Multivariate analysis of the effectiveness of using antibody induction therapy according to the degree of HLA mismatches

OBJECTIVE: HLA mismatches have a strong impact on acute rejection and renal allograft survival. The objective of this study was to evaluate the effectiveness of antibody induction according to the degree of HLA mismatches. METHODS: Of 20,429 deceased donor (DD) transplantations and 12,859 living donor (LD) transplantations reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% of DD and 45% of LD transplant recipients received induction therapy. Propensity scores (PS) were calculated to indicate independent factors associated with the use of induction. Levels of HLA match examined for DD transplant recipients were 0 ABDR (n = 3239), 0 DR (n = 4210), and DR mismatched transplants (n = 12,980), and 0 (n = 1133), 1 (n = 3836), and 2 (n = 7890) haplotype mismatches for LD transplant recipients. Outcome parameters were reported as hazard ratios (HR) for graft loss and odds ratios (OR) for first-year acute rejection. RESULTS: Recipients with HLA mismatches were more likely to receive induction antibody for DR mismatch in DDs (PS = 1.11, 95% confidence interval [CI] 1.04-1.19) and for haplotype mismatch in LDs (PS = 1.36, 95% CI 1.22-1.52). Induction reduced the likelihood of acute rejection for DD transplant recipients regardless of the level of HLA mismatch (OR = 0.70; 95% CI 0.57-0.85 in 0 ABDR MM; OR = 0.76, 95% CI 0.64-0.89 in 0 DR MM; and OR = 0.69, 95% CI 0.62-0.77 in DR MM), and for 2 haplotype mismatched LD transplant recipients (OR = 0.82, 95% CI 0.70-0.96); in other LD transplant recipients, reductions in acute rejection rates were observed but not statistically significant. Induction reduced the risk of graft loss for DR mismatched DD transplant recipients by about 12% (HR = 0.88; 95% CI 0.80-0.97). CONCLUSIONS: Antibody induction resulted in a significant reduction of acute rejection and graft loss for patients with HLA mismatch.     

Long‐term impact of human leukocyte antigen mismatches combined with expanded criteria donor on allograft outcomes in deceased donor kidney transplantation

The long‐term impact of human leukocyte antigen (HLA) mismatches combined with expanded criteria donors (ECD) on clinical outcomes has not been fully evaluated in recipients of deceased donor (DD) kidney transplantations. Of 595 DD renal transplant recipients in our center between 1991 and 2011, 210 recipients (36%) had 0–3 HLA mismatches/standard criteria donor (SCD), 353 (59%) had 4–6 HLA mismatches/SCD or 0–3 HLA mismatches/ECD, and 32 (5%) had 4–6 HLA mismatches/ECD. The mortality rate was significantly highest in the patients with 4–6 HLA mismatches/ECD (p = 0.040). The most common cause of death in this group was infection (50%). There were no significant differences in overall graft survival and death‐censored graft survival. The biopsy‐proven acute rejection rate was significantly higher in the 4–6 HLA mismatches/ECD group (p = 0.011). Cox‐regression multivariate analyses showed that 4–6 HLA mismatches plus ECD (adjusted hazard ratio [AHR], 3.2; 95% confidence interval [CI], 1.17–10.56) and diabetes (AHR, 4.3; 95% CI, 1.50–12.28) were significant predictors of recipient mortality. In conclusion, ≥4 HLA mismatches plus ECD were associated with significantly higher rates of biopsy‐proven acute rejection and mortality compared with other groups undergoing DD kidney transplantation.     

Daclizumab Versus Rabbit Antithymocyte Globulin in High‐Risk Renal Transplants: Five‐Year Follow‐up of a Randomized Study

We previously reported a randomized controlled trial in which 227 de novo deceased‐donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy‐proven acute rejection (BPAR) and steroid‐resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG‐treated patient (0.9%) and one daclizumab‐treated patient (1.0%) developed BPAR after 1 year. Five‐year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high‐immunological‐risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low‐risk cohorts.     

