ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis.

Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl].

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients.

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals.

Antibodies against ARHGDIB are associated with long-term kidney graft loss.

The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation.

A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival.

BACKGROUND: Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs. METHODS: To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay. RESULTS: Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11). CONCLUSION: This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term.

Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients.

BACKGROUND: Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. METHODS: We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. RESULTS: Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n = 542), CsA/mycophenolate mofetil (MMF)/Pred (n = 857) and tacrolimus (TAC)/MMF/Pred (n = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P < 0.0001) and CsA/Pred (64%, P < 0.0001). CONCLUSION: These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival.

Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure.

Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients.Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay.Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; P=0.93). Patients without DSA had a 10-year graft survival of 78%.Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure.

Coronary Artery Calcification in Hemodialysis and Peritoneal Dialysis.

BACKGROUND: Vascular calcification is seen in most patients on dialysis and is strongly associated with cardiovascular mortality. Vascular calcification is promoted by phosphate, which generally reaches higher levels in hemodialysis than in peritoneal dialysis. However, whether vascular calcification develops less in peritoneal dialysis than in hemodialysis is currently unknown. Therefore, we compared coronary artery calcification (CAC), its progression, and calcification biomarkers between patients on hemodialysis and peritoneal dialysis. METHODS: We measured CAC in 134 patients who had been treated exclusively with hemodialysis (n = 94) or peritoneal dialysis (n = 40) and were transplantation candidates. In 57 of them (34 on hemodialysis and 23 on peritoneal dialysis), we also measured CAC progression annually up to 3 years and the inactive species of desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), fetuin-A, osteoprotegerin. We compared CAC cross-sectionally with Tobit regression. CAC progression was compared in 2 ways: with linear mixed models as the difference in square root transformed volume score per year (ΔCAC SQRV) and with Tobit mixed models. We adjusted for potential confounders. RESULTS: In the cross-sectional cohort, CAC volume scores were 92 mm3 in hemodialysis and 492 mm3 in peritoneal dialysis (adjusted difference 436 mm3; 95% CI -47 to 919; p = 0.08). In the longitudinal cohort, peritoneal dialysis was associated with significantly more CAC progression defined as ΔCAC SQRV (adjusted difference 1.20; 95% CI 0.09 to 2.31; p = 0.03), but not with Tobit mixed models (adjusted difference in CAC score increase per year 106 mm3; 95% CI -140 to 352; p = 0.40). Peritoneal dialysis was associated with higher osteoprotegerin (adjusted p = 0.02) but not with dp-ucMGP or fetuin-A. CONCLUSIONS: Peritoneal dialysis is not associated with less CAC or CAC progression than hemodialysis, and perhaps with even more progression. This indicates that vascular calcification does not develop less in peritoneal dialysis than in hemodialysis.

Extraosseous calcification in end-stage renal disease: from visceral organs to vasculature.

In earlier days, periarticular accumulations of calcium phosphate causing tumor-like depositions were considered the result of passive precipitation and referred to as metastatic calcifications. From sophisticated computer tomographic studies and growing insight, we have learned that calcifications in the cardiovascular system are far more threatening and in fact one of the most important sequela of end-stage renal disease. The histologic characteristic of uremia-related calcification is arteriosclerosis of the media. In addition, there is atherosclerosis of the intima, due to the high prevalence of classic cardiovascular risk factors in renal disease. The two vascular features can frequently exist at different sites in the vasculature. Novel diagnostic techniques are helping to elucidate the pathogenetic mechanisms of active conversion of vascular smooth muscle cells to osteochondritic cells. Through this process, extensive calcification of the central and peripheral vasculature ensues, influenced by different promotors and inhibitors. Calciphylaxis is a special form of extraosseous calcification leading to skin necrosis. The factors that trigger the development of calciphylaxis are not completely understood, but this syndrome shares part of the pathophysiologic basis of extraosseous calcification in general. However, the therapeutic approach must be prompt and aggressive, because of the poor prognosis. Frequently, a fatal outcome cannot be avoided in calciphylaxis.

Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival.

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants.

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation.

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.

T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation.

CD4+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.

Progression of coronary artery calcification in conventional hemodialysis, nocturnal hemodialysis, and kidney transplantation.

INTRODUCTION: Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients. METHODS: We measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (≥4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (ΔCAC SQRV) using linear mixed models. Reference category was conventional hemodialysis. RESULTS: The mean age of the study population was 53 ±13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12-56) months. Median CAC score at enrollment was 171 (IQR 10-647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models. CONCLUSIONS: Nocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk.

Toward a Sensible Single-antigen Bead Cutoff Based on Kidney Graft Survival.

BACKGROUND: There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody. METHODS: To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants. RESULTS: First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background. CONCLUSIONS: With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.

Health-related quality of life compared between kidney transplantation and nocturnal hemodialysis.

BACKGROUND: Health-related quality of life (HRQOL) is an important outcome measure in patients with end-stage renal disease. HRQOL is assumed to improve with kidney transplantation and also with nocturnal hemodialysis compared to conventional hemodialysis. However, there is no evidence regarding HRQOL to support the optimal treatment choice for patients on nocturnal hemodialysis who hesitate opting for transplantation. We therefore compared HRQOL between patients who were treated with kidney transplantation or nocturnal hemodialysis for one year. METHODS: We assessed HQROL using the Kidney Disease Quality of Life-Short Form questionnaire in a cross-sectional sample of patients who were treated with kidney transplantation (n = 41) or nocturnal hemodialysis (n = 31) for one year. All patients on nocturnal hemodialysis were transplantation candidates. Using linear regression, we compared HRQOL between kidney transplantation and nocturnal hemodialysis, and adjusted for age, sex, dialysis duration, cardiovascular disease, and presence of residual urine production. RESULTS: At one year follow-up, mean age of the study population was 54 ±13 years, and median dialysis duration was 3.2 (IQR 2.1-5.0) years. Kidney transplantation was associated with significantly higher HRQOL on the domain "effects" compared to nocturnal hemodialysis (adjusted difference 12.0 points, 95% CI 3.9; 20.1). There were potentially clinically relevant differences between kidney transplantation and nocturnal hemodialysis on the domains "burden" (adjusted difference 11.1 points, 95% CI -2.6; 24.8), "social support" (adjusted difference 6.2, 95% CI -6.6; 19.1), and the physical composite score (adjusted difference 3.0, 95% CI -2.0; 8.1), but these were not significant. CONCLUSIONS: After kidney transplantation, HRQOL is especially higher on the domain "effects of kidney disease" compared to nocturnal hemodialysis. This can be useful when counseling patients on nocturnal hemodialysis who may opt for transplantation.

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation.

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.

Development and Validation of a Multiplex Non-HLA Antibody Assay for the Screening of Kidney Transplant Recipients.

The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.