Anti-intercellular adhesion molecule 1 monomaintenance therapy induced long-term liver allograft survival without chronic rejection.

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

Pancreas after kidney transplantation, is it the time to overcome the stigma?

BACKGROUND: Pancreas transplantation is the most effective treatment to improve quality of life and overcome complications in patients with end-stage renal disease and diabetes mellitus. One of the main approaches for concurrent renal disease and diabetes mellitus which has been underutilized during the past decade is a pancreas transplant after kidney transplantation. Our study aimed to quantify outcomes following pancreas after kidney transplants (PAKs) in the United States from 2001 to 2020 with an emphasis on graft and patient survival. METHODS AND MATERIALS: A retrospective registry analysis was performed by accessing the OPTN/UNOS database for PAKs that were performed in the United States from January 2001 to April 2020. The study population was divided into two subgroups: patients receiving a pancreas transplant between 2001 and 2010 and those receiving a pancreas transplant between 2011 and 2020. RESULTS: The study examined a total number of 3706 PAK recipients; patients who received a PAK from January 2001 through December 2010 (n = 2892) and those who received a PAK from January 2011 to April 2020 (n = 814). The selection process of transplant recipients did not drastically change throughout the 2001-2010 and 2011-2020 periods. Length of stay at the hospital after the transplantation improved significantly in the 2011-2020 group relative to the 2001-2010 group (8.48 vs. 10.08 days, mean, p < 0.01). Additionally, more transplantation with 4-6 human leukocyte antigen mismatch occurred in the 2011-2020 group than in the 2001-2010 group (80.6% vs. 71.4%, p < 0.01). The pancreas preservation time of 13.35 h in the 2001-2010 group decreased significantly to 11.17 h in the 2011-2020 group (p < 0.001). The mean donor's amylase and lipase also decreased significantly in the 2011-2020 cohort. Significant graft survival improvement was observed in the 2011-2020 group compared to the 2001-2010 group after a long-term follow-up (p < 0.001). The mean Calculated Pancreas Donor Risk Index was 1.08 for the 2001-2010 group and 0.99 for the 2011-2020 group with a significant difference (p < 0.001). CONCLUSION: The beneficial results and improved outcomes observed in PAK patients demonstrate the effectiveness of the operation for individuals in need of a pancreas transplant. PAKs can prove to be a meaningful solution to overcome long waiting times, decrease the donor-recipient imbalance, expand the donor pool, and overcome the current underutilization in order to improve the short- and long-term quality of life in the groups of interest.

Outcome of surgical parathyroidectomy for tertiary hyperparathyroidism in kidney transplant recipients: tertiary hyperparathyroidism should not be ignored, for the sake of precious allografts.

Tertiary hyperparathyroidism is a complication of kidney transplantation. This complicated condition carries over from the dialysis period and varies according to the function of the transplanted allograft. Treatments include pharmacotherapy (mainly using calcimimetics) and parathyroidectomy, but calcimimetics are currently not covered by the national insurance system in Japan. Two types of parathyroidectomy can be performed: subtotal parathyroidectomy; and total parathyroidectomy with partial autograft. Both types can be expected to improve hypercalcemia. Concerns about the postoperative deterioration of allograft function are influenced by preoperative allograft function, which is even more likely to be affected by early surgery after kidney transplantation. In general, transient deterioration of allograft function after surgery is not expected to affect graft survival rate in the medium to long term. Tertiary hyperparathyroidism in kidney transplant recipients negatively impacts allograft and patient survival rates, and parathyroidectomy can be expected to improve prognosis in both kidney recipients and dialysis patients. However, studies offering high levels of evidence remain lacking.

TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival.

Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated the tolerability and activity of a novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), in a nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. TNX-1500 contains a rupluzimab fragment antigen-binding region and an immunoglobin G4 crystallizable fragment region engineered to reduce binding to the crystallizable fragment gamma receptor IIa and associated risks of thrombosis. Recipients were treated for 6 months with standard-dose TNX (sTNX) monotherapy, low-dose TNX monotherapy (loTNX), or loTNX with mycophenolate mofetil (MMF) (loTNX + MMF). Results were compared with historical data using chimeric humanized 5c8 monotherapy dosed as for loTNX but discontinued at 3 months. Median survival time was similar for humanized 5c8 and both loTNX groups, but significantly longer with sTNX (>265 days) than with loTNX (99 days) or loTNX + MMF (88 days) (P < 0.05 for both comparisons against sTNX). Standard-dose TNX prevented antidonor alloantibody elaboration, inhibited chronic rejection, and was associated with a significantly reduced effector T cells/regulatory T cells ratio relative to loTNX with MMF. No thrombotic complications were observed. This study demonstrated that TNX was well tolerated, prolongs allograft survival, and prevents alloantibody production and cardiac allograft vasculopathy in a stringent preclinical nonhuman primate heart allotransplant model.

A Multi-Step Precision Pathway for Predicting Allograft Survival in Heterogeneous Cohorts of Kidney Transplant Recipients.