Three‐month pancreas graft function significantly influences survival following simultaneous pancreas‐kidney transplantation in type 2 diabetes patients

Successful simultaneous pancreas‐kidney transplantation (SPK) improves quality‐of‐life and prolongs kidney allograft and patient survival in type‐1 diabetic (T1DM) patients. However, the use of SPK in type‐2 diabetic (T2DM) patients remains limited. We examined a national transplant registry for 35 849 T2DM kidney disease patients who received transplant between 2000 and 2016 and survived the first 3 months with a functioning kidney, and categorized as: deceased‐donor kidney transplant alone (DD‐KA, 68%), living‐donor kidney transplant alone (LD‐KA, 30%), or SPK (2%). Among SPK recipients, 6% had pancreas allograft failure within 3 months (SPK,P‐) and 94% had a functional pancreas (SPK,P+). Associations of transplant type with kidney allograft failure and death (multivariable‐adjusted hazard ratio, _95%LCLaHR_95%UCL), over follow‐up through December 2018, were quantified by multivariable inverse probability of treatment weighted survival analyses. SPK recipients had better kidney graft and patient survival than LD‐KA or DD‐KA recipients. Compared to SPK,P+, DD‐KA, or LD‐KA recipients had significantly higher risk of kidney allograft failure (DD‐KA: aHR _1.532.20_3.17; LD‐KA: aHR _1.291.87_2.71) and death (DD‐KA: aHR _2.123.25_5.00; LD‐KA: aHR _1.542.35_3.59). SPK,P‐ recipients had significantly higher risk of death (aHR _1.683.30_6.50). Similar to T1DM, T2DM patients with SPK have a survival benefit compared to those with kidney transplant alone, but this benefit depends upon successful early pancreas function.     

Soluble CD30 and ELISA‐detected human leukocyte antigen antibodies for the prediction of acute rejection in pediatric renal transplant recipients

Biomarker‐based post‐transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well‐controlled prospective randomized trial was analyzed pre‐ and post‐transplant for soluble CD30 (sCD30), a biomarker reflecting mainly T‐cell reactivity, and anti‐human leukocyte antigen (anti‐HLA) antibody reactivity, a biomarker for B‐cell activation. A sCD30 concentration ≥40.3 U/ml on day 14 was able to discriminate between patients with or without biopsy‐proven acute rejection (BPAR) with a sensitivity of 100% and a specificity of 76%. Six of seven patients (86%) with BPAR showed a sCD30 above this cut‐off, whereas only 3/21 patients (14%) without BPAR had a sCD30 above this cut‐off (P = 0.004). For pre‐ and post‐transplant anti‐HLA class II reactivities by enzyme‐linked immunosorbent assay, a cut‐off value of 140 optical density was able to discriminate rejecters from nonrejecters with a sensitivity of 86% or 71% and a specificity of 81% or 90%, respectively. Withdrawal of steroids was associated with a approximately twofold higher serum sCD30 compared to controls, but did not affect anti‐HLA reactivities. An increased post‐transplant sCD30 serum concentration and positive pre‐ and post‐transplant anti‐HLA class II reactivities are informative biomarkers for impending BPAR in pediatric renal transplant recipients. (TWIST, Clinical Trial No: FG‐506‐02‐43)     

Organ allocation in pediatric renal transplants: is there an optimal donor?

The 2005 revised allocation scheme for pediatric renal transplantation made the decision of whether to transplant an available living‐donor (LD) kidney or use a deceased‐donor (DD) kidney controversial. The aim of this study was to examine kidney allograft utilization, sensitization, and outcomes of pediatric transplant recipients. Between January 2000 and December 2009, 91 consecutive pediatric kidney recipients (<20 yr) were transplanted. The LD (n = 38) and DD (n = 53) groups were similar in age, gender, dialysis status at transplant, warm ischemia time, and overall patient survival. LD recipients were more likely to be Caucasian (92 vs. 69%), receive older allografts (39 ± 10 vs. 23 ± 9 yr), and have fewer human leukocyte antigen (HLA) mismatches (3.3 ± 1.6 vs. 4.4 ± 1.5, p < 0.01 for all). Graft survival at one, three, and five yr post‐transplant was longer for LD recipients (97%, 91%, 87% vs. DD 89%, 79%, 58%, respectively, p < 0.05). At the time of transplant, 17 (33%) DD recipients had an available LD (mean age 40 yr). A greater proportion of all patients were moderately (PRA 21–79%) sensitized post‐transplant (p < 0.05). A multivariable analysis of graft survival indicated that the advantage in LD organs was likely due to fewer HLA mismatched in this group. Nonetheless, LD organs appear to provide optimal outcomes in pediatric renal transplants when considering the risk of becoming sensitized post‐transplant complicating later use of the LD kidney.     

