendation 184.108.40.206, Grade 1A).
- We suggest using additional tests (such as cystatin C or a clearance measurement) for confirmatory testing in specific circumstances when eGFR based on serum creatinine is less accurate (Recommendation 220.127.116.11: Grade 2B).
- We recommend that clinicians (Recommendation 18.104.22.168, Grade 1B):
- ○ Use a GFR estimating equation to derive GFR from serum creatinine (eGFRcr) rather than relying on the serum creatinine concentration alone.
- ○ Understand clinical settings in which eGFRcr is less accurate.
- We recommend that clinical laboratories should (Recommendation 22.214.171.124, Grade 1B):
- ○ Measure serum creatinine using a specific assay with calibration traceable to the international standard reference materials and minimal bias compared to isotope-dilution mass spectrometry (IDMS) reference methodology.
- ○ Report eGFRcr in addition to the serum creatinine concentration in adults and specify the equation used whenever reporting eGFRcr.
- ○ Report eGFRcr in adults using the 2009 CKD Epidemiology Collaboration (CKD-EPI) creatinine equation. An alternative creatinine-based GFR estimating equation is acceptable if it has been shown to improve accuracy of GFR estimates compared to the 2009 CKD-EPI creatinine equation.
- When reporting serum creatinine:
- ○ We recommend that serum creatinine concentration be reported and rounded to the nearest whole number when expressed as standard international units (μmol/L) and rounded to the nearest 100th of a whole number when expressed as conventional units (mg/dL).
- When reporting eGFRcr:
- ○ We recommend that eGFRcr should be reported and rounded to the nearest whole number and relative to a body surface area of 1.73 m2 in adults using the units mL/min per 1.73 m2.
- ○ We recommend eGFRcr levels less than 60 mL/min per 1.73 m2 should be reported as “decreased.”
- If cystatin C is measured, we suggest that health professionals (Recommendation 126.96.36.199, Grade 2C):
- ○ Use a GFR estimating equation to derive GFR from serum cystatin C rather than relying on the serum cystatin C concentration alone.
- ○ Understand clinical settings in which eGFRcys and eGFRcr-cys are less accurate.
- We recommend that clinical laboratories that measure cystatin C should (Recommendation 188.8.131.52, Grade 1B):
- ○ Measure serum cystatin C using an assay with calibration traceable to the international standard reference material.
- ○ Report eGFR from serum cystatin C in addition to the serum cystatin C concentration in adults and specify the equation used whenever reporting eGFRcys and eGFRcr-cys.
- ○ Report eGFRcys and eGFRcr-cys in adults using the 2012 CKD-EPI cystatin C and 2012 CKD-EPI creatinine-cystatin C equations, respectively, or alternative cystatin C-based GFR estimating equations if they have been shown to improve accuracy of GFR estimates compared to the 2012 CKD-EPI cystatin C and 2012 CKD-EPI creatinine-cystatin C equations.
- When reporting serum cystatin C:
- ○ We recommend reporting serum cystatin C concentration rounded to the nearest 100th of a whole number when expressed as conventional units (mg/L).
- When reporting eGFRcys and eGFRcr-cys:
- ○ We recommend that eGFRcys and eGFRcr-cys be reported and rounded to the nearest whole number and relative to a body surface area of 1.73 m2 in adults using the units mL/min per 1.73 m2.
- ○ We recommend eGFRcys and eGFRcr-cys levels less than 60 mL/min per 1.73 m2 should be reported as “decreased.”
- We suggest measuring GFR using an exogenous filtration marker under circumstances where more accurate ascertainment of GFR will impact on treatment decisions (Recommendation 184.108.40.206, Grade 2B).
GFR as an Index of Kidney Function
The level of GFR is widely accepted as the best overall index of kidney function in health and disease. The foundations for this acceptance are the well-known relationships of alterations in kidney structure and GFR in kidney disease, and well known pathophysiologic relationships of kidney disease complications to decreased GFR. Normative levels of GFR are expressed per 1.73 m2 because GFR is proportional to kidney size, which is proportional to body size. Adjusting GFR to body surface area (BSA) reduces the variability in GFR in healthy individuals, allowing communication of GFR threshold for decision-making that can applied to most donors across the usual distribution of body size.
Based on a large body of evidence, mean GFR in healthy young adult white individuals is approximately 125 mL/min per 1.73 m2, with a wide range.126 There is some evidence that the normal level of GFR varies among ethnic groups.127 GFR is affected by numerous physiologic and pathologic conditions and varies with time of day, dietary protein intake, exercise, age, pregnancy, obesity, hyperglycemia, use of antihypertensive drugs, surfeit or deficit of extracellular fluid, and acute and chronic kidney disease. Despite these limitations, no other measure has been proposed as an overall index of kidney function in the general population or in kidney donor candidates. Thus, it is important that the evaluation of kidney function in kidney donor candidates take into account factors that can affect GFR.
It is not possible to directly measure GFR in humans; thus, the “true” GFR cannot be known with certainty. GFR can be measured indirectly as the clearance of exogenous filtration markers or estimated from serum levels of endogenous filtration markers, but both measured GFR (mGFR) and estimated GFR (eGFR) are associated with error in their determination. We recommend that the transplant program use the best available method to assess GFR in donor candidates, recognizing that at many centers, more than one method may be available. The accuracy of various methods for measuring and estimating GFR is not known with sufficient certainty to define specific threshold for each method.
The KDIGO 2012 CKD guidelines for GFR evaluation in the general population recommend expressing kidney function as GFR and not as serum creatinine concentration, and recommend expressing GFR in mL/min per 1.73 m2 rather than mL/min.124 The guidelines recommend 2-stage testing (initial testing followed by confirmatory testing as necessary). The WG concluded that these general recommendations were applicable to living kidney donor candidates.
The eGFR based on serum creatinine (eGFRcr) is the recommended initial test. Serum creatinine assays should be traceable to the international reference standard. In North America, Europe, and Australia, the 2009 CKD CKD-EPI creatinine equation should be used unless other equations have been shown to be more accurate. eGFRcr using the 2009 CKD-EPI creatinine equation has minimal bias at normal GFR; however, it is imprecise (Figure 5), thus it is most useful for an initial evaluation.128 In regions other than North America, Europe, and Australia, the 2009 CKD-EPI creatinine equation is less accurate. In these regions, other equations are recommended if they are more accurate than the 2009 CKD-EPI creatinine equation.
GFR estimating equations are developed using regression methodologies to relate the mGFR to steady state serum creatinine concentration and a combination of demographic and clinical variables as surrogates of the non-GFR determinants of serum creatinine. By definition, GFR estimates using serum creatinine concentration are more accurate in estimating mGFR than the serum creatinine concentration alone in the study population in which they were developed. Sources of error in GFR estimation from serum creatinine concentration include nonsteady-state conditions, nonGFR determinants of serum creatinine, measurement error at higher GFR, and interferences with the creatinine assays (Table 12). GFR estimates are less precise at higher GFR levels than at lower levels. The clinician should remain aware of caveats for any creatinine-based estimating equation which may influence the accuracy in a given individual.
A variety of confirmatory tests for GFR are available. In the general population, the 2012 KDIGO guideline suggests confirmation of GFR with either GFR estimation using cystatin C or a clearance measurement in specific circumstances when eGFR based on serum creatinine is less accurate (Box 1, 2012 CKD Recommendation 220.127.116.11). KDIGO further suggests measuring GFR using an exogenous filtration marker under circumstances where more accurate ascertainment of GFR will impact treatment decisions (Box 1, 2012 CKD Recommendation 18.104.22.168), including the evaluation of living organ donors). Based on these recommendations, the WG concluded that confirmation of GFR using the most accurate method available at the transplant center. In the United States, OPTN policy requires a clearance measurement (measured creatinine clearance [mCrCl] or mGFR) for confirmation of GFR.
Many methods for mGFR determination using exogenous filtration markers and clearance calculations are available, with variable accuracy. Recommendations for specific methods are based on a recent systematic review.129 mGFR is not available at all centers, so other alternatives are acceptable. mCrCl is less accurate than mGFR,129 but it is acceptable if mGFR is not available. mCrCl overestimates mGFR due to creatinine secretion.130 The magnitude of overestimation is 15% or more at normal GFR, based on older data using nonstandardized serum creatinine assays. The magnitude of overestimation may be higher using standardized assays. In principle, mCrCl is available worldwide, however, in some donor candidates, mCrCl may not be available due to logistical difficulties in collecting or transporting a timed urine collection.
A recent study suggests that eGFR may be sufficiently accurate for decision-making without the need for mGFR in many cases.8 A web-based calculator is available to compute posttest probabilities for mGFR above or below threshold probabilities for decision-making: http://ckdepi.org/equations/donor-candidate-gfr-calculator/. Post-test probabilities are computed from pretest probabilities for mGFR and test performance for eGFR using serum creatinine (eGFRcr) or the combination of creatinine and cystatin C (eGFRcr-cys). Very high posttest probabilities provide reassurance that mGFR is above the threshold level for decision-making, while very low posttest probabilities provide reassurance that mGFR is below the threshold levels for decision-making. Transplant programs can determine what posttest probabilities are sufficient for clinical decision-making in the absence of mGFR and mCrCl. One study validating these computations in donor candidates has been reported.131 Future studies should address prediction accuracy among racial and ethnic groups for whom the accuracy of eGFR is less certain (eg, nonblack, nonwhite persons).
In general eGFRcys is not more accurate then eGFRcr; however using 2 filtration markers improves precision of GFR estimates compared with using either marker alone; thus eGFRcr-cys is generally recommended over eGFRcr or eGFRcys.132,133 Advantages of cystatin C compared with creatinine are that cystatin C is not affected by muscle mass and current equations do not require specification of race. Therefore, eGFRcys maybe more accurate than eGFRcr-cys in people with very large or very small muscle mass, very high or very low meat intake, or race-ethnicity other than black (African American or African European) or white. If cystatin C is measured, cystatin C assays should be traceable to international reference standard (which is in the early stages of implementation) and the 2012 CKD-EPI eGFRcys equation or eGFRcr-cys equation should be used unless other equations have been shown to be more accurate. If cystatin C is not available, eGFRcr can be used for decision-making. As with creatinine, sources of error in GFR estimation from serum cystatin C concentration include non–steady-state conditions, nonGFR determinants of serum cystatin C, measurement error at higher GFR, and interferences with the cystatin C assays (Table 13).
Single (“divided” or “split”) kidney GFR can be assessed by radionuclide imaging, but is not required in all kidney donor candidates. However, all kidney donor candidates undergo kidney imaging to detect parenchymal, vascular or urologic abnormalities, and asymmetry in kidney size suggests asymmetry in kidney function.
Selection: Criteria for Acceptable Predonation GFR
GFR in the General Population
GFR in young men and women of 90 mL/min per 1.73 m2 or greater is generally considered normal.124 GFR between 60 and 89 mL/min per 1.73 m2 is considered to be decreased compared with the usual level for young adults, but does not meet the KDIGO criterion for CKD.
GFR declines with age, although the cause of decline is not known and the rate of decline appears widely variable. Most data are based on cross-sectional studies, in which mean GFR is lower in older populations than in young populations. Other kidney functions are also lower in older populations (eg, renal plasma flow, maximal urinary concentration) and kidney structure is altered in older populations (eg, cortical atrophy, global glomerulosclerosis, nephrosclerosis). There is debate about whether abnormalities in kidney function and structure in older people represents normal aging or disease.
Decreased GFR in the general population is associated with a higher risk of complications of CKD, including ESKD, cardiovascular disease (CVD) and death. In general populations, compared with a reference eGFR of 95 mL/min per 1.73 m2, the RR for complications related to decreased eGFR is apparent between 60 and 75 mL/min per 1.73 m2 and is exponentially higher at lower eGFR.134 Similar relationships of lower eGFR with adverse outcomes have been observed in subgroups including patients with known CKD (Figure 6).134-137 KDIGO 2012 guideline defines GFR less than 60 mL/min per 1.73 m2 for 3 months or more as satisfying the criteria for CKD. GFR 15 to 30 mL/min per 1.73 m2 is defined as severely reduced, and GFR less than 15 mL/min per 1.73 m2 is defined as kidney failure. However, the association of lower eGFR with a higher risk of adverse outcomes may be related to other conditions that co-occur with low GFR, such as hypertension, diabetes and CVD. Lower GFR in older people is associated with increased risk for CKD outcomes, including ESKD, CVD and death. The RR for these outcomes in older people with lower eGFR compared with the reference eGFR is less than the RR in younger people, however the increment in absolute risk is higher in older people than in younger people.138
A recent meta-analysis based on data from nearly 5 million healthy persons identified from 7 general population cohorts who are similar to kidney donor candidates found that lower GFR (in the absence of donation) is associated with an increased risk for ESKD over median cohort follow-up of 4 to 16 years.7 After calibration to annual ESKD incidence in the US healthy population, variations in the projected 15-year and lifetime risks of ESKD based on level of eGFR were generated according to age, sex, and race for healthy persons (assuming systolic BP (SBP) 120 mm Hg, urine albumin-to-creatinine ratio (ACR) 4 mg/g [0.4 mg/mmol], BMI 26 kg/m2, and absence of diabetes mellitus) (Figures 7 and 8). This analysis demonstrates that lower eGFR is associated with increased lifetime risk for ESKD in all demographic subgroups. For eGFR of 90 mL/min per 1.73 m2 or greater and other optimal characteristics (see above), lifetime risk for white men and white women was less than 1% at all ages, but was higher among young black men and women (Figure 8). Lifetime risk for eGFR 60 to 89 mL/min per 1.73 m2 was less than 1% at ages older than 60 years. While these displays are useful for visualizing the impact of baseline eGFR on ESKD risk, we endorse consideration of eGFR as part of the assessment of predicted long-term ESKD risk based on a donor candidate’s complete demographic and health profile (as opposed to consideration of single risk factors in isolation).
GFR after Kidney Donation
GFR declines after kidney donation. A person with a predonation GFR of at least 90 mL/min per 1.73 m2 would be expected to have a 1-year postdonation GFR of at least 60 mL/min per 1.73 m2. In general, a donor immediately loses approximately 50% of renal mass, but there is rapid compensatory hyperfiltration leading to a net reduction in GFR of approximately 30% (25% to 40%) after donation (decrement in GFR of 25 to 40 mL/min per 1.73 m2).139-141
In prior guidelines a GFR level of 80 mL/min is frequently cited as the minimal threshold for an acceptable level of kidney function for donation.38,142 Limited data show a higher risk for lower GFR after donation among kidney donors with lower predonation GFR.3 (Evidence Report Table 16, SDC,http://links.lww.com/TP/B434, and Supplemental Appendix Table D13, SDC,http://links.lww.com/TP/B432).
There is theoretical justification for concern about development of kidney disease after nephrectomy. In experimental animals, hemodynamic alterations associated with hyperfiltration after reduction in renal mass are followed by development of structural and functional abnormalities associated with kidney disease. In general, the severity of reduction in renal mass is directly associated with the rate of development of subsequent kidney disease. A recent study in humans documents similar hemodynamic alterations associated with hyperfiltration after kidney donation.143,144
The risk of ESKD after kidney donation does not exceed ESKD risk in the general population.140,145,146 An analysis of living kidney donors in the United States between 1994 and 2003 quantified a postdonation ESKD rate of 0.134 per 1000 person-years over an average follow-up of 9.8 years, which was not higher than the ESKD rate in the general population, even though GFR is lower.147 However, the general population is a limited comparison group given that donors undergo careful medical evaluation and selection.4 The ERT identified 2 recent studies suggesting that donation is associated with an increase in the risk of ESKD compared to risk in nondonors selected for baseline good health, although the risk increase is small and the absolute postdonation risk remains low (Supplemental Appendix Table D5, SDC,http://links.lww.com/TP/B432). The quality of this evidence was rated as moderate. In comparing 1901 kidney donors with 32 621 healthy, demographically matched controls, Mjøen et al reported that 0.47% of donors (n=9) developed ESKD versus 0.07% of healthy nondonors (n=22) over a median 15.2-year follow-up.32 Based on linking 96 217 donors from the US donor registry and healthy participants drawn from the National Health and Nutrition Examination Survey III to national ESKD reporting forms, Muzzale et al estimated that the cumulative incidence of ESKD at 15 years was 30.8 per 10 000 in donors compared with 3.9 per 10 000 in matched donors (risk attributable to donation of 26.9 per 10 000).30 In this study, the incidence of ESKD was higher in individuals who are older versus younger at the time of donation, in men versus women, in blacks versus whites, and in biologically related versus unrelated donors, but risk based on predonation eGFR was not reported. Based on these findings, the likelihood of a small increase in ESKD risk should be discussed with donor candidates; such counseling is endorsed by a 2015 AST Live Donor Community of Practice consensus statement,148 and is required in the US by the OPTN Informed Consent Policy beginning in 2017.51
Single Kidney GFR
Many factors determine the preferred kidney to remove for transplantation. If GFR is acceptable, but there are parenchymal, vascular or urological abnormalities or asymmetry in kidney function, it is preferable to transplant the more severely affected kidney or the kidney with lesser function (see also chapter 16).
