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Kidney Paired Donation Protocol for Participating Donors 2014

Richardson, Robert1,2; Connelly, Maureen3; Dipchand, Christine4,5; Garg, Amit X.6,7; Ghanekar, Anand2,8; Houde, Isabelle9; Johnston, Olwyn10; Mainra, Rahul11; McCarrell, Ruth12; Mueller, Thomas13,14; Nickerson, Peter15,16,17; Pippy, Christine18; Storsley, Leroy16,19; Tinckam, Kathryn1,2,15,21; Wright, Linda22,23; Yilmaz, Serdar24; Landsberg, David25; for the Protocols Working Group of the Canadian Blood Services’ Living Donation Advisory Committee

doi: 10.1097/TP.0000000000000918
Supplement

1 Division of Nephrology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.

2 University of Toronto, Toronto, Ontario, Canada.

3 Living Kidney Donation, St. Michael’s Hospital, Toronto, Ontario, Canada.

4 Living Kidney Donation, Multi-Organ Transplant Program of Atlantic Canada (MOTP), QEII Health Sciences Centre, Halifax, Nova Scotia, Canada.

5 Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

6 Living Kidney Donation, London Health Sciences Centre, London, Ontario, Canada.

7 Epidemiology & Biostatistics, Western University, London, Ontario, Canada.

8 Kidney Transplant Program, University Health Network, Toronto, Ontario, Canada.

9 Kidney Transplant Program, Centre hospitalier de l’université de Québec, Pavillon l’Hôtel-Dieu de Québec, Quebec City, Quebec, Canada.

10 Kidney Transplant Program, Vancouver General Hospitall, Vancouver, British Columbia, Canada.

11 Saskatchewan Transplant Program, Saskatoon Health Region, St. Paul’s Hospital, Saskatoon, Saskatchewan, Canada.

12 Kidney Transplant Program, Providence Health Care, St. Paul’s Hospital, Vancouver, British Columbia, Canada.

13 The Living Donor Services Program, University of Alberta Hospital, Edmonton, Alberta, Canada.

14 Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

15 Donation and Transplantation, Canadian Blood Services, Ottawa, Ontario, Canada.

16 Transplant Manitoba, Winnipeg, Manitoba, Canada.

17 Transplant Immunology Lab, Winnipeg Health Sciences Centre, Winnipeg, Manitoba, Canada.

18 Division of Nephrology, Horizon Health Network, Saint John Regional Hospital, Saint John, New Brunswick, Canada.

19 Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

20 Transplantation, Canadian Blood Services, Toronto, Ontario, Canada.

21 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario Canada.

22 University Health Network, Toronto, Ontario, Canada.

23 Department of Medicine and Joint Centre for Bioethics, University of Toronto, Toronto, Ontario, Canada.

24 Division of Transplant Surgery, Southern Alberta Transplant Program, Foothills Medical, Calgary, Alberta, Canada.

25 Kidney Transplant Program, British Columbia Transplant Society, St. Paul’s Hospital, Vancouver, British Columbia, Canada.

Prepared by the Protocols Working Group of the Canadian Blood Services' Living Donation Advisory Committee.

Production of this Protocol has been made possible in part through financial contributions from Health Canada and the provincial and territorial governments. The views expressed herein do not necessarily reflect the views of the federal, provincial, or territorial governments of Canada.

First Edition 2014

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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Purpose of the Protocol

This Protocol has been developed to ensure the harmonization of donor assessment and acceptance practices for enrolling living donors in the Kidney Paired Donation Program, managed and operated by Canadian Blood Services in collaboration with the provincial Living Kidney Donation and Transplant programs across the country. Assessment and acceptance criteria for living donors vary between programs across Canada as shown throughout this Protocol. This variability has two primary effects on the Kidney Paired Donation Program: declines of matched donors and delays in accepting a donor by the recipient’s program because of the need for additional testing to meet local assessment and acceptance criteria. Implementation of this protocol by participating Living Kidney Donation programs should help to minimize the problem of donors being declined when matched with a candidate in the Kidney Paired Donation Program.

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SECTION ONE: INTRODUCTION

Glossary of Acronyms and Abbreviations

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Background

The Canadian Kidney Paired Donation Protocol for Participating Donors (hereafter called “the Protocol”) was prepared by a joint working group of the Canadian Blood Services' Living Donation Advisory Committee.

Living kidney donation is an accepted, highly valued and effective practice to improve access to transplantation for patients with end-stage renal disease (ESRD). For many patients it is the treatment of choice due to the scarcity of kidneys available through deceased donation and the superior outcomes in posttransplant renal function. Despite this success, it is paramount that

* the safety of the potential living donor is not overlooked in the desire to optimize living donor transplantation; and

* the potential living donor's offered kidney has been assessed in terms of its quality and the risk of transmitting disease to the recipient.

Safety is paramount to the success and sustainability of the Kidney Paired Donation Program.

With donor safety being paramount, it is essential that the Kidney Paired Donation (KPD) Program (formerly known as the Living Donor Paired Exchange Program [LDPE]) implement safeguards to inspire public and professional confidence in the quality of the program, and reduce complacency that may lead to compromised donor and transplant recipient outcomes. These safeguards will include the development of interprovincial policies, protocols, procedures, and guidelines for the ongoing management of the protocol and clinical practice related to potential living donors participating in the KPD Program.

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Ethical Principles

By its nature, living donor transplantation has raised, and continues to raise, many ethical issues, especially where there may be pressures to consider potential living donors who may be considered by some to have “minor” risk factors. The challenge to expanding the acceptance criteria for potential living donors is the lack of evidence to suggest that expanded criteria are safe and unlikely to cause unanticipated health outcomes. To this end, principles were developed to guide the development of the Protocol as well as the policies, procedures, and clinical guidelines related to the administration of the KPD Program.

* The duty to proceed with a living donor nephrectomy only when it is undertaken with the potential living donor’s informed and freely given consent.

○ The potential living donor has the capacity to understand the likely risks and benefits of donation.

○ The potential living donor is provided with a detailed description of the risks and benefits of donation.

○ The potential living donor is able to demonstrate an understanding of the risks and benefits of donation.

○ The potential living donor is acting voluntarily and is under no coercion to donate.

○ Consent to becoming a living donor is an ongoing process.

* The duty to respect the autonomy of the potential living donor.

○ The choice to donate or not donate is respected.

○ The potential living donor has a right to change his or her mind about donation at any time.

○ Donor autonomy does not overrule medical judgment and decision-making.

* The duty to protect the potential living donor from anticipated harm as a direct result of donation.

○ It is the responsibility of the living donor evaluation team to establish and adhere to criteria for acceptance of a living donor based on current knowledge and practice.

○ To minimize an actual or perceived a conflict of interest, it is considered best practice to have a separation of roles between the donor medical team and the recipient medical team.

○ Minimization of potential living donor risk is the principle priority guiding all aspects of the evaluation and donation, including the timing of surgery.

○ The potential living donor will be given the opportunity and privacy to provide health care experts with a full report, to the best of his or her knowledge, of any and all health concerns, issues, and/or behaviours that might disqualify donation or cause health risks to the recipient.

○ It is the responsibility of the living donation team to follow up with the donor postsurgery.

* The duty to be transparent with respect to the knowledge of health risks associated with living donation.

○ Disclosure will include information about the risks associated with investigation procedures and surgery.

* The duty to ensure that the Kidney Paired Donation Protocol for Participating Donors reflects current knowledge.

○ Acceptable assessment criteria are established for the KPD Program and are reviewed periodically to ensure they are informed by evidence and acceptable medical practice.

○ Policies and procedures may require revision as new evidence, laws, and regulations come into being, or as program leads identify a need for additions, changes, and/or deletions.

○ Policies and procedures must be reviewed at least every 5 years, and sooner if indicated.

○ The Living Donation Advisory Committee is responsible for the review and revision of the policies and procedures.

* The duty to inform the potential living donor of previously undiagnosed health conditions, and to take acceptable action to refer the individual to the appropriate resources for intervention.

○ Continuation of the potential living donor’s workup will depend upon the health condition discovered and the potential donor’s willingness to complete any available and/or applicable treatment options.

○ Based on the discovery of an undiagnosed health condition, the living donor evaluation team may decide to discontinue the donor workup if donation could cause harm to the potential donor.

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Scope of the Protocol

The Protocol has been developed by clinical experts based on current knowledge and practice with respect to the standard testing and acceptance criteria for a potential living kidney donor (hereafter called the “potential donor”). The overarching challenge to those drafting the Protocol was the lack of information with respect to potential donor outcomes based on specific predonation risk factors. The Protocol therefore errs on the side of conservatism where evidence was not forthcoming and where there was nonuniform practice within Canada and elsewhere.

The need for additional testing does not address all possible medical situations. Physician discretion is required as to the need for further clinical investigations based on a potential donor’s medical and family history and the results from the general assessment. In addition, it is inevitable that new knowledge will need to be considered where evidence suggests alternative approaches or considerations as to what can be considered appropriate risk for living kidney donation. The Living Donation Advisory Committee will consider new evidence when it undertakes periodic reviews of the Protocol.

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Evidence Review

The Living Donation Advisory Committee reviewed current literature, which resulted in a considerable amount of evidence to support the Protocol. It did not, however, undertake a “Graded Evidence Review” of the living kidney donation literature, as Canadian Blood Services and the Committee are supporting the Graded Evidence Review being undertaken by the Kidney Disease: Improving Global Health Outcomes (KDIGO).1 The Living Donation Advisory Committee will review the reports published by KDIGO as they become available and will make revisions to the Protocol where appropriate.

The Protocol was also informed by:

* the Health Canada Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO Regulations, available at: http://laws-lois.justice.gc.ca/eng/regulations/SOR-2007-118/)2

* the Health Canada Guidance Document for Cell, Tissue and Organ Establishments: Safety of Human Cells, Tissues and Organs for Transplantation (CTO Guidance document, available at: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/reg-init/cell/cto_gd_ld-eng.php)3

* the Canadian Standards Association (CSA) Cells, Tissues, and Organs for Transplantation: General Requirements (CAN/CSA–Z900.1-12, available at: http://shop.csa.ca/en/canada/transplantation/cancsa-z9001-12/invt/27017362012)4 and

* the Canadian Standards Association (CSA) Perfusable Organs for Transplantation (CAN/CSA–Z900.2.3-12, available at: http://shop.csa.ca/en/canada/transplantation/cancsa-z90023-12/invt/27017652012)5

All programs must comply with the health assessment regulations and standards as set out in the most current version(s) of these regulatory documents.

In addition, the following evidence-based guidelines were reviewed:

* the United Kingdom Guidelines for Living Donor Kidney Transplantation, available at: http://www.bts.org.uk/Documents/Guidelines/Inactive/I6.pdf 6

* the Australian (Australia) Organ and Tissue Donation by Living Donors—Guidelines for Ethical Practice for Health Professionals, available at: http://www.nhmrc.gov.au/guidelines/publications/e71,7 and

* the Organ Procurement and Transplantation Network Policies, available at: http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf (United States, Organ Procurement and Transplantation Network Policies–OPTN).8

Input was also received from participants who attended the April 2013 Workshop on the Harmonization of Assessment and Acceptance Criteria for Living Kidney Donors Participating in the Canadian Transplant Registry – Living Donor Paired Exchange Program.

Further input and guidance were received throughout the consultation sessions held in the Fall of 2013 with individual living kidney donor and renal transplant programs participating in the KPD Program.

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Management of the Protocol

The Living Donation Advisory Committee, with the support of Canadian Blood Services, will develop a procedure for managing the Protocol, as well as mechanisms for programs to bring forward unique living kidney donor issues and have them addressed.

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Contributing Authors

The Kidney Paired Donation Protocol for Participating Donors was developed by the Protocols Working Group of the Canadian Blood Services’ Living Donation Advisory Committee.

Dr. David Landsberg (British Columbia)

Maureen Connelly, RN (Ontario)

Dr. Christine Dipchand (Nova Scotia)

Dr. Amit Garg (Ontario)

Dr. Anand Ghanekar (Ontario)

Dr. Isabelle Houde (Quebec)

Dr. Olwyn Johnston (British Columbia)

Dr. Rahul Mainra (Saskatchewan)

Ruth McCarrell, RN (British Columbia)

Dr. Thomas Mueller (Alberta)

Dr. Peter Nickerson (Canadian Blood Services)

Dr. Christine Pippy (New Brunswick)

Dr. Robert Richardson (Ontario)*

Dr. Leroy Storsley (Manitoba)

Dr. Kathryn Tinckam (Canadian Blood Services)

Linda Wright, RSW (Ontario)

Dr. Serdar Yilmaz (Alberta)

Acknowledgements

Brian Sandilands, Manager, Living Donation, Canadian Blood Services

Kathy Yetzer, Associate Director, Living Donation and Transplantation, Canadian Blood Services

Kimberly Young, Director, Donation and Transplantation, Canadian Blood Services

*Primary author

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SECTION TWO: GENERAL HEALTH ASSESSMENT

The primary goal of the assessment of the potential donor’s health status is to ensure the suitability, safety, and well-being of the potential donor. This involves an in-depth review of the potential donor’s medical and psychosocial history, as well as an assessment of the potential donor’s general health, to identify contraindications and medical risks. The required tests and examinations in this Protocol are now considered as the standard for Canadian practice when enrolling donors in the KPD Program. Individual Living Kidney Donation programs are expected to develop or modify their respective SOPs to comply with this Protocol.

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General Health

A. Assessment of Potential Donors

1. It is expected that there be, at a minimum, annual contact with the potential donor to assess the individual’s ongoing health status and willingness to donate.

2. To be compliant with the Health Canada CTO Regulations2, the physical examination and assessment of the potential donor’s general health should:

(a) occur at the time of the initial assessment, and

(b) be reviewed annually while registered in the KPD Program, and

(c) occur within 30 days of donation surgery, and

(d) include serologic testing for infectious diseases at the time of donation as per standard CAN/CSA–Z900.2.3-125 (12.2.3.8).

B. Minimum Required Tests

(1) Chemistry: sodium, potassium, chloride, bicarbonate, calcium, phosphate, ALP, urea, urate, albumin, AST or ALT, bilirubin, creatinine repeated on 2 occasions, FBG repeated on 2 occasions as per the Canadian Diabetes Association Clinical Practice Guidelines (http://guidelines.diabetes.ca/),9 A1C, fasting lipid profile as per current Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult (http://www.onlinecjc.ca/article/S0828-282X(12)01510-3/fulltext).10

(2) Hematology: CBC and INR/PTT.