Prednisone‐free maintenance immunosuppression in obese kidney transplant recipients

Obese transplant recipients (BMI ≥ 30 kg/m²) have decreased posttransplant patient and graft survival compared with their nonobese counterparts. At the same time, many prednisone‐related side effects (eg, new‐onset diabetes) are similar to those associated with obesity. Using SRTR data, we studied outcomes associated with prednisone‐free maintenance immunosuppression (rapid discontinuation of prednisone—RDP). Between January 1, 2000, and December 31, 2014, 44 635 first transplant recipients with BMI ≥ 30 kg/m² had a first kidney transplant (28 176 DD; 16 459, LD); 12,994 (29%) were discharged from the hospital on a prednisone‐free protocol. We compared outcomes to those discharged on a protocol incorporating maintenance prednisone (intention‐to‐treat analysis). RDP‐treated obese first DD recipients had significantly better patient survival (HR, 0.88; CI, 0.81‐0.96) and graft survival (HR, 0.93; CI, 0.88‐0.99) compared with their counterparts on maintenance immunosuppression. Although not statistically significant, the same trends were seen for LD recipients. For both DD and LD recipients, there was no difference between groups for death‐censored graft survival, suggesting that the benefit of RDP was due to improved patient survival. Our findings suggest that kidney transplant recipients with BMI ≥ 30 kg/m² benefit from a protocol that incorporates RDP.     

A randomized,controlled trial of everolimus‐based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Kidney transplant recipients receiving calcineurin inhibitor‐based immunosuppression incur increased long‐term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36‐month, prospective, multinational, open‐label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI‐WD); everolimus with mycophenolate and steroid withdrawal (steroid‐WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI‐WD versus control was 65.1 ml/min/1.73 m² vs. 67.1 ml/min/1.73 m² by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI‐WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow‐up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.     

Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non‐sensitized renal transplant patients treated with rapid steroid withdrawal

Alemtuzumab and rabbit antithymocyte globulin (rATG) are commonly used for induction therapy in renal transplantation. This retrospective, single‐center, cohort study evaluated cumulative incidence of one‐yr biopsy‐proven acute rejection (BPAR) among 200 consecutive primary non‐sensitized kidney transplant recipients who received either alemtuzumab (n = 100) or rATG (n = 100) induction followed by rapid steroid taper, tacrolimus, and mycophenolate mofetil. Protocol biopsies, plasma and urine BK virus PCR, serum creatinine and iothalamate glomerular filtration rate (iGFR), were obtained at 1, 4, and 12 months from transplantation. The one‐yr BPAR rates were similar between the alemtuzumab and rATG groups; however, rejection Banff IA and higher was more common in the alemtuzumab arm (18% vs. 5%, p = 0.047). After adjusting for confounding variables, alemtuzumab was still associated with Banff IA and higher rejection (adjusted OR: 3.7, CI: 1.2–10.5, p = 0.02). Despite similar rates of BK viremia, more patients in the alemtuzumab arm developed BK nephropathy (16% vs. 3%, p = 0.046). One‐year iGFR (53.4 ± 20.2 vs. 71.9 ± 27.2 mL/min/1.73 m², p = 0.002) and three‐yr graft survival (89.5% vs. 95%, p = 0.05) were lower in the alemtuzumab group. In low immunological risk kidney transplant recipients on steroid‐free immunosuppression, alemtuzumab was associated with more severe rejection and BK nephropathy compared to rATG.     

Subclass analysis of donor HLA‐specific IgG in antibody‐incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure

Donor HLA‐specific antibodies (DSAs) can cause rejection and graft loss after renal transplantation, but their levels measured by the current assays are not fully predictive of outcomes. We investigated whether IgG subclasses of DSA were associated with early rejection and graft failure. DSA levels were determined pretreatment, at the day of peak pan‐IgG level and at 30 days post‐transplantation in eighty HLA antibody‐incompatible kidney transplant recipients using a modified microbead assay. Pretreatment IgG₄ levels were predictive of acute antibody‐mediated rejection (P = 0.003) in the first 30 days post‐transplant. Pre‐treatment presence of IgG₄ DSA (P = 0.008) and day 30 IgG₃ DSA (P = 0.03) was associated with poor graft survival. Multivariate regression analysis showed that in addition to pan‐IgG levels, total IgG₄ levels were an independent risk factor for early rejection when measured pretreatment, and the presence of pretreatment IgG₄ DSA was also an independent risk factor for graft failure. Pretreatment IgG₄ DSA levels correlated independently with higher risk of early rejection episodes and medium‐term death‐censored graft survival. Thus, pretreatment IgG₄ DSA may be used as a biomarker to predict and risk stratify cases with higher levels of pan‐IgG DSA in HLA antibody‐incompatible transplantation. Further investigations are needed to confirm our results.     