On average, kidney function and size are correlated. The average length and volume of a single kidney in healthy adults are approximately 11 cm and 150 mL, respectively, but vary based on age, sex, and body size.149-151 On average the normal right kidney is approximately 5% smaller than the normal left kidney. Asymmetry in kidney size is generally considered as a difference in kidney size greater than 10% (for example, a difference in kidney length > 1.1 cm or kidney volume > 15 mL). An equivalent difference in kidney function would be greater than 10% (>55% vs <45% in split kidney function). Based on low quality evidence, 1 prior guideline suggested considering a radionuclide imaging study if the difference between kidney lengths is greater than 2 cm, and that a difference in function of 10% or greater between the kidneys may be considered significant.48 No studies were found meeting criteria for review by the ERT.
What Prior Guidelines Recommend
Some guidelines recommend that GFR of 80 mL/min or greater is acceptable for donation, based on the level of GFR in the donor (not adjusted for BSA) that was associated with acceptable outcomes in the recipient, not the donor.152 Alternatively, some guidelines recommend a GFR level within 2 standard deviations of normal for age and sex. In general, the guidelines do not specify the GFR measurement method to be used, whether the threshold value should be adjusted for BSA, or provide standardized reference values based on sex, race, and age.153
A 2007 survey of practices by transplant programs in the United States revealed that approximately 90% of programs used mCrCl to measure kidney function, while the other 10% of programs used the clearance of an exogenous filtration marker, and that approximately 67% of transplant programs used a threshold of 80 mL/min or more to accept donors, while 25% used a threshold based on age and sex.154
In our view, there is not sufficient evidence to justify a single threshold value of 80 mL/min not adjusted for BSA, nor age-specific thresholds. In contrast, our recommendations are more consistent with accepted measurement methods and thresholds in general clinical practice, and acknowledge that there is variation in GFR measurement methods and uncertainty in the appropriate threshold to accept or decline donor candidates. For this reason, we recommend GFR measurement by urinary or plasma clearance of specific exogenous filtration markers, which are known to be more accurate than mCrCl, but allow other methods. We recommend a higher threshold value of GFR (≥90 mL/min per 1.73 m2) to routinely accept a donor candidate, and lower threshold value of GFR (<60 mL/min per 1.73 m2) to routinely decline a donor candidate, and a wide intermediate range of GFR (60-89 mL/min per 1.73 m2) in which transplant programs can individualize decisions based on other risk factors. Of note, this intermediate range would generally include a mCrCl of 80 mL/min as well as previously recommended age and sex thresholds for mGFR.
- Evaluate the accuracy of eGFRcr, eGFRcys and eGFRcr-cys for the prediction of mGFR in the evaluation and selection of living donor candidates.
- Evaluate long-term risks, including lifetime risk of ESKD, in living donor candidates and living donors according to predonation GFR.
CHAPTER 6: PREDONATION ALBUMINURIA
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 6 and therefore the following recommendations are “Not Graded.” Some of the recommendations extrapolated from the 2012 KDIGO CKD Guideline124 were not part of the ERT review for this guideline and as such they are also “Not Graded.”
- 6.1: Donor proteinuria should be measured as albuminuria, not total urine protein.
- 6.2: Initial evaluation of donor albuminuria (screening) should be performed using urine albumin-to-creatinine ratio (ACR) in a random (untimed) urine specimen.
- 6.3: Donor albuminuria should be confirmed using:
- Albumin excretion rate (AER, mg/day [mg/d]) in a timed urine specimen
- Repeat ACR if AER cannot be obtained.
- 6.4: Urine AER less than 30 mg/d should be considered an acceptable level for donation.
- 6.5: The decision to approve donor candidates with AER 30 to 100 mg/d should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
- 6.6: Donor candidates with urine AER greater than 100 mg/d should not donate.
The goals of the evaluation of albuminuria in living donor candidates are to:
- Provide an accurate assessment of the amount of albuminuria and long-term risk of ESKD based on albuminuria and other factors.
- Exclude donor candidates whose postdonation risk is expected to exceed the acceptable risk threshold for ESKD established by the transplant program.
- Provide counseling regarding level of risk for donor candidates whose long-term risk for ESKD is expected to be below the acceptable risk threshold established by the transplant program.
- Provide counseling regarding follow-up of albuminuria after donation.
In this section, recommendations are based on physiological principles and recommendations for general clinical practice from the 2012 KDIGO CKD guideline.124 There is no evidence to suggest or a reason to think that kidney donors differ from the general population regarding these recommendations.
Proteinuria as a Marker of Kidney Damage
Urine protein is composed of small amounts of high molecular weight proteins (principally albumin) that are not normally filtered, low molecular weight serum proteins that are normally filtered by the glomeruli and reabsorbed by the tubules, and proteins secreted by the urinary tract.
Increased urinary protein is generally considered a marker of kidney damage: albuminuria reflects increased permeability of the glomeruli (glomerular proteinuria), and low molecular weight proteinuria reflects decreased tubular reabsorption (tubular proteinuria). CKD due to either glomerular or tubulointerstitial diseases is generally associated with both glomerular and tubular proteinuria (albuminuria and low molecular weight proteinuria). Some tubulointerstitial diseases may cause predominantly tubular proteinuria, including Dent disease, toxicity due to heavy metals (eg, cadmium and lead) or aristolochic acid (Balkan and Chinese herb) nephropathy, Sjogren syndrome, multiple myeloma or hereditary diseases associated with Fanconi syndrome, and acute tubular necrosis. Conditions other than kidney disease can also cause proteinuria: low molecular weight proteinuria may also reflect overproduction (eg, light chain proteinuria in lymphoproliferative disorders) and high and low molecular weight proteins may arise from increased secretion of urinary tract proteins (due to lower urinary tract diseases).
Urine albumin is the preferred measure of urine protein for assessment of kidney damage. Tests for total urine protein cannot be standardized because they are not traceable to a standard reference material due to the varying composition of urine protein. Current efforts to standardize albuminuria assessment are directed to establishing traceability of tests for urine albumin to standardized reference material for serum albumin. Other urine proteins are less well standardized than albumin.
The albumin loss rate (hereafter referred to as albumin excretion rate, AER) is not regulated in health and is widely accepted as a marker of kidney damage. Increased AER is associated with a wide range of complications and increased AER is one of the criteria for the definition of CKD. In diabetic kidney disease and other glomerular diseases, increased AER generally occurs before the decline in GFR.
The KDIGO 2012 CKD guideline for the evaluation of albuminuria in the general population recommends 2-stage testing (initial testing followed by confirmatory testing).124 The current living donor guideline WG concluded that these general recommendations were applicable to kidney donor candidates.
Initial tests, in order of preference, and the rationale are described below. In all cases an early morning urine sample is preferred as it minimizes variation due to diurnal variation in albumin excretion and urine concentration.
Urine Albumin-to-Creatinine Ratio (ACR)
The rationale for preferring ACR to albumin concentration is that urine concentration and dilution can vary by more than 10-fold among individuals and during the day. The KDIGO CKD guideline therefore recommends that clinical laboratories measure creatinine when albumin is requested, and express the results as ACR in addition to albumin concentration. Indexing urine albumin by urine creatinine concentration overcomes variation due to urine concentration and dilution, but introduces variation by creatinine generation.
Recently, some investigators have proposed estimating creatinine excretion rate and multiplying this quantity by ACR to estimate AER.155 The lower limit of detection for urine albumin in the clinical laboratory where the test is performed can be used for computation of urine ACR if the clinical laboratory reports “below the detectable limit.” Factors affecting urine ACR in addition to kidney disease are shown in Table 14.
One study reported excellent performance of ACR to detect AER of 30 mg/d. The area under the receiver operator curve was 0.93.156 An ACR threshold of ≥10 mg/g was associated with sensitivity and specificity of 88% each for detecting AER ≥30 mg/d. There was minor variation in area under the receiver operator curve based on age, sex, race, and body weight.
Urine Protein-to-Creatinine Ratio (PCR)
Tests for total urine protein cannot substitute for tests for urine albumin. PCR is less sensitive than ACR, so even negative tests must be confirmed by tests for albumin. Increased PCR suggests increased ACR, but nonalbumin protein can cause a positive test, so positive tests should be confirmed by tests for albumin. Patients with elevated PCR and negative tests for albumin may have tubular proteinuria, light chain proteinuria or urinary tract disease. Specific assays are available for α1-microglobulin, β2 microglobulin, monoclonal heavy or light chains.
Reagent Strip Urinalysis for Total Protein with Automated Reading
Reagent strips allow point-of-care, semi-quantitative assessment of total urine protein concentration. Reagent strips (“dipsticks”) are more sensitive to albumin than other proteins, but lack specificity. Automated readers are more accurate than manual reading of reagent strips.
Reagent Strip Urinalysis for Total Protein with Manual Reading, if the Above Measures are not Available
Because of variability in urine ACR and its relationship to urine AER, the WG recommends confirmation in all cases. The preferred confirmatory test is urine AER, expressed as mg/d. If urine AER is not available, a repeat ACR is acceptable. Consistent with the 2012 KDIGO CKD guideline, testing for specific urine proteins such as α1-microglobulin, β2 microglobulin, monoclonal heavy or light chains (also known as “Bence Jones” proteins) can be undertaken if significant nonalbumin proteinuria is suspected. These assays can be performed at the same time as tests for albuminuria.
Selection: Criteria for Acceptable Predonation Albuminuria
AER in the General Population
The normal level of AER in healthy young men and women is less than 10 mg/d. The coefficient of variation for repeated measurements is approximately 30%.157 Because of the high coefficient of variation, repeated measurements are preferred for assessment of albuminuria.
AER rises with age, although the cause of rise is not known and the rate of rise appears widely variable. Most data are based on cross-sectional studies and mean AER is higher in older populations than in young populations. As discussed in chapter 5, there are often abnormalities in kidney function and structure in the elderly and there is debate about whether higher AER in older people represents normal aging or disease.
Higher albuminuria in the general population is associated with a higher risk of complications of CKD, including ESKD, CVD and death. In general populations, compared with a reference ACR of 5 mg/g (0.5 mg/mmol), the RR for complications related to increased ACR rises at higher ACR, without an apparent threshold when expressed on the log scale.134 The risk of higher ACR is independent of the eGFR. Similar relationships of high albuminuria with adverse outcomes have been observed in subgroups including patients with known CKD (Figure 6).134-137 KDIGO 2012 CKD guideline defines AER >30 mg/d for 3 months or more as satisfying the criteria for CKD. AER less than 30 mg/d in young men and women is considered normal to mildly increased, with 10 to 29 mg/d considered as “high normal”; AER 30 to 300 mg/d is defined as moderately increased compared with the young adult level; and AER greater than 300 mg/d is defined as severely increased compared with the young adult level. Approximate ranges for other measures of urine protein are as shown in Table 15. The association of higher albuminuria with higher risk of adverse outcomes may be related to other conditions that co-occur with high albuminuria, such as hypertension, diabetes and CVD. The RR for these adverse CKD outcomes (ESKD, CVD, death) in older people with higher urine ACR compared with the reference urine ACR is less than the RR in younger people; however the increment in absolute risk in older people is higher in older people than in younger people.138
A recent meta-analysis based on data from nearly 5 million healthy persons identified from 7 general population cohorts found that each 10-fold increase in urinary ACR was associated with 3 times the risk of ESKD over median cohort follow-up of 4 to 16 years, although the finding was not statistical significant (95% Lower Confidence Limit adjusted hazard ratio [aHR] 95% Upper Confidence Limit; 0.992.948.75).7 After calibration to annual ESKD incidence in the US healthy population, variations in the projected 15-year and lifetime risks of ESKD based on urine ACR were generated according to age, sex, and race for healthy persons (assuming age-specific eGFR, SBP 120 mm Hg, BMI 26 kg/m2, and absence of diabetes mellitus; Figures 9 and 10). This analysis demonstrates that higher albuminuria is associated with higher lifetime risk of ESKD in all subgroups, with higher risk in men than women and blacks than whites. For urine ACR less than 10 mg/g and other optimal risk factors (see above), lifetime risk for white men and white women was less than 1% at all ages, but exceeded 2% for black men younger than 40 (Figure 10). For urine ACR less than 30 mg/g, the lifetime risk was less than 1% in white men at age >50 years, black men at age >70, and black women at age >60. While these displays are useful for visualizing the associations of baseline ACR with ESKD risk, we endorse consideration of ACR as part of the assessment of predicted long-term ESKD risk based on a donor candidate’s complete demographic and health profile (as opposed to consideration of single risk factors in isolation).
Proteinuria after Kidney Donation
Some but not all studies demonstrate donors have an increase in proteinuria compared with nondonor control groups (Figures 11 to 12).139-141 In prior guidelines a protein excretion rate (PER) <150 mg/d was frequently cited as acceptable for donation.48,50,158,159 This level corresponds roughly to AER less than 30 mg/d, which includes normal and mildly increased (Table 15).124 However, the risk associated with albuminuria in kidney donors is uncertain.
There is theoretical justification for concern about development of kidney disease after nephrectomy. First, in experimental animals, reduction in renal mass is associated with increased glomerular permeability to albumin followed by other structural and functional abnormalities associated with kidney disease. Second, given that GFR declines after kidney donation, the filtered load of albumin would be expected to decline. Unchanged or higher albuminuria after donation suggests increased albumin filtration per nephron.
In a prior systematic review, the incidence of clinical proteinuria after donation was quantified in 42 studies, that followed 4793 living donors for an average of 7 years (range, 2-25 years).141 There was significant heterogeneity between the studies (P < 0.0001). Some studies reported an incidence of proteinuria over 20%, whereas in others the incidence was less than 5%. The pooled incidence of proteinuria was 12% (95% CI, 8-16%). These results were similar in a supplementary analysis limited to 9 studies which consistently defined proteinuria as greater than 300 mg/d based on 24-hour urine. The pooled incidence of proteinuria among these 9 studies, which followed a total of 1799 donors for 7 years, was 10% (95% CI, 7-12%).
What Prior Guidelines Recommend
Some guidelines recommend that accepted living donor candidates have a PER less than 150 to 300 mg per day, based on the usually accepted normal range, generally without reference to measurement methods. A survey of practices by transplant programs in the United States reported in 2007 found that approximately 76% of programs used a PER in a 24-hour urine collection for donor evaluation, and that 36% used PER > 150 mg/d as a threshold for donor exclusion (unless proteinuria is postural), while 44% reported higher exclusion thresholds of 300-1000 mg/d.154
By comparison, our recommendations are more consistent with the recently accepted criterion standard, measurement methods and thresholds in general clinical practice, but acknowledge that there is variation in ascertainment of albuminuria for screening and uncertainty in the appropriate threshold to accept or decline donor candidates. For these reasons, we recommend measurement of albumin rather than total protein, and AER in a timed urine collection rather than ACR in a spot urine specimen if possible. We recommend an AER threshold of less than 30 mg/d to routinely accept a donor candidate, which corresponds to normal to mildly increased. We recommend an intermediate range of AER 30 to 100 mg/d corresponding to the lower range for moderately increased AER, in which to individualize decisions based on other risk factors. We acknowledge that AER of 30 to 100 mg/d meets the criteria for CKD, and past recommendations have strived to exclude donor candidates with CKD. We have not excluded candidates solely on the basis of AER 30 to 100 mg/d because estimated projected predonation lifetime risk of ESKD in older persons with ACR in this range is very low in the absence of decreased GFR and other health risk factors.7 Thus, we concluded that universal exclusion would not be consistent with a Framework that would allow donation from other candidates with similar risk due to other clinical risk factors.
We do not require tests of total urine protein in addition to albumin because there are no accepted normal ranges for urine nonalbumin protein excretion; disorders associated with predominant tubular proteinuria (tubulointerstitial kidney disease) and overproduction proteinuria (plasma cell or B-lymphocyte disorders) are uncommon, and patients with these disorders usually have other clinical abnormalities that would be discovered during the donor evaluation.