(3) Blood typing—2 tests repeated at different time intervals:

(a) blood group (A, B, AB, or O), and

(b) Rh factor.

(4) Histocompatibility: HLA typing.

(5) Infectious diseases: screening tests for HIV, HTLV-I, HTLV-II, HBsAg, HBcAb, HCV, CMV, EBV, and syphilis.

(6) Imaging:

(a) chest X-ray, and

(b) abdominal CT angiogram with specific comment on the radiology report of renal anatomy and vasculature and the appearance of the liver and spleen.

(7) Cancer screening: breast, cervical, prostate, and colon cancer screening undertaken as per Canadian Cancer Society guidelines (http://www.cancer.ca/en/prevention-and-screening/early-detection-and-screening/screening/?region=on).11

(8) Urine:

(a) urinary protein—2 tests, each done on a different day:

(1) 24-hour protein, measured in mg/day, and

(2) random spot urine for ACR, measured in mg/mmol.

(b) hematuria—2 random urine samples, each collected on a different day and tested with dipstick; and

(c) urine culture and sensitivity.

(9) Other: height, weight, waist circumference, calculated BMI, ECG, either 24-hour urine to assess creatinine clearance on 2 separate occasions and/or direct measure of GFR (eg, DTPA scan), and BP repeated on 2 occasions by a health care provider according to the Canadian Hypertension Education Program (CHEP) 2014 Recommendations(http://www.hypertension.ca/en/chep).12

C. Minimum Clinical Examination Requirements

(1) Completion of a physical examination and documentation of the findings on the standard physical examination form (see Appendix Three).

D. Additional Testing

The following tests are recommended if a concern has been identified once the preliminary testing, family history, ethnicity, and physical examinations have been completed:

(1) TSH

(2) hemoglobin electrophoresis/sickle cell screen

Abnormalities identified in initial blood and urine testing will result in further testing. (These tests are covered in subsequent sections of the Protocol.)

E. Acceptance Criteria

(1) To be considered in conjunction with the medical and social history questionnaire (Appendix One), the psychosocial assessment (Appendix Two), the physical examination (Appendix Three), and the initial blood and urine tests.

(2) If risk factors for disease transmission are identified, consideration may be given, in limited cases only, for the potential donor to donate under the Exceptional Distribution provisions in Sections 40 to 42 of the Health Canada CTO Regulations (http://laws-lois.justice.gc.ca/eng/regulations/SOR-2007-118/).2

F. Absolute Contraindications/Exclusions for Donation

(1) Exclusion criteria as defined in the latest published edition of the CAN/CSA-Z900.1.12 (13.1.3)4

(2) All other decisions to exclude will be case-specific, taking into consideration many factors.

G. Practice

Review of Current Canadian Practice

Table 1 lists the laboratory and radiology tests currently being performed by Canadian Living Kidney Donation programs.

Review of International Assessment and Acceptance Criteria (United States, United Kingdom, Australia)

The OPTN (United States) Policies (http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf)8 and the United Kingdom Guidelines (http://www.bts.org.uk/Documents/Guidelines/Inactive/I6.pdf)6 recommended testing similar to what the majority of Canadian programs are currently performing; the Australian Guidelines (http://www.nhmrc.gov.au/guidelines/publications/e71)7 are generally less stringent.

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Malignancy

The issue of previous abnormal cancer screening tests or other evidence relating to a previous malignancy has to be managed by the potential donor’s clinician on a case-by-case basis. Not all cases would need further assessment by an oncologist.

(A) Minimum Required Tests

(1) Screening for breast, prostate, cervical, and colon cancer as per current Canadian Cancer Society guidelines. (http://www.cancer.ca/en/prevention-and-screening/early-detection-and-screening/screening/?region=on)11a

(B) Minimum Clinical Examination Requirements

(1) Completion of a physical examination and documentation of the findings on the standard living donor Physical Examination Form (Appendix Three).

(C) Additional Testing

(1) As needed to rule out an abnormality identified at screening or at the time of a physical examination.

(2) Individuals with a family history of “familial cancers” to be further assessed by an oncologist.

(D) Acceptance Criteria

(1) Potential donors with no history of malignancy.

(2) Potential donors with a malignancy history pertaining to non-melanoma “precancerous” skin cancer conditions.

(3) Potential donors NOT requiring follow-up as a result of a cancer screening examination/test undertaken within the previous 3 years.

(4) Potential donors with a history of malignancy who are currently considered to have a minimal risk of recurrence of the cancer by the individual's oncology team.

(E) Absolute Contraindications/Exclusions for Donation

(1) Potential donors with active malignancy.

(2) Potential donors with a history of malignancy that continues to be considered at risk of recurring by the individual's oncology team.

(3) Potential donors previously diagnosed with melanoma.

(F) Practice

Review of Current Canadian Practice

Table 2 lists the cancer screening tests recommended by Canadian provinces and territories.

Current Canadian Guidelines on Cancer Screening

(1) Prostate Cancer Screening13

* Screening should be offered to all men 50 years or older with at least a 10-year life expectancy. If there is a higher risk of prostate cancer (PCa), (ie, the potential donor has a family history of PCa or is of African descent), then screening should be done at age 40 years or older.

* Annual screening has been standard, but new literature suggests that screening is beneficial every 2 to 4 years.

* Initial screening should include DRE and PSA.

* PSA and free/total PSA ratio are currently the most reliable serum markers.

* No strict PSA cutoff point for all patients; the lowest cutoff point in phase III trials thus far was 2.5 ng/mL.

* There may be benefit in offering a baseline PSA to men aged 40 to 49 years to establish future PCa risk.

Other recommendations about biopsy/location of biopsy, and so on, are also included in these guidelines.

(2) Cervical Cancer Screening14

The most recent guidelines on Pap smears suggest that they start at age 21 years, and then be performed every 3 years thereafter. If the woman is not sexually active, then defer until such a time. There is more information coming out now about using HPV DNA-based screening protocols (with no recommendation about age of initiation).

(3) Breast Cancer Screening (Mammography)15

For women aged 40 to 49 years, routine mammography screening is not recommended; for women aged 50 to 74 years, routine mammography screening is recommended every 2 to 3 years.

Routine MRI screening, routine clinical breast examinations alone or in conjunction with mammography, and routine breast self-examination are not recommended.

(4) Colon Cancer Screening16

The Canadian Association of Gastroenterology feels that colon cancer screening is the standard of care in Canada for patients aged 50 to 75 years.

Summary: Biannual FOBT or FIT for average-risk individuals. Flexible sigmoidoscopy should be offered to all average-risk patients, and repeated at 10-year intervals if normal.

Colonoscopy, barium enema, and CT colonography are not recommended for population screening. For opportunistic screening (ie, screening occurring outside of a programmatic approach), FOBT/FIT, flexible sigmoidoscopy, and colonoscopy are appropriate.

Review of International Assessment and Acceptance Criteria (United States, United Kingdom, Australia)

United Kingdom Guidelines (2011)6

History of previous malignancy:

* Absolute contraindication: melanoma, testicular cancer, renal cell cancer, choriocarcinoma, hematological malignancy, lung cancer, breast cancer, or monoclonal gammopathy.

* Relative contraindication: treated cancer with a high probability of cure after 5 to 10 years, ie, favorable classification and staging (eg, colon cancer Dukes' stage A more than 5 years ago, nonmelanoma skin cancer, or carcinoma in situ of the cervix or vulva).

* Bilateral angiomyolipomata is an absolute contraindication to living kidney donation.

* Kidneys containing lesions of 4 cm or larger can be used if excision of tumour is straightforward. Kidneys with lesions <1 cm can be used if monitored with serial U/S imaging. Lesions between 1 cm and 4 cm are assessed on case-by-case basis and used with informed consent.

United States (OPTN) Policies (2008)8

The potential donor's history determines that he or she does not need both kidneys to help tolerate anticancer treatment, and that he or she does not have a tumour that would be transferred to recipient.

Other testing is based on gender, age, and family history:

* Pap for all women.

* Screening mammogram for all women over 40 years or according to family risk.

* PSA for all men older than 50 years; older than 40 years for men of African descent or men from a high-risk family.

* Colonoscopy for all potential donors older than 50 years, or younger based on family history.

* Chest CT for those with a history of smoking.

Australian Guidelines (2007–2010)7

Nothing specified in the guidelines.

(G) Literature and References

Ison and Nalesnik reported on a number of potential donor-derived malignancy transmissions with solid organ transplantation (including renal cell, lung, lymphoma, ovarian, liver, pancreas, and melanoma).17

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Infection

(A) Minimum Required Tests

(1) The infection screening and evaluation must comply with Health Canada Regulations and the tests identified in “Section Two: General Health Assessment” of this Protocol.

(B) Minimum Clinical Examination Requirements

(1) Completion of the physical examination and documentation of the findings on the standard Physical Examination form (Appendix Three).

(C) Additional Testing

(1) Additional testing will be based on the specific findings from general screening and the potential donor’s medical, sexual, and social history:

(a) TB skin test for individuals from a high-risk population.18

(b) For individuals with a positive skin test for TB or latent TB, a consultation with the TB or infectious diseases services is required.

(c) NAT testing for all potential donors at high risk of HIV, HBV, and HCV.

(d) Potential donors to be tested for WNV if donating between May and November.

(e) HBsAb and HBV NAT for donors who are HBcAb positive and HBsAg negative.

(D) Acceptance Criteria

(1) The potential donor has no identifiable infection or risk of infection that would cause an unacceptable risk or harm to the recipient.

(2) The potential donor has not been skin-tested for TB and is from a documented low-risk population.

(3) The potential donor has tested positive for syphilis, has been treated, and is no longer at risk of transmitting syphilis, based on the opinion of an infectious disease specialist.

(4) In the following situations, a donor’s kidney may be considered for use when the benefit of the transplant is felt to outweigh the risk of disease transmission. These kidneys are used under the Health Canada exceptional distribution provisions:

(a) a potential donor with a positive skin test for TB who has not undergone an acceptable course of treatment before donation, or

(b) a potential donor who is HTLV-ll positive, or

(c) a potential donor with a documented risk factor(s) for HIV, HBV, and HCV.

(d) a potential donor who is HBcAb positive, HBsAg negative, HBsAb positive and HBV NAT negative.

(E) Absolute Contraindications/Exclusions for Donation

A potential donor with:

(1) Any active viral, bacterial, or other infection at the time of assessment.

(2) Confirmed active HIV, HTLV-I, HBV, or HCV infection.

(3) Documented risk factors for HIV, HBV, or HCV where the risk of disease transmission is felt to outweigh the benefit of the transplant.

(4) Active TB infection.

(5) Untreated syphilis infection or syphilis under treatment that continues to be considered contagious by infectious disease specialists.

(6) Recent bite (6 months before or less) from an animal suspected of carrying rabies.

(7) Suspected or confirmed WNV.

(8) Suspected or confirmed SARS.

The CAN/CSA-Z900.2.3-125 (13.1.2) and CAN/CSA-Z900.1-124 (Annex E) provide a complete list of contraindications for donation based on infectious disease transmission risk.

(F) Practice

Review of Canadian Practice

Table 3 lists the Health Canada requirements for effective infectious disease testing of organ or islet donors.

Review of Current Health Canada Requirements

Table 4 lists additional infectious disease tests routinely performed on potential donors by Canadian Living Kidney Donation programs.

Health Canada recommends these tests at the time of the initial evaluation, in the 30 days preceding organ donation, and on the day of transplant.

Health Canada also has specific requirements with regard to medical history:

* Ask the potential donor about risk factors for HBV, HCV, and HIV.

* The potential donor should have a complete physical exam, including exams not usually performed routinely by transplant physicians and surgeons (ie, gynecological).

There is no indication in the current Health Canada recommendations, updated in December 2012, about the frequency of taking the potential donor’s medical history when there is a delay between the initial evaluation and the organ procurement.

In a document currently under revision titled (in French) Règlement sur la sécurité des cellules, tissus, organes humaines destinés à la transplantation,19 the following information can be found:

* Health Canada recommends a physical exam at the closest possible date to organ procurement. Under normal circumstances, it should be conducted within the 30 days before the scheduled date of organ procurement. If there is an unexpected delay in the procedure, the program will take responsibility for deciding if a physical exam should be repeated, according to the clinical condition of the potential donor.

* Potential Donor Suitability Assessment: CAN/CSA–Z900.2.3-125(12.2.2.3, 12.2.2.4).

* Contraindications or Exclusion Criteria: CAN/CSA–Z900.2.3-125 (13.1.2, 13.1.1.3).

* Annex E: Factors and Behaviours Associated With a Higher Risk Factor of Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV): CAN/CSA–Z900.1-12.4

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia)

* There is no specific recommendation in the Australian guidelines.7

* The United States (OPTN) Policies8 suggest potential donor evaluation, but provide no specific criteria for acceptance of organs.

* The United Kingdom guidelines6 have specific recommendations for mandatory exams; optional exams to be performed according to the potential donors’ intrinsic endemic risks.

(G) Other Literature and References

1. Grossi PA, Fishman JA; AST Infectious Disease Community of Practice. Donor-derived infections in solid organ transplant recipients. AMJ. 2009;9 Suppl 4:S19-S26. doi: 10.1111/j.1600-6143.2009.02889.x.

2. Fischer SA, Avery RK; AST Infectious Disease Community of Practice. Screening of donor and recipient before solid organ transplantation. AMJ. 2009;9 Suppl 4:S7-18. doi: 10.1111/j.1600-6143.2009.02888.x.

3. Levitsky J, Doucette K; AST Infectious Diseases Community of Practice. Viral hepatitis in solid organ transplant recipients. AMJ. 2009;9 Suppl 4:S116-130. doi: 10.1111/j.1600-6143.2009.02902.x.

4. Ison MG, Nalesnik MA. Update on donor-derived disease transmission in organ transplantation. AMJ. 2011; 11(6):1123–1130. doi: 10.1111/j.1600-6143.2011.03493.x.

