Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper : Transplantation

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Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper

Crespo, Marta MD, PhD1; Zárraga, Sofía MD2; Alonso, Ángel MD3; Beneyto, Isabel MD4; Díaz Corte, Carmen MD, PhD5; Fernandez Rodriguez, Ana M. MD6; Franco, Antonio MD7; Hernández, Domingo MD, PhD8; González-Roncero, Francisco Manuel MD9; Jiménez Martín, Carlos MD10; Jimeno, Luisa MD11; Lauzurica Valdemoros, Luis-Ricardo MD12; Llorente, Santiago MD11; Mazuecos, Auxiliadora MD13; Osuna, Antonio MD14; Ramos, Javier Paúl MD15; Rodríguez Benot, Alberto MD, PhD16; Ruiz San Millán, Juan Carlos MD, PhD17; Sánchez Fructuoso, Ana MD, PhD18; Torregrosa, Josep-Vicent MD19; Guirado, Lluis MD, PhD20; GREAT Study Group and Spanish Network for Research in Renal Diseases (REDINREN, RED16/0009)

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Transplantation 104(8S2):p S1-S12, August 2020. | DOI: 10.1097/TP.0000000000003270
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INTRODUCTION

Following renal transplantation (RT), the occurrence of specific anti-HLA antibodies directed against one of the donor antigens (ie, donor-specific antibodies [DSAs])is associated with an increased risk of graft loss. This is one of the criteria, along with histological data derived from renal biopsy, employed for the diagnosis of antibody-mediated rejection (AMR) or humoral rejection (active or chronic). Therefore, these antibodies should be specifically searched for in patients with suspected rejection. However, the true significance of isolated DSAs in the absence of AMR is currently unknown. It has been postulated that this finding could anticipate AMR or indicate under immune suppression.1,2

Given the relevance of DSAs and the variability in their detection and monitoring,3 this expert consensus document has been drafted based on the best scientific evidence available and clinical experience. To this end, an in-depth analysis of both the literature and experience of Spanish RT units was performed beforehand.

The article’s objective was to generate simple recommendations that are applicable to patients with DSAs, involving prevention, detection, and monitoring of DSAs, as well as the immunosuppressive treatment options should DSAs be detected. The article’s primary aim is to reduce the variability in clinical practice with respect to medium- and long-term DSA monitoring.

Several expert documents had earlier been published about the immunological monitoring of kidney transplant patients.4,5 Although clinically relevant and practical, these reports have not provided sufficient information on the methodology used to attain their conclusions. In spite of its eminently clinical orientation, our report has been based on a critical review of all available literature.

Although all types of antibodies can develop, our article is focused on DSAs against HLA antigens that are formed before, termed preformed DSAs, or after RT, termed de novo DSAs.

MATERIALS AND METHODS

Nominal group, systematic review, and Delphi techniques were used for the preparation of this document.

First Nominal Group Meeting

The nominal group consisted of a panel of expert nephrologists from the Spanish Group of Transplant Activities (GREAT) responsible for RT. This expert group from 20 transplanting hospitals in Spain agreed to participate in scientific meetings focused on new RT research projects. Beforehand, the document’s coordinators (M.C. and L.G.), in collaboration with the coordinator of the GREAT group (S.Z.), had prepared a discussion outline covering the document’s topics and sections. During the meeting, the panelists, guided by an expert methodologist, defined the document’s objectives, scope, and potential users in a first step, along with its various sections. Subsequently, different features and issues related to DSA monitoring and immune suppression management in RT patients were discussed for each section. This generated a document matrix upon which we continued our research work. We also identified areas wherein controversy may exist and decided to undertake a systematic literature review.