- Assess the accuracy of urine ACR compared with AER for evaluation and selection of living donor candidates.
- Evaluate the association of urine albumin with other kidney measures (eg, GFR and kidney size) at the time of donor evaluation and with kidney measures and outcomes (eg, GFR change, ESKD, survival) after donation.
CHAPTER 7: PREDONATION HEMATURIA
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 7 and therefore the following recommendations are “Not Graded.”
- 7.1: Donor candidates should be assessed for microscopic hematuria.
- 7.2: Donor candidates with persistent microscopic hematuria should undergo testing to identify possible causes, which may include:
- Urinalysis and urine culture to assess for infection
- Cystoscopy and imaging to assess for urinary tract malignancy
- 24-hour urine stone panel to assess for nephrolithiasis and/or microlithiasis
- Kidney biopsy to assess for glomerular disease (eg, thin basement membrane nephropathy, IgA nephropathy, Alport syndrome)
- 7.3: Donor candidates with hematuria from a reversible cause that resolves (eg, a treated infection) may be acceptable for donation.
- 7.4: Donor candidates with IgA nephropathy should not donate.
Evaluation and Definitions
Persistent microscopic hematuria is most often defined as more than 2 to 5 red blood cells per high-power field of urinary sediment on 2 to 3 separate occasions, unrelated to exercise, trauma, sexual activity or menstruation.160-163 Consensus-based guidelines of the American Urological Association state that while a positive dipstick reading warrants microscopic examination to confirm the diagnosis of asymptomatic microhematuria, a positive dipstick alone does not define microhematuria, and evaluation should be based solely on findings from microscopic examination of urinary sediment.161 Causes of a positive dipstick reading in the absence of red blood cells in the urine include hemoglobinuria, myoglobinuria, a dilute urine sample, or simply a false-positive test.
The estimated prevalence of microscopic hematuria varies widely from 0.18% to 16%.160 A recent population study of 1.2 million persons aged 16 to 25 years in Israel identified prevalent asymptomatic persistent microscopic hematuria in 0.3% of individuals.163 Persistent microscopic hematuria may be associated with urologic abnormalities (eg, stones, tumors) or glomerular disease. The most common glomerular causes of persistent isolated microscopic hematuria are IgA nephropathy, thin basement membrane nephropathy (TBMN) and Alport syndrome.164-167
There are consensus-based guidelines for the evaluation of asymptomatic microhematuria in the general population. For example, the 2012 recommendations from the American Urological Association161 include assessment of risk factors for urinary tract malignancies (eg, irritative voiding symptoms, current or past tobacco use, chemical exposures), radiological evaluation (eg, multiphasic computed tomography urography, without and with intravenous contrast, or magnetic resonance urography), and cystoscopy in patients age 35 years or older regardless of history of use of anticoagulation therapy. Urine cytology and urine biomarkers are not recommended as a part of the routine evaluation of asymptomatic microhematuria.
The presence of dysmorphic urinary red blood cells detected by conventional microscopy, phase-contrast microscopy, or automated analyzer has a broad a range of sensitivities (32% to 100%) and specificities (from 33% to 100%) for glomerular causes of microhematuria.161 The presence of dysmorphic red blood cells or cellular urinary casts and other clinical information can be used to prioritize the evaluation for glomerular causes of hematuria. However, the presence of dysmorphic red blood cells does not exclude underlying urologic disease.161
Although isolated microscopic hematuria in young persons is often considered “benign,” a recent population-based study of 1.2 million Israeli persons aged 16 to 25 years with up to 35 years of follow-up identified small but significant increase in long-term renal risk associated with persistent asymptomatic isolated microscopic hematuria, with ESKD rates of 34.0 versus 2.05 per 100 000 person-years among those with versus without persistent microscopic hematuria (adjusted HR, 12.418.527.6).163 While participants were required to have serum creatinine values “within the normal range” and 24-hour urine protein less than 200 mg, this study does not provide information on ESKD risk after comprehensive evaluation and selection including measured kidney function.
The sequence of the evaluation for microscopic hematuria, like other testing in this guideline, is designed to perform less invasive/expensive tests before more invasive/expensive tests, and only if the less invasive/expensive tests do not preclude donation (Figure 13).168 Reversible causes of microscopic hematuria, for example, treatable urinary tract infection, should generally not preclude donation. In the absence of a family history suggesting possible TBMN or Aport disease, additional testing to rule out these causes is generally not necessary. Please refer to chapter 14 for a related discussion on genetic testing in the donor candidate.
Epidemiological studies of TBMN suggest increased risks of hypertension and proteinuria compared with the general population over time, but progression to ESKD is rare and thought to require an additional insult.169 Data on outcomes of living kidney donor evaluation and donation in persons with TBMN are limited to small series with short-term follow-up.170,171 A series of 512 consecutive donors at a US center identified asymptomatic, microscopic hematuria for at least 1 month in 2.7% (n = 14). Hematuria resolved after treatment for urinary tract infection in 2. Kidney biopsy was performed in 10/12, and showed: TBMN (5/12); normal (2/12); nonhomogeneous basement membrane abnormalities (1/12); IgA nephropathy (1/12); and greater than 20% glomerulosclerosis in a patient with a family history of Schimke's syndrome (immune-osseous dysplasia). Two of the 4 with TBMN, aged 44 and 53 years, proceeded with donation; after 15 months follow-up, donors were free of hypertension, proteinuria, and recipients had “excellent” graft function.170 A Korean series including 5 living donors with TBMN defined by predonation biopsy reported favorable short-term outcomes, including mean serum creatinine 0.94 ± 0.32 mg/dL (83 ± 28.3 μmol/L) and no cases of new-onset hypertension or proteinuria over mean follow-up period of 34.7 ± 42.5 months.171
Notably, TMBN is often defined based on pathological description rather than as a distinct clinical entity. Carrier states for Alport mutations may present as TBMN. High rates of proteinuria (75%) and ESKD (8-30%) have been reported in female carriers of X-linked Alport syndrome mutations.172 A recent study identified adverse kidney outcomes in 234 Alport carriers (including 29 autosomal recessive and 205 X-linked mutation carriers): ESKD developed in 17.5% at a median age of 49 years, and outcomes including ESKD, proteinuria and impaired kidney function were similar in X-linked and autosomal recessive carriers,173 although the number of autosomal recessive carriers was small. Among 6 female Alport carriers (5 X-linked, 1 autosomal recessive) who donated to their children at several European centers and were followed for an average 6.7 years, 3 developed new-onset hypertension and 2 developed new-onset of proteinuria.174 Creatinine clearance remained greater than 40 mL/min in all donors after up to 14 years. Thus, while data are limited, female carriers of X-linked Alport syndrome (ie, COL4A5 mutation) should be discouraged from kidney donation because of their own increased risk of hypertension and adverse kidney outcomes even in the absence of donation.
IgA nephropathy that presents with hematuria and minimal proteinuria is often a progressive disease.175 In one series in Hong Kong, 72 consecutive patients with IgA nephropathy presenting as hematuria and minimal proteinuria (0.4 g/day or less) were followed for a median of 84 months; 33% developed proteinuria, 26% became hypertensive, and 7% developed impaired kidney function.176 The presence of hematuria and glomerular IgA deposition is associated with increased risk of progressive kidney disease even in the absence of other clinical findings.175 For this reason, there is broad consensus that people with known IgA nephropathy should not donate a kidney. Examination of a series of 510 implantation biopsies at a large center in Tokyo (including 446 living donors) found latent mesangial IgA deposition to be relatively common in healthy Japanese living donors, present in 16.1% of living donor allograft biopsies.177 Mesangial IgA deposition was associated with a mild degree of microhematuria, mesangial proliferation and glomerular macrophage infiltration in some of the affected individuals, especially with C3 deposition.
Persistent hematuria without defined renal histopathology has been associated with proteinuria after kidney donation. In a series of 242 living kidney donors at one center in Japan, persistent predonation hematuria was identified in 8.3% (18.6% vs 6% in those with vs without family history of IgA nephropathy or Alport syndrome).178 95% of those with persistent predonation hematuria continued to have persistent hematuria after donation over median 27 month follow-up (compared with 28% of those with predonation occasional hematuria and 5% without predonation hematuria). Predonation hematuria was associated with increased likelihood of persistent proteinuria (dipstick ≥ 1+) after donation (without dysmorphic red blood cells: adjusted OR 3.8; with dysmorphic red blood cells: adjusted OR 12.3). Predonation hematuria was not associated with postdonation GFR, but persistent postdonation hematuria with dysmorphic red blood cells was associated with significant GFR decline over the study period.
What Prior Guidelines Recommend
Previous guidelines recommend that evaluation of donor candidates for causes of hematuria include urine culture and imaging,48 cystoscopy if older than 40 years,48 urine cytology and “complete” urological evaluation.54 A recent Canadian protocol recommends tests of urine culture, urine cytology, 24-hour urine calcium, metabolic stone workup, and then if the cause of hematuria is undetermined, cystoscopy and a native kidney biopsy.179 In the absence of an identified cause, evaluation by kidney biopsy has been advised if hematuria is >1 + 48 or possibly caused by glomerular disease38,54
While a number of prior living donor guidelines recommend kidney biopsy as part of the evaluation of persistent microhematuria before donation,48,180 few articulate criteria for donor selection. The 2011 British Transplantation Society guidelines offer a “moderate quality” recommendation that “glomerular pathology precludes donation, with the possible exception of thin basement membrane disease.”48 Canadian Blood Service’s protocol for KPD defines IgA nephropathy and Alport syndrome (including carrier status) as exclusions to donation.179
The 2013 “Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy” include several consensus-based recommendations related to living donation selection181: A) “Individuals with TBMN may be kidney donors if they have normal BP, proteinuria, and renal function” and if a biopsy is done and Alport syndrome is excluded.” Close monitoring and use of nephroprotective strategies are advised; B) “Individuals from families with autosomal recessive Alport syndrome who have only one of the causative mutations (parents, offspring, some siblings) may be kidney donors if they have normal BP, proteinuria levels, and renal function; if coincidental kidney disease has been excluded by kidney biopsy; and if X-linked Alport syndrome has been excluded by genetic testing.” The document recommends “discouraging affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure.”
- Perform long-term follow-up studies of living donors with infrequent clinical conditions including:
- ○ Alport female “carrier” state
- ○ TBMN
- ○ Incidental IgA deposition in glomeruli and isolated hematuria
- ○ Nephrolithiasis
- These studies should include appropriate controls and examine endpoints including CKD and kidney failure, premature death, and health-related quality of life.
CHAPTER 8: KIDNEY STONES
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 8 and therefore the following recommendations are “Not Graded.”
- 8.1: Donor candidates should be asked about prior kidney stones, and related medical records should be reviewed if available.
- 8.2: The imaging performed to assess anatomy before donor nephrectomy (eg, computed tomography angiogram) should be reviewed for the presence of kidney stones.
- 8.3: Donor candidates with prior or current kidney stones should be assessed for an underlying cause.
- 8.4: The acceptance of a donor candidate with prior or current kidney stones should be based on an assessment of stone recurrence risk and knowledge of the possible consequences of kidney stones after donation.
- 8.5: Donor candidates and donors with current or prior kidney stones should follow general population, evidence-based guidelines for the prevention of recurrent stones.
Transplant programs typically assess donor candidates with past or present, symptomatic or asymptomatic kidney stones. In a cohort of approximately 2000 living kidney donor candidates who underwent computed tomography (CT) angiograms/urograms at a large US center (mean age, 43 years; 92% white; 58% women), 3% of candidates had past symptomatic kidney stones, and 11% had evidence of stones on renal imaging.182
A kidney stone in an individual with a solitary kidney can potentially obstruct the ureter, leading to acute kidney injury, and may result in urgent hospital attention and even surgical intervention. Donor candidates should have a detailed evaluation including a careful history and medical record review of any prior or current kidney stones. In the case of a prior history of stones, additional details that should be assessed include the time and location of prior episodes, and any prior investigations or treatments. The frequency of kidney stones varies by sex, race and climate. The overall prevalence of kidney stones is approximately 6 to 9% in men, and 3 to 4% in women, and most stones are composed of calcium oxalate.183 Living kidney donors without a predonation history of kidney stones have no difference in the risk of developing kidney stones after donation, or in receiving a urologic procedure for kidney stones after donation, compared with selected nondonors matched for similar baseline health.184
Asymptomatic Kidney Stones Seen on Imaging
Approximately 5% of individuals have evidence of an asymptomatic kidney stone on CT angiography performed as part of the donor evaluation.185 Such CT scans may detect very small calcifications in the kidneys in patients who are asymptomatic and have no history of a clinically recognized kidney stone; very small 1 to 2 mm calcifications in the renal papillae found on CT scans are referred to as Randall’s plaques. These plaques have uncertain prognostic significance.
Evaluation of Donor Candidates and Donors with Prior or Current Kidney Stones
Donor candidates and donors with current or prior kidney stones should have an evidence-based evaluation of nephrolithiasis. For example, the 2014 American Urological Association Guideline provides comprehensive consensus and evidence-based recommendations for the evaluation of adult patients with kidney stones186:
- A clinician should perform a screening evaluation consisting of a detailed medical and dietary history, serum chemistries and urinalysis on a patient newly diagnosed with kidney or ureteral stones. (clinical principle)
- Serum intact parathyroid hormone (PTH) concentration should be obtained as part of the screening evaluation if primary hyperparathyroidism is suspected. (clinical principle)
- When a stone is available, a stone analysis should be performed at least once. (clinical principle)
- Clinicians should obtain or review available imaging studies to quantify stone burden. (clinical principle)
- Additional metabolic testing should be performed in high-risk or interested first-time stone formers and recurrent stone formers. (moderate evidence)
- Metabolic testing should consist of one or two 24-hour urine collections obtained on a random diet and analyzed at minimum for total volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium and creatinine. (expert opinion)
Similarly, the 2016 European Association of Urology guideline also provides comprehensive expert and evidence-based recommendations on the evaluation of adults with kidney stones,187 as do the Caring for Australians with Renal Impairment (CARI) guidelines.183
Risk Factors for Recurrent Stones
Prospective studies have shown the median recurrence rate of kidney stones is 15 per 100 person-years.188 However, the risk of recurrence after a single stone is difficult to predict in an individual. Compared with older adults, younger adults have more remaining years to live, and so have a higher lifetime chance of kidney stone recurrence.
Characteristics associated with a higher lifetime risk of stone recurrence include183:
- Younger age (<40 years)
- A family history of kidney stones
- Frequent, recurrent kidney stones
Characteristics associated with a lower lifetime risk of stone recurrence include:
- Older age (≥40 years)
- No prior symptoms of kidney stones
- A kidney stone that is less than 15 mm, solitary and unilateral
Selection and Management
The acceptance of a donor candidate with prior or current kidney stones should be based on an assessment of stone recurrence risk and knowledge of the possible consequences of kidney stones after donation.
As recommended in chapter 5 (Predonation Kidney Function), when asymmetry in GFR, parenchymal abnormalities (including stones), vascular abnormalities, or urological abnormalities are present but do not preclude donation, the more affected kidney should be used for donation.
Possible Consequences of Kidney Stones
Kidney stones may be associated with a higher risk of CKD and ESKD, with possible mechanisms including obstructive uropathy or pyelonephritis, crystal plugs at tips of the renal papilla and parenchymal injury from treatments such as shockwave lithotripsy.183,189 One or more episodes of kidney stones were associated with a 2-fold higher risk of ESKD in one population-based study from Alberta, Canada.190 The association was stronger in patients with 2 or more episodes of kidney stones versus a single episode of kidney stones. A National Health and Nutrition Examination Survey also reported that a history of kidney stones was associated with CKD and ESKD, however the effect was largely confined to women.191 Among 10 678 patients in the Atherosclerosis Risk in Communities study, nephrolithiasis history was associated with a 29% (HR, 1.071.291.54) higher risk of CKD in demographic-adjusted analyses, but the association was no longer statistically significant after multivariable adjustment (HR, 0.901.091.32;).192 To inform this guideline, CKD-PC analyzed multiple cohorts (see chapter 1).7 They found the association between a prior history of kidney stones and ESKD was not significant in the meta-analysis; for this reason a history of kidney stones does not appear as a characteristic in the online tool to predict the 15-year and lifetime chance of kidney failure in the absence of donation.7
Ex-vivo Removal of Kidney Stones
There are reports of nephrolithiasis-related adverse events for recipients of an allograft with a stone left in situ.193 There are also reports on the safety and success of ex vivo ureteroscopy to remove stones from explanted donor kidneys before transplantation.185
Donors and donor candidates who develop kidney stones should follow general population evidence-based guidelines for dietary and pharmacologic-based strategies to prevent recurrent kidney stones. Recent systematic reviews and clinical practice guidelines summarize this evidence.194,195 For example, there is low-strength evidence that increased fluid intake to achieve a urine output of at least 2 liters per day (vs normal fluid intake) and reduced soft-drink consumption lowers the risk of recurrent stones. In patients with multiple past calcium stones, most of whom increased their fluid intake, there is moderate-strength evidence that thiazide diuretics, citrate supplements, and allopurinol each further reduce the risk of future stones compared with placebo or control, although the benefit from allopurinol seemed limited to patients with baseline hyperuricemia or hyperuricosuria.