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SECTION THREE: RISK OF CARDIORENAL DISEASE

Ethnicity

Race and ethnic origins for some potential donors may contribute to a heightened risk for developing ESRD, hypertension, and type 2 diabetes mellitus (type 2 diabetes). People in African, Hispanic, Southeast Asian, Caribbean, Aboriginal, or Torres Strait Islander ethnic groups have a higher risk or rate of progression to ESRD than people in other ethnic groups, independent of age and obesity risk factors. Ethnicity would never be considered a contraindication to donation, but it must be considered in light of family history, general health assessment, as well as any additional tests to assess conditions to which the potential donor may be predisposed.

(A) Practice

Review of Current Canadian Practice

All Canadian programs obtain a family history on potential donors and take into consideration family history and ethnicity for future risk of cardiorenal disease.

Review of Current Health Canada Requirements

None applicable.

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia)

United Kingdom Guidelines (2011)6

* Cardiac disease: Although a family history of CVD has not always been considered as a risk factor, it would seem reasonable that a confirmed diagnosis of coronary artery disease in a first-degree relative under the age of 55 years would elevate the potential donor into the “high-risk” group. Using these factors, the probability of significant angiographically evident coronary disease can be estimated in a population of similar individuals. Modifying the risk stratification (Chest Pain of Recent Onset: NICE Guideline, available at: http://guidance.nice.org.uk/CG95/NICEGuidance/pdf/English20) to look at asymptomatic people, subjects may be grouped according to risk.

* Ethnicity and risk of hypertension: There are few data on the long-term outcome of nephrectomy in potential donors from ethnic groups who may be at greater risk of developing complicated HTN, eg, African American and Hispanic potential donors.

* Diagnosis of type 2 diabetes: A FBG of >7.0 mmol/L indicates diabetes. Values of between 5.6 and 6.9 mmol/L indicate IFG, which, together with a family history of type 2 diabetes (sibling or parental), is associated with a 30% 5-year risk of diabetes, and donation is usually contraindicated. Individuals with a family history (first-degree relative) of type 2 diabetes are at higher risk of developing the disease (relative risk 3.0). Because the prevalence of type 2 diabetes is much higher than the prevalence of type 1 diabetes, the absolute risk of developing type 2 diabetes is high (lifetime risk is 38%). The combination of family history and obesity (BMI >30 kg/m2) places an individual at very high risk of type 2 diabetes in later life. Individuals of Southeast Asian and Caribbean descent are at increased risk of type 2 diabetes, independent of age and obesity. Individuals at high risk of type 2 diabetes because of a positive family history and/or obesity should undergo an OGTT, and should only be considered further as potential donors if the result is normal. For individuals with a normal OGTT, the risk of developing type 2 diabetes within 5 years is approximately 1% overall and is modulated by ethnicity and obesity. If there is a history of transient gestational diabetes, the lifetime risk of type 2 diabetes is very high and kidney donation is relatively contraindicated.

Australian Guidelines (2007–2010)7

* Potential donors at high risk of developing type 2 diabetes (ie, family history, age >45 years, Aboriginal or Torres Strait Islander, or obesity) should be screened with a 2-hour OGTT.

* If the 2-hour OGTT results are:

○ >11.1 mmol/L, then the potential donor is diabetic and this is an absolute contraindication to living kidney donation.

○ 7.8 mmol/L to 11.0 mmol/L, then the potential donor has IGT and this is an absolute contraindication to living kidney donation.

○ <7.8 mmol/L is normal and not a contraindication to donation.

* A past history of gestational diabetes is an absolute contraindication to living kidney donation.

(B) Literature and References

* Organ Procurement and Transplantation Network (OPTN) Living Kidney Donor Medical Evaluation Checklist (http://optn.transplant.hrsa.gov/search-results?q=%22medical%20evaluation%22)21 references family history as an essential part of the potential donor history.

* Ibrahim et al.22 conclude that African American and Hispanic donors are at higher risk of developing chronic kidney disease (CKD), HTN, and diabetes, and that the evidence of ESRD risk is mixed.

* Lentine et al.23 concluded that the absolute prevalence of diabetes among all donors does not exceed the general population, but the prevalence of HTN exceeds National Health and Nutrition Examination Survey (NHANES) estimates in black and Hispanic donors.

* Vigneault et al.24 noted that the risk of IFG or IGT increases a person’s risk of developing diabetes by 5% to 10% per year, but other variables including ethnicity, weight, lipid profile, and family history affect this propensity.

* Nogueira et al.25 concluded that African-American donors experience a substantial incidence of HTN and a modest drop in estimated GFR (eGFR), and that obesity may compound the rate of decline.

* Davis et al.26 reviewed OPTN data from January 1988 to December 2008 and concluded that one quarter of living donors have medical conditions that may be associated with future health risks. The authors suggest that the pool of donors may be less healthy than in previous years, thus making the results of previous donor follow-up studies less applicable to today’s donors and the informed consent process.

* The Amsterdam Forum27 noted that the risk of diabetes in donors who have borderline elevation in BP and a family history of HTN has not been conclusively determined.

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Tobacco Smoking

While tobacco smoking in a potential donor can negatively affect donor and recipient renal function, smoking in itself is not a contraindication to living donation. Smoking is only one of many risk factors that must be considered. Should any potential donor be actively smoking at the time of assessment, they should be advised to stop smoking before the donation surgery and should be provided with the necessary resources to assist them to stop smoking. Smoking is a risk factor for perioperative cardiovascular and pulmonary complications (See Section Five: Risks of Perioperative Complications).

(A) Additional Testing

1. For potential donors with a history of smoking, further testing such as a cardiac stress test or pulmonary function tests should be considered, depending on the results of the medical history and the physical examination.

(B) Acceptance Criteria

1. Life-long nonsmoker.

2. Current or ex-smoker with no evidence of coronary, cerebrovascular or peripheral vascular disease, or pulmonary disease.

(C) Absolute Contraindications/Exclusions for Donation

1. Active smoker with coronary, cerebrovascular or peripheral vascular disease, or significant pulmonary disease.

(D) Practice

Review of Current Canadian Practice

During the assessment visit, the majority of Canadian living donation programs inquire about the use of tobacco and the frequency of smoking.

Review of Current Health Canada Requirements

There are no specific requirements from Health Canada related to smoking in living donors. Relevant legislation includes the 1997 Tobacco Act.28

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia):

The United States policies8 and the Kidney Health Australia—Caring for Australasians with Renal Impairment(CARI) Guidelines (http://www.cari.org.au/Transplantation/transplantation_guidelines.html)29 recommend inquiring about smoking history, but do not make any recommendations about the acceptance of potential donors who are current smokers.

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History of Toxemia in Pregnancy

There is some evidence to suggest a relationship between toxemia in pregnancy and a latent risk of developing HTN and kidney disease in otherwise healthy living donors.30 It is therefore important to have a well-documented obstetrical history, and to err on the side of making a relatively conservative decision on a case-by-case basis. Further controlled prospective studies with long periods of follow-up are needed before Living Kidney Donation programs can better delineate the risks of these chronic conditions developing following living kidney donation in females with a history of one or more episode(s) of toxemia in pregnancy. The findings from the KDIGO evidence review of living donor assessment and acceptance criteria1 will be an important first step in this regard.

(A) Additional Testing

1. For women with a history of toxemia in pregnancy, a further detailed description of the obstetrical history, including the number of pregnancies, episodes of toxemia in pregnancy, and other clinical events and sequelae, should be documented.

(B) Acceptance Criteria

1. Postmenopausal potential donor with a history of toxemia in pregnancy more than 10 years previously, and who now has normal renal function, no HTN, and no proteinuria.

2. Premenopausal potential donor with a single episode of toxemia more than 10 years previously, who had normal subsequent pregnancies, whose family is complete, who has had either a tubal ligation or a hysterectomy, and who now has normal renal function, no HTN, and no proteinuria.

C. Absolute Contraindications/Exclusions for Donation

1. Premenopausal potential donor with a history of toxemia in pregnancy <10 years ago.

2. Potential donor with a history of toxemia in pregnancy in recurrent pregnancies.

3. Premenopausal potential donor with a history of toxemia in pregnancy and whose family is incomplete.

D. Practice

Review of Current Canadian Practice

Most programs have documented that an obstetrical history is taken.

Review of Current Health Canada Requirements

There are currently no direct Health Canada requirements.

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia)

The United States guidelines8 and the Australian guidelines7 recommend taking an obstetrical history.

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Lipids

The Canadian Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult (http://www.onlinecjc.ca/article/S0828-282X(12)01510-3/fulltext)10 are published by the Canadian Cardiovascular Society (CCS). The lipid profile targets published by the CCS, as well as other risk markers, should be incorporated into a risk calculator that would determine the need for the potential donor to undergo further cardiac testing. Dyslipidemia alone is not generally a contraindication to kidney donation, and a potential donor’s lipid profile should not be considered in isolation of other risk factors.

A. Practice

Review of Current Canadian Practice

Almost all Canadian programs require fasting cholesterol and triglyceride levels. However, a few programs also perform a lipid profile, which includes serum levels of cholesterol, triglycerides, HDL, and LDL, as well as total cholesterol/HDL ratio (risk ratio).

Review of Current Health Canada Requirements

There are no specific Health Canada requirements related to lipids in living organ donors.

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia)

Neither the United Kingdom guidelines,6 the United States (OPTN) policies,8 nor the Australian guidelines7 have specific recommendations for lipid requirements for potential donors.

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Body Mass Index and Obesity

Obesity is defined by a body mass index (BMI) of >30 kg/m2. Because data suggest the association between obesity and kidney disease (HTN and a long-term drop in GFR), diabetes, and perioperative morbidity, all potential donors should have their BMI calculated. Overweight and obese potential donors should be counselled regarding the increased perioperative risk, advised to lose weight before undergoing the donor nephrectomy, and encouraged to achieve their ideal weight following donation.

A. Acceptance Criteria

1. BMI <30 kg/m2.

2. BMI >30 kg/m2 and <35 kg/m2 with no other significant cardiovascular risk factors.

B. Absolute Contraindications/Exclusions for Donation

1. BMI >35 kg/m2.

2. BMI >30 kg/m2 when other associated comorbid conditions are present.

C. Practice

Review of Current Canadian Practice

The majority of programs calculate BMI. It is unclear from the information provided what each program uses as a cutoff for BMI in terms of eligibility for living donation.

Review of Current Health Canada Requirements

Not applicable.

Review of International Assessment and Acceptance Criteria

While there is a lack of data with respect to potential donors with a BMI >30 kg/m2, the general practice among international programs is to exclude potential donors with a BMI >35 kg/m2 and to consider the absence of other cardiovascular risk factors before accepting a potential donor with a BMI >30 kg/m2 and <35 kg/m2.

United Kingdom Guidelines (2011)6

* BMI 25 kg/m2 to 30 kg/m2: Consider potential donor if he or she is otherwise healthy.

* BMI 30 kg/m2 to 35 kg/m2:

○ exclude CVD, respiratory disease, and renal disease,

○ provide counselling about the increased risk of perioperative complications extrapolated from outcomes on the very obese,

○ provide counselling re: long-term risk of kidney disease, and

○ provide advice on weight loss and maintenance of BMI.

* BMI >35 kg/m2: Limited safety data, so discourage donation.

United States (OPTN) policies (2008)8

No specific comments re: exclusions based on BMI.

Australian Guidelines (2007–2010)7

No specific comments re: exclusions based on BMI.

D. Literature and References

Background Information Summarizing the Literature on Surgical Risk

* Obesity is associated with increased morbidity (HTN, diabetes, metabolic syndrome) and mortality.31

* Obesity is generally considered a relative contraindication to living donation because of increased perioperative morbidity (and the major concern of the adverse impact of obesity on the long-term function of the remaining kidney).32

* A meta-analysis of 484 obese living donors (mean BMI, 34.5 kg/m2) reported no deaths, but did report statistically significant (clinically insignificant) differences in operative time, blood loss, and hospital stay between obese and nonobese.33

* Retrospective analysis of a United States healthcare registry using discharge data for 3,074 patients from 28 centres identified comorbidities and complications at the perioperative period (using ICD-9 codes). Obesity was associated with an overall increased risk of complications (OR 1.92, 95% CI 1.06 to 3.46); however, the numbers were too small to assess the impact of obesity on the incidence of major complications, and the study was not able to discriminate between open and laparoscopic nephrectomy.34

* Similar results have been reported from a number of single-center studies, demonstrating an increase in minor complications in obese donors for both open and laparoscopic nephrectomy. Complications are predominantly wound-related and include wound infection, seroma, and hernia.35–37

* In a very large study of 80,347 living donors during a 15-year period in the United States, 22.6% were obese (BMI ≥30 kg/m2), but obesity was not associated with a statistically significant difference in surgical mortality (3.1 per 10,000 donations, 95% CI 2.0 to 4.6).38

* In a retrospective, cross-sectional analysis of 6,320 cases, obesity was identified in only 2% of donors, but was an independent predictor of donor risk; 28.3% of obese patients had complications compared with 18.2% of nonobese patients.32

* A retrospective analysis of 73 patients examined the outcome of unilateral nephrectomy done for clinical indication (ie, not donors) with a median follow-up of 13.6 years. BMI was independently associated with proteinuria/renal dysfunction on multivariate analysis (OR 1.34, 95% CI 1.03 to 1.76) at 10 years following nephrectomy.39

* At mean follow-up of 12 years after donation, a higher BMI was associated with both HTN requiring medication and a GFR that was lower than 60 mL/min/1.73 m2.23

* In the Norwegian National Hospital Living Donor Registry, which includes the data of 1006 donors, postoperative wound infection was associated with BMI >25 kg/m2.40

* African American living donors with a BMI >35 might be at particularly high risk of developing a significant renal function decline after donation.26

* Donors with high BMI often have a further increase in weight following donation.41 No study estimated the absolute additional long-term risk in young obese donors as compared with their nondonor counterparts.