Systematic Literature Review

For each controversial aspect, a population, intervention, comparator, and outcome question were posed (Table 1), thereby generating the inclusion and exclusion criteria for each question to review. With the help of a Librarian, different search strategies were designed. The bibliographic databases screened from inception to February 2017 were as follows: Medline, Embase, and the Cochrane Library. MeSH and free text terms were used. We searched for articles that included patients with RT. Depending on the question, the studies were required to have analyzed different aspects of DSA development, in addition to the efficacy and safety of immunosuppressive treatments. Only studies with one of the following designs were considered: meta-analysis, systematic review, randomized clinical trial (RCT), and observational, prospective, and retrospective, studies involving >100 patients. For each review, 2 reviewers (Estíbaliz Loza, María Jesús García) independently analyzed the articles retrieved via the aforementioned search strategy in the different bibliographic databases. In the event of discrepancies, a third reviewer (Loreto Carmona) was called upon to resolve the conflict. The Jadad scale for RCTs6 and the Oxford scale for observational studies7 were employed to assess the methodological quality of the studies, with evidence and outcome tables created to summarize their main characteristics and results. Subsequently, a secondary search was performed focused on the bibliography of the included articles. The non-peer-reviewed literature was also reviewed, namely conferences and proceedings of interest over the past 2 y, along with documentation provided by the coordinators in case this was not already captured by the search strategies.

T1
TABLE 1.:
PICO questions, base for the systematic literature review

Preliminary Recommendations and Document

While the SLR was being performed, the panel worked on the document’s matrix, adding editorial content to different sections. Once the SLR was finalized, a series of preliminary recommendations was generated, with an overall, though preliminary, document drafted.

Second Nominal Group Meeting

Before the meeting, the SLR results were sent to all panelists. At this meeting, the SLR results were presented and discussed, along with the preliminary recommendations. The overall draft document was then developed, including the definitive recommendations.

Delphi

The final recommendations were submitted to an online Delphi vote (2 rounds) to test the level of agreement. Participants were invited to vote on each recommendation according to one of the following categories: strongly disagree, basically disagree, basically agree, or fully agree. Agreement (A) was defined if at least 70% of the responses belonged to the full agreement category. Recommendations with A <70% were reevaluated and, if appropriate, reedited and voted on in a second round. It was, additionally, possible to add new recommendations after the first round.

Final Document

After the Delphi vote, the final document was created. With the assistance of the methodologist, each recommendation was assigned a level of evidence (LE) and grade of recommendation (GR), in line with the evidence-based medicine of the Oxford Centre for Evidence-Based Medicine.7 The A from the final Delphi vote was then added. The document was circulated among the experts for their final assessment and final comments.

RESULTS

The consensus paper has been divided into 2 main sections: monitoring of DSAs and actions to be taken in the presence of DSAs. Each section has been presented in recommendation format, each with the LE, GR, and A, followed by an explanation or clarification highlighting the available evidence.

The Delphi results are shown in Table 2. At the end, 17 recommendations, some with several subsections, were accepted upon the second round.

T2
TABLE 2.:
Recommendations in tabulated format, with LE and GR based on Oxford Centre of Evidence-based Medicine guidelines, agreement obtained from Delphi, and round in which final agreement was reached

Monitoring of DSAs

R1. The patient’s immune risk should be stratified before deciding on the DSA monitoring regimen (LE 2a; GR B; A 70%)

As DSA presence is associated with an increased risk of AMR and decreased transplant survival,8–10 it requires several detection, interpretation, and management actions. However, different DSA types confer different levels of risk—from the absence of damage to indolent conditions or active or chronic AMR with graft loss,11–14 therefore, these actions should be diverse and individually adapted to the characteristics of each patient.