What Prior Guidelines Recommend
Several prior guidelines and US policy requirements describe evaluation methods and/or acceptance criteria for donor candidates with prior or current kidney stones.38,48,51,55,179 Generally, most prior guidelines recommend complete metabolic testing (serum PTH, 24-urine collection for calcium, phosphate, oxalate, citrate, urate, creatinine and sodium), and one guideline recommends all such candidates be assessed by a urologist.179 Several prior guidelines recommend the current presence of bilateral kidney stones, multiple stones, or nephrocalcinosis precludes donation, while a current small single stone may be eligible to proceed with donation.38,54,55,179,196
- Perform follow-up studies of approved donors with current stones, risk factors for recurrent stones, or small calcifications discovered on imaging to determine impact of these factors on long-term outcomes compared to donors without these characteristics, and also compared to nondonors with similar risk factors.
- Develop a tool to estimate the risk of postdonation kidney stones according to predonation clinical and demographic factors.
CHAPTER 9: HYPERURICEMIA, GOUT, AND MINERAL AND BONE DISEASE
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 9 and therefore the following recommendations are “Not Graded.”
- 9.1: Donor candidates should be asked about prior episodes of gout.
- 9.2: Donor candidates may be informed that donation is associated with an increase in serum uric acid concentration, which may increase the risk for gout.
- 9.3: Donor candidates and donors with prior episodes of gout should be informed of recommended methods to reduce their risk of future episodes of gout.
Hyperuricemia and Gout
High serum uric acid concentration is a potent risk factor for gout, for which the 10-year incidence is estimated to be 1%, 5%, and 49% for uric acid levels of < 7.0, 7.0-8.9, and ≥ 9.0 mg/L respectively.197,198 A decline in GFR results in less uric acid excretion and a higher serum uric acid concentration.199,200 These changes are evident with the 25% to 40% reduction in GFR that occurs after living kidney donation.139,201,202 For example, one prospective US cohort study found that at 6 months after nephrectomy, donors versus healthy nondonor controls had 8.2% higher serum uric acid level [mean values of 5.3 ± 1.1 mg/dL (315.2 ± 65.4 µmol/L; standard deviation) vs 4.9 ± 1.2 mg/dL (291.5 ± 71.4 µmol/L); P < 0.001], that persisted over 36 months of follow-up.139,201 Another study found donors to have 20% higher serum uric acid concentrations at a mean of 7 years after nephrectomy compared with predonation.203
In a study of 1988 living kidney donors from Ontario, Canada, who were followed for a median of 8.8 years (maximum, 20.8 years), living kidney donors were more likely to be diagnosed with gout compared to matched nondonors with similar baseline health, although the absolute risk remained low (3.5 vs 2.1 events per 1000 person-years; HR 22.214.171.124;).203 At 8 years, the cumulative incidence of gout was 1.4% higher in donors compared to nondonors (3.4% vs 2.0%).203 This report was not reviewed by the ERT but would be expected to have a moderate risk of bias similar to other reported outcomes from this cohort. Based on this report, some transplant teams may decide to inform donor candidates that donation is associated with an increase in serum uric acid concentration, which may increase the risk of gout. However, the authors of the primary report suggested the finding first be corroborated in other studies. In this guideline we endorse that donor candidates be asked about prior gout episodes, but given the limitations of existing information, we did not propose measuring uric acid as a standard part of evaluation or follow-up processes at this time. The risk of gout after kidney donation may vary based on demographic characteristics. A study of 4650 kidney donors from the US including 13.1% African Americans, found that, by 7 years, African Americans were almost twice as likely to develop gout as white donors (4.4% vs 2.4%; adjusted HR, 1.01.83.2).204 Postdonation gout risk also increased with older age at donation and was nearly 3-times higher in men compared with women.204
In nondonor populations hyperuricemia is associated with a higher risk of CVD and new-onset CKD.203,205 However, the prognostic significance of hyperuricemia in living kidney donors is currently uncertain and warrants additional study. In the US cohort study mentioned above, compared with matched donors without gout, donors with gout had more frequent diagnoses of acute kidney injury, CKD, and other disorders of the kidney.
Donor candidates and donors with prior episodes of gout should be informed of recommended methods to reduce their risk of future episodes of gout. Previous clinical practice guidelines cite modest to low evidence for certain diet and lifestyle measures (eg, avoiding excessive alcohol, and avoiding ingestion of organ meats high in purine content) and possibly pharmacological therapies.206 The prevention and treatment of hyperuricemia and gout may be complicated by decreased kidney function. The dose of allopurinol, which is frequently used to treat increased serum uric acid and prevent gout, should be adjusted in patients with decreased kidney function. Dose reductions may not be necessary with newer uricosuric agents.207 Nonsteroidal anti-inflammatory drugs should probably be used cautiously in patients with decreased kidney function including living kidney donors. The treatment of choice for acute gout is colchicine, however the dose of colchicine should be reduced in patients with decreased kidney function.
Metabolic Bone Disease
The effect of the modest decrease in GFR on the development of metabolic bone disease among kidney donors is not clear. Several recent studies describe changes in measures of bone mineral metabolism in kidney donors. These changes include a decline in the serum concentration of 1, 25-dihydroxyvitamin D and phosphate, a decline in tubular phosphate reabsorption, and a rise in the concentration of serum PTH.139,201,202,208 For example, one study showed that kidney donors had higher serum concentrations of fibroblast growth factor-23 and greater fractional excretion of inorganic phosphate compared with nondonor controls.209 The Assessing Long Term Outcomes of Living Donation prospective cohort study found a 23% higher PTH concentration among 206 donors assessed at 6 months postdonation compared with concentrations among 198 healthy controls (52.7 vs 42.8 pg/mL, respectively)201 that persisted at 36-month follow-up.139 Similarly, the Chronic Renal Impairment in Birmingham study of 68 donors at 2 United Kingdom centers reported larger increases in serum fibroblast growth factor-23 and parathyroid hormone concentrations compared with prospective changes in these parameters among healthy nondonors.202
The long-term effects of these changes on the risk of fractures, CVD, or other outcomes important to donors is uncertain, therefore the WG made no recommendations for managing mineral and bone disorders that would differ from guidelines for the general population. The ERT identified a single study of fractures in kidney donors (moderate risk of bias, with only a single study the quality of evidence was deemed very low; Evidence Report Table 8, SDC,http://links.lww.com/TP/B434; Supplemental Appendix Table D5 SDC,http://links.lww.com/TP/B432). In this study, 2015 kidney donors in Ontario, Canada, experienced no increase in the risk of non–trauma-related upper- or lower-extremity fractures compared with healthy nondonors.210
What Prior Guidelines Recommend
As many of the studies on hyperuricemia, gout and mineral and bone disease in living kidney donors are recent, these issues have generally not been addressed in prior donor guidelines. The British Transplantation Society describes the importance assessing a history of gout as part of the candidate evaluation.48 Amsterdam Forum and Spanish Society of Nephrology and Spanish National Transplant Organisation guidelines describe serum uric acid as a standard test in the evaluation of all living kidney donor candidates.38,54
- Determine the effects of hyperuricemia in living kidney donor candidates and donors on the incidence of gout and CVD.
- Perform long-term follow-up of donors and healthy nondonor controls to determine the impact of kidney donation on gout recurrence.
- Perform long-term follow-up of donors and healthy nondonor controls to determine the impact of kidney donation (if any) on fracture risk.
CHAPTER 10: PREDONATION BLOOD PRESSURE
Except in the case of Recommendation 10.6, the ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 10 and therefore the following recommendations are “Not Graded.”
- 10.1: Blood pressure should be measured before donation on at least 2 occasions by clinical staff trained in accurate measurement technique, using equipment calibrated for accuracy.
- 10.2: When the presence or absence of hypertension in a donor candidate is indeterminate based on history and clinic measurements (eg, blood pressure is high normal or variable), blood pressure should be further evaluated using ambulatory blood pressure monitoring (ABPM) or repeated using standardized blood pressure measurements.
- 10.3: Normal blood pressure, as defined by guidelines for the general population in the country or region where donation is planned, is acceptable for donation.
- 10.4: Donor candidates with hypertension that can be controlled to systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg using 1 or 2 antihypertensive agents, who do not have evidence of target organ damage, may be acceptable for donation. The decision to approve donor candidates with hypertension should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
- 10.5: Donor candidates should be counseled on lifestyle interventions to address modifiable risk factors for hypertension and cardiovascular disease, including healthy diet, smoking abstinence, achievement of healthy body weight, and regular exercise according to guidelines for the general population. These measures should be initiated before donation and maintained lifelong.
- 10.6: We suggest that donor candidates should be informed that blood pressure may rise with aging, and that donation may accelerate a rise in blood pressure and need for antihypertensive treatment over expectations with normal aging. (2D)
Evaluation and Definitions
BP Measurement and Classification
It is important to use an accurate, well-calibrated device and an appropriately sized BP cuff based on arm length and circumference. An overly small cuff will overestimate and an excessively large cuff will underestimate true BP levels. The donor candidate should be seated quietly with back supported, feet on the floor and arm supported at heart level for the measurements. It is advisable to measure BP on at least 2 separate occasions by trained staff, or on one occasion plus ambulatory BP monitoring (ABPM) to minimize anxiety effects in donor candidates.211 Automated serial BP measurements can also eliminate a “white coat” effect.212 Multiple prior guidelines and policies for the evaluation and care of living kidney donor candidates recommend assessment of predonation BP on several occasions,212,213 and/or consideration of ABPM in donor candidates with elevated office readings, receiving antihypertensive therapy, or who are older at evaluation.38,50,51,196,214,215
Hypertension is defined by office readings of systolic SBP of 140 mm Hg or greater or diastolic BP (DBP) of 90 mm Hg or greater, out-of-office daytime mean ABPM or home measurements of SBP of 135 mm Hg or greater or DBP of 85 mm Hg or greater,213 or the need for medication to control BP. Note that some antihypertensive agents may be used for indications other than BP treatment (eg, diuretics for edema or beta-blockers for migraine headache prevention), and that the indication for the prescribed medications should be determined as part of the evaluation.
White coat hypertension is defined as hypertension by office BP measurements with normal out of office measurements by ABPM or home readings. Individuals with white coat hypertension have lower cardiovascular risk than persons with hypertension, but may carry increased risk for future hypertension.212,216 Population-based studies suggest that 20-25% of adults may have white coat hypertension.216 Individuals with treated hypertension may also have a “white coat effect,” such that elevated BP is recorded in the medical environment even when treated BP is controlled by ABPM or home readings.
Masked hypertension is defined as normal BP by office measurements with hypertension by ABPM or home readings. Like sustained hypertension, masked hypertension is accompanied by increased risk for hypertensive target organ damage, and thus treatment is warranted if identified. Population-based studies suggest that 10-30% of adults may have masked hypertension.216,217 Masked hypertension cannot be identified in donor candidates in whom BP is measured by office readings alone, but the implications of requiring ABPM or home readings to screen for masked hypertension in donor candidates (eg, outcomes, cost, efficiency) are not defined.
Hypertension Risk Factors and Counseling
Potentially modifiable risk factors for hypertension include use of certain medications (eg, nonsteroidal anti-inflammatory agents, decongestants, stimulants) and presence of certain lifestyle factors (eg, excess alcohol intake, high sodium diet, use of dietary supplements, or smoking).218-220 Nonmodifiable hypertension risk factors include a family history of hypertension, race, and age. Additional considerations include women with a history of preeclampsia or gestational hypertension. In this setting we suggest predonation counseling on the potential for increased cardiovascular risk and emphasis on healthy behaviors to reduce cardiovascular risk. Risk factors for hypertension by themselves do not constitute contraindications to donation in a normotensive person. Consistent with recommendations for the general population,221 British Transplantation Society and Renal Association guidelines48 recommend lifestyle measures in kidney donors to reduce the risk of hypertension and its consequences, including frequent exercise, smoking cessation, and weight loss where appropriate.
Target organ damage may be manifest as prior occurrence of a cardiovascular event such as myocardial infarction or stroke, urine AER greater than 30 mg/d (ACR > 30 mg/g or 3 mg/mmol), reduced kidney function (eg, GFR < 60 mL/min per 1.73 m2), hypertensive retinopathy, and/or evidence of left ventricular hypertrophy.213
Lifestyle modification can effectively treat hypertension without medication or with fewer medications and lower dosages required to achieve BP control.221 Lifestyle modifications include healthy diet, smoking cessation, weight loss if overweight, regular exercise, and discontinuation of potential contributing medications according to guidelines for the general population. Follow-up of patents with hypertension is critical for monitoring of control in relation to targets and for monitoring and management of complications. The importance of access to healthcare and regular follow-up have also been emphasized in the selection and care of hypertensive donor candidates in 2 prior guidelines,38,54 whereas the Spanish Society of Nephrology and Spanish National Transplant Organisation guidelines specify “reasonable guarantee that the donor will follow the check-up period and treatment indefinitely” among the criteria for acceptance of a hypertensive donor candidate.54
Impact of Reduced GFR on BP in the General Population and After Donation
Reduced kidney function may cause or worsen hypertension in the general population.222 While it is documented that BP often rises with aging,223 GFR reduction from kidney donation may accelerate the risk or progression of hypertension over time to a greater extent than expected from normal aging, possibly due to physiological alterations (eg, hyperfiltration in the remaining kidney, changes in vascular tone and renin-angiotensin-aldosterone regulation) and/or heightened detection at donor follow-up.224,225 Existing retrospective studies examining the impact of kidney donation on hypertension risk have been limited by short follow-up times, high rates of loss to follow-up, lack of controls and/or comparisons to unselected general rather than healthy populations. Use of antihypertensive medications was lower in a cohort of privately-insured donors compared with age- and sex-matched unscreened beneficiaries in the same insurance plan.226 In contrast, a systematic review including data for 5145 predominantly white donors estimated 6 mm Hg higher weighted mean SBP and 4 mm Hg higher weighted mean DBP in donors compared with controls after an average of 7 years224 (Supplemental Appendix Tables D1 and D2, SDC,http://links.lww.com/TP/B432). An administrative claims linkage study of 1278 (primarily white race) living donors in Ontario, Canada followed for a mean of 6 years (range, 1-16 years) found a higher incidence of claims-based hypertension diagnoses (16.3% vs 11.9%; HR, 126.96.36.199) among living donors compared with matched controls who were also screened for the absence of baseline comorbidities through administrative claims.225
Among more recent donor cohorts, higher rates of postdonation hypertension and antihypertensive medication use in African American compared with white donors have been reported.226-228 While these patterns parallel hypertension prevalence differences in the general population,228 one small study found higher rates of postdonation hypertension among 103 African American donors compared with race-matched “healthy” nondonor controls (41% vs 18% at an average of 6.8 years postdonation)229 (Supplemental Appendix Table D10, SDC,http://links.lww.com/TP/B432). Furthermore, many donors in this study were unaware of their hypertension. Associations of age at donation and sex with postdonation hypertension have been inconsistent (Supplemental Appendix Tables D7 and D9, SDC,http://links.lww.com/TP/B432).
Based on these data, we suggest that donor candidates should be informed that BP may rise with aging, and that donation may accelerate the rise in BP and the need for antihypertensive treatment over that expected with normal aging, especially if BP is high-normal before donation and among African American donor candidates. Furthermore, antihypertensive medication is more likely to be prescribed after donation.