Relevant Literature

Surgical Risk

* Heimback et al.: Compared with donors with BMI <25, donors with BMI >35 had slightly longer operating room times (mean 19 min), more overall perioperative complications (mostly minor wound issues), but the same rate of major surgical complications and a similar length of stay. After 6 to 12 months no differences in renal function and microalbuminuria were observed between the two groups.36

* Weisenthal et al.: In a prospective study of postoperative recovery and quality of life (using the Postoperative Recovery Scale preoperatively and every 4 weeks postoperatively [×4]), it was found that BMI <30 was one of the factors that predicted an expedited recovery.42

Renal Reserve Capacity

* Rook et al.: Reserve capacity was measured before and after donation in 125 consecutive donors. On logistic regression, BMI was one of the independent predictors for renal function impairment (25% of the donors) without evidence of reserve capacity. GFR was measured by iothalamate, and reserve capacity was assessed by measuring stimulated GFR with dopamine and amino acid infusions.43

* Rook et al.: A study using similar methods measured GFR 4 months before and 2 months after donation with iothalamate. After donor nephrectomy, the response of GFR to dopamine infusion was decreased with increased BMI (particularly in younger donors), suggesting a decreased renal reserve postdonation that was not present predonation in these patients.44

Donor Renal Function/CVD Risk

* Mjoen et al.: A Norwegian study assessed donor renal function 1 year after donation. Data were available for 721 of 1,067 donors from 1997–2009. At 1 year after donation, BMI >25 was found to be associated with a relative increase in creatinine (using multivariate analysis).45

* Tavakol et al.: Another study assessed the risk of renal dysfunction and CVD risk several years after donation. Ninety-eight (98) postdonation patients aged 5 to 40 years were studied and matched with NHANES controls with two kidneys. Renal function in donors with BMI >30 was found to be similar to renal function in donors with BMI <30, and renal function in both donor BMI groups was < renal function in the controls. BMI >30 donors and controls had a higher prevalence of HTN and lipid disorders, but no significant difference in the prevalence of HTN and lipid disorders was found between donors and controls within each BMI category. The authors felt that obese donors are not at higher risk of reduced renal function compared with nonobese donors, and that the increased risk of HTN and lipid disorders was related to obesity, not donation.46

Effect on recipient outcomes

* Espinoza et al.: The long-term follow-up of organ recipients from 37 donors with BMI >30 was compared with the long-term follow-up of recipients who received their organs from donors with normal BMI. Mean follow-up was 50.8 months. Lower GFR (71.7 mL/min versus 80.1 mL/min) and a higher rate of acute rejection episodes were observed in recipients of organs from obese donors (67.5% versus 29.7%). The transplants were performed between 1992 and 1999.47

Effect on Health-Related Quality of Life

* de Groot et al.: One study administered the SF-36 questionnaire to 316 people who donated a kidney between 1997 and 2009. Twelve per cent (12%) had a reduced physical score, which was associated with a higher predonation BMI. Mean BMIs were 26.2, so the clinical significance of this finding is unclear.48

Other References

1. Nogueira JM, Weir MR, Jacobs S, et al. A study of renal outcomes in obese living kidney donors. Transplantation. 2010;90(9):993–999. doi: 10.1097/TP.0b013e3181f6a058.

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Type 2 Diabetes/Glucose Intolerance

Type 2 diabetes (diabetes) is predominantly a disease that occurs later in life. It is more prevalent in individuals with a family history of the disease, those who are obese, or women with a history of gestational diabetes. The risk of diabetes is also higher in groups whose ethnicity is Southeast Asian, Caribbean, African, Hispanic, Aboriginal, or Torres Strait Islander, independent of age and obesity.

Individuals with diabetes are at higher risk of ESRD and CVD; therefore, a diagnosis of diabetes is an absolute contraindication to living donation. Potential donors with significant risk factors for developing diabetes should be evaluated carefully and considered as suitable for donation if the results of glucose tolerance tests are acceptable according to the current Canadian Diabetes Association Clinical Practice Guidelines (http://www.diabetes.ca/files/cpg2008/cpg-2008.pdf)9 for the testing and diagnosis of diabetes. (The guidelines define whether someone has active diabetes or is prediabetic.)

A. Additional Testing

For potential donors who have risk factors for diabetes or who had elevated FBG or A1C at the time of general health screening:

1. Additional tests as indicated by the results of medical history and the physical examination.

2. If there is either an IFG or an A1C 6.0% to 6.4% on at least one occasion, then the potential donor should have further testing according to the Canadian Diabetes Association Clinical Practice Guidelines.9

B. Acceptance Criteria

1. Potential donors with a FBG × 2 <6.1 mmol/L and A1C <6.0% × 2.

2. Potential donors with a FBG between 6.1 mmol/L and 6.9 mmol/L (IFG) or A1C 6.0% to 6.4% on at least one occasion with 2-hour OGTT <7.8 mmol/L.

3. Patients at high risk of developing type 2 diabetes with a normal FBG (ie, family history, ethnicity, or obesity) with a 2-hour OGTT <7.8 mmol/L.

C. Absolute Contraindications/Exclusions for Donation

1. Potential donors with a FBG ≥7 mmol/L on 2 occasions or A1C >6.5% (confirms a diagnosis of type 2 diabetes according to the Canadian Diabetes Association Clinical Practice Guidelines).9

2. Potential donors with a FBG between 6.1 mmol/L and 6.9 mmol/L (IFG) or A1C of 6.1% to 6.4% on at least one occasion with 2-hour OGTT >7.8 mmol/L.

3. A premenopausal potential donor with a past history of gestational diabetes.

4. A postmenopausal potential donor with a history of gestational diabetes <10 years previously.

5. A potential donor with a past history of gestational diabetes and a 2-hour OGTT >7.8 mmol/L, independent of the results of the FBG.

D. Practice

Review of Current Canadian Practice

The minimum screening requirement at most Canadian programs was FBG on two separate occasions. Two programs did not document how they screen for diabetes and several described additional baseline testing including A1C and OGTT.

Review of Current Health Canada Requirements

Health Canada suggests following the Canadian Diabetes Association Clinical Practice Guidelines9 for the definition of diabetes. However, Health Canada does not have any direct requirements on this topic related to donors.

Review of International Assessment and Acceptance Criteria

United States (OPTN) policies8 recommend asking the potential donor about the following: history of diabetes (including family history); weight change; obstetrical history (gestational diabetes), and birth weight of offspring.

United States (OPTN) policies8 and Australian guidelines7 recommend checking BMI and body fat distribution on physical examination.

United Kingdom Testing Practices

Recommended testing for diabetes in the United Kingdom guidelines6 includes:

* Urinalysis for glucose at least × 2.

* All potential donors must have their FBG level checked.

* OGTT: An FBG level between 5.6 mmol/L and 6.9 mmol/L indicates an IFG, and an OGTT must be undertaken. Potential donors with an increased risk of type 2 diabetes because of a family history, ethnicity, or obesity should also undergo an OGTT. If the OGTT reveals a persistent IFG and/or an IGT, then the risk of the potential donor developing diabetes after donation must be carefully considered.

Consideration of patients with diabetes as potential donors requires very careful evaluation of the risks and benefits. In the absence of evidence of target organ damage, and having ensured that other cardiovascular risk factors such as obesity, HTN, or hyperlipidemia are optimally managed, diabetics can be considered for kidney donation after a thorough assessment of the lifetime risk of CVD and progressive renal disease in the presence of a single kidney.

United States Testing Practices

The United States (OPTN) policies8 recommend testing FBG and, if the potential donor is at increased risk of diabetes (family history of diabetes, gestational diabetes, or elevated triglyceride levels), they recommend performing an OGTT and including calculations for insulin secretion/insulin resistance index and A1C.

Australian Testing Practices

The Australian guidelines7 recommend that potential donors have a FBG level performed on at least 2 occasions. If these are:

* >7 mmol/L on both occasions, then the potential donor is diabetic and this is an absolute contraindication to living kidney donation.

* 6.1 mmol/L to 6.9 mmol/L on at least one occasion, then the patient should have a 2-hour OGTT.

* <6.1 mmol/L, then this is normal and not a contraindication to donation.

* patients at high risk of developing type 2 diabetes (ie, family history, age older than 45 years, Aboriginal or Torres Strait Islander, or obesity) should be screened with a 2-hour OGTT.

If the results of the 2-hour OGTT are:

* >11.1 mmol/L, then the patient is diabetic and this is an absolute contraindication to living donation.

* 7.8 mmol/L to 11.0 mmol/L, then this patient has IGT and this is an absolute contraindication to living kidney donation.

* <7.8 mmol/L is normal and not a contraindication to living kidney donation.

E. Literature and References

Tools for predicting diabetes:

* The Finnish Diabetes Risk Score (FINDRISC, available at: http://canadiantaskforce.ca/ctfphc-guidelines/2012-type-2-diabetes/clinician-findrisc/)49: This tool uses age, BMI, central obesity, daily exercise, diet, drug-treated HTN, history of high blood glucose, and family history to calculate the risk of diabetes.

* The Diabetes Personal Health Decisions (PHD) risk assessment tool powered by the Archimedes algorithm (http://www.diabetesarchive.net/diabetesphd)50: Unlike FINDRISC, ethnicity is included as a variable in the PHD. This online model considers the time-dependent interrelationship of each variable and reports 30-year risks for the development of diabetes, myocardial infarction (MI), cerebrovascular accident, and renal failure. It has been validated against 18 clinical trials. However, it does not include tools to assess ‘’unacceptable risk.”

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Metabolic Syndrome

Metabolic syndrome defines a combination of clinical abnormalities associated with an increased risk of developing type 2 diabetes and CVD.

A. Absolute Contraindications/Exclusions for Donation

1. Living kidney donation is contraindicated in a potential donor diagnosed with metabolic syndrome.

The World Health Organization criteria for metabolic syndrome require the presence of any one of the following conditions:

* type 2 diabetes

* IGT

* impaired FBG

* insulin resistance

AND any two of the following conditions:

* BP ≥140/90 mmHg

* dyslipidemia: triglycerides ≥1.695 mmol/L and HDL-C ≤0.9 mmol/L (male) or ≤1.0 mmol/L (female)

* central obesity: waist to hip ratio >0.90 (male) or >0.85 (female), or BMI >30 kg/m2

* microalbuminuria: urinary albumin excretion ratio ≥20 μg/min or ACR ≥30 mg/gm

B. Practice

Review of Current Canadian Practice

* The majority of programs measure BMI, FBG, cholesterol, triglycerides, and BP.

* A minority of programs check abdominal obesity (waist circumference).

Review of Health Canada Requirements

There are no specific Health Canada requirements.

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia)

United Kingdom Guidelines (2011)6

* History/physical: BP, BMI, abdominal fat distribution.

* Lab investigations: FBG, OGTT (if indicated), fasting lipid screen (if indicated).

United States (OPTN) Policies (2008)8

* History/physical: BP, BMI, waist circumference.

* Lab investigations: FBG, fasting lipid profile; seek consent to assess risk of metabolic syndrome if >3 risk factors are present.

Australian Guidelines (2007–2010)7

* History/physical: BP, BMI.

C. Literature and References

The literature surrounding this topic as it pertains to living kidney donors is sparse. At an American Heart Association (AHA) consensus conference on the definition of metabolic syndrome, it was agreed that CVD is the primary clinical outcome of the metabolic syndrome. In addition, the risk of type 2 diabetes is higher, and diabetes is a major risk factor for CVD. The conference did not specifically recommend one criterion over another for the definition of the metabolic syndrome, but suggested the Adult Treatment Panel III (ATP III, available at: https://http://www.nhlbi.nih.gov/guidelines/cholesterol/) criteria provided a practical tool to identify patients at increased risk of CVD. The World Health Organization (WHO) criteria51 and the American Association of Clinical Endocrinologists (AACE) criteria51 are similar, but require OGTT if IFG is abnormal and diabetes is absent. Regardless of the diagnostic criteria used, there was agreement that weight reduction and increased exercise are the front-line therapy for metabolic syndrome. Drug treatment to directly reduce insulin resistance is promising, but no drugs have been recommended for the purpose of reducing CVD risk in subjects with metabolic syndrome. In patients where lifestyle changes have failed to reverse the metabolic risk factors, the specific abnormalities should be treated with drugs according to current guidelines.

One study showed the possibility that corporeal weight gain and metabolic syndrome may be an additional overburden on the GFR of the remaining kidney.52

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Hypertension

Potential donors diagnosed with an elevated BP at initial assessment should be further evaluated to confirm a diagnosis of HTN, according to the Canadian Hypertension Education Program (CHEP) 2014 Recommendations.12

Although HTN is a risk factor for future renal disease, the incremental risk is low and is mitigated by treatment. The prevalence of HTN in the general population is extremely high; excluding all potential donors with HTN, especially those who are otherwise healthy over the age of 50 years, may be too restrictive. An otherwise healthy potential donor with well-controlled HTN on a single antihypertensive therapeutic agent is accepted in most countries. More research is required on the outcomes and progression of disease of living donors who are diagnosed with HTN and who are taking one or more antihypertensive therapeutic agents predonation.

Although a potential donor’s HTN may be controlled (as defined by current CHEP Guidelines12) by a single antihypertensive therapeutic agent, he or she should not be considered as eligible for living donation until additional risk factors have been assessed, ie, family history, ethnicity, age, metabolic syndrome, dyslipidemia, obesity, smoking, and the predisposition to developing CVD.

A. Additional Testing

For potential donors with an initial elevated BP:

1. BP measured according to CHEP Guidelines12 to diagnose HTN.

2. Other diagnostic testing as required to determine further risk factors and predisposition to developing CVD and metabolic conditions.

B. Acceptance Criteria

1. Normotensive potential donor.

2. Hypertensive potential donor 50 years of age or older with controlled BP on one antihypertensive therapeutic agent for the treatment of HTN and with no other additional cardiovascular or metabolic risk factors.

C. Absolute Contraindications/Exclusions for Donation

1. Hypertensive potential donor on more than one antihypertensive therapeutic agent.

2. Potential donor with noncontrolled BP (as per CHEP Guidelines12).

3. Any hypertensive potential donor with end-organ damage related to HTN.

4. A potential donor with controlled HTN on one antihypertensive therapeutic agent with other cardiovascular and metabolic risk factors.

5. Hypertensive potential donor with controlled BP and who is <50 years of age.

D. Practice

Review of Current Canadian Practice

* Most programs measure BP on at least 2 or 3 occasions.

* ABPM is used in 11 of the 13 programs for which information was obtained, but the selection criteria for the use of ABPM were not always defined.

* One program routinely performs cardiac ultrasound on all hypertensive patients.

In a Canadian review of 371 living donors, an expected variability in the acceptance rate of hypertensive donors was noted.53 Whereas some programs refused all hypertensive potential donors, one program accepted 11.5% (3/26) of hypertensive donors. Countrywide, the average acceptance rate is 4%.