Allorecognition can generate antibodies to multiple nonself-epitope mismatches even on a single molecule. Traditional HLA matching based on typing by low-resolution antigen or high-resolution allele methods are used for risk stratification to minimize de novo DSA development (reference 10). An alternative approach uses a refined epitope-based matching method in which multiple potential immunogenic sites of the HLA molecule are evaluated. Individual HLA epitopes contribute collectively to the overall immunogenicity of the mismatch, with epitope load or specific immunogenic HLA epitopes driving the formation of de novo DSA.15

It is estimated that 2% to 35% of RT patients develop de novo DSA.10,16–43 The appearance of de novo DSAs over time is variable and dependent on several factors, such as HLA matching as noted, pretransplantation anti-HLA sensitization, adherence to treatment, intraindividual variability of immunosuppressant levels, cutoff of medium fluorescence intensity (MFI) to define DSAs, and others.10,16–27,44

DSAs may occur in the first year post-RT10,21–24 from the third month10 onwards or several years after RT.10,16–43 The overall mean time for their appearance is within 2 to 4 y post-RT, whereas the proportion of RT patients exhibiting DSAs increases with time.43 The most common anti-HLA antibodies are class II,10,43 mainly anti-DQ,22 followed by anti-DR and, very occasionally, DP. In the long-term, Class I and II antibodies can appear combined in rare occasions, whereas isolated DSAs directed against class I are very rare.10,43

The temporal relationship between DSA detection and AMR is poorly described.10,20,21 In some patients, AMR proves to be concurrent with DSA detection,10 but in others, AMR develops over time.10,20

The moment at which DSAs are detected significantly depends on the study design and practice protocols. Since DSAs have been included in the diagnostic criteria for AMR, they are investigated on many occasions at the time of AMR. When AMR occurs following de novo DSA detection, the occurrence time varies from months to several years, although this time period may be influenced by the therapeutic actions taken upon DSA detection. DSAs have been reported to be associated, in the long-term, with active or chronic AMR, the latter either with or without activity, and with graft loss.10

Based on the above, DSA monitoring should be adapted according to the patient’s stratum of immune risk, ranging from rather low to higher immune risk, as should immunosuppression management. Below, we have further outlined the immune risk levels, wherein the main risk factors are anti-HLA antibody presence pre-RT, transplantation, and acute rejection8,11,12,45:

  • Low: No anti-HLA antibodies, no sensitizing events, and first RT.10,30,32,46,47
  • Medium: Anti-HLA antibodies (panel reactive antibodies, calculated by the most sensitive technique available,<80%) with previous sensitizing events but no DSAs, re-RT, DR-DQ incompatibility, or acute rejection.
  • High: Anti-HLA antibodies (>80%) with DSA levels detected pre-RT.10,12,16–32

An international expert paper was recently published revealing that this classification, although necessary and useful in daily practice, has its limitations and may not be sufficiently sensitive in relation to the low-risk group.5 For this reason, the panel recommends to take this into consideration and be especially careful with patients classified at medium immunological risk. Note that research that is currently being carried out is specifically aimed to improve these models.5,11

R2. The panel recommends requesting at least 1 DSA determination between 3 and 12 mo post-RT in all patients (LE 4; GR D; A 95%)

R3. For subsequent determinations

  1. In the presence of renal function stability in low-risk patients, the screening study on the Luminex platform should be performed at least every 12 to 24 mo (LE 5; GR D; A 70%).
  2. In the presence of renal function stability in medium- and high-risk patients, it is suggested to perform a study of an isolated or single antigen on the Luminex platform every 12 mo (LE 5; GR D; A 75%).

Different consensus documents have stratified the risk and issued a series of recommendations on DSA monitoring.4,12 Given that in these articles, the cutoff points, though based on a certain evidence level, were likely to be rather arbitrary, each case must thus be individualized. Other factors, such as the patient’s clinical status and that of being potentially insensitive in low-risk patients, must be taken into account.5

R4. The monitoring periodicity should be adjusted according to the patient’s clinical situation (LE 4; GR D; A 85%)

In all cases, the monitoring should be individualized in relation to other clinical circumstances and collected data.