Clinical outcomes of ABO‐ and HLA‐incompatible kidney transplantation: a nationwide cohort study

This was a nationwide cohort study to investigate the impact of anti‐A/B and donor‐specific anti‐HLA (HLA‐DSA) antibodies on the clinical outcomes in kidney transplant recipients (KTRs). We classified a total of 1964 KTRs into four groups: transplants from ABO‐incompatible donors (ABOi, n = 248); transplants in recipients with HLA‐DSA (HLAi, n = 144); transplants from combined ABOi and HLAi donors (ABOi + HLAi, n = 31); and a control group for whom neither ABOi nor HLAi was applicable (CONT, n = 1541). We compared the incidence of biopsy‐proven acute rejection (BPAR), allograft and patient survival rates. The incidence of BPAR was higher in the HLAi and ABOi + HLAi groups relative to the CONT group; in contrast, it was not higher in the ABOi group. Death‐censored graft survival rates did not differ across the four groups. However, relative to the CONT group, patient survival rate was reduced in the ABOi and ABOi + HLAi groups, and with infection being the most common cause of death. Further, multivariable analysis revealed that desensitization therapy because of ABOi or HLAi was independent risk factors for patient mortality. HLAi was a more important risk factor for BPAR compared with ABOi. However, pretransplant desensitization therapy for either ABOi or HLAi significantly increased the risk of infection‐related mortality.     

Anti‐IL‐2R blockers comparing with polyclonal antibodies: Higher risk of rejection without negative mid‐term outcomes after ABO‐incompatible kidney transplantation

There is no recommendation regarding the type of induction therapy to use in ABO‐incompatible (ABOi) kidney transplantation. The aim of this retrospective study was to compare the outcome of ABOi living donor kidney transplant (LDKT) recipients who received either polyclonal antibodies or anti‐interleukin‐2 receptor (IL‐2R) blockers as an induction agent. All ABOi HLA‐compatible patients that received a LDKT between 03/11 and 03/18 in three French transplantation center (Paris Saint‐Louis, Paris Necker, and Toulouse) were included in the study. Fifty‐eight patients were given polyclonal antibodies and 39 patients received anti‐IL‐2R blockers. We identified by a Cox proportional hazard model the use of polyclonal antibodies as a protective factor against acute rejection (HR = 0.4, 95%CI [0‐0.9], P < .05). However, pathological findings on protocol biopsies at 1 year were similar in both groups, as were patient and graft survivals, renal function, and complications. We conclude that the acute rejection rate was significantly higher in patients given anti‐IL‐2R blockers compared to polyclonal antibodies. However, in our series, there was no negative impact on mid‐term outcome.     

Machine perfusion following static cold storage preservation in kidney transplantation: donor‐matched pair analysis of the prognostic impact of longer pump time

The impact of machine perfusion (MP) time on kidney transplant outcome is mixed in previous studies using multivariable analyses. In an analysis of 66 pairs of donor‐matched adult, first transplant recipients (N = 132) with identical donor characteristics except for pump time, tests of association of shorter versus longer pump time (first versus second kidney removed) by delayed graft function(DGF), slow graft function(SGF), and biopsy proven acute rejection(BPAR) were performed using McNemar’s test. Freedom‐from‐BPAR, graft and patient survival, and renal function were also compared. Mean ± SD pump times for paired recipients with first and second kidneys were 22.7 ± 7.3 h and 31.2 ± 7.9 h, respectively (mean difference: 8.5 ± 4.5 h, P < .000001). There was no significant impact of pump time on DGF or SGF, with discordant pairs favoring less SGF with longer pump time (N.S.). The incidence of BPAR during the first 12 months post‐transplant yielded a borderline difference favoring longer pump time (P = .09), and freedom‐from‐BPAR during the first 12 months was significantly more favorable for longer pump times (95% vs. 84%, P = 0.04). No differences were observed in graft and patient survival, and renal function. While offering significantly favorable protection from BPAR, this analysis of donor‐matched recipient pairs corroborates longer MP (pump) times having no unfavorable effect on other clinical outcomes.     

Clinical relevance of the de novo production of anti‐HLA antibodies following intestinal and multivisceral transplantation

Despite a negative pretransplant cross‐match, intestinal transplant recipients can mount humoral immune responses soon after transplantation. Moreover, the development of donor‐specific anti‐HLA antibodies (DSAs) is associated with severe graft injury. Between June 2000 and August 2011, 30 patients (median age 37.6 ± 9.8 years) received isolated intestinal transplantations (ITX, n = 18) or multivisceral transplantations (MVTXs, n = 12) at our center. We screened for human leukocyte antigen (HLA) antibodies pre‐ and post‐transplant. If patients produced DSAs, treatment with plasmapheresis and intravenous immunoglobulin (IVIG) was initiated. In the event of DSA persistence and/or treatment‐refractory rejection, rituximab and/or bortezomib were added. Ten patients developed DSAs and simultaneously showed significant signs of rejection. These patients received plasmapheresis and IVIG. Eight patients additionally received rituximab, and two patients were treated with bortezomib. DSA values decreased upon antirejection therapy in 8 of the 10 patients. The development of DSAs following ITX is often associated with acute rejection. We observed that the number of mismatched antigens and epitopes correlates with the probability of developing de novo DSAs. Early diagnosis and therapy, including B‐cell depletion and plasma cell inhibition, are crucial to preventing further graft injury.     