Review of Current Health Canada Requirements

There are no specific recommendations from Health Canada about HTN and donation.

Review of International Assessment and Acceptance Criteria (United Kingdom, United States, and Australia)

United Kingdom Guidelines (2011)6

Evaluation

* Office BP measurements are sufficient for the assessment of the majority of potential donors. ABPM should be considered for potential donors who have HTN (BP >140/90 mmHg or who are taking one or more antihypertensive therapeutic agents); if this is normal, then donor nephrectomy is not contraindicated.

* Potential donors with BP <140/90 mmHg should be considered as normotensive and therefore suitable for nephrectomy on the basis of BP.

* Potential donors with “high-normal” BP (>130/85 mmHg) should be warned about the greater future risk of developing HTN and associated cardiovascular events and the need for monitoring (which should be recommended irrespective of nephrectomy). Additional assessment (ABPM) should be considered, but is not required.

What is acceptable/unacceptable?

The presence of mild to moderate HTN that is controlled with 1 to 2 antihypertensive therapeutic agent(s) is not a contraindication to kidney donation, provided that significant end-organ damage has been excluded.

Evidence of hypertensive end-organ damage, poorly controlled HTN, or HTN that requires more than 2 antihypertensive therapeutic agents to achieve adequate control are relative contraindications to donor nephrectomy.

United States (OPTN) Policies (2008)8

United States policies recommend that BP be taken × 3 (at 3 different times); if possible, it is preferable to perform an ABPM.

Australia (2007–2010)7

Australian guidelines recommend that potential living kidney donors have their BP measured on at least 3 occasions with a level <140/90 mmHg on all 3 occasions.

* If 1 or more office BP measurements are elevated, white coat hypertension may be excluded by:

○ 12 home-based BP measurements with an average <135/85 mmHg or

○ 24-hour ABPM with an average <135/85 mmHg.

* An elevated BP on the above definitions is a relative contraindication to donation.

E. Other Literature and References

1. Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. NEJM. 2009;360(5):459–469. doi: 10.1056/NEJMoa0804883.

2. Morgan BR, Ibrahim HN. Long-term outcomes of kidney donors. Curr Opin Nephrol Hypertens. 2011;20(6):605–609. doi: 10.1097/MNH.0b013e32834bd72b.

3. Lentine KL, Schnitzler MA, Xiao H, et al. Racial variation in medical outcomes among living kidney donors. NEJM. 2010;363(8):724–732. doi: 10.1056/NEJMoa1000950.

4. Vigneault CB, Asch WS, Dahl NK, Bia MJ. Should living kidney donor candidates with impaired fasting glucose donate? Clin J Am Soc Nephrol. 2011;6(8):2054–2059. doi: 10.2215/CJN.03370411.

5. Nogueira JM, Weir MR, Jacobs S, et al. A study of renal outcomes in African American living kidney donors. Transplantation. 2009; 88(12):1371–1376. doi: 10.1097/TP.0b013e3181c1e156.

6. Davis CL, Cooper M. The state of United States living kidney donors. Clin J Am Soc Nephrol. 2010;5(10):1873–1880. doi: 10.2215/CJN.01510210.

7. Delmonico FA; Council of the Transplantation Society. Report of the Amsterdam Forum on the Care of the Live Kidney Donor: data and medical guidelines. Transplantation. 2005;79(6) Suppl: S53-66. http://www.ncbi.nlm.nih.gov/pubmed/15785361. (Accessed: January 21, 2015).

8. Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA. 2010;303(10):959–966. doi: 10.1001/jama.2010.237.

9. Taber DJ, Ashcraft E, Cattanach LA, et al. No difference between smokers, former smokers, or nonsmokers in the operative outcomes of laparoscopic donor nephrectomies. Surg Laparosc Endosc Percutan Tech. 2009;19(2):153–156. doi: 10.1097/SLE.0b013e31819f42f4.

10. Heldt J, Torrey R, Han D, et al. Donor smoking negatively affects donor and recipient renal function following living donor nephrectomy. Adv Urol. 2011;2011:929263. doi: 10.1155/2011/929263.

11. Andrews PA. Review of living kidney donor guidelines is out of date before publication. Transplantation. 2012;93(5):e18; Author reply e18-19. doi: 10.1097/TP.0b013e318245b2ed.

12. Wang IK, Muo CH, Chang YC, et al. Association between hypertensive disorders during pregnancy and end-stage renal disease: a population-based study. CMAJ. 2013;185(3):207–213. doi: 10.1503/cmaj.120230.

13.Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult—2009 recommendations. Can J Cardiol. 2009;25(10):567–579. http://www.ncbi.nlm.nih.gov/pubmed/19812802. (Accessed: January 21, 2015).

14. Heimbach JK, Taler SJ, Prieto M, et al. Obesity in living kidney donors: clinical characteristics and outcomes in the era of laparoscopic donor nephrectomy. AJT. 2005;5(5):1057–1064. http://www.ncbi.nlm.nih.gov/pubmed/15816886. (Accessed: January 21, 2015).

15. Wiesenthal JD, Schuler TD, Honey RJ, Pace KT. Predictors of health-related quality of life recovery following laparoscopic simple, radical and donor nephrectomy. BJU Int. 2011;107(4):636–641. doi: 10.1111/j.1464-410X.2010.09571.x.

16. Rook M, Hofker HS, van Son WJ, Homan van der Heide JJ, Ploeg RJ, Navis GJ. Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after living kidney donation. AJT. 2006;6(7):1653–1659. http://www.ncbi.nlm.nih.gov/pubmed/16827867. (Accessed: January 21, 2015).

17. Rook M, Bosma RJ, van Son WJ, et al. Nephrectomy elicits impact of age and BMI on renal hemodynamics: lower post donation reserve capacity in older or overweight kidney donors. AJT. 2008;8(10):2077–2085. doi: 10.1111/j.1600-6143.2008.02355.x.

18. Mjoen G, Øyen O, Midtvedt K, Dahle DO, Norby G, Holdaas H. Age, gender, and body mass index are associated with renal function after kidney donation. Clin Transplant. 2011;25(6):E579-583. doi: 10.1111/j.1399-0012.2011.01503.x.

19. Tavakol MM, Vincenti FG, Assadi H, et al. Long-term renal function and cardiovascular disease risk in obese kidney donors. Clin J Am Soc Nephrol. 2009;4(7):1230–1238. doi: 10.2215CJN.01350209.

20. Espinoza R, Gracida C, Cancino J, Ibarra A. Effect of obese living donors on the outcome and metabolic features in recipients of kidney transplantation. Transplant Proc. 2006;38(3):888–889. http://www.ncbi.nlm.nih.gov/pubmed/16647499. (Accessed: January 21, 2015).

21. de Groot IB, Stiggelbout AM, van der Boog PJ, Baranski AG, Marang-van de Mheen PJ, PARTNER-study group. Reduced quality of life in living kidney donors: association with fatigue, societal participation and pre-donation variables. Transplant Int. 2012;25(9):967–975. doi: 10.1111/j.1432-2227.2012.01524.x.

22. Pham PC, Wilkinson AH, Pham PT. Evaluation of the potential living kidney donor. Am J Kidney Dis. 2007;50(6):1043–1051. http://www.ncbi.nlm.nih.gov/pubmed/18037107. (Accessed: January 21, 2015).

23. Boudville N, Kanellis J; CARI. The CARI Guidelines. Donors at Risk: Proteinuria. Nephrology (Carleton). 2010;15 Suppl 1:S106-110. doi: 10.1111/j.1440-1797.2009.01218.x.

24. Vigneault CB, Asch WS, Dahl NK, Bia MJ. Should living kidney donor candidates with impaired fasting glucose donate? Clin J Am Soc Nephrol. 2011;6(8):2054–2059. doi: 10.2215/CJN.03370411.

25. Lindstrom J, Tuomilehto J. The Diabetes Risk Score: a practical tool to predict type 2 diabetes risk. Diabetes Care. 2003;26(3):725–731. http://www.ncbi.nlm.nih.gov/pubmed/12610029. (Accessed: January 21, 2015).

26. Eddy DM, Schlessinger L. Archimedes: a trial-validated model of diabetes. Diabetes Care. 2003;26(11):3093–3101. http://www.ncbi.nlm.nih.gov/pubmed/14578245. (Accessed: January 21, 2015).

27. Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation. 2004;109(3):433–438. doi: 10.1161/01.CIR.0000111245.75752.C6.

28. Ferreira-Filho SR, da Silva Passos L, Ribeiro MB. Corporeal weight gain and metabolic syndrome in living kidney donors after nephrectomy. Transplant Proc. 2007;39(2):403–406. http://www.ncbi.nlm.nih.gov/pubmed/17362742. (Accessed: January 21, 2015).

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SECTION FOUR: RENAL ASSESSMENT

Nephrolithiasis

Potential donors who have no history of urinary tract stones (nephrolithiasis) and no evidence of stones at the time of pre-donation imaging do not require a metabolic stone workup.

A. Additional Testing

1. Potential donors with a history of previous stone(s) or (an) asymptomatic unilateral stone(s) detected on imaging will require a metabolic stone workup.

2. Potential donors with a known family history of nephrolithiasis in a first-degree relative(s) should have a metabolic stone workup.

3. The standard metabolic stone workup includes:

a) Serum PTH, and

b) 24-hour urine collection for calcium, phosphate, oxalate, citrate, urate, creatinine, and sodium.

4. All potential donors with stones should be assessed by an urologist.

B. Acceptance Criteria

1. Potential donors older than 40 years with an asymptomatic small (<5 mm) unilateral stone found at the time of potential donor workup, a negative metabolic screen, and no history of recurrent symptomatic kidney stones are potential donors for participating in the KPD Program as long as:

a. the kidney with the stone is used for transplantation, and

b. the kidney stone is removed after donor nephrectomy if deemed necessary by the recipient transplant physician/surgeon.

C. Exclusions for Donation

1. Potential donors younger than 40 years with an asymptomatic small or unilateral stone and negative metabolic workup are not candidates for living donation, given the high lifetime risk of recurrent stones after kidney donation and the associated decrement in GFR.

2. Potential donors with asymptomatic or symptomatic bilateral kidney stones found on imaging.

3. Potential donors with staghorn calculus, or a history of struvite stones (anatomical defect that leads to infectious stone) or cystine stones (or cystinuria) are not acceptable for living donation.

4. Potential donors with a history of stones and a metabolic predisposition to stones that is not modifiable (not correctable). Metabolic predispositions include oxaluria (including enteric hyperoxaluria and recurrent stones from intestinal bypass procedures or inflammatory bowel disease), uricosuria, renal tubular acidosis, and metabolic acidosis.

5. Potential donors with 2 or more asymptomatic unilateral stones (evident on imaging at the same time).

6. Potential donors with symptoms of a kidney stone within the preceding 3 years are not candidates for participating in the KPD Program until they achieve a 3-year asymptomatic period.

7. Potential donors who have undergone lithotripsy and/or stenting for stones.

D. Practice

Review of Current Canadian Practice

* All but three programs routinely measure calcium.

* Five programs reported measuring uric acid.

* Donor Nephrectomy Outcomes Research (DONOR) Network data as of Spring 2011 (369 donors enrolled across 12 Canadian programs): 4% (15 of 369) of the donors ever had a kidney stone, and 0.8% (3 of 369) of the donors had had a kidney stone in the 3 years before donation.

Table 5 shows current Canadian practice with respect to stone evaluation. Table 6 shows the history of kidney stones (ever) among actual living kidney donors presenting to Canadian Living Kidney Donation programs.

Review of International Assessment and Acceptance Criteria

Nephrolithiasis was not an absolute contraindication to living donation. However, five guidelines recommended that potential donors with nephrocalcinosis or bilateral stone disease, metabolic conditions, obstructions, multiple stones, or kidney stones that have a potentially high recurrence rate should not donate.54

United Kingdom Guidelines (2011)6

* In the absence of a significant metabolic abnormality, a person with a limited history of previous small calcium stones, or who has a small renal calculus seen on imaging, may still be considered as a potential donor. Full counselling must be offered to both the potential donor and the recipient, and long-term follow-up must be offered to the donor.

* Potential donors with metabolic abnormalities detected on screening should be referred to a specialist in renal stone disease.

United States (OPTN) Policies (2008)8

Nothing specified re: stones.

Australian Guidelines (2007–2010)7

Nothing specified re: stones.

AST/ASTS/NATCO/UNOS Joint Societies Work Group (2010)55

* Nephrolithiasis may complicate the decision to accept a potential donor who may otherwise be a suitable kidney donor. Currently, CT scans are widely used to detect very small calcifications in the kidneys of potential donors who are asymptomatic and who have never passed a kidney stone. Very small (1 mm to 2 mm) calcifications in the renal papillae found on CT scans (Randall’s plaques) can either be of no consequence or may be the nidus of future stones.

* The most common type of kidney stone is calcium oxalate. A person who develops a symptomatic calcium oxalate stone has a 50% chance of developing a recurrent stone.

* The following should be considered as exclusion criteria for potential donors with nephrolithiasis:

○ Potential donors who develop frequent calcium oxalate stones.

○ Potential donors who have metabolic stone disease such as cystinuria, oxaluria, uricosuria, renal tubular acidosis, metabolic acidosis, or sarcoid.

○ Potential donors with an anatomic defect that leads to infection (struvite stones).

○ Asymptomatic potential donors with multiple stones in one kidney or bilateral kidney stones detected on radiographic imaging.

○ Patients with enteric hyperoxaluria and recurrent stones:

i. after an intestinal bypass procedure, or

ii. in the presence of inflammatory bowel disease.

* An asymptomatic potential donor with a past medical history of a single stone may be suitable for kidney donation in the absence of any exclusion criteria.

* An asymptomatic potential donor may be suitable for kidney donation if a solitary stone is present:

○ The kidney with the stone should be removed, leaving the donor stone free.

○ The current stone is <1.5 cm in size, and/or potentially removable during the transplant procedure.

In general, guidelines for potential donors with a past medical history of stones or asymptomatic stones seen on imaging have evolved over time, from complete exclusion to acceptance if certain high-risk features are excluded; however, they lack hard evidence.

E. Literature and References

Potential for Nephrolithiasis-Related Permanent Kidney Damage56,57

While there is concern about the symptoms and potential interventional requirements of kidney stones in an individual with only one kidney, the concern about the potential for nephrolithiasis-related permanent kidney damage and GFR decline also exists.