R5. Regardless of the risk level, proceeding to DSA assessment has been previously suggested in the following circumstances

  1. In cases where in a significant change in medication is considered (dose minimization/suspension/conversion) (LE 4; GR D; A 80%).
  2. In cases where in there is a significant variability in the calcineurin inhibitor drug levels (LE 4; GR D; A 70%).
  3. If poor adherence to immunosuppressive therapy is suspected (LE 4; GR D; A 75%).
  4. If graft dysfunction is detected (increased creatinine or proteinuria) (LE 4; GR D; A 80%).

There are a number of clinical situations wherein DSA determination must be performed, regardless of the immune risk level or the timing. It is crucial to take this into account when deciding on a significant change in medication for any reason (eg, suspension), expected to be maintained over time, as well as in cases of relevant drug level variability, especially with tacrolimus. It is paramount to remember that this variability may be due to factors other than therapeutic compliance, such as diarrhea or interaction with other drugs, which must be ruled out first.10 Should renal function deteriorate, DSA must be determined, after first ruling out nonimmunological causes. In the context of a protocol biopsy, the findings may possibly lead to DSA determination, even in the absence of other findings warranting their determination or whether or not the protocol itself requires such a determination.

The panel considers that patients should undergo at least 1 antibody determination with solid-phase techniques, preferably using the Luminex platform,48,49 along with studies using donor cells before RT. These would enable specific antibodies to each donor antigen to be studied, thereby producing quick results. This proves to be essential for the therapeutic decision-making process.8 These tests, either qualitative or semiquantitative in nature, could be, screening-, mixed-, or single-antigen type (this latter more expensive and sensitive). Concerning the most recommended technique, the panel suggested that any of them would be appropriate, whereas it was considered preferable (1) to perform before single antigen screening studies in patients with low immunological risk,48,49 and (2) direct single antigen tests in patients with medium and high immunological risk.12,32,36,38–40,50–58

The antibody detected can be against the HLA A, B, C, DRB1, B3, B4, B5, DQB1, DQA1, DPB1, or DPA1 antigens, and the assay interpretation proves to be more complex than strictly the MFI level of each antibody when deciding whether or not DSAs exist. The combination of DQA and DQB or DPA and DPB antigens in isolated antigen beads or the nonspecificity of the reaction in some cases, due to the use of denatured antigens, entails difficulty in the interpretation of the assay.

One of the criteria used to define the positivity of DSAs is the MFI, a level that may differ depending on the commercial assay, the lot used, or the laboratory performing the determination.11 It has become clear that this system has limitations.12,50–52,59 Although the technique is improving, it is currently not possible to establish a specific recommendation as to the MFI level that determines the positivity of DSAs. In this context, the standard fluorescence intensity is an attempt to normalize the MFI, but its use has not become widespread because of its complexity. Furthermore, although higher MFI levels have been found to correlate with AMR or histological rejection data,29,33–35 this strategy exhibits several limitations (eg, it is not reproducible, differences among commercial kits, and among lots of the same brand, etc). This renders it currently impossible to stratify the risk according to the absolute or normalized MFI level.12

With all this in mind, the panel considers that regarding the assay interpretation (ie, the immune response or reaction it provokes), it is more relevant to define the existence of DSAs.60,61 Several groups have set the strength of antibodies into weak, medium, or strong, depending on whether the MFI is <5000 or 10 000. A workshop of Spanish experts has indicated that most laboratories have a cutoff point of antibodies detected by Luminex between 1500 and 3000.62

To be more precise in determining the detection and clinical significance of DSAs, different areas are being investigated. One of them is the characterization of antibodies and their ability to predict damage and loss of an RT. Others, such as the ability of DSAs to bind complement and the IgG subclass.21,29,31,32,35–37,53,55–58,63–65 However, this is a very complex issue around which there is much controversy.11 Therefore, a higher LE is needed to establish robust recommendations. A recent meta-analysis argued that the ability of DSAs to fix C1q-shaped complement on the Luminex platform is associated with poorer graft survival and a higher prevalence of AMR.66 There is controversy as to whether the detection of these C1q+ pre- or post-RT DSAs has the same impact. The detection of IgG subclasses is controversial because of the reagents available for their assessment, and the fact that a mixture of them is usually produced.