Accurate prediction of allograft survival after kidney transplantation allows early identification of at-risk recipients for adverse outcomes and initiation of preventive interventions to optimize post-transplant care. Many prediction algorithms do not model cohort heterogeneity and may lead to inaccurate assessment of longer-term graft outcomes among minority groups. Using data from a national Australian kidney transplant cohort (2008-2017) as the derivation set, we developed P-Cube, a multi-step precision prediction pathway model for predicting overall graft survival in three ethnic subgroups: European Australians, Asian Australians and Aboriginal and Torres Strait Islander Peoples. The concordance index for the European Australians, Asian Australians, and Aboriginal and Torres Strait Islander Peoples subpopulations were 0.99 (0.98-0.99), 0.93 (0.92-0.94) and 0.92 (0.91-0.93), respectively. Similar findings were observed when validating P-cube using an external dataset [Scientific Registry of Transplant Recipient Registry (2006-2020)]. Six sub-categories of recipients with distinct risk factor profiles were identified. Some factors such as blood group compatibility were considered important across the entire transplant population. Other factors such as human leukocyte antigen (HLA)-DR mismatches were unique to older recipients. The P-cube model identifies allograft survival specific risk factors within a heterogenous population and offers personalized survival predictions in a diverse cohort.

Long term outcomes following kidney transplantation in children who weighed less than 15 kg - report from the UK Transplant Registry.

BACKGROUND: Kidney transplantation is the treatment of choice in chronic kidney disease (CKD) stage 5. It is often delayed in younger children until a target weight is achieved due to technical feasibility and historic concerns about poorer outcomes. METHODS: Data on all first paediatric (aged < 18 years) kidney only transplants performed in the United Kingdom between 1 January 2006 and 31 December 2016 were extracted from the UK Transplant Registry (n = 1,340). Children were categorised by weight at the time of transplant into those < 15 kg and those ≥ 15 kg. Donor, recipient and transplant characteristics were compared between groups using chi-squared or Fisher's exact test for categorical variables and Kruskal-Wallis test for continuous variables. Thirty day, one-year, five-year and ten-year patient and kidney allograft survival were compared using the Kaplan-Meier method. RESULTS: There was no difference in patient survival following kidney transplantation when comparing children < 15 kg with those ≥ 15 kg. Ten-year kidney allograft survival was significantly better for children < 15 kg than children ≥ 15 kg (85.4% vs. 73.5% respectively, p = 0.002). For children < 15 kg, a greater proportion of kidney transplants were from living donors compared with children ≥ 15 kg (68.3% vs. 49.6% respectively, p < 0.001). There was no difference in immediate graft function between the groups (p = 0.54) and delayed graft function was seen in 4.8% and 6.8% of children < 15 kg and ≥ 15 kg respectively. CONCLUSIONS: Our study reports significantly better ten-year kidney allograft survival in children < 15 kg and supports consideration of earlier transplantation for children with CKD stage 5. A higher resolution version of the Graphical abstract is available as Supplementary information.

Prognostic value of the 7-year protocol biopsy of adult kidney allografts: impact of mesangiosclerosis and proteinuria.

AIM: The aim of the present study was to clarify the relationship between the Banff score of the 7-year protocol biopsy and the allograft outcome. METHODS: One-hundred-and-eighty-four patients received kidney transplantation from 2002 to 2008. We excluded patients aged <20 years at transplantation (n = 24), those who did not undergo a 7-year protocol biopsy (n = 66), and those who underwent for-cause biopsy (n = 5). Consequently, 89 patients who underwent a 7-year protocol biopsy were enrolled. We analyzed the relationship between the clinicopathological findings 7 years after transplantation and the estimated glomerular filtration rate (eGFR) change per year and allograft survival. Histological evaluation was performed using the Banff 2015 classification. RESULTS: Among the clinicopathological findings, each Banff mesangial matrix increase (mm) score ≥1 and proteinuria ≥1+ was independently associated with the eGFR decline per year during a median follow-up of 73 months. Furthermore, in the model of the clinicopathological findings including the presence of mm with proteinuria, mm ≥1 alone and mm ≥1 with proteinuria were each independently associated with the eGFR decline. The graft survival was significantly worse for those with mm ≥1 with proteinuria than those with mm ≥1 without proteinuria. CONCLUSION: Among the 7-year protocol biopsy findings, the presence of mm alone and mm with proteinuria were each significant predictors of eGFR decline. The presence of both proteinuria and mm had a negative impact on graft survival. These results underscore the significance of the Banff mm score and proteinuria at the time of the 7-year protocol biopsy to predict the allograft outcome.

Are short-term complications associated with poor allograft and patient survival after liver transplantation? A systematic review of the literature and expert panel recommendations.