Natural History of Nephrolithiasis58–60

Following is an abbreviated list of articles; other, older, articles are referenced in these articles.

* Staghorn calculi have high intervention and recurrence rates and significant potential morbidity.

* Asymptomatic calyceal stones are a management dilemma for urologists. Up to 77% of people with such stones have disease progression, and 26% requiring surgical intervention. Stones >4 mm, lower pole location, and elevated urine or serum uric acid were associated with greater odds of progression and surgical intervention.

Surveys of Practices in Other Countries With Respect to Living Donors With Stones

Practice patterns in evaluation of living kidney donors in United States Organ Sharing (UNOS)61

* 84% of responding centres accept a potential donor with a history of stones.

* 66% accept potential donors with a single stone.

* 57% accept a potential donor only if there is no hypercalciuria, hyperoxaluria, cystinuria, metabolic acidosis, or hyperuricemia.

* 41% accept potential donors with unilateral stones.

* 43% require normal CT-IVP before accepting a potential donor with a history of stones.

Attitude Toward Stones in the Potential Living Kidney Donors in German Kidney Transplant Centres62

* 38 German transplant centres were surveyed, with a 74% response rate:

○ A current diagnosis of stones is an absolute contraindication to living kidney donation in 36% of centres.

○ A past history of stones is an exclusion criterion in only one centre.

○ 50% of surveyed centres require a potential donor to be stone free <2 years; the other 50% required a potential donor to be stone free >2 years.

Practice Patterns in United States Transplant Centres63,64

There is a tendency toward increased acceptance of donors with a history of kidney stones.

Outcomes Data/Reports of Centres Accepting LKDs With Stones65–69

* It appears as though centres are carefully selecting older potential donors (>40) with

○ asymptomatic stones if small (<5 mm),

○ unilateral stones,

○ no history of stones,

○ no underlying metabolic medical condition that would predispose the potential donor to stones,

○ no family history of stones, and

○ no staghorn/struvite/cystine or other predisposition to stone formation.

* The data are limited; however, it appears from the small numbers reported that no significant adverse effects have been seen in either donors or recipients as long as good follow-up is done to look for complications of the stones in the unilateral kidney.

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Ruling Out PKD and Other Genetic Diseases in First-Degree Relatives

A potential donor who is a first-degree relativeb of a recipient whose renal disease may have a genetic basis (including, but not limited to PKD, Alport syndrome, aHUS, MPGN, or TTP) must undergo genetic or other acceptable testing, as required, in order to rule in or rule out the possibility of a shared genetic susceptibility and a consequent future disease risk.

Mutations of PKD1 (∼75% of PKD cases) and PKD2 (∼25% of PKD cases) account for most cases of Autosomal Dominant Polycystic Kidney Disease (ADPKD). PKD2 mutations result in less severe disease than PKD1 and the disease is diagnosed later in life. (Early in life, kidney cysts may not be detectable by conventional imaging techniques, whereas later in life the diagnosis of PKD2 is usually straightforward.)

Having a first-degree relative who developed ESRD at ≤55 years of age suggests a diagnosis of PKD1, whereas having a first-degree relative who developed ESRD at ≥70 years of age suggests a diagnosis of PKD2.

A. Additional Testing for ADPKD

a) If there is a possibility of ADPKD, and if, after imaging, it remains uncertain whether a potential donor has ADPKD (ie, an older donor with a few renal cysts, or a donor under the age of 30 with no cysts on imaging), then he or she should undergo DNA testing to establish or refute the diagnosis before donation. In DNA testing (linkage analysis and direct mutation screening), blood is collected and sent to a clinical laboratory where DNA is extracted from peripheral white blood cells for analysis.

b) Direct mutation analysis may only require a blood sample from the potential donor, and can detect previously reported ADPKD disease-associated mutations.

c) In linkage analysis, the blood of a first-degree relative with ADPKD and typically, a minimum of three affected family members in two generations, is also required.

d) The major limitation of direct DNA testing is that definitive ADPKD-associated mutations are found in only 40% to 60% of people who truly have ADPKD.

e) Likely, disease-associated mutations may be detected in an additional 26% to 38% of people who truly have ADPKD.

In general, for direct mutation screening, test a definitively affected family member first to identify any potentially disease-causing variants, then test for these variants in the potential donor.

B. Exclusions for Donation

1. If a genetic abnormality predisposing to disease cannot be definitively ruled out, the potential donor is not eligible to donate in the interests of their own safety.

2. Anyone with ADPKD is not suitable to become a donor.

NOTE: Number of cysts on ultrasound to make ADPKD diagnosis in the presence of a positive family history of ADPKD:

a) ≥3 unilateral or bilateral renal cysts in a person aged 18 to 39.

b) ≥2 cysts in each kidney in a person aged 40 to 59.

c) ≥4 cysts in each kidney in a person aged 60 or older.

3. A potential donor who is under 30 and who has a family history of PKD where genetic testing is inconclusive should be excluded until he or she is older and can undergo further testing.

4. When there is uncertainty following further testing and the potential donor is young, err on the side of not accepting the potential donor as a living donor.

C. Literature and References

1. Pei Y, Watnick T. Diagnosis and screening of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis. 2010;17(2):140–152. doi: 10.1053/j.ackd.2009.12.001.

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Persistent Hematuria

Persistent microscopic hematuria is defined as the presence of blood in more than 50% of urine samples, confirmed by the finding of >4 RBCs per HPF on microscopy.

Persistent hematuria in the potential donor requires a full investigation to identify the underlying cause and to quantify the risks with respect to proceeding to donation. Tests should determine whether there is lower-tract cause of bleeding, and a search for evidence to rule out glomerular disease should be conducted. Consideration should be given to the results of the standard tests of renal clearance, urine protein, BP, and kidney imaging in order to proceed with donation when a potential donor has persistent hematuria.

A. Additional Testing

Additional testing of potential donors is based on a family history of hereditary kidney disease, evidence of microscopic hematuria on dipstick, and results from initial assessment tests for renal clearance, urine protein, kidney imaging, and BP.

(1) Potential donors should be considered for:

(a) urine culture (to treat evidence of bacteriuria to see if hematuria resolves),

(b) urine cytology,

(c) 24-hour urine calcium (to assess hypercalciuria),

(d) metabolic stone workup, and

(e) urine microscopy (for dysmorphic red blood cells).

(2) Potential donors with persistent hematuria where the cause of bleeding is undetermined require:

(a) cystoscopy, and if the cause of hematuria remains undetermined, then

(b) a native kidney biopsy should be undertaken and the results assessed before being accepted for donation, provided they meet acceptance criteria for GFR and protein.

(B) Acceptance Criteria

(1) A potential donor with thin basement membrane disease (TBMD) when all other testing is normal and when there is an absence of any significant glomerular pathology.

(2) A potential donor with hematuria who has no abnormality found on imaging, cystoscopy, and kidney biopsy.

(3) Following a native kidney biopsy, the potential donor should be cleared for acceptance if criteria are met following CT imaging.

(C) Exclusion for Donation

1. Evidence of IgA nephropathy.

2. Diagnosis of Alport syndrome.

(D) Practice

Review of Current Canadian Practice

Table 7 shows the current methods of hematuria investigation in Canadian Living Kidney Donation programs.

Background

* Microscopic hematuria is common (2% to 21% of the general population, depending on the definition). Persistent microscopic hematuria is less common, but is still found in up to 3% of the general population.

* Persistent hematuria may be associated not only with underlying urologic abnormalities (stones, tumours), but also with underlying glomerular pathology. IgA nephropathy and thin basement membrane nephropathy (TBMN) are the two most commonly encountered abnormalities.

Relevant Studies: Living Donors

* Koushik et al. studied 512 potential living donors at the Mayo Clinic.70 Hematuria was defined as >1 RBC/HPF on repeated urinalyses over at least one month. Fourteen (2.7%) of donors had hematuria; 13 were women, and hematuria resolved in 2 women after treatment for UTI. Ten potential donors were biopsied. Four (4) biopsies showed TBMN, 2 biopsies were normal, 1 showed IgA, 1 showed an abnormal basement membrane, and 2 showed glomerulosclerosis. Four of the 14 actually donated (2 with normal biopsy and 2 with TBMN).

* Suzuki et al. studied 510 actual donors with 0-hour biopsies in Japan (446 LD, 64 DD).71 Mesangial IgA was seen in 16.1% of the LDs. Higher-grade hematuria was more common in donors with IgA, but there was no difference in lower-grade hematuria (<5 RBCs/HPF) between the two groups. No donor follow-up was reported.

* Kido et al. studied 242 Japanese living donors.72 Hematuria was defined as 5 or more RBCs/HPF, and was considered persistent if present for longer than 3 months.

○ 20 donors (8.3%) had persistent hematuria predonation:

○ Hematuria persisted postdonation in 95% of donors with predonation hematuria.

○ Predonation hematuria was a risk factor for postdonation proteinuria (OR 3.8; if dysmorphic RBCs were present, the OR was 12.3).

○ Postdonation hematuria was associated with a decline in GFR.

* Two other studies considered donors with preexisting microscopic hematuria:

○ One of the studies73 had 5 actual donors with a family history of Alport syndrome. After a mean follow-up of 4.7 years, 2 developed new-onset HTN, 3 had proteinuria, and 3 had creatinine clearances ranging from 31 mL/min to 52 mL/min.

○ The other study followed 3 actual donors with biopsy-confirmed IgA nephropathy. After 7 years, 2 had normal renal function, urinalysis, and BP, and 1 had a GFR of <15 mL/min.74

The literature strongly supports a role for kidney biopsy in the evaluation of potential donors with persistent microscopic hematuria.

Other Guidelines

CARI Guidelines (2010)75

* The discovery of microscopic hematuria in potential donors needs further investigation to determine if it is clinically significant. Underlying urological and renal disease should be excluded before proceeding to donation.

* No recommendation is made regarding potential donors with TBMD.

Amsterdam Forum27

* Patients with persistent microscopic hematuria should not be considered for kidney donation unless urine cytology and a complete urologic workup are performed. If urological malignancy and stone disease are excluded, a kidney biopsy may be indicated to rule out glomerular pathology such as IgA nephropathy.

United Kingdom Guidelines (2011)6

* All potential donors should have dipstick urinalysis performed on at least 2 separate occasions.

* A potential donor with 2 or more positive dipstick tests, including trace positive, should be considered to have persistent nonvisible hematuria (PNVH).

* If PNVH is present, perform urine culture and renal imaging to exclude common urologic causes including infection, nephrolithiasis, and urothelial carcinoma.

* If no cause is found, perform cystoscopy in patients age older than 40 years to exclude bladder pathology.

* If no cause is found and the donor still wishes to donate, a kidney biopsy should be considered, and is recommended if hematuria is >1+ on dipstick testing.

* Glomerular pathology, with the possible exception of TBMD, is a contraindication to donation.

European Renal Best Practice Guideline on the Management and Evaluation of the Kidney Donor and Recipient (http://ndt.oxfordjournals.org/content/28/suppl_2/ii1.full.pdf)76

* Recommend considering persistent hematuria of glomerular origin as a contraindication to living donation because it may indicate renal disease in the potential donor.

* However, they acknowledge TBMD might be an exception.

(E) Other Literature and References

1. Delmonico FL, Dew MA. Living donor kidney transplantation in a global environment. Kidney Int. 2007;71(7):608–614.

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Proteinuria

There are no long-term studies of living donors with significant proteinuria predonation. However, proteinuria predicts the development of both CKD and CVD in the general population. Even low levels of dipstick-positive proteinuria can predict the development of ESRD.77 In patients with CKD, proteinuria is a significant predictor of disease progression. A meta-analysis of studies in prior living donors has shown that levels of proteinuria are higher than in the general population (approximately 66 mg/day higher), with 10% of donors developing proteinuria after seven years.

Significant proteinuria is generally considered a contraindication to living donation.

(A) Additional Testing

Additional testing as indicated by proteinuria findings on initial screening:

1. If either the 24-hour urine protein or the urine ACR is abnormal, the test should be repeated because transient proteinuria or transient albuminuria does not rule out living donation.

(B) Acceptance Criteria

1. Normal quantified urine protein levels are required to become a living donor. (The upper limits defining normality are 24-hour urine protein <150 mg/day and a random urine ACR <3 mg/mmol.)

2. Individuals with 150 mg to 300 mg of proteinuria/day may be acceptable as donors, on a case-by-case basis, if all other tests are normal. Evidence of mild proteinuria with evidence of abnormalities in any of these other parameters of renal health precludes donation.

3. Proteinuria can, on occasion, be transient (related to exercise, fever). An isolated elevated reading with a number of repeat normal measures may permit donation.

(C) Exclusions for Donation

1. Significant proteinuria (>300 mg/day).

2. Persistent microalbuminuria (≥3.0 mg/mmol).

(D) Practice

Assessing Proteinuria

Total protein or albumin may be measured by either a 24-hour urine collection or spot urine, indexed to urinary creatinine for standardization. Normal values for these various tests are as follows:

* 24-hour urine protein excretion: <150 mg/day (may be up to 300 mg/day in some labs).

* 24-hour urine albumin excretion: <30 mg/day.

* PCR: <15 mg/mmol to 30 mg/mmol.

* ACR: <3 mg/mmol.

Review of Current Canadian Practice

The Canadian Living Kidney Donation programs that were surveyed assessed proteinuria using one or more of the methods listed above, with the vast majority (11/13) performing a 24-hour urine collection for protein, and 10/13 also performing an ACR.

DONOR Network data (280 donors enrolled across 12 Canadian programs): Results of a single random urine ACR that resulted in acceptance for donation (Table 8).

International Clinical Practice Guidelines

CARI Guidelines (2010)78

* Potential living donors should have their urinary protein excretion measured using either a 24-hour urine collection (daily excretion) or a spot urinary PCR.

* A urine protein excretion of >300 mg/day (24-hour urine collection) or a spot urinary PCR of >30 mg/mmol is usually a contraindication to living donation.

* Further investigations are warranted when urine protein excretion is >150 mg/day but <300 mg/day (corresponds approximately with spot urinary PCR >15 mg/mmol but <30 mg/mmol). Repeat urinary protein estimation, as well as measurement of urinary albumin excretion may help in further assessing potential living donors.