R6. In the event of de novo DSA+ in a stable situation, this finding must be confirmed (LE 2b-3a; GR C; A 70%)

When DSA+ is detected post-RT, subsequent action should always be guided by the clinical situation (Table 3) (eg, assess the intraindividual tacrolimus variability). This initially consists in confirmation of the finding. For example, in men without sensitizing events in the pre-RT period, false positives directed against denatured HLA molecules have been detected, as have been false negatives due to intrinsic or extrinsic factors that interfere with the single antigen bead assay.49

T3
TABLE 3.:
Actions to be taken when detecting de novo DSA

R7. In the event of DSA+, adherence must be evaluated (LE 2b; GR B; A 90%)

At this point, the panel considers it appropriate to actively question the adequacy of treatment and evaluate adherence to it, preferably through validated questionnaires. If noncompliance with treatment is suspected, an attempt can be made to confirm this by evaluating the medication collection in the pharmacy if it can be accessed (hospital and community), or by analyzing the variability coefficient of drug levels.

R8. Upon detection of DSA+ post-RT, the panel suggests closer monitoring of the patient (LE 5; GR D; A 95%)

This point is relevant, given the risk of rejection or other complications. The panel considers that monitoring should be individualized as stated in previous sections, valuing other intercurrent processes and the possibility of increasing visits or some other procedures.

R9. Upon detection of DSA+ post-RT, the panel suggests considering the patient as high risk (LE 5; GR D; A 80%)

This involves following the recommendations previously given for this category of risk classification.

R10. Upon detection of DSA+ post-RT, the panel recommends assessing the need to increase the immunosuppression (LE 4; GR D; A 70%)

Different strategies can be proposed (see Management section).

R11. If DSA+, the panel suggests—unless contraindicated—performing a renal biopsy (LE 5; GR D; A 74%)

Renal biopsy is the technique used to determine what is happening in an RT.10 Given this context, the panel wishes to emphasize that in cases in which a biopsy is requested by de novo DSA positivity, even if the result proves to be negative for graft damage, this does not rule out that a rejection may develop in the future. Thus, new biopsies may be requested if deemed appropriate.

Management of DSAs

R12. The panel considers that one of the objectives of RT treatment in relation to DSAs is to prevent their occurrence (LE 5; GR D; A 100%)

This point is relevant, given the absence of a truly effective treatment that can reverse or control the impact of DSAs.

One preventive strategy is to assess factors associated with DSA occurrence. These may include (1) young age (partly in relation to nonadherence),16 (2) female gender (probably due to the effect of pregnancies, as these induce the production of anti-HLA antibodies),10,23,67 (3) presence of pre-RT antibodies other than DSAs,23 (4) large number of HLA disidentities, especially DR and DQ,10,23,65,67 (5) re-RT or other sensitizing events like transfusions or pregnancies,16,68,69 (6) early T-cell–mediated rejection,68,70 (7) episodes of acute rejection,71,72 (8) nonadherence to treatment, (9) intraindividual variability of immunosuppression levels, (10) discontinuation/reduction of calcineurin inhibitor (ICN) dosage, which may lead to excessive calcineurin minimization, and (11) the use of mammalian target of rapamycin inhibitors (mTORi) without ICN.16,73–75

Regarding immunosuppression, different prestigious groups have highlighted the relevance of under immunosuppression as for DSA development and survival of the graft.8

R13. It is recommended to avoid or at least control the factors that may increase tacrolimus level variability as much as possible(LE 2b; GR B; A 90%)

Tacrolimus is an ICN widely used in RT. It has been observed that tacrolimus level variability (especially if high, ie, intrapatient variability with a variation coefficient >30%) may increase the risk of DSA development2 and negatively affect RT outcome.1,2,76–80