Hypertension as a Cause of CKD in the General Population
Hypertension is a contributing cause of CKD in the general population, although in many cases, CKD may be the cause of hypertension. A recent meta-analysis based on data from nearly 5 million healthy persons identified from 7 general population cohorts found that every 20 mm Hg increase in SBP was associated with a 42% increase (adjusted HR, 1.271.421.58) in the risk of ESKD over median cohort follow-up of 4 to 16 years. Use of antihypertensive medications was also associated with increased ESKD risk (adjusted HR, 1.011.351.82 over cohort follow-up).7 After calibration to annual ESKD incidence in the US healthy population, variations in the projected 15-year and lifetime risks of ESKD based on level of SBP from this analysis were generated according to age, sex, and race for healthy persons (assuming age-specific GFR, urine ACR 4 mg/g [0.4 mg/mmol], BMI 26 kg/m2, and absence of diabetes mellitus; (Figures 14 and 15). While these figures are useful for visualizing the impact of higher SBP on increased ESKD risk, we endorse consideration of BP as part of the assessment of predicted long-term ESKD risk based on a donor candidate’s complete demographic and health profile (as opposed to consideration of single risk factors in isolation).
Clinical consequences of hypertension vary by race in the general population. Treating mild-to-moderate primary hypertension may not halt kidney disease progression in nondiabetic African Americans, whereas hypertension control appears to slow kidney disease progression in European Americans.230-234 Recent literature supports that at least a portion of kidney failure previously attributed to hypertensive nephrosclerosis in persons of African descent may be genetically mediated by coding variants in the gene for APOL1 and not modifiable by antihypertensive therapy (see chapter 14).235-238
Predonation Hypertension as a Risk Factor for Adverse Outcomes after Kidney Donation
Living donor candidates undergo a rigorous evaluation process which includes measurement of kidney function and urine protein, but subtle scarring of the kidney from hypertensive nephrosclerosis may not be detected by these tests.239 Compensatory hyperfiltration in the remaining kidney is normal after nephrectomy240,241; however, subclinical pathology or aging processes may impair compensation and reduce postdonation GFR.240,242
The ERT identified 3 studies, rated as very low quality in reporting postdonation outcomes according to predonation BP or hypertension status (Evidence Report Table 19, SDC,http://links.lww.com/TP/B434, and Supplemental Appendix Table D16, SDC,http://links.lww.com/TP/B432). In a combined cohort of donors and matched healthy nondonors in Norway, each 1 mm Hg increase in SBP was associated with a small increase in cardiovascular death and ESKD during up to 25 years of follow-up.32 A study of only 6 hypertensive donors reported CKD in 4 (67%) compared with 22% of nonhypertensive donors during an average of 5.4 years follow-up.243 A third study of 16 hypertensive donors was deemed at high risk of bias.244 A systematic review by Young et al concluded that results from this and 2 additional studies were substantially heterogeneous and thus results were not pooled.26
Additional studies that did not meet criteria for the ERT evidence review include a large study based on linkage of the US Transplant Registry with national death records that found higher perioperative mortality among donors with versus without predonation hypertension (36.7 vs 1.3 per 10 000).23 While reported baseline hypertension was not associated with long-term mortality, SBP of 140 mm Hg or greater at donor registration was associated with 3-times the adjusted RR of death over 12 years compared to SBP less than 120 mm Hg (adjusted HR 188.8.131.52). A single-center study of 24 white, older (mean age, 53 years) donors with predonation hypertension (awake ABPM > 135/85 mm Hg and clinic/nurse-measured BP > 140/90 mm Hg) that was not included in the evidence review based on sample size found similar postdonation GFR reduction and urine protein excretion as in normotensive donors, and no increase in urinary protein excretion compared with predonation values over a mean 282 days of follow-up.245 A recent US registry study found that ESKD among donors was more likely to be attributed to hypertension if the duration of follow-up was more than 10 years compared with less than 10 years.31
The WG concluded that the decision to approve donation in candidates with hypertension should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold. Donor candidates with hypertension should be treated according to guidelines for the general population in the country or region where donation will occur. BP control should be confirmed by standardized BP measurements over at least several weeks before donation. Donor candidates with hypertension should be informed that donation may accelerate the rise in BP and the need for antihypertensive treatment over expectations with normal aging, and that uncontrolled hypertension may cause target organ damage to their remaining kidney, and be counseled on the importance of maintaining a healthy lifestyle and BP control before and after donation.
What Prior Guidelines Recommend
Multiple prior guidelines for the evaluation and care of living kidney donor candidates identify hypertensive end-organ damage (eg, proteinuria, microalbuminuria, left ventricular hypertrophy, and hypertensive retinopathy), as relative contraindications or exclusion criteria for kidney donation.38,48,50,54,55,196,214,215 Other relative contraindications or exclusion criteria for donation defined in prior guidelines include uncontrolled hypertension48,55,196,214; need for more than 1,54 or more than 2 antihypertensive agents214,215 for adequate control; hypertension and age younger than 50 years at evaluation196; non-white or African American race54,196; or the presence of several comorbidities or cardiovascular risk factors.50,196,214 We concur that uncontrolled hypertension or hypertension with target organ damage should be exclusions to kidney donation. However, based on our evidence review, we also conclude that there is limited evidence from the donor population to make recommendations for donor acceptance based on hypertension status alone. Rather we endorse adherence to the general framework that compares predicted individual long-term ESKD risk according to baseline profile of demographic and health characteristics including BP to the transplant program’s acceptable risk threshold.
- Define optimal strategies for measuring BP during the donor candidate evaluation.
- Determine optimal strategies for treatment of hypertension in kidney donor candidates before donation, and in accepted donors after donation.
- Quantify the impact of living kidney donation on hypertension risk, as well as the impact of hypertension before and after donation on clinical outcomes including CVD and lifetime ESKD risk.
- Evaluate possible variation in the risk and consequences of hypertension at donation according to other characteristics, including baseline demographic and other clinical factors.
CHAPTER 11: PREDONATION METABOLIC AND LIFESTYLE RISK FACTORS
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 11 and therefore the following recommendations are “Not Graded.”
Identification of Metabolic and Lifestyle Risk Factors
- 11.1: Risk factors for kidney and cardiovascular disease should be identified before donation and addressed by counseling to promote long-term health.
- 11.2: Body mass index (BMI) should be computed based on weight and height measured before donation, and classified based on World Health Organization (WHO) criteria for the general population or race-specific categories.
- 11.3: The decision to approve donor candidates with obesity and BMI >30 kg/m2 should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
- 11.4: Donor candidates who have had bariatric surgery should be assessed for risk of nephrolithiasis.
- 11.5: Donor candidates should be asked about prior diagnosis of diabetes mellitus, gestational diabetes, and family history of diabetes.
- 11.6: Glycemia should be assessed by fasting blood glucose and/or glycated hemoglobin (HbA1c) before donation.
- 11.7: 2-hour glucose tolerance testing or HbA1c testing should be performed in donor candidates with elevated fasting blood glucose, history of gestational diabetes, or family history of diabetes in a first-degree relative, and results should be used to classify diabetes or prediabetes status using established criteria for the general population.
- 11.8: Donor candidates with type 1 diabetes mellitus should not donate.
- 11.9: The decision to approve donor candidates with prediabetes or type 2 diabetes should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
- 11.10: Donor candidates with prediabetes or type 2 diabetes should be counseled that their condition may progress over time and may lead to end-organ complications.
- 11.11: Fasting lipid profile (including total cholesterol, LDL-C, HDL-C and triglycerides) should be measured as part of an overall cardiovascular risk assessment before donation.
- 11.12: The decision to approve donor candidates with dyslipidemia should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
- 11.13: The use of tobacco products should be assessed before donation.
- 11.14: Donor candidates who use tobacco products should be counseled on the risks of perioperative complications, cancer, cardio-pulmonary disease and kidney failure, should be advised to abstain from use of tobacco products, and should be referred to a tobacco cessation support program if possible.
- 11.15: The decision to approve donor candidates who are active tobacco users should be individualized based on demographic and health profile in relation to the transplant program’s acceptable risk threshold.
Goals of Evaluation and Definitions
This section addresses the evaluation and management of metabolic and lifestyle risk factors associated with ESKD, CVD and/or all-cause mortality, as applicable to the care of donor candidates. Some of the factors considered do not have currently known associations with ESKD risk, but are relevant to a comprehensive predonation health assessment. Even if donation does not increase the risk, traditional CVD risk factors are expected to have at least the same effect in donors as in the general population. Attention to these risk factors is intended to prevent or delay the onset and progression of comorbid diseases, kidney disease, and CVD. All risk factors considered in this section are potentially modifiable by lifestyle and/or medical care.
According to World Health Organization (WHO), the prevalence of diabetes mellitus increased from 108 million people worldwide in 1980 to 422 million in 2014.246 The rising prevalence of diabetes is linked with the obesity epidemic and 2.1 billion adults worldwide were estimated to be overweight or obese in 2013.247 Underlying causes of the obesity epidemic may be modifiable, and include sedentary lifestyles, high-fat and energy-dense diets, and increased urbanization.248-250 The WHO defines obesity based on thresholds of BMI, a measure of weight scaled for height, as: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obese (30-34.9 kg/m2), and morbidly obese (>35 kg/m2).248 While BMI is recognized to be an imperfect measure of body composition, the components of BMI are easily measured, recorded, and followed over time, and have prognostic implications. Optimal BMI-based thresholds for obesity may differ from WHO standards in non-whites, and race-specific thresholds have been proposed. Measurement of waist circumference and/or waist-to-hip ratios may also be considered to characterize the distribution of adiposity in obese persons.251
Multiple prior guidelines and policies for the evaluation and care of living donors recommend measurement of fasting plasma glucose and consideration of oral glucose tolerance testing and/or glycated hemoglobin (HbA1c) as part of the donor evaluation.38,48,51,196,252 The WHO defines diabetes mellitus as: fasting plasma glucose of 7.0 mmol/L or greater (≥126 mg/dL), random plasma glucose of 11.1 mmol/L or greater (≥200 mg/dL), or plasma glucose concentration of 11.1 mmol/L or greater (≥200 mg/dL) 2 hours after a 75-g anhydrous glucose load in an oral glucose tolerance test. A 2011 addendum included recognition of HbA1c of 48 mmol/mol or greater (6.5%) as an additional criterion for diagnosing diabetes if assays are standardized to criteria aligned with international reference values, but also indicated that HbA1c less than 48 mmol/mol (6.5%) does not exclude diabetes diagnosed using glucose tests.246
The WHO defines Impaired Glucose Tolerance as fasting plasma glucose less than 7.0 mmol/L (<126 mg/dL) or 2-hour post–load plasma glucose of 7.8 or greater and less than 11.1 mmol/L (≥140 and < 200 mg/dL), while Impaired Fasting Glucose is defined as fasting plasma glucose 6.1 to 6.9 mmol/L (110 to 125 mg/dL) or 2-hour post–load plasma glucose less than 7.8 mmol (<140 mg/dL).253 Currently there are various definitions of prediabetes and the equivalent term used by WHO, intermediate hyperglycemia, is defined by fasting plasma glucose of 6.1 to 6.9 mmol/L (110-125 mg/dL) and 1-hour post–load plasma glucose of 7.8-11.0 mmol/L (140-199 mg/dL).254
Dyslipidemias are classified based on elevations in total cholesterol and low-density lipoprotein cholesterol (LDL-C), and low concentrations of high-density lipoprotein cholesterol (HDL-C). Hypertriglyceridemia is an independent CVD risk factor.255
Increased risk of perioperative complications including wound and surgical site infections in obese patients is well established in the general surgical literature.256 The ERT report identified 2 systematic reviews that examined perioperative outcomes after donor nephrectomy according to BMI, with quality of source studies rated as low. Among 8 studies reporting operative time, all but one found a modest increase in operative time (mean difference of 16.9 minutes) among donors with BMI of 30 or greater compared to those with BMI less than 30 kg/m2 (Supplemental Appendix Table C7, SDC,http://links.lww.com/TP/B432). While warm ischemia times were reported to be longer for obese donors in all but one study, this difference was not significant on meta-analysis. Pooled results showed no differences in blood loss or length of stay among obese compared with normal weight donors.
In the general population, obesity has been identified as a risk factor for diabetes mellitus and it may also be a risk factor for kidney disease, particularly obesity-related glomerulopathy.257 The ERT identified 5 studies comparing long-term outcomes among donors by predonation BMI, rated as low quality, with follow-up ranging from 6.7 to 15.1 years (Supplemental Appendix Table D12, SDC,http://links.lww.com/TP/B432). One study found that BMI was associated with cardiovascular mortality but not all-cause mortality.32 In contrast, another registry study found no association between BMI and death over 12 years.23 A few studies of variable quality examined associations between BMI and intermediate outcomes.140,244,258
Multiple prior guidelines for the evaluation and care of living kidney donor candidates recommend BMI greater than 35 kg/m2 as an absolute or relative contraindication to donation.38,48,50,54,196,215,259 and other guidelines recommend careful evaluation for other comorbidities in donor candidates with BMI greater than 30 kg/m2.48,54 With regard to other metrics of obesity aside from BMI, the Spanish Society of Nephrology and Spanish National Transplant Organisation guidelines define waistline greater than 82 cm in women or greater than 102 cm in men as additional relative contraindications to donation.54 CARI guidelines advise measurement of waist circumference within the assessment of overweight and obese donor candidates,259 and a US Joint Societies work group consensus statement includes abdominal circumference as part of the definition of metabolic syndrome.196 In contrast, the ERT concluded that there is limited evidence from the donor population to make recommendations for donor acceptance based on BMI alone among obese donor candidates.
A recent meta-analysis based on data from nearly 5 million healthy persons identified from 7 general population cohorts found a modest association of BMI greater than 30 kg/m2 with increased risk of ESKD over median cohort follow-up of 4 to 16 years (adjusted HR, 1.041.161.29).7 Projected 15-year and lifetime risks of ESKD for healthy persons varied according to BMI and age, sex, and race (Figures 16 and 17). A recent study of 119 769 US donors published after the ERT systemic review found a stronger association of higher BMI at donation with postdonation ESKD risk over 20 years than the predonation risk relationship observed in the general population cohorts.260 We endorse consideration of BMI as part of the assessment of predicted long-term risk based on a donor candidate’s complete demographic and health profile (as opposed to consideration of single risk factors in isolation). Findings from the recent US study260 suggests more uncertainty when drawing inferences about long-term postdonation risk in obese donor candidates, and the need to develop individualized postdonation risk estimates according to demographic and health profile. Acceptance thresholds for donor candidate BMI can incorporate perinephrectomy complications along with long-term risks of ESKD and other complications as data become available.
We agree with prior recommendations that obese donor candidate should be counseled about the long-term risks of obesity, advised to pursue weight loss before donation, and to maintain a healthy body weight after donation.38,48,50,215
Type 2 diabetes is a leading cause of CKD worldwide and accounts for approximately 50% of acquired, adult-onset ESKD.261,262 Patients with diabetes mellitus are commonly excluded from living kidney donation. One report of 71 donors with baseline glucose intolerance including 27 older patients (mean age, 58 years) with diabetes defined by 2-hour glucose tolerance testing found no ESKD events and similar survival compared to donors without glucose intolerance over a mean follow-up of 88 months (Supplemental Appendix Table D14, SDC,http://links.lww.com/TP/B432).263
A recent meta-analysis based on data from nearly 5 million persons identified from 7 general population cohorts found that, compared with nondiabetic persons, those with type 2 diabetes but otherwise good health had 3-times the risk of ESKD over median cohort follow-up of 4 to 16 years (adjusted HR, 1.913.014.74).7 The 15-year and lifetime risks of ESKD for healthy persons varied by type 2 diabetes and age, sex, and race (Figures 18 and 19). Multiple prior guidelines for the evaluation and care of kidney donors recommend that diabetic persons be excluded from kidney donation.38,54,179,196,215,252 However, the European Best Practice Guideline qualifies an exception of “exceptional circumstances”215 and the British Transplantation Society recommends that “diabetics can be considered for kidney donation after a thorough assessment of the lifetime risk of cardiovascular and progressive renal disease in the presence of a single kidney.”48 The WG concluded that persons with type 1 diabetes should be excluded from kidney donation. However, consistent with the framework of integrated risk assessment, we endorse individualizing the decision to approve donation in persons with prediabetes or type 2 diabetes based on the severity of illness and predicted long-term risk (considering complete demographic and health profile) in relation to the transplant program’s acceptable risk threshold. The WG considers that older candidates with type 2 diabetes with well-controlled glycemia, not requiring insulin and without end-organ damage, might be considered for donation.