Should Pediatric Patients Wait for HLA‐DR‐Matched Renal Transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA‐DR mismatches on graft survival. Zero HLA‐DR‐mismatched kidneys had statistically comparable 5‐year graft survival (71%), to 1‐DR‐mismatched kidneys (69%) and 2‐DR‐mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel‐reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA‐A, ‐B or ‐DR mismatch of the first transplant, nor was there a ‘dose effect’ when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN) allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA‐DR‐matched kidney.     

Allograft outcome following repeat transplantation of patients with non‐adherence‐related first kidney allograft failure: a population cohort study

Nonadherence is an important risk factor for premature allograft failure after kidney transplantation, but outcomes after re‐transplantation remain uncertain. Using data from the Australian and New Zealand Dialysis and Transplant registry, the associations between causes of first allograft failure and acute rejection‐related and non‐adherence‐related allograft failure following re‐transplantation were examined using competing risk analyses, treating the respective alternative causes of allograft failure and death with functioning graft as competing events. Fifty‐nine of 2450 patients (2%) lost their first allografts from nonadherence. Patients who lost their first kidney allograft from nonadherence were younger at the time of first kidney allograft failure but waited longer for a second allograft (>5 years: 54% vs. 20%, P < 0.001) compared with other causes. Compared with patients who lost their first allograft from causes other than nonadherence, the adjusted subdistribution hazard ratio (HR and 95% CI) for acute rejection‐related second allograft failure was 0.58 (0.08, 4.07; P = 0.582) for patients with allograft failure attributed to nonadherence and was 6.30 (1.34, 29.67; P = 0.020) for non‐adherence‐related second allograft failure. In this cohort of transplant recipients who have received second allografts, first allograft failure secondary to nonadherence was associated with a marginally greater risk of allograft failure attributed to nonadherence in subsequent transplantation.     

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.     

A donor risk index for graft loss in pediatric living donor kidney transplantation

Pediatric kidney transplant candidates often have multiple potential living donors (LDs); no evidence‐based tool exists to compare potential LDs, or to decide between marginal LDs and deceased donor (DD) kidney transplantation (KT). We developed a pediatric living kidney donor profile index (P‐LKDPI) on the same scale as the DD KDPI by using Cox regression to model the risk of all‐cause graft loss as a function of living donor characteristics and DD KDPI. HLA‐B mismatch (adjusted hazard ratio [aHR] per mismatch = _1.041.27_1.55), HLA‐DR mismatch (aHR per mismatch = _1.021.23_1.49), ABO incompatibility (aHR = _1.203.26_8.81), donor systolic blood pressure (aHR per 10 mm Hg = _1.011.07_1.18), and donor estimated GFR (eGFR; aHR per 10 mL/min/1.73 m² = _0.880.94_0.99) were associated with graft loss after LDKT. Median (interquartile range [IQR]) P‐LKDPI was ?25 (?56 to 12). 68% of donors had P‐LKDPI <0 (less risk than any DD kidney) and 25% of donors had P‐LKDPI >14 (more risk than median DD kidney among pediatric KT recipients during the study period). Strata of LDKT recipients of kidneys with higher P‐LKDPI had a higher cumulative incidence of graft loss (39% at 10 years for P‐LDKPI ≥20, 28% for 20> P‐LKDPI ≥?20, 23% for ?20 > P‐LKDPI ≥?60, 19% for P‐LKDPI <?60 [log rank P < .001]). The P‐LKDPI can aid in organ selection for pediatric KT recipients by allowing comparison of potential LD and DD kidneys.     

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation‐05 Study

Identification of biomarkers that assess posttransplant risk is needed to improve long‐term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)‐05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy‐proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti‐HLA‐ and auto‐antibodies, angiogenic proteins, peripheral blood allo‐reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti‐HLA antibody (p < 0.04). Recipient CMV‐negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor‐C (OR 20; 95%CI:1.9–218) combined with decreases in endothelin‐1 (OR 0.14; 95%CI:0.02–0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.     

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label,single‐arm,one‐way crossover study

There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.