Its oral bioavailability is low (average 25%), with high intrapatient variability (5% to 90%).81–83 Its extended-release formulation produces an extended oral absorption profile, enabling it to be absorbed through the gastrointestinal tract and undergo extensive presystemic metabolism. Tacrolimus taken once a day improves treatment adherence and, compared with tacrolimus taken twice a day, decreases its intrapatient variability.84–88

Another possible source of variability may be the conversion to generic formulations or the combination of different formulations. Based on the available evidence, it has been found in some patients/circumstances that bioequivalence between drugs may be inadequate.89,90 Therefore, it is recommended that this conversion be performed by an RT specialist under close monitoring of tacrolimus.8 Finally, other factors that may affect drug level variability could include diarrhea, vomiting, anemia, hypoalbuminemia, diet, drugs that interact with tacrolimus through enzymatic induction or inhibition, as well as pregnancy.83,84,91 Similar effects have been reported for other ICNs, such as cyclosporine.84,92

R14. As much as possible (in the absence of clinical indications like cancer or infections), minimization of tacrolimus dosage in combination with mycophenolic acid should be avoided to prevent DSA occurrence (LE 2a; GR B; A 74%)

Several studies have stated that if tacrolimus dosage is significantly decreased, DSAs may occur, with an increased risk of graft loss.1,76,93–98 In one of these studies, low tacrolimus levels (<8 ng/mL) during the first year post-RT were associated with an increased (adjusted) risk of de novo DSAs and active humoral rejection at 1 y, as well as an increased risk of graft loss at 5 y.93 Concerning specific tacrolimus levels, <5 ng/mL levels have been reported to be associated with an increased risk of de novo DSA and graft loss.96,97 Finally, another study observed that mean tacrolimus levels of 6.4 and 6.5 ng/mL at 1 and 3 y, respectively, were associated with improved graft survival compared with standard cyclosporine or low-dose sirolimus.98

Meanwhile, an article reporting the results of 2 RCTs67 analyzed patients who were randomized to continue either with cyclosporine, mycophenolate mofetil (MMF), and corticoids or with a conversion of cyclosporine by everolimus without steroids soon after transplantation. The patients in the everolimus group without steroids had an increased risk of de novo DSAs and AMR in relation to insufficient immunosuppressive therapy.

For all the aforementioned reasons, the panel states that (1) it is necessary to be very strict in the clinical monitoring of the immunosuppression in the RT recipient and to control ICN to avoid nonadherence or other situations that entail a minimization and could cause the occurrence of DSAs and, consequently, worsen the prognosis; (2) before reducing, suspending, or performing an immunosuppression conversion, it appears essential to carefully evaluate this issue, analyze drug levels, and assess the risk-benefit of these actions; (3) if minimization is necessary (eg, because of direct toxicity or immunosuppression-related undesirable effects), alternatives such as conversion to an inhibitor of mTORi, MMF, or azathioprine with corticosteroids may be considered.

R15. The panel recommends actively encouraging adherence to immunosuppressive therapy in kidney transplant recipients, for example, through patient education or the use of drugs that require less frequent intake (LE 5; GR D; A 85%)

As previously mentioned, nonadherence to immunosuppressive therapy is associated with the development of DSAs.73,99 Multiple factors associated with nonadherence100 have been described, such as immunosuppression-related undesirable events or treatment complexity (eg, chronic, with a high number of comedications, dosage frequency). To improve this, a series of actions have been proposed, including the implementation of educational programs or strategies for greater treatment involvement of younger patients (eg, the use of long-acting parenteral immunosuppression or medications taken only once a day).101–103

Pharmacological Management

R16. Immunosuppression management in DSA+ patients should be based on the patient’s clinical profile (LE 5; GR D; A 85%)

The panel considers it essential to individualize each case, taking into account different clinical features like renal function and biopsy results.