* Although overt proteinuria may be absent, the presence of microalbuminuria (urinary albumin excretion of >30 mg/day or >20 mg/min or ACR >2.5 mg/mmol) should be considered a relative contraindication to living donation.

* Microalbuminuria or mild proteinuria (<300 mg/day) occurring in the presence of another associated clinical or laboratory abnormality (eg, HTN, obesity, glucose intolerance, glomerular hematuria) should be considered a relative contraindication to living donation.

* In potential living donors with a minor degree of proteinuria or albuminuria, a renal biopsy may help in further assessing the potential donor’s risk of developing progressive renal disease following donation.

Amsterdam Forum27

* A 24-hour urine protein of >300 mg is a contraindication to donation.

* Microalbuminuria determination may be a more reliable marker of renal disease, but its value as an international standard of evaluating potential donors has not been determined.

United Kingdom Guidelines (2011)6

* Urine protein excretion should be quantified in all potential living donors.

* A urine ACR performed on a spot urine sample voided after waking is the recommended screening test, although both urine PCR and 24-hour urine protein collection are acceptable alternatives.

* Significant proteinuria is an ACR >30 mg/mmol, PCR >50 mg/mmol or 24-hour total protein >300 mg/day, and is usually a contraindication to donation.

* The significance of microalbuminuria (ACR 3.5 mg/mmol to 30 mg/mmol) and of 24-hour urine protein of 150 mg/day to 300 mg/day (PCR 15 mg/mmol to 30 mg/mmol) has not been fully evaluated in living kidney donors. However, since both the risk of CKD and cardiovascular morbidity increase progressively with increasing albuminuria, such potential donors require careful evaluation and counselling about the risks of donation.

European Renal Best Practice Guideline on the Management and Evaluation of the Kidney Donor and Recipient76

* Recommend quantifying urinary protein excretion in all potential living donors.

* Recommend that overt proteinuria [24-hour total protein >300 mg/day, or spot urinary PCR >300 mg/g (or >30 mg/mmol)] be a contraindication to living donation.

* Recommend that potential donors with persistent proteinuria (<300 mg/day, more than 3 measurements with a 3-month interval between each measurement) be further evaluated by quantifying microalbuminuria to assess their risk for living donation.

* Suggest that a potential donor with persistent microalbuminuria (30 mg/day to 300 mg/day, more than 3 measurements with a 3-month interval between each measurement) be considered a high risk for donation.

AST/ASTS/NATCO/UNOS Joint Society Work Group 201055

* Proteinuria, and specifically albuminuria, are sensitive indicators of early kidney damage. Nonpostural albuminuria and nonpostural proteinuria are known predictive risk factors for the development of CKD and future CVD. The risk of CKD increases as the degree of proteinuria increases. The most reliable way to measure urinary protein or albumin is by a timed urine collection, with the albumin excretion rate reported per unit of time or per gram of creatinine.

* Microalbuminuria is defined as:

○ urine albumin excretion >30 mg/day but <300 mg/day in both men and women, or

○ >17 mg/gm but <250 mg/gm creatinine in men, and >25 mg/gm but <355 mg/gm creatinine in women.

* Clinical proteinuria is defined as:

○ urine protein excretion >300 mg/day in both men and women, or

○ >250 mg/gm creatinine in men, and >355 mg/gm creatinine in women.

* Potential donors with microalbuminuria or clinical proteinuria should be considered to be at increased risk of future kidney disease and may not be suitable candidates for unilateral nephrectomy.

E. Other Literature and References

1. Andrews PA, Burnapp L, Manas D, et al. Summary of the British Transplantation Society/Renal Association United Kingdom guidelines for living donor kidney transplantation. Transplantation. 2012;93(7):666–673. doi: 10.1097/TP.0b013e318247a7b7.

2. Delmonico FL, Dew MA. Living donor kidney transplantation in a global environment. Kidney Int. 2007;71:608–614. http://www.ncbi.nlm.nih.gov/pubmed/17290291. (Accessed: January 21, 2015).

3. Garg AX, Muirhead N, Knoll G, et al. Proteinuria and reduced kidney function in living kidney donors: a systematic review, meta-analysis, and meta-regression. Kidney Int. 2006;70:1801–1810. http://www.ncbi.nlm.nih.gov/pubmed/17003822. (Accessed: January 21, 2015).

4. Boudeville N, Kanellis J. The CARI Guidelines. Donors at Risk: Proteinuria. Nephrology. (Carleton). 2010;15 Suppl 1:S106-S110. doi: 10.1111/j.1440-1797.2009.01218.x.

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Level of GFR Appropriate for Kidney Donation and Split Kidney Function

Glomerular filtration rate (GFR) is defined as the quantity of glomerular filtrate formed each minute in the nephrons of both kidneys.

A. Minimum Required Tests

Kidney function tests required of the potential donor:

1. Serum creatinine on 2 separate occasions; each reported serum creatinine should also report an eGFR using one of the following equations: CKD-EPI or Cockcroft-Gault. Express all results both in mL/min and mL/min/1.73m2.

2. 24-hour urine to assess creatinine clearance on 2 separate occasions (ensure the urine collection is adequate based on volume and measured creatinine) AND/OR measured GFR (such as DTPA, EDTA, iohexol, iothalamate) on at least 1 occasion.

3. When should split function be assessed, and what kidney should be retained by the potential donor in the setting of differential split function?

a) An assessment of split function of the kidneys is not required in all potential donors. However, if there is evidence of asymmetrical kidney size (>1 cm difference in kidney length between the two kidneys), then perform an assessment of split function (ie, using 99mTc-DTPA).

b) If the difference in kidney function between the two kidneys is ≥5% (ie, >55% function in one kidney, and < 45% function in the other kidney; leave the potential donor with the kidney that has the greater function (and donate the other kidney).

B. Acceptance Criteria

1. GFR results:

a) If the potential donor is aged 18 to 30 years: GFR ≥90 mL/min/1.73 m2.

b) If the potential donor is aged 31 to 40 years: GFR ≥85 mL/min/1.73 m2.

c) If the potential donor is aged 41 to 65 years: GFR ≥80 mL/min/1.73 m2.

d) If the potential donor is aged >65 years: GFR ≥75 mL/min/1.73 m2.

C. Practice

Review of Current Practice in Canada

Table 9 shows the current practice in Canada with respect to assessing GFR and split kidney function in potential donors.

A survey of Canadian Living Kidney Donation programs of current acceptance criteria for the level of GFR in otherwise healthy potential donors (Table 10).

For 252 donors enrolled across 12 Canadian programs. Results of a single (nuclear) GFR measurement as part of the donor evaluation that resulted in acceptance for donation (Table 11).

D. Literature and References

What existing guidelines say about the minimum level of GFR for donation: Biologically, it would be expected that patients with kidney disease or a low GFR before donation would be at higher risk of kidney failure after donation. There is no empirical evidence to provide guidance on the impact of GFR on long-term donor outcomes when GFR is either < or >80 mL/min/1.73 m2 before donation.79 Rather, the thresholds were partly established based on the impact of GFR before donation on long-term recipient outcomes.79 In general, recipients of kidneys from a donor with a higher GFR tended to have better graft survival, patient survival, and kidney function.

With respect to GFR, the exclusion criteria for potential donors vary according to the different guidelines. Some indicate a GFR <80 mL/min/1.73 m2, while others have age-specific criteria (with a lower contraindication threshold for older individuals).80

Generally, past studies have indicated that in the decade following donation (with donors of all ages), about 15% of donors demonstrated an eGFR <60 mL/min/1.73m2.

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SECTION FIVE: RISKS OF PERIOPERATIVE COMPLICATIONS

Perioperative Risks Due to Medical Risk Factors

A. Goals

1. Ensure the safety of the surgical procedure for the potential donor.

2. Detect unrecognized disease and potential medical risk factors, and hence reduce perioperative and postoperative medical complications related to the surgery.

B. Background

Overt disease will exclude most individuals as potential donors, as only a healthy individual will pass the workup process and be considered eligible as a living kidney donor. This section considers the assessment of the potential donor’s perioperative risk. Living donors do not require surgery and derive no clinical benefit from the donation. While surgery is part of an altruistic act, it is nevertheless associated with morbidity and mortality. As such, potential donors should undergo a more rigorous evaluation, and stricter-than-usual criteria need to be applied to define risk.

While the incidence of perioperative complications is low, pulmonary embolism, bleeding, and cardiac events have been reported. The issue is to identify the most appropriate method of determining which potential donors require additional testing to detect occult disease.

The overall surgical risk of donating a kidney is low in healthy individuals. The following information gives a general overview about medical risk factors and complications related to the surgical procedure.

Perioperative mortality is approximately 1 in 3,000 (0.03%) after living donor open nephrectomy.81,82,83,84 A recent study of more than 80,000 donors showed a 90-day mortality of 3.1 in 10,000 donations (0.03%), despite increasing age and obesity in the donor population.38 The most common causes of death after living donation are pulmonary embolism and cardiac events (MI and arrhythmias).82,85,86

Information pertaining to perioperative morbidity for living donor nephrectomy patients have been summarized for a large number of single-center studies.6,84 The mean overall complication rate was 32% and the major perioperative complication rate was 4.4%.

The estimated major complication rate in a survey by Bay and Hebert was 1.8%,83 whereas the American Society of Transplant Physicians (ASTP) survey81 reported that 22 out of 9,692 (0.23%) kidney donors experienced “potentially life-threatening or permanently debilitating” complications.

An overview of perioperative complications given by Kok et al.87 showed that specific surgical complications after living donation included wound-related problems (such as sepsis and hernia), chronic pain, the conversion from laparoscopic to open surgery, bleeding, the requirement for blood products, and cosmetic consequences.

C. Potential Medical Risk Factors Associated With Perioperative Complications in Patients Requiring General Surgery

Exercise capacity is a key determinant of overall surgical risk. The ability to walk two blocks on level ground or to carry two bags of groceries up one flight of stairs without symptoms can give a rough assessment. These activities expend approximately 4 metabolic energy equivalents (METS) and translate into a low risk of major postoperative complications.

A functional capacity of >4 METS predicts a very low perioperative risk.88,89

Age is an independent risk factor for postoperative pulmonary complications, predominantly due to an increasing number of comorbidities associated with aging.90 A meta-analysis of publications comparing older and younger donors regarding operative time, surgical blood loss, and length of hospital stay did not show significant differences and indicated that surgical complications were not significantly higher for older or obese donors.33

Obesity is not a risk factor for most major adverse postoperative outcomes, with the exception of pulmonary embolism. Obesity increases the rate of wound infections,91,92,93,94 and deep venous thrombosis (DVT) and associated pulmonary embolism.90 In a study by Young et al., obese and nonobese (usually BMI <30 kg/m2) donors were compared on operative time, blood loss, and hospital stay. Differences were statistically significant but clinically insignificant. Surgical complications (eg, minor infections, hemorrhage, pneumonia, or pneumothorax) were not significantly higher for older or obese donors.33

Obstructive sleep apnea increases the risk of postoperative medical complications including hypoxemia, respiratory failure, unplanned re-intubation, and ICU transfer.95 As most patients are undiagnosed it is reasonable to screen patients for obstructive sleep apnea before surgery.

Alcohol misuse: Patients who misuse alcohol on a regular basis have an increased risk of postoperative complications including surgical site infections, other infections, and cardiopulmonary complications.96

Smoking: Current smoking is associated with postoperative morbidity and mortality. Smoking cessation leads to fewer complications such as decreased wound healing and pulmonary complications.97,98,99

Anesthetic complications: Malignant hypertension is a rare, inherited complication. The preoperative assessment should include questioning about either a personal or family history of complications from anesthesia.

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Perioperative Risks Due to Cardiovascular Conditions

All potential donors should undergo minimum testing and assessment according to the current American Heart Association guidelines (http://www.heart.org/)100 and Canadian Heart and Stroke Foundation guidelines (http://www.heartandstroke.com/).101

A. Gender

Men older than 55 years and postmenopausal women are at greater risk of heart disease. Until women reach menopause, they have a lower risk of stroke than men.

B. Family History

The risk of heart disease is increased if close family members (parents, siblings, or children) developed heart disease before age 55 or, in the case of female relatives, before menopause.

The risk of stroke is increased if close family members (parents, siblings or children) had a stroke before age 65.

C. Ethnicity

Aboriginal peoples and people of African or Southeast Asian descent are more likely to have HTN, and diabetes, and are therefore at greater risk of heart disease and stroke than the general population.

Communication with the potential donor and, if necessary, the potential donor’s family doctor over the time frame following initial acceptance as a potential donor, is essential to ensuring that the potential donor continues to be considered as a suitable candidate. Cardiovascular risk is one area that may need ongoing or further investigation pending the time interval since registration.

D. Additional Testing

1. Additional testing is indicated for the following potential donors based on the medical questionnaire, the physical examination, and screening test results, as per current American Heart Association guidelines100 and Canadian Heart and Stroke Foundation guidelines.101

a) Men 50 years and older;c

b) Women 60 years and older;c

c) Potential donors in whom the 10-year CVD risk (where calculated) is >10% based on the Framingham risk calculator or other similar calculator;c

d) Potential donors with one or more cardiovascular risk factors (HTN, hypercholesterolemia, and/or smoking).c

2. If there is a change in risk factors since the initial assessment, a cardiology consultation is appropriate.

E. Acceptance Criteria

1. Based on total assessment findings and in accordance with current American Heart Association guidelines100 and Canadian Heart and Stroke Foundation guidelines.101

F. Exclusions for Donation

1. To be considered in conjunction with the medical questionnaire, the physical examination, functional capacity, ECG, chest X-ray, and the cardiology report.

G. Literature and References

Background Information: Summarizing the Literature

The major predictors of surgical complications related to CVD are a history of:

* high-risk surgery (vascular, cardiovascular),

* ischemic heart disease,

* congestive heart failure,

* cerebrovascular disease,

* diabetes treated with insulin, and/or

* significantly reduced GFR.

A potential donor presenting with one or more of these conditions would be excluded from donating.

Nephrectomy is not considered a high-risk operation. People with known CVD, diabetes, or significantly impaired kidney function are excluded from donating according to international guidelines and Canadian practice.