Prediabetes represents an intermediate category of hyperglycemia, which poses increased risks for future type 2 diabetes mellitus and CVD.261 Important risk factors for diabetes and prediabetes in the general population include increasing age, high-risk ethnicity or race, obesity, and history of diabetes in a first degree relative. Approximately 5-10% of individuals with prediabetes progress to diabetes per year264 but the risk of progression can be reduced with lifestyle changes and weight loss.265 The younger the individual with risk factors for prediabetes, the higher the likelihood that diabetes and subsequent kidney disease will develop in that person’s remaining lifetime.266
A small cohort study found that carefully screened prediabetic living kidney donors may revert to normal fasting glucose and did not have an increased risk of impaired kidney function in the short term267 (Evidence Report Table 17, SDC,http://links.lww.com/TP/B434; Supplemental Appendix Table D14, SDC,http://links.lww.com/TP/B432). However, quality of this study was very low. A recent study linking US national donor registry data to ESKD registry data for 125 427 living donors examined causes of ESKD after donation.31 The finding that early postdonation ESKD was predominantly reported as due to glomerulonephritis while late postdonation ESKD was more frequently reported as diabetic-ESKD and hypertensive-ESKD could be consistent with an effect of donation on diabetes and hypertension as causes for ESKD. These findings emphasize the importance of counseling donor candidates with prediabetes regarding their increased lifetime risk for progression to diabetes and subsequent end-organ complications, and the importance of healthy lifestyle behaviors to reduce risks. Those who are approved to donate should be counseled on the importance of regular medical follow-up after donation including surveillance for hyperglycemia and kidney function for many decades after donation, and prompt institution of appropriate management.
Prior recommendations regarding candidacy of persons with prediabetes for kidney donation are conflicting. The European Best Practice Guideline states that impaired glucose tolerance is not an absolute contraindication to donation50,215; other guidelines consider prediabetes a relative contraindication54,196 or a condition warranting careful consideration,48 while CARI considers prediabetes as well as past history of gestational diabetes to be absolute contraindications.252 Given the lack of current data specific to the donor population, we endorse individualizing the decision to approve donation in persons with prediabetes based on their predicted long-term risk in relation to the transplant program’s acceptable risk threshold.
Dyslipidemia is a modifiable risk factor for CVD, and hypertriglyceridemia and low HDL-C are components of the metabolic syndrome. With regard to associations of lipid levels with outcomes after donation, one study identified by the ERT compared kidney function and albuminuria at 5 years among donors with versus without predonation metabolic syndrome (Evidence Report Table 18, SDC,http://links.lww.com/TP/B434; Supplemental Appendix Table D15, SDC,http://links.lww.com/TP/B432). Although small differences in the outcomes were suggested, statistical comparisons were not performed. No studies were identified comparing postdonation outcomes based on lipid status alone. A recent meta-analysis based on data from nearly 5 million persons identified from 7 general population cohorts found no associations of total cholesterol or LDL-C with ESKD risk over median cohort follow-up of 4 to 16 years.7
Several prior guidelines recommend fasting lipid profiling as part of the donor evaluation,51,54,59,196 but do not define donor selection criteria based on lipid levels alone. A US Joint Societies work group consensus statement recognizes hypertriglyceridemia and low HDL-C as components of the metabolic syndrome, and considers impaired fasting glucose and other components of metabolic syndrome to be relative contraindications to donation in persons younger than age 50 years.196 We endorse individualizing the decision to approve donation in persons with dyslipidemia based on their predicted long-term risk (considering complete demographic and health profile) in relation to the transplant program’s acceptance threshold.
Cigarette smoking is a strong, modifiable risk factor for CVD (as well as other adverse health outcomes such as lung disease and cancer); smoking may also cause direct renal damage through microvascular injury and promotion of atherosclerosis, and has been associated with CKD in the general population.268,269 A recent meta-analysis based on data from nearly 5 million persons identified from 7 general population cohorts found that, compared with nonsmokers over median cohort follow-up of 4 to 16 years, current smokers had a 76% increase in the risk of ESKD (adjusted HR, 1.291.762.41) and past smokers had a 45% increase in risk (adjusted HR, 1.231.451.71).7 After calibration to annual ESKD incidence in the US healthy population, variations in the projected 15-year and lifetime risks of ESKD based on smoking status were generated according to age, sex, and race for healthy persons (assuming age-specific GFR, urine ACR 4 mg/g [0.4 mg/mmol], SBP 120 mmHg, BMI 26 kg/m2, and absence of diabetes mellitus; Figures 20 and 21).
Although data on the outcomes associated with smoking among living kidney donors are limited, an analysis of linked US transplant registry and national death records found that while smoking was not significantly associated with perinephrectomy mortality, donors who smoked had approximately 5-times the adjusted mortality over 12 years compared with nonsmoking donors.23 See chapter 4 (Preoperative Evaluation) for a discussion of the smoking-related risks before general surgery.
Some prior guidelines for the evaluation and care of living donors advise assessment of smoking, but make no recommendations concerning smoking in the selection of donors.51,196 Others advise encouraging smoking cessation without defining an exclusion criterion.48,50,215 Two guidelines recommend smoking cessation 4 weeks before donor nephrectomy,38,54 and guidelines from the Spanish Society of Nephrology and Spanish National Transplant Organisation emphasize long-term abstinence.54 The 2000 National Kidney Foundation (NKF)/AST guidelines recommend considering acceptance of donor candidates who smoke only if they abstain form use of tobacco products for 6 months and have normal pulmonary studies.18 We endorse individualizing the decision to approve donation in active smokers based on their predicted long-term risk (considering complete demographic and health profile) in relation to the transplant program’s acceptance threshold.
Impact of Donation on Cardiac Risk
The ERT identified 2 studies comparing cardiovascular events in donors versus healthy nondonors (very low quality of evidence; Evidence Report Table 8, SDC,http://links.lww.com/TP/B434; Supplemental Appendix Table D5, SDC,http://links.lww.com/TP/B432). In a study comparing 2028 living kidney donors in Ontario, Canada (1992 to 2009) with 20 280 healthy, demographically matched nondonors, the risk of death or major cardiovascular events over a median 7 years follow-up (maximum, 18 years) was lower in donors than in healthy nondonors (2.8 vs 4.1 events per 1000 person-years, adjusted HR, 0.480.660.90).270 The risk of death-censored major cardiovascular events was similar among donors and nondonors (1.7 vs 2.0 events per 1000 person-years).
A study with longer follow-up compared cardiovascular and all-cause mortality in 1901 kidney donors with a group of 32 621 healthy, matched controls selected from a population-based survey in Norway (Nord-Trøndelag Health Study [HUNT] I).32 Mortality was similar in donors versus nondonors over the first 15 years, but at 25 years after donation, cumulative all-cause mortality was approximately 18% among donors versus 13% among healthy nondonors (adjusted HR 184.108.40.206). Limitations of this study include differences in accrual periods and in baseline characteristics (including age) between the donors and nondonors.271,272 Continued study is needed to assess the impact of donation on long-term survival in large, representative cohorts.
Limited data are available on the impact of donation on the pathophysiology of CVD. The Chronic Renal Impairment in Birmingham (CRIB)-Donor study included 68 donors at 2 United Kingdom centers (2011 to 2014), of whom 90% were white, and prospectively examined changes in left ventricular mass and other CVD surrogate markers at 12 months postdonation versus predonation, compared with changes in these parameters in healthy nondonors.202 Donors had a greater increase in left ventricular mass (+7 ± 10 vs −3 ± 8 g; P < 0.001) and mass:volume ratio (+0.06 ± 0.12 vs −0.01 ± 0.09 g/mL; P < 0.01), but decreased aortic distensiblity; donors were also more likely than controls to develop detectable highly sensitive troponin T levels. The increase in left ventricular mass among donors was independently associated with the magnitude of decrease in mGFR. These pilot observations warrant replication efforts in larger cohorts with longer follow-up to better define the impacts of donation on CVD surrogates and clinical events.
- Evaluate the outcomes of donors with metabolic and lifestyle risk factors for CVD, including perinephrectomy complications, long-term mortality, CVD events, CKD/proteinuria and ESKD. Develop integrated risk assessment tools tailored for demographic and health profiles.
- Quantify the direct effects of donation on CVD risk.
- Assess effectiveness of predonation interventions including counseling and weight or lifestyle changes on long-term donor outcomes.
- Assess the impact of the duration and durability of predonation weight loss on donor acceptance and postdonation outcomes in those who proceed to donation.
CHAPTER 12: PREVENTING INFECTION TRANSMISSION
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 12 and therefore the following recommendations are “Not Graded.”
- 12.1: Risk for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections should be assessed before donation.
- 12.2: Donor candidates should be assessed for factors associated with an increased likelihood of endemic or unexpected infections, including geographic, seasonal, occupational, animal and environmental exposures.
- 12.3: Donor candidates should complete a urinalysis and testing for HIV, HBV, HCV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Treponema pallidum (syphilis).
- 12.4: If indicated by regional epidemiology or individual history, donor candidates should complete testing for Mycobacterium tuberculosis, Strongyloides, Trypanosoma cruzi, West Nile virus, Histoplasmosis, and/or Coccidiomycosis.
- 12.5: Transplant programs should develop protocols to screen donor candidates for emerging infections in consultation with local public health specialists.
- 12.6: In general, donor infection risk factor and microbiological assessments should be performed or updated as close in time to donation as possible. For HIV, HBV and HCV, screening should be current within 28 days of donation.
12.7: If a donor candidate is found to have a potentially transmissible infection, then the donor candidate, intended recipient and transplant program team should weigh the risks and benefits of proceeding with donation.
Goals of Evaluation and Definitions
The goals of infection screening in donor candidates are to identify illnesses that may affect the donor candidate or the intended recipient.273-276 Evaluation of donor candidates to reduce the risk of transmissible infections should include assessment of the individual’s history of past infections and infectious disease risk factors (eg, risk of local endemic infections or travel to endemic areas), awareness of current patterns of geographically endemic infections, and focused microbiological screening.
Donor-derived infections can be classified as “expected” versus “unexpected.”274,276 The risks of “expected” donor-derived infection transmission are defined by donor and recipient screening, such as in high-risk scenarios for transmission of cytomegalovirus (CMV), Epstein-Barr virus (EBV) or toxoplasmosis from a seropositive donor to a seronegative recipient. “Expected” transmissions occur frequently and are managed by surveillance and/or prophylaxis strategies in the recipient after transplantation.277-282 “Unexpected” donor-derived infections arise despite routine donor screening, such as human immunodeficiency virus (HIV) or hepatitis C virus (HCV) transmission due to false negative serologic testing or infection in a “window period.” The 2013 US Public Health Service (PHS) Guideline provides an evidence-based instrument to screen for behavioral factors associated with recent HIV, hepatitis B virus (HBV), or HCV infection (Table 16).71 “Unexpected” infectious disease transmissions through organ transplantation are rare, but may result in serious morbidity and mortality.274,283 Although most “unexpected” disease transmissions have involved deceased donors, cases of HIV and HCV transmissions from living donors have been reported.283,284 Notably, while reporting of suspected or documented donor-derived infection transmissions is required in the United States, reporting is voluntary in many other countries, and thus true incidence may be underestimated.
Infection transmission events may also be categorized according to the certainty that the donor is the origin of the infection, as opposed to reactivation or de novo infection in the recipient.285 Consensus-based definitions have been offered to standardize categorization as: “proven,” “probable,” “possible,” “unlikely,” “excluded,” “intervened upon without documented transmission,” and “positive assay without apparent disease transmission” events.285 “Proven” denotes clear evidence of the same infectious disease in the donor and at least one of the recipients, while “probable” is based on strong evidence suggesting but not proving a disease transmission. Use of standardized nomenclature may facilitate global tracking and study of such infectious disease transmissions as well as the comparison of data between published studies and reports collected globally.285
The risk of donor-derived disease transmission can be mitigated by the donor evaluation, including history taking (clinical, social/behavioral, travel) and microbiological testing. While microbiological testing should be performed in all donors for some pathogens [HIV, HBV, HCV, CMV, EBV, syphilis], focusing testing for other pathogens based on regional epidemiology and individual clinical, social or geographic risk factors should reduce the likelihood of procuring an organ that could transmit infection, while preserving opportunities for donation (avoiding false-positive test results) (Table 17). Approaches to screening should consider the virulence of a particular pathogen, available testing assays, and residual window periods for transmission despite screening283,286 as discussed according to specific pathogen below.71,273,275,276,286-291 Risks versus benefit must be balanced in the decision to use organs from infected donors, incorporating predonation treatment and recipient prophylaxis where appropriate. It is also necessary to inform the recipient and their care team of any known risks from the potential donated kidney.
Hepatitis B Virus
Evaluation of donor candidates should include US PHS risk factor screening for increased risk of HBV infection.71 All donor candidates should undergo testing for IgG hepatitis B core antibody (anti-HBcAb) and hepatitis B surface antigen (HBsAg).71,273,275 HBV DNA nucleic acid testing (NAT) can further stratify transmission risk in donor candidates from HBV endemic areas who are anti-HBcAb+, those with possible mutant HBV infections, and those with abnormal liver function tests or a past history of liver disease of unknown etiology. Testing for HBV should be performed as close as possible to the date of the organ recovery, but within no longer than 28 days before donation.71
Transplantation of kidneys from HBsAg+ donors is contraindicated for HBV- recipients, but may be considered for HBsAg+ recipients or recipients with HBV protective immunity,275 with informed consent of the recipient, possible antiviral HBV treatment of the recipient and posttransplant monitoring. Kidney transplant recipients from anti-HBcAb+/HBsAg-/HBV DNA- donors appear to have little risk of acquiring active HBV infection.275,292 HBV NAT testing should be performed in donor candidates with isolated HBcAb+ status to further define risk of transmission. If the donor is anti-HBc + and HBV DNA-, the risk of transmission is negligible,293 especially if the recipient is anti-HBsAb + or has been effectively immunized against HBV. Still, the recipient should be informed of the small potential risk of disease transmission, and posttransplant monitoring should be performed.
Hepatitis C Virus
Evaluation of donor candidates should include US PHS risk factor screening for increased risk of HCV infection.71 Additional HCV risk factors identified by the US Centers for Disease Control for the general public (not specific to organ donation) include: persistently abnormal alanine aminotransferase concentrations, receipt of blood transfusion or blood components before 1992, receipt of clotting factor concentrates produced before 1987, recognized exposure among healthcare workers, and children born from HCV+ mothers.294 Regardless of past risk factors, all donor candidates should undergo testing for HCV infection as close as possible to the date of the organ recovery, but within no longer than 28 days before donation.71 Thus, behavioral risk factor assessment is used to inform pretest probability for interpretation of microbiological test results and to guide counseling to avoid infection after testing, not to determine which donor candidates should be tested. Approximately 15% of people with anti-HCV antibodies will not have detectable HCV-RNA in the serum. The 2013 US PHS guideline recommends that all living donor candidates should be tested for both anti-HCV antibody and for HCV RNA by NAT.71
Before the advent of new direct-acting antiviral agents, active HCV infection in a donor candidate was considered a contraindication to living donation, not only because of the risk of transmitting HCV to the recipient but also because of the risk of glomerular disease in the donor.295 HCV has been transmitted to naïve organ recipients from infected living and deceased donors.296 Organ transplantation from an HCV+ donor is associated with significant risk of HCV transmission, especially to HCV- recipients.297 However, how to handle the situation when an otherwise suitable living kidney donor is HCV+ may evolve in the era of effective treatment with direct-acting antiviral agents. It is of course best to use a living donor who is not HCV+. However, if research protocols are developed to assess living kidney donation from HCV+ persons, then regardless of the HCV status of the recipient it would make sense that protocols require donor treatment with direct-antiviral agents for at least 12 weeks, the treatment duration when most studies show sustained virologic response, before donating a kidney.298
Human Immunodeficiency Virus
Evaluation of donor candidates should include US PHS risk factor screening for increased risk of HIV infection.71 All donor candidates should undergo microbiological testing for HIV infection as close as possible to the date of the organ recovery, but within no longer than 28 days before donation.71,275 HIV infection is a contraindication to organ donation to HIV- recipients as the transmission of HIV by organ transplantation is well documented. Tests to detect HIV include antibodies generated against HIV antigens, direct detection of viral nucleic acid (NAT testing) or HIV antigen p24. Currently, antibodies against HIV antigens remain the most commonly used method for detection of HIV. The period from HIV exposure to the development of HIV antibodies is approximately 22 days, but can be up to 6 months. Thus the donor may be seronegative while potentially infectious.283 NAT testing can reduce the window period for HIV to between 5.6 and 10.2 days.299
In contrast to undetected donor disease transmission, medical advancements in HIV antiviral therapy have led to consideration of planned kidney transplantation from HIV+ donors to HIV+ recipients, such as recent experience described in South Africa.300 In the United States, the National Organ Transplant Act (NOTA) of 1984 prohibited the knowing procurement or transplantation of organs from an HIV infected donor, but in 2013 the HIV Organ Policy Equity (HOPE) Act repealed this prohibition and authorized the OPTN to develop standards for use of organs from known HIV infected individuals in HIV infected recipients. At this time, such donations and transplantation should occur only within the context of research protocols; protocols in the United States were developed by the National Institutes of Health (NIH).301
Increased Risk Donors and Window Periods for HBV, HCV and HIV
Serological testing for infections has been highly effective in reducing the risks of donor-derived disease transmission. However, seroconversion requires the elaboration of antibodies against a specific pathogen and could be delayed for several weeks after infectious exposure. Testing during the window period for seroconversion may generate false-negative test results and could lead to inadvertent infection transmissions. Cases of donor-derived infection transmissions related to window period infections missed by serologic screening of donors have been reported.274,283 The period from HIV exposure to the development of HIV antibodies is 22 days on average, but can be up to 6 months.274 HBsAg enzyme-linked immunosorbent assays (ELISAs) have a window period of 38.3 to 49.7 days, while the time from HBV exposure to positive NAT testing ranges from 20.4 to 25.7 days. The window period for detection of HCV infection by ELISA is 38 to 94 days, but the duration of the window is substantially reduced to 6.1 to 8.7 days by the use of NAT.274
In 2007 in the United States, a previously uninfected deceased donor kidney transplant recipient tested positive for HIV and HCV infection. Routine donor serologic screening for HIV and HCV infection was negative; the donor's only known risk factor for HIV was having sex with another man. Four organs (2 kidneys, liver and heart) were transplanted to 4 recipients. NAT of donor sera and posttransplant sera from all recipients were positive for HIV and HCV.302 This case highlighted the potential for donors to harbor HIV and HCV infection during the window period, when infection cannot be detected by antibody screening.