R17. In patients who develop de novo DSA

  1. With normal biopsy and renal function, the panel suggests not lowering immunosuppression (LE 5; GR D; A 75%).
  2. With normal renal function and microinflammation in the biopsy, the panel suggests optimizing immunosuppression (LE 5; GR D; A 80%).
  3. Without the possibility of performing a renal biopsy (eg, anticoagulated patient or patient decision), the panel suggests not to decrease the immunosuppression and, in some cases, to even increase it (LE 5; GR D; A 70%).
  4. With acute dysfunction, the panel suggests combining treatment with plasma exchange or immune-adsorption or polyclonal gamma globulin with or without rituximab (RTX; LE 3a; GR C; A 70%).
  5. With proteinuria or subacute/chronic renal function deterioration, the panel suggests optimizing immunosuppressive therapy and introducing renin-angiotensin-aldosterone system inhibitors (LE 5; GR D; A 80%).
  6. The panel suggests following the same recommendations that immunosuppressive therapy be given in relation to the patient’s tolerance for drugs commonly used in RT (LE 5; GR D; A 75%).

Currently, there is not enough evidence to define the best therapeutic option among different patient profiles. Fortunately, an immunosuppression arsenal is available for RT patients, consisting of either monotherapy or combination treatments including corticosteroids, plasmapheresis, immunoadsorption, and intravenous immunoglobulins, standard ICNs like tacrolimus or cyclosporine, MMF, azathioprine, and mTORi (everolimus or sirolimus), or biological therapies like RTX, bortezomib, eculizumab, anti-C1, and tocilizumab.104–118

Concerning patients with a biopsy compatible with active AMR and altered renal function, the available data were obtained from individual studies of low to moderate quality. Several comprehensive SLRs119,120 have shown that in these patients, immunoadsorption with protein A121 or plasmapheresis122–130 is likely to decrease DSA levels and improve histological and renal function data. Some studies have analyzed the role of ivIg administration, usually in combination with other therapies. Although some benefits have been shown, it is difficult to analyze the effects of such administration in isolation.126

The use of RTX is controversial. In a previously published SLR,119,120 it was used in most cases in combination with other therapies, with an overall positive effect on DSAs and RT in some studies.126,128,129,131,132 However, an RCT including 40 patients with plasma exchange as well as ivIg administration and corticosteroids was subsequently published. This publication reported that adding RTX did not produce greater benefits at 1 y.109 In both groups, there was a rapid and significant decline in DSAs. Although at day 12, slightly > 50% of patients did not show a significant improvement in renal function, a trend towards improvement throughout the study was revealed in both groups. Biopsy data additionally improved in all patients, although 30% to 40% of patients exhibited persistent AMR data at 6 mo. Proteinuria did not significantly decrease in either group, there were no deaths, and only 2 grafts were lost (1 in each group). Recently, another double-blinded placebo-controlled trial involving patients with chronic AMR and RTX along with ivIg133 found no differences at 1 y in glomerular filtration rate (GFR), proteinuria, DSA levels, or Banff scores.

Another drug that has been evaluated in this patient population is bortezomib. A small, low-quality controlled trial showed a trend towards improvement in survival in the bortezomib group without providing data on DSA levels.129 Another report found no difference with RTX use in terms of graft survival and renal function (both groups were additionally treated with ivIg and plasmapheresis).132 Recently, a placebo-controlled RCT134 that analyzed DSA positive patients with antibody-mediated late rejection was published. In this publication, at 2 y, no difference was found between bortezomib and placebo in terms of GFR, graft survival, urinary protein concentration, DSA levels, or molecular morphological rejection phenotypes in biopsies. However, a greater number of undesirable effects were reported in the bortezomib group. Note that no additional treatment was permitted in this study.