The ACC/AHA guidelines,102 which apply to individuals undergoing noncardiac surgery, do not recommend any further cardiac testing for those with no active heart disease who have reasonable functional capacity (defined as ≥4 METS). These guidelines do NOT recommend baseline ECG for individuals with no risk factor for cardiac disease. However, as explicitly described in the United Kingdom guidelines6, the transplant community has established that potential donors should undergo more rigorous evaluation given that donation is an altruistic act associated with morbidity, and potentially, mortality.

The issue is: “What is the most appropriate method of determining which potential donors require additional testing to detect occult coronary artery disease?” The literature suggests two approaches:

* One approach is to use conventional risk factors and available calculators to determine whether an individual is at low (<10%), intermediate (10% to 20%), or high risk (>20%) for a cardiovascular event in the next 10 years, and then perform further testing on those above a certain risk level, usually >10%. To put this in perspective, for nonsmoking men with a systolic BP of 130 and total cholesterol/HDL cholesterol ratio of 4, the 10-year risk of CVD increases with age and reaches a value of >10% at about age 55; for women with similar characteristics, a risk of >10% is not reached until age 65 to 70.

* The second approach is to assess the potential donor’s functional capacity by determining his or her ability to perform various tasks, which can be converted into METS. Impaired functional capacity (<4 METS) has been associated with increased perioperative risk. Good exercise tolerance is an excellent predictor of good outcomes, even when coronary disease exists. The ACC/AHA guidelines102 identify poor functional capacity (<4 METS) as a potential indication for further cardiac testing, but only if there are other cardiac risk factors or if the surgery is high risk.

United States (UNOS) Guidelines (2008)8

* chest X-ray,

* ECG,

* echo and/or exercise stress test if the potential donor is older than 50 years or has a risk factor (eg, HTN, smoking, hyperlipidemia, family history, and/or shortness of breath from exercise) or physical findings that demonstrate increased risk of heart disease (including, but not limited to, borderline HTN, abnormal ECG, abnormal chest X-ray, and murmur), and

* pulmonary function tests for smokers.

United Kingdom Guidelines (2011)6

* A low threshold should be set for screening potential donors for CVD, and for their exclusion from donation.

* Potential donors with an exercise capacity of <4 METS or >10% estimated risk of significant coronary atherosclerosis should undergo formal cardiology assessment.

* Potential donors with exercise capacity >10 METS are at very low cardiac risk.

* Screening of higher-risk potential donors should be performed by CT calcium scan scoring and/or functional assessments such as dynamic stress tests.

Review of Current Canadian Practice

The Canadian Living Kidney Donation programs that were surveyed request ECGs. There is no uniform practice with respect to stress testing or echocardiography (Table 13).

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Perioperative Risks Due to Pulmonary Conditions

While some pulmonary conditions would not necessarily be a contraindication to kidney donation, they regardlessly pose significant perioperative risks to the potential donor. These conditions include a history of asthma, smoking, sleep apnea, and chronic obstructive pulmonary disease (COPD).

A. Additional Testing

1. Additional testing is indicated based on the findings documented in the medical history and/or the physical examination, as applicable in the following situations:

a) smoking history,

b) COPD,

c) asthma,

d) obstructive sleep apnea, and/or

e) unexplained dyspnea and/or cough.

2. If the potential donor has a history of any of the risk factors listed above, they should be referred for an anesthesia and/or pulmonology consult. Also, additional testing (see tests a to e below) should be undertaken to estimate the disease severity and the associated medical and perioperative risks:

a) pulmonary risk indices calculations,103,104

b) preoperative oxygen saturation,

c) pulmonary function testing,

d) exercise testing (ie, cardiovascular stress testing), and

e) arterial blood gases.

B. Acceptance Criteria

1. If the potential donor has a negative history and physical exam: no concerns.

2. If the potential donor is older than 50 years: no concerns, but information regarding the risk of postoperative pulmonary complications should be given to the donor based on risk indices calculations.

3. If the potential donor has a smoking history: no concerns if overall assessment and determination shows minimal perioperative risk and no sign of compromised pulmonary function (see Section Three: Risk of Cardiorenal Disease).

4. If the potential donor has a history of asthma: acceptance depends on the severity of the disease, the results of additional tests, and the results of anesthesia and pulmonology consults.

C. Exclusions for Donation

1. Exercise capacity <4 METS.

2. COPD with impairment of oxygenation or ventilation.

3. Sleep apnea: A potential donor with mild sleep apnea might be accepted, but only in conjunction with an anesthesia and/or pulmonology consult; a potential donor with obstructive sleep apnea associated with pulmonary hypertension will be excluded.

D. Practice

shows the current practice of testing for perioperative risk in Canadian Living Kidney Donation programs.

E. Literature and References

Background Information Summarizing the Literature

* Postoperative pulmonary complications add significantly to morbidity and mortality.

* Major risk factors for postoperative pulmonary complications such as COPD, poor general health status, pulmonary hypertension, heart failure, and metabolic factors are unlikely to occur in potential donors after they have passed the workup process.

* Simple screening questionnaires and a thorough physical examination will rule out, to a large extent, significant pulmonary diseases.

* Contributing clinical findings are more predictive of the risk of postoperative pulmonary complications than are spirometric results.

The Web-based textbook UpToDate gives an excellent overview of perioperative risk and the medical complications associated with general surgery. This information is not covered sufficiently by the existing living donor literature and the international guidelines. As such, two references for this Protocol were chosen from UpToDate.

Other Selected References

1. Brooks-Brunn JA. Predictors of postoperative pulmonary complications following abdominal surgery. Chest. 1997;111:564–567. http://www.ncbi.nlm.nih.gov/pubmed/9118688. (Accessed: January 21, 2015).

2. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology. 2008;108:812–821. doi: 10.1097/ALN. 0b013e31816d83e4.

3. Kaw R, Pasupuleti V, Walker E, Ramaswamy A, Foldvary-Schafer N. Postoperative complications in patients with obstructive sleep apnea. Chest. 2012;141(2):436–441. doi: 10.1378/chest.11-0283.

4. Kroenke K, Lawrence VA, Theroux JF, Tuley MR, Hilsenbeck S. Postoperative complications after thoracic and major abdominal surgery in patients with and without obstructive lung disease. Chest. 1993;104(5):1445–1451. http://www.ncbi.nlm.nih.gov/pubmed/8222804. (Accessed: January 21, 2015).

5. Lawrence VA, Page CP, Harris GD. Preoperative spirometry before abdominal operations: a critical appraisal of its predictive value. Arch Intern Med. 1989;149:280–285.

6. McAlister FA, et al. Accuracy of the preoperative assessment in predicting pulmonary risk after nonthoracic surgery. Am J Respir Crit Care Med. 2003;167:741–744. http://www.ncbi.nlm.nih.gov/pubmed/2644901. (Accessed: January 21, 2015).

7. Nakagawa M, Tanaka H, Tsukuma H, Kishi Y. Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery. Chest. 2001;120(3):705–710. http://www.ncbi.nlm.nih.gov/pubmed/11555496. (Accessed: January 21, 2015).

8. Qaseem A, Snow V, Fitterman N, et al. Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the American College of Physicians. Ann Intern Med. 2006;144(8):575–581. http://www.ncbi.nlm.nih.gov/pubmed/16618955. (Accessed: January 21, 2015).

9. Smetana GW. Preoperative pulmonary evaluation. NEJM. 1999;340:937–944. http://www.ncbi.nlm.nih.gov/pubmed/10089188. (Accessed: January 21, 2015).

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Perioperative Risks Due to Liver Disease and Bleeding Disorders

Hematological abnormalities and diseases can place both the donor and recipient at risk. A history of jaundice, alcohol misuse, liver disease, bleeding disorders including anemia, bruising, and/or clotting disorders (DVT or pulmonary embolism) should be obtained at the time of the medical history and the physical examination.

A. Additional Testing

Additional testing as determined from the medical history, the physical examination, and initial general health screening tests:

1. Hematology and hepatology consultations may be indicated for the investigation of a history of bleeding or thrombosis, or abnormalities in liver function tests uncovered during screening investigations.

B. Acceptance Criteria

1. The decision whether to accept a potential donor is made in consideration of the overall clinical assessment and perioperative risk.

C. Exclusions for Donation

1. To be determined following a full clinical evaluation.

D. Practice

Background Information

Rationale

The presence of an underlying bleeding or clotting disorder places a potential donor at a higher risk of significant bleeding complications or thrombotic complications. As such, potential donors should be evaluated for such disorders before surgery.

International practice

1. European Renal Best Practice (ERBP) Guideline on the Management and Evaluation of the Kidney Donor and Recipient: no comment on this topic.

2. United Kingdom Guidelines (2011): assess for a history of thromboembolic disease; measure PT/PTT and CBC; thrombophilia screen where indicated.

3. OPTN Policies (2008): assess for history of clotting disorders or DVT.

Review of Current Canadian Practice

shows that PT/PTT is done in almost all programs. Platelet count is done in a minority of programs (per survey, but in practice it is universally performed with CBC).

In 1983, Rapaport published a seminal review of preoperative hemostatic evaluation, and his recommendations remain relevant. He recommended that patients who undergo surgery should be questioned about their response to various bleeding challenges, and he recommended seven questions.

* Have you ever bled for a long time or developed a swollen tongue or mouth after cutting or biting your tongue, cheek, or lip?

* Do you develop bruises larger than a silver dollar without being able to remember when or how you injured yourself? If so, how big was the largest of these bruises?

* How many times have you had teeth pulled, and what was the longest time that you bled after an extraction? Has bleeding ever started up again the day after an extraction?

* What operations have you had, including minor surgery such as skin biopsies? Was the bleeding after surgery ever hard to stop? Have you ever developed unusual bruising in the skin around an area of surgery or injury?

* Have you had a medical problem within the past 5 years requiring a doctor’s care? If so, what was its nature?

* What medications, including aspirin or any other remedies for headaches, colds, menstrual cramps, or other pains, have you taken within the past 7 to 9 days?

* Has any blood relative had a problem with unusual bruising or bleeding after surgery? Were blood transfusions required to control this bleeding?

A positive history should prompt further evaluation, and referral to a hematologist, if indicated. However, the history may be unreliable due to a forgetful physician, an unreliable patient (forgetful or unaware), or an unchallenged patient (no prior surgeries/extractions). For these reasons, basic screening in the form of a PT/PTT and platelet count is recommended for moderate-risk or high-risk surgery.

E. Other Literature and References

1. Coutre S. Preoperative assessment of hemostasis. In: UpToDate. Available at http://www.uptodate.com/contents/preoperative-assessment-of-hemostasis. Last updated October 27, 2014. (Accessed: January 21, 2015).

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aCancer screening guidelines are developed by each Canadian province and territory and, as such, there are slight differences among provincial and territorial program recommendations. Therefore, until the Public Health Agency of Canada recommends national guidelines for cancer screening, the guidelines published by the Canadian Cancer Society will be used to assess the suitability of a potential donor wishing to participate in the Kidney Paired Donation Program.

bA first-degree relative refers to a genetic mother, father, sibling, or child. (See CAN/CSA- Z900.2.5-12 – Lymphohematopoietic Cells for Transplantation.)

cAccording to cardiovascular risk calculator and documented risk factors.

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Appendices

APPENDIX ONE: LIVING KIDNEY DONOR MEDICAL AND SOCIAL HISTORY QUESTIONNAIRE GUIDANCE DOCUMENT

A. Introduction

Donor screening is one component of the potential living kidney donor (potential donor) suitability assessment, and is intended to gather general health information and identify risk factors that could potentially impact the safety of the donor and/or the donated kidney. Not all risks that are identified will necessarily lead to exclusion of the potential donor, but the information gathered is important for clinical decision-making.

The Health Canada regulation Safety of Human Cells, Tissues and Organs for Transplantation outlines specific requirements related to potential donor information and history that must be gathered during the assessment. The CAN/CSA-Z900.1-12 (Annex E) compares potential donors at “higher risk” with the Canadian population in general; the term “higher risk” reflects the disproportionately greater chance that a person with an identified risk factor or risk behaviour could have contracted one of the infectious diseases named in the Regulations (eg, HIV, HBV, or HCV).

Exceptions for donor enrollment may be given, in limited cases, where risk factors have been identified. Health Canada provisions allow for the use of organs from a donor for whom any of the contraindications or exclusions apply if the recipient team feels that the benefit of the transplant outweighs the risk of disease transmission and if the recipient gives informed consent. Any potential donor with identified risk factors is prohibited from enrolling in the KPD Program registry until the sponsoring program has received written approval from the Living Donation Advisory Committee and the Kidney Transplant Advisory Committee that enrollment is acceptable.

Potential donor screening also aids in assessing the potential impact of donation on the long-term health of the donor. The Kidney Paired Donation Protocol for Participating Donors 2014 outlines standard testing and acceptance criteria for a potential donor wishing to participate in the KPD Program.

Health Canada recommends that screening be performed as close to the time of procurement of the kidney as possible. The 30-Day Medical and Social History Questionnaire (MSHQ) should be completed within 30 days of surgery to determine if any information has changed since the documentation of the previous (long-form) MSHQ.

All questions in the MSHQ are asked to ensure the protection and safety of all Canadian transplant recipients and potential donors. The rationale for each screening question in the MSHQ can be found in Section D of Appendix One. For more information related to the questions in the MSHQ, please consult the following documents:

* CAN/CSA-Z900.1 Cells, Tissues and Organs for Transplantation: General Requirements4 (13.1.3, Annex E)

* CAN/CSA-Z900.2.3 Perfusable Organs for Transplantation5 (12.2.2.3, 12.2.3.7, 13.1.2)

* The Kidney Paired Donation Protocol for Participating Donors, 2014

* Health Canada Guidance Document for Cell, Tissue and Organ Establishments — Safety of Human Cells, Tissues and Organs for Transplantation.3

It is the responsibility of each program to consult the most current versions of the reference documents listed above.

APPENDIX ONE B: MEDICAL AND SOCIAL HISTORY QUESTIONNAIRE (LONG FORM)

APPENDIX ONE C: 30-DAY MEDICAL AND SOCIAL HISTORY QUESTIONNAIRE

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APPENDIX ONE D: MEDICAL AND SOCIAL HISTORY QUESTIONNAIRES (MSHQs) — RATIONALE DOCUMENT

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APPENDIX TWO: PSYCOSOCIAL ASSESSMENT

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APPENDIX THREE: PHYSICAL EXAMINATION FORM

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APPENDIX FOUR: LIVING KIDNEY DONOR SURGICAL REVIEW FORM

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