In 2009, a case of unexpected HIV transmission from a living organ donor in New York City was also reported.284 Based on this case, it was suggested that to reduce the risk for transmission of HIV through living donor organ transplantation, transplant programs should screen living donors for HIV as close to the time of organ recovery as possible, using sensitive tests for both chronic and acute infections, namely, antibody and NAT testing.284
In 2013, the US PHS updated their “Guideline for Reducing HIV, HBV and HCV Transmission through Organ Transplantation,” including recommended risk factor assessment in all donor candidates (Table 16).71 Living donor candidates with behaviors associated with increased risk of acquiring HIV, HBV or HCV identified during evaluation should receive individualized counseling on specific strategies to prevent exposure to these viruses during the period before donation surgery. Recommendations regarding microbiological testing include:
- All potential organ donors (living or deceased) should be tested for antibodies to HIV (ie, anti-HIV 1/2 Ab or HIV antigen/antibody [Ag/Ab] combination assay). All potential organ donors identified as being at increased risk for HIV infection should also be tested for HIV RNA by NAT or HIV antigen (eg, HIV Ag/Ab combination assay). Donor blood specimens should be obtained before procurement. Ab or Ag/Ab test results should be made available before transplantation.
- All potential organ donors (living or deceased) should be tested for both anti-HCV Ab and for HCV RNA by NAT. Donor blood specimens should be obtained before procurement. Antibody test results should be made available before transplantation.
- All potential organ donors (living or deceased) should be tested for anti-HBcAb and for HBsAg. Donor blood specimens should be obtained before procurement. Ag/Ab test results should be made available before transplantation.
- As noted above, the guideline recommends that all living donor candidates should be tested for HIV, HBV and HCV as close as possible to the date of the organ recovery operation, but within no longer than 28 days before surgery.
Whether retesting closer to the time of transplantation (eg, within 7 to 10 days before donation) is warranted to detect new infections and reduce the window period, overall or among high-risk donor candidates, remains controversial.303,304 A survey of living donor transplant programs in New York State in 2012 found that most responding programs had policies to retest living donors within 14 days of donation and while there were rare cases of delays in donation associated with repeat testing, no cancellations occurred.305
Epstein Barr Virus
The presence of anti-EBV antibodies signifies prior donor infection, with potential for reactivation of the latent virus and subsequent infection of the immunosuppressed recipient. While detection of the EBV in the living donor generally will not preclude donation, knowing that the kidney comes with latent EBV infection may be important in posttransplant recipient care.306 Infection with EBV manifests as a spectrum of diseases ranging from asymptomatic viremia to infectious mononucleosis to posttransplant lymphoproliferative disorder (PTLD).307 EBV disease and associated PTLD are more frequently seen when primary EBV infection occurs after transplant, a common scenario in EBV- pediatric solid organ transplant recipients who receive a kidney from an EBV+ donor. In the United States, the cumulative 1- and 5-year incidence of PTLD in 2010 was reported to be 1.3% and 2.4%, respectively, for pediatric kidney recipients but less than 0.2% and 0.6% respectively, for adult recipients.307 When the donor is EBV+ and the recipient is EBV-, particularly in pediatric recipients, clinical vigilance is required after transplantation to detect PTLD.308 Intensity of EBV viral load and immunosuppressive therapies influence the risk for PTLD.307
Cytomegalovirus disease may result from reactivation of latent infection or primary infection transmitted by a kidney from a CMV+ donor. The laboratory methods for CMV diagnosis are serology, culture, antigenemia, and molecular methods such as CMV NAT, which is most commonly performed using real-time polymerase chain reaction.309 The main clinical utility of CMV serology is stratification of a transplant recipient’s risk of CMV disease based on donor and recipient status.279,280,310
The presence of anti-CMV antibodies in a donor candidate indicates prior infection, with the potential that the latent virus will reactivate and cause infection, particularly in the CMV- recipient. The detection of anti-CMV antibodies does not preclude donation, and infection risk can be anticipated and managed. Primary CMV infection is generally more severe than reactivation and recipients at highest risk are those who are CMV seronegative and receive a kidney transplant from a CMV seropositive donor. Matching CMV seronegative recipients with CMV seronegative donors is an effective strategy for reducing the risk of CMV infection but is rarely practical in the context of living donor kidney transplantation. CMV seropositive recipients may develop disease reactivation or donor-related infection. Thus organ donors and recipients should be tested for prior (latent) CMV infection using anti-CMV antibody for risk stratification and guidance of appropriate surveillance and/or antiviral prophylaxis after transplantation.311
Transmission of syphilis by organ transplantation has been documented.312 In the United States, all assays currently FDA-approved for detecting evidence of T. pallidum infection in organ and tissue donors are serologic assays.313 There are 2 types of serologic assays: nontreponemal and treponemal. Nontreponemal assays use a combination of cardiolipin, cholesterol, and other lipid substances released from damaged cells as the antigenic source to detect antibodies against cardiolipin, which circulates in the sera of individuals infected with syphilis and may also be present in individuals with a variety of other conditions. Reactivity to cardiolipin generally disappears within a year or 2 after successful treatment of syphilis.313 Treponemal assays detect T. pallidum antibodies, which tend to remain elevated for life. Therefore, treponemal assays cannot distinguish between recent, remote, and previously treated infection. Donors are screened for serological evidence of syphilis with a nontreponemal assay such as the rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) test, which should be confirmed later with a treponemal Ab immunoassay. A recent study found that current screening of deceased organ donors by RPR yields a significant number of false-positive results. Use of alternative tests or the routine use of confirmatory tests may reduce the frequency of false-positive syphilis results in potential deceased and living organ donors.314
As there are multiple available syphilis assays providing different types of information, no single blood assay can conclusively define an individual’s disease status. For donor candidate testing, specimen collection and the time available to perform testing must be considered in choosing an appropriate donor screening assay.313 Living donor candidate evaluation is less time constrained than the screening of deceased donors, and thus screening with nontreponemal assays followed by confirmation with treponemal assays is preferred if feasible.
Transmission of syphilis has been reported in the United Kingdom to 2 recipients from a deceased donor with a past history of treated disease, supporting recommendations of penicillin for treatment of recipients of deceased donor organs from serologically reactive donors.312 Donation from living persons with latent syphilis may be considered after treatment of the donor candidate before donation (eg, with penicillin), informed consent of the recipient, and recipient monitoring after transplant.
The incidence of posttransplant TB varies substantially depending on the local prevalence of TB infection, which ranges from 1% in Germany to nearly 14% in India.290 Studies in the United States and Europe have estimated that 0.35% to 6.6% of transplant recipients develop TB (across organ and donor types), and that 4% posttransplant TB cases are donor-derived.290,315 TB is one of the more common bacterial causes of donor-derived infection in the United States.316
Consensus-based recommendations for the diagnosis and management of TB in organ donors include:288,290,317
- Risk stratification of all donor candidates, according to:
- ○ Place of birth, residence or travel to a geographically endemic region, with increased risk defined by residence greater than 3 months or relief work in a high prevalence region
- ○ Social risk factors including working in healthcare, prison exposure/incarceration, known TB contact, homelessness, alcohol or other substance abuse
- ○ Medical risk factors including history of untreated TB or radiographic evidence of prior TB; underweight BMI and diabetes have also been correlated with increased TB risk
- Chest radiograph in all donor candidates
- Consideration of urinalysis with microscopy, genitourinary imaging, urine acid-fast bacilli smear and culture in living donor candidates from countries with intermediate to high TB prevalence
- Consideration of immune-based diagnostic testing by tuberculin skin testing (TST) or the interferon-gamma release assay (IGRA)
- ○Diagnostic tests for latent TB infection are limited in sensitivity and have a relatively low predictive value for development of active TB.318 The specificity of TST is related to the burden of TB in that region or country, and IGRA has superior specificity in populations where use of Bacillus Calmette-Guérin vaccination is common based on use of specific antigens absent in Bacillus Calmette-Guérin strains
- ○Immune testing of all donor candidates or selective testing based on risk profile are considered acceptable options
- ○Persons with positive immune-based TB testing who are asymptomatic and do not have signs of active TB are considered to have latent TB infection
- Donation from persons with active TB is contraindicated. Risk of transmission from donors with prior appropriately treated active TB appears to decline with longer time from treatment. Donation may be considered with informed consent of the recipient, consideration of recipient chemoprophylaxis under the guidance of an infectious disease specialist, and recipient monitoring after transplant.
- Living donor candidates with latent TB infection should be offered chemoprophylaxis according to local or national guidelines. Donation may be considered from persons with latent TB infection with informed consent of the recipient and recipient monitoring after transplant. As there are no data on optimal duration of treatment before donation, individualization of the timing of donation in relation to start of donor chemoprophylaxis is recommended. Chemoprophylaxis of recipients from donors with latent TB infection should also be considered, especially if the donor did not complete chemoprophylaxis before donation.317
A recent study in Korea, a country with an intermediate prevalence of TB, prospectively evaluated living donors using the TST and Mycobacterium tuberculosis-specific enzyme-linked immunosorbent spot (ELISPOT) IGRA.319 Among the 205 living donors, 31% had a positive TST and 47% had a positive ELISPOT. Based on the high rate of suspected latent TB infection detected by screening living donors using TST and ELISPOT in a country with a TB intermediate prevalence, the authors recommended further study of the cost effectiveness of recipient TB chemoprophylaxis.319
Urine should be sent for culture from all donor candidates at evaluation, and ideally repeated close to the time of donation (eg, within the preceding 2 weeks). Acute symptomatic urinary tract infection is a reason to postpone donation. However, detection of asymptomatic bacteriuria is not infrequent, especially in female donors. A history of urinary tract infection in a donor candidate, particularly if there is a family history of reflux nephropathy, or in a male, requires detailed imaging of the kidneys (eg, assessment for cortical scarring). Any active bacterial or fungal infection in the donor should be treated and, ideally, resolved before donation and transplantation.283 Antibiotic prophylaxis should be given to the recipient if resolution of infection is not confirmed before donation, as a positive urine culture early after transplantation, even when asymptomatic, may be associated with increased risk of acute rejection in the recipient.320,321
Seasonal and Geographically Endemic Infections
The donor candidate evaluation should include assessment of place of residence, travel, seasonal, occupational, and recreational risks, as well as prior infections in the donor candidate and family members (Table 17). A number of geographically endemic and seasonal diseases have been transmitted through organ donors including: Strongyloides, Trypanosoma cruzi (Chagas disease), West Nile virus, histoplasmosis, coccidiomycosis, Aspergillus, toxoplasmosis, malaria, Creutzfeldt–Jacob disease, human T-cell lymphotrophic virus infection, and schistosomiasis.273,275,286 Other viral, fungal, bacterial and parasitic pathogens recognized as sources of organ donor-derived infection transmissions are listed in Table 18. Living donation affords sufficient time for microbiological testing, donor treatment and deferral of donation and transplantation until resolution of infection. Organ donation may be possible after treatment of the donor candidate before donation, informed consent of the recipient, as well as recipient monitoring and possible prophylaxis after transplant (Table 19).
Strongyloidiasis typically occurs only in the setting of specific environmental exposures. Donor-derived Strongyloides hyperinfection cases with high associated mortality have been reported, including from kidney transplantation.322-324 Consensus-based recommendations of the 2013 AST Infectious Diseases Community of Practice work group and the OPTN Ad Hoc Disease Transmission Advisory Committee (DTAC) support screening for Strongyloides in the following potential organ donors286,287:
- Persons who were born in or lived in tropical or subtropical countries where sanitation conditions are substandard, including candidates with prior military service in endemic areas. The WHO emphasizes a correlation between improved sanitation and human waste disposal with the disappearance of Strongyloidiasis.325 Strongyloidiasis has occurred in most countries with the exception of Canada, Japan and Northern Europe.
- Persons with significant exposure to soil in Appalachia or the Southeastern United States, including walking barefoot.
- Persons with unexplained eosinophilia and travel to endemic area.
- Persons reporting a prior history of Strongyloides infection.
Serologic Ab testing is the preferred screening test for Strongyloides infection, as the sensitivity of stool testing is limited and multiple stool screening tests may be negative in asymptomatic chronic infection.286Strongyloides IgG antibody testing (ELISA-based) is available in many reference labs.
Infected donor candidates should be treated with a minimum of 2 doses of ivermectin before donation (200 µg/kg orally daily on 2 consecutive days)286,287 Because of the potential for persistence of migrating larvae and eggs in the tissues, some experts recommend repeating this treatment 2 weeks later to cover an autoinfection cycle. After treatment, follow-up laboratory testing of the donor candidate before donation to confirm cure has been deemed unnecessary, unless reexposure has occurred286,287
Chagas disease is transmitted through contact with infected triatomine “kissing” bugs, and residents of poorly constructed housing where these insects reside are at greatest risk of acquiring infection. Transmission has also been reported from mother to infant, through blood transfusion, and through organ transplantation. Consensus-based recommendations of the 2011 Chagas in Transplant Working Group, the 2013 AST Infectious Diseases Community of Practice work group, and OPTN DTAC support screening in the following potential organ donors286,287,289:
- Those who were born in or lived in an endemic region in Mexico, Central or South America
- Children of women who lived in endemic regions and whose T. cruzi infection status is positive or unknown
- Persons who received a blood transfusion in endemic regions
- Persons reporting a prior history of Chagas disease
Assessment of outcomes of 32 transplant recipients who received organs from 14 T. cruzi seropositive donors in the United States from 2001 to 2011 confirmed transmission in 9 recipients from 6 donors, including 2 of 15 (13%) kidney recipients, 2 of 10 (20%) liver recipients and 3 of 4 (75%) heart recipients.326 Recommended monitoring posttransplant comprised regular testing by polymerase chain reaction, hemoculture, and serologic testing. Thirteen recipients had no or incomplete monitoring; transmission was confirmed in 5 of these recipients; 4 of the 5 recipients had symptomatic disease and all 4 died, although death was directly related to Chagas disease in only one. Nineteen recipients had partial or complete monitoring for T. cruzi infection with weekly testing by polymerase chain reaction, hemoculture and serologic testing; transmission was confirmed in 4 of the 19 recipients with no cases of symptomatic disease. Based on such evidence, recent guidelines support consideration of kidney donation from donors with T. cruzi infection on an individual basis with consent of the recipient.286,287,289 Recipients must be informed of the need for participation in close monitoring and the available therapeutic interventions in the event of infection, as the medications available for treatment are not FDA-approved and are generally only available through specific protocols. Consideration of the recipient’s access to testing and monitoring is imperative, as geographic concerns may impact the ability to follow the recipient closely.