Concerning eculizumab, a low-quality blinded pilot RCT analyzed 15 patients with angiotensin-converting enzyme-mediated chronic kidney damage. Data analysis revealed a greater change in GFR in patients with C1q-positive DSAs versus C1q-negative. This report additionally compared eculizumab with a patient group that was simply observed to be evolving, with no change in DSA levels observed. The authors suggested that this drug may stabilize kidney function in these patients.135

Some data are also available on tocilizumab. In a series of 36 patients with chronic AMR, DSAs, and RT glomerulopathy refractory to RTX and ivIg treatment, it was found that using tocilizumab improved graft and patient survival at 6 y (81% and 91%, respectively), significantly decreased DSA levels, and stabilized renal function at 2 y118 compared to a historical group.

There is no evidence that DSAs are associated with a worse safety profile for drugs used in RT. Therefore, the recommendations generated for using these drugs, as well as the indications stated in drug data sheets, remain applicable.

DISCUSSION

To improve clinical practice in relation to RT recipients and the possibility of DSAs, it is essential to provide explicit recommendations that guide clinicians in the management of these patients in different scenarios.

In recent years, interest in DSAs has grown enormously. Their specific role in relation to immune rejection or graft loss is becoming increasingly clear.1,2 Therefore, considering the variability in their detection and monitoring strategies,3 this document primarily sought to generate clinical recommendations, both simple and implementable in daily practice, on the monitoring and management of patients with DSAs. Following an exhaustive review of the evidence available, with a low LE for many recommendations, we would like to highlight the high level of agreement reached on all points, thereby reinforcing our recommendations’ validity. In addition, these recommendations were generated and agreed upon by a large group of Spanish RT experts.

The panelists were eager to convey several key messages. The first of these messages highlights the need to stratify the risk in patient RT.8,11,12,45 Although there are no universally accepted criteria and still many unknowns in this area, the panel considered this a very useful tool to guide the monitoring of AEDs. However, given this context, the panel also considered that based on the latest findings,5 each case should always be individualized, especially concerning patients with apparently less worrisome risk.

With regard to DSA determination, it was agreed that patients should have undergone antibody determination by means of a Luminex platform assay. Although different cutoff points have been described to define DSA positivity, these are not well validated. Therefore, the panel considered that the assay interpretation, that is, the immune response or reaction it provokes, appears more relevant for defining the positivity.60,61 Once de novo DSAs have developed, clinicians will find in this paper a detailed description of the steps to follow, along with their underlying rationale.

This document has highlighted the relevance of taking biopsies from patients with de novo DSAs. It must, however, be noted that their systematic indication generated some controversy.10 Again, when analyzing each case individually in clinical practice, it is possible that we may find a case for which, exceptionally, such a biopsy may not be requested. In addition, the expert panel wanted to emphasize that, even though the biopsy results may not indicate anything pathological, clinicians should not forget that such patients may still be high risk. Kidney damage may develop later and, therefore, another biopsy should be performed.

Another fundamental point highlighted in the document concerned the guidelines to follow to prevent DSA development. The panel agreed to follow the guidelines, many of which are related to the handling of certain drugs and therapy adherence. This could potentially prevent the development of DSAs. Furthermore, it was considered of vital importance for both DSA monitoring and management to individualize each case, always bearing in mind the clinical situation and characteristics of each patient.

Finally, concerning immunosuppression management of a patient with DSAs, the expert panel offered some general guidelines for clinicians to follow. There is no one single treatment or a combination of maintenance treatments that have proven more effective than the others among different patient profiles. It is thus essential to individualize each case while taking into account the clinicians’ experience with the different treatments. Despite scarce evidence, we have an important therapeutic arsenal for RT that may be beneficial for patients with de novo DSAs, especially in case of acute transplant dysfunction.104–118

In summary, this document has proposed a series of practical recommendations based on scientific evidence and expert opinions. We strongly think that these recommendations may be relevant and useful for clinicians in their day-to-day lives, possibly complementing other general clinical practice guidelines for RT.

Acknowledgments

The authors want to acknowledge the support of Astellas, the Spanish Society of Nephrology (SEN), the Spanish Society of Transplantation (SET), and the Spanish Network for Research in Renal Diseases (REDINREN, RED16/0009).

REFERENCES

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