West Nile Virus is a flavivirus that is transmitted by mosquitoes in an enzootic cycle with birds. When testing is indicated, screening living donor candidates by West Nile virus NAT within 7 to 14 days of donation has been recommended.273,291 Proposed strategies for when to begin testing living donor candidates for West Nile virus include when regional blood banks start performing NAT screening or testing during a defined period of time that reflects the peak of local West Nile virus infection.291 The 2013 AST Infectious Diseases Community of Practice work group recommended delaying donation for 28 days when NAT screening is positive, followed by repeat NAT and immunoglobulin M (IgM) Ab testing with the following management pathways based on the results273:
- NAT+: Defer donation for at least 120 days. Donation deemed likely to be safe if clearance of viremia demonstrated by NAT testing after 120 days
- NAT-/IgM Ab−: Consider initial NAT testing to reflect a false positive result. Donation may be considered after infectious disease consult
- NAT-/IgM Ab+: Suggests infection with clearance of viremia. Donation may be considered after infectious disease consult
Transplant programs must maintain awareness of new and emerging infections that may be transmissible through organ donation. Availability of microbiological testing for new infections may be limited or available only at specialized laboratories, emphasizing the importance of careful assessment of exposure history in the donor candidate evaluation. For example, during the Ebola virus outbreak of 2014, the OPTN DTAC recommended that evaluation of candidates for organ donation should include screening for travel and epidemiologic risk factors for Ebola exposure, including327:
- Travel to a country where an Ebola outbreak occurred within the past 21 days
- Contact with blood, other body fluids, or human remains of a patient known or suspected to have Ebola
- Exposure as a healthcare worker to patients known to have Ebola
- Direct handling of bats or nonhuman primates from disease-endemic areas
If risk factors for Ebola are identified, the OPTN DTAC recommends aborting the evaluation process and excluding donation.
Zika virus is a mosquito-borne pathogen that gained attention in association with an outbreak of primary microcephaly among children born to infected mothers in Brazil in 2015, followed by rapid geographic spread across the Americas, prompting recognition as a global health emergency.328 Other complications of Zika virus infection include acute autoimmune neuropathies such as Guillain-Barré syndrome. Guidance from the OPTN DTAC, the AST, and the ASTS recommend considering donor deferral if there is history of travel to Zika-endemic areas in the 28 days before donation.329 In the case of potential living donors with Zika infection, donation should be deferred where possible.
Transplant programs should develop and maintain screening protocols to address emerging infections, including awareness of evolving geographic exposure patterns in consultation with local public health specialists. Current information on global health outbreaks are reported by organizations such as the US Centers for Disease Control.330
What Prior Guidelines Recommend
US OPTN Policy for Medical Evaluation Requirements for Living Donors mandates similar screening tests as recommended in our current guideline: anti-CMV Ab, anti-EBV Ab, anti-HIV 1,2 Ag/Ab, HBsAg, anti-HBcAb, anti-HCV Ab, and syphilis testing.51 US transplant programs are required to determine whether the donor has TB exposure risk factors and to test accordingly. US programs are also required to develop protocols to determine who to screen for geographically endemic and seasonal infections such as Strongyloides, Trypanosoma cruzi and West Nile virus.
The British Transplantation Society has also recommended testing for HBV, HCV, EBV, CMV and HIV as part of donor candidate evaluation.48 The Spanish Society of Nephrology and Spanish National Transplant Organization recommendations for living donor kidney transplantation included the following as routine tests in the donor candidate evaluation: HIV [a], Hepatitis B: HBsAg [a], anti-HBcAb IgM/IgG [b], HBsAb, HBV DNA in plasma if anti-HbcAb+, Hepatitis C (ELISA and polymerase chain reaction) [a], CMV IgG/IgM [b], EBV IgG/IgM [b], Toxoplasma test, Syphilis (RPR- fluorescent treponemal antibody) [b], Brucella [b]. Here, [a] stands for ‘Donation is contraindicated with positive results’ and [b] stands for ‘Donors and/or recipients have to undergo treatment with positive results’.54
In contrast to this recommendation, we believe that testing for Toxoplasma and Brucella should be guided by geography and risk factors for possible exposure. Also, since the Spanish Society of Nephrology and Spanish National Transplant Organization guidelines were published in 2010,54 new research published above supports revision of some categories of [a] ‘Donation is contraindicated with positive results.’
- Define the incidence of donor-derived disease transmission through improved monitoring and reporting. This is critical since determining the relative importance of specific pathogens and risk mitigation strategies requires collection of global data.
- Develop and validate risk assessment questionnaires and protocols for living donor-derived infections, taking into consideration behavioral, occupational, hobby-related, geographic and seasonal exposures.
- Optimize and standardize methods of microbiological assays for donor infection screening and diagnosis.
- Assess results of planned US NIH studies of transplantation from HIV+ donors to HIV+ recipients to develop guidance on appropriate consideration of such transplants in clinical practice.
- Determine, through clinical trials or observational protocols with informed consent, whether kidney donation and transplantation can be performed with acceptable safety and outcomes for the donor and recipient in the following scenarios:
- ○ Donation from HCV+ living donors to HCV+ recipients after antiviral treatment of the donor
- ○ Donation from HBsAg + living donors to HBsAg + recipients or recipients with HBV
CHAPTER 13: CANCER SCREENING
The ERT search parameters did not identify evidence from eligible studies pertinent to the recommendations in chapter 13 and therefore the following recommendations are “Not Graded.”
- 13.1: Donor candidates should undergo cancer screening consistent with clinical practice guidelines for the country or region where the donor candidate resides. Transplant programs should ensure that screening is current according to guideline criteria at the time of donation.
- 13.2: In general, donor candidates with active malignancy should be excluded from donation. In some cases of active malignancy with low transmission risk, a clear management plan and minimal risk to the donor, donation may be considered.
- 13.3: A kidney with a small simple (Bosniak I) cyst can be left in the donor, particularly if there are compelling reasons for donating the contralateral kidney.
- 13.4: Donation of a kidney with a Bosniak II renal cyst should proceed only after assessment for the presence of solid components, septations, and calcifications on the preoperative computed tomography scan (or magnetic resonance imaging) to avoid accidental transplantation of a kidney with cystic renal cell carcinoma.
- 13.5: Donor candidates with high grade Bosniak renal cysts (III or higher) or small (T1a) renal cell carcinoma curable by nephrectomy may be acceptable for donation on a case-by-case basis.
- 13.6: Donor candidates with a history of treated cancer that has a low risk of transmission or recurrence may be acceptable for donation on a case-by-case basis.
Goals of Evaluation
The goals of malignancy screening are two-fold. First, it is necessary to identify cancers to protect the health of the donor candidate. Reduced kidney function may compromise long-term health outcomes in individuals requiring cancer treatments with nephrotoxic or cardiovascular side effects (eg, some chemotherapies or radiation treatments). Potential psychosocial stresses of living donation may also be prohibitive in individuals faced with stress of an active cancer diagnosis and treatment. Second, the evaluation must mitigate risks of donor-derived malignancy transmission to the transplant recipient.
General Population Cancer Screening and Incidence
Most jurisdictions have regional recommendations for which members of the general population should be screened for common cancers, including frequency of screening and acceptable testing modalities. These include screening recommendations for colon, breast, cervical, prostate, and lung cancer.331-333 There are potential harms associated with cancer screening, as with any form of screening, if additional testing and procedures are undertaken in patients who ultimately do not have cancer. These risks should be included in the consent for evaluation of the living donor candidate. Transplant programs in countries without local clinical practices guidelines can refer to guidelines from countries or regions most similar to their population.331-333
The limited available data on cancer diagnoses after living kidney donation support that donor evaluation and selection practices reduce the incidence of postdonation cancer below that of general population controls, although risk reduction may dissipate with time after donation.334 However, cases of cancer diagnoses including melanoma and uterine cancer within less than 1 year of donation have been reported,334 emphasizing the need for up-to-date assessment for malignancy before donation.
Recurrence Risk after Treated Cancer
Recurrence rates after treated cancer from the general population may be used to guide observation periods after cancer treatment before considering organ donation. Average times to recurrence vary by cancer type. Consideration of living donation from a person with a history of treated cancer should include consultation with the donor candidate’s oncologist to confirm that individual case factors are associated with “low” (eg, less than 1%) risks of both lifetime recurrence and disease transmission, and that long-term surveillance will not require frequent imaging that may be restricted by reduced GFR (eg, CT scans with iodinated contrast or magnetic resonance imaging (MRI) scans requiring gadolinium).
Donor-Derived Malignancy Transmission
Cases of malignancy transmission from deceased or living organ donors to recipients have been reported. A recent systematic review examined all case reports, case series and registry studies describing the outcomes of kidney transplant recipients with donor-derived cancer transmission published through December 2012.335 Among 104 donor-transmitted cancer cases identified from 69 studies, the most common transmitted cancer types were renal cancer (n = 20, 19%), followed by melanoma (n = 18, 17%), lymphoma (n = 15, 14%) and lung cancer (n = 9, 9%). Recipients with transmitted renal cancers had the best outcomes, with more than 70% of recipients surviving for at least 24 months after transplantation. Patients with melanoma and lung cancers had the worst prognosis, with less than 50% of recipients surviving beyond 24 months from transplantation. While these data support that donor-derived cancer transmission is uncommon, potential reporting-bias prevents accurate incidence estimates. This report highlights the high mortality associated with donor-derived melanoma and lung cancer transmission.
A history of melanoma is particularly concerning when evaluating a living donor candidate. Aside from the potential for late recurrence and subsequent complications in the donor, melanoma transmission to transplant recipients has been reported after apparent dormancy in the donor for decades, supporting the ability of melanoma cells to remain dormant at distant sites for decades and then reactivate upon exposure to immunosuppression,336,337 and transmission can be fatal. The Israel Penn International Transplant Tumor Registry, a voluntary registry of more than 250 cases of organs transplanted from donors with a history of malignancy that captures tumor histology, donor risk factors, method of tumor presentation and recipient outcome, described 13 donors with a history of melanoma (but deemed free of the disease at donation) who provided organs to 28 recipients.338,339 Melanoma transmission occurred in 21 recipients (75%), of whom 13 (62%) died from metastatic disease. The time to diagnosis ranged from 2.5 to 42 months (median, 10.5 months), and the only patients who survived were those who underwent nephrectomy and cessation of immunosuppression. While some prior general population guidelines such as the US Preventative Services Task Force state that there is insufficient evidence to recommend routine whole body skin exam screening among general adults,340 skin examinations for donor candidates with increased recreational or occupational exposure to sunlight, family or personal history of skin cancer, or clinical evidence of precursor lesions may be warranted. Pathology reports of living donor candidates with a prior history of skin cancer resection should be reviewed to ensure that the cancer was not a melanoma before approving donation.
In 2011, the OPTN DTAC Malignancy Subcommittee published a classification of 6 risk categories for donor-derived malignancy transmission and suitability of organ donation from persons with active or prior malignancy histories341; this was also recently reviewed in Kirchner et al.273 Classification was based on review of cancer registry reports, published literature, and data submitted to the OPTN. This article did not differentiate between cancer transmissions from living compared with deceased donors due to limited data.
- “No significant risk” was defined as benign tumors where malignancy has been excluded.
- “Minimal risk” was defined as tumors with 0% to 0.1% transmission events per organ transplanted from donors with the specific tumor, and includes nonmelanoma skin cancers, noninvasive carcinoma of the bladder (for nonrenal transplants only), small papillary or follicular carcinoma of the thyroid and solitary, well-differentiated (≤1 cm) renal cell carcinoma.
- “Low risk” (0.1-1% transmission events per organ transplanted from affected donors) includes small renal cell carcinoma (1-2.5 cm), low grade central nervous system (CNS) tumors, primary CNS mature teratoma, solitary papillary thyroid carcinoma (0.5-2.0 cm), minimally invasive follicular carcinoma (1.0-2.0 cm), and history of treated non-CNS malignancy (≥5 years prior) with greater than 99% probability of cure.
- “Intermediate risk” (1-10% transmission events per organ transplanted from affected donors) includes breast and colon carcinoma in situ, resected well differentiated renal cell carcinoma (4-7 cm) and history of treated non-CNS malignancy (≥5 years prior) with probability of cure between 90-99%.
- “High risk” (>10% transmission events per organ transplanted from affected donors) includes current or past history of melanoma, leukemia/lymphoma or neuroendocrine tumors, breast or colon cancer stage 1 or higher, choriocarcinoma, any CNS tumor with vetriculoperitoneal or ventriculoarterial shunt, metastasis or high grade (III/IV) histology, metastatic carcinoma, sarcoma, lung cancer Stage I-IV, and renal cell carcinoma greater than 7 cm. The high risk category also included any treated non-CNS malignancy with insufficient follow-up to predict behavior, incurable or with <90% probability of cure, or any other active cancer not previously classified.
- Tumors of “unknown risk” were defined as a final category.
The authors suggested that donors in the “no significant risk” category are standard, and that organs from donors with “minimal risk” malignancies may be used for transplantation based on clinical judgment with informed consent of the recipient. The authors also proposed that organs from donors with “intermediate risk” malignancies could be considered for transplantation with informed consent for recipients who face substantial mortality without transplantation. This classification scheme should be updated with new information as data become available.
Considerations Related to Renal Cysts and Renal Cell Carcinoma
The development of kidney cancer in a patient with a single kidney is very concerning because the surgical treatment of renal tumors may result in loss of function of the remaining kidney. The age-stratified lifetime cumulative incidence of kidney cancer is low. In a matched cohort study of 2119 donors in Ontario Canada (1992-2010) and 21 190 nondonors from the general population with similar baseline health, no living kidney donor in the cohort received a partial or total nephrectomy of their remaining kidney during follow-up.342
The decision to approve donation in a person with kidney cysts depends on radiographic characteristics (Tables 20 and 21). Because simple (Bosniak I) renal cysts are not associated with increased risk of complications, organ dysfunction, or cancer, simple cysts are not contraindications to kidney donation. Cases of back table excision of small renal cell carcinomas after donor nephrectomy, followed by use of the kidney for transplantation have been reported.345-348 Based on review of cancer registry reports, published literature and disease transmission cases reported to the OPTN, a 2011 OPTN DTAC Malignancy Subcommittee concluded, from a disease-transmission perspective, that “… kidneys with small, solitary, well differentiated renal cell carcinoma may be usable for transplantation provided the lesion itself is completely resected."341 While partial (rather than complete) nephrectomy is often the treatment choice for small renal cell carcinomas for the purpose of nephron-sparing with comparable cure rates in affected individuals, persons planning kidney donation intend to undergo complete nephrectomy. Thus, the decision to proceed with donor nephrectomy in an individual with a high grade Bosniak cysts or suspected kidney cancer based on predonation imaging should incorporate considerations of the anticipated risk of future carcinoma in the donor’s contralateral kidney, risk of disease transmission to the recipient (including whether the lesion is amenable to complete back table excision), chances of possible discard without transplantation after nephrectomy. Donation of a kidney with a Bosniak II renal cyst should proceed only after assessment for the presence of solid components, septations, and calcifications on the preoperative computed tomography scan (or magnetic resonance imaging) to avoid accidental transplantation of a kidney with cystic renal cell carcinoma. Procurement and transplantation of living donor kidneys with Bosniak (III or higher) renal cysts or small (T1a) renal cell carcinoma curable in the donor by nephrectomy and amenable to complete excision before implantation should proceed only after detailed informed consent of donor and recipient, and donor and recipient understanding and acceptance of these risks. In most circumstances, Bosniak IIF or higher cysts should not be left in the donor but such decision should be individualized.
What Prior Guidelines Recommend
Prior guidelines and policies for the evaluation and care of living donors recommend history, clinical examination, and investigation to exclude occult malignancy before donation, especially in those older than 50 years or with risk factors including family history.38,48,51 The Amsterdam Forum recognized that risks of specific cancers may vary across countries.38 “Active malignancy” is commonly cited as a contraindication to living kidney donation,38,48,51 although exceptions were noted for low-grade nonmelanoma skin cancer.38 Renal cell carcinoma was considered a contraindication to donation in some prior guidelines,38,48 but is currently permissible under US policy in selected cases.51
Past cancers considered to be an absolute contraindication to donation in prior guidelines include melanoma, testicular cancer, choriocarcinoma, hematological malignancy, monoclonal gammopathy, bronchial cancer, and metastatic cancer.38,48 Breast cancer is included, although the European Association of Urology qualifies the restriction to “advanced” disease.55 Criteria for which donation may be acceptable despite a prior history of malignancy articulated in prior guidelines include that the specific cancer is curable and the potential transmission of the cancer can reasonably be excluded (eg, colon cancer (Dukes A, > 5 years ago), nonmelanoma skin cancer, or carcinoma in situ of the cervix).