BACKGROUND: Maximizing patient and allograft survival after liver transplant (LT) is important from both a patient care and organ utilization perspective. Although individual studies have addressed the effects of short-term post-LT complications on a limited scale, there has not been a systematic review of the literature formally assessing the potential effects of early complications on long-term outcomes. OBJECTIVES: To identify whether short-term complications after LT affect allograft and overall survival, to identify short-term complications of particular clinical interest and significance, and to provide recommendations to improve post-LT graft and patient survival. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: A systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. RESULTS: The literature review and analysis provided show that short-term complications have a large impact on allograft and patient survival after LT. The complications with the strongest effect on survival are acute kidney injury (AKI), biliary complications, and early allograft dysfunction (EAD). CONCLUSION: This panel recommends taking measures to reduce the risk and incidence of short-term complications post-LT. Clinicians should pay particular attention to preventing or ameliorating AKI, biliary complications, and EAD (Quality of evidence; Moderate | Grade of Recommendation; Strong).

The volume-outcomes relationship in donation after circulatory death liver transplantation.

BACKGROUND: Donation after circulatory death (DCD) liver transplantation (LT) has become an effective mechanism for expanding the donor pool and decreasing waitlist mortality. However, it is unclear if low-volume DCD centers can achieve comparable outcomes to high-volume centers. METHODS: From 2011 to 2019 utilizing the United Network for Organ Sharing (UNOS) database, liver transplant centers were categorized into tertiles based on their annual volume of DCD LTs. Donor selection, recipient selection, and survival outcomes were compared between very-low volume (VLV, n = 1-2 DCD LTs per year), low-volume (LV, n = 3-5), and high-volume (HV, n > 5) centers. RESULTS: One hundred and ten centers performed 3273 DCD LTs. VLV-centers performed 339 (10.4%), LV-centers performed 627 (19.2%), and HV-centers performed 2307 (70.4%) LTs. 30-day, 90-day, and 1-year patient and graft survival were significantly increased at HV-centers (all P < .05). Recipients at HV-centers had shorter waitlist durations (P < .01) and shorter hospital lengths of stay (P < .01). On multivariable regression, undergoing DCD LT at a VLV-center or LV-center was associated with increased 1-year patient mortality (VLV-OR:1.73, 1.12-2.69) (LV-OR: 1.42, 1.01-2.00) and 1-year graft failure (VLV-OR: 1.79, 1.24-2.58) (LV-OR: 1.28, .95-1.72). DISCUSSION: Increased annual DCD liver transplant volume is associated with improved patient and graft survival.

Survival After Simultaneous Pancreas-Kidney Transplantation in Type 1 Diabetes: The Critical Role of Early Pancreas Allograft Function.

Simultaneous pancreas-kidney transplantation (SPK) carries about a 7%-22% risk of technical failure, but the impact of early pancreas allograft loss on subsequent kidney graft and patient survival is not well-defined. We examined national transplant registry data for type 1 diabetic patients who received SPK between 2000 and 2021. Associations of transplant type (i.e., SPK, deceased-donor kidney transplant [DDKA], living-donor kidney transplant [LDKA]) with kidney graft failure and patient survival were estimated by multivariable inverse probability of treatment-weighted accelerated failure-time models. Compared to SPK recipients with a functioning pancreas graft 3 months posttransplant (SPK,P+), LDKA had 18% (Time Ratio [TR] 0.82, 95%CI: 0.70-0.95) less graft survival time and 18% (TR 0.82, 95%CI: 0.68-0.97) less patient survival time, DDKA had 23% (TR 0.77, 95%CI: 0.68-0.87) less graft survival time and 29% (TR 0.71, 95%CI: 0.62-0.81) less patient survival time, and SPK with early pancreas graft loss had 34% (TR 0.66, 95%CI: 0.56-0.78) less graft survival time and 34% (TR 0.66, 95%CI: 0.55-0.79) less patient survival time. In conclusion, SPK,P+ recipients have better kidney allograft and patient survival compared with LDKA and DDKA. Early pancreas graft failure results in inferior kidney and patient survival time compared to kidney transplant alone.

Corrigendum: Survival After Simultaneous Pancreas-Kidney Transplantation in Type 1 Diabetes: The Critical Role of Early Pancreas Allograft Function.

[This corrects the article DOI: 10.3389/ti.2022.10618.].

Impact of de novo donor-specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function.

BACKGROUND: This retrospective multicenter long-term cohort study investigates de novo donor-specific HLA antibodies (dnDSA) impact on allograft survival in pediatric kidney transplantation (KTx), depending on allograft function at dnDSA detection. METHODS: Seventy patients with dnDSA screening in the context of acute allograft dysfunction (AAD) (>50% serum creatinine increase) or routine follow-up were included during a 20-year period. Number of dnDSA specificities and HLA total mean fluorescence intensity (MFI-sum) were collected. RESULTS: Median follow-up time was 8.6 years. Among the 22 dnDSA+ patients, 8 patients presented AAD. Compared with dnDSA- patients, allograft survival was shorter only in dnDSA+/AAD+ patients, regardless of dnDSA detection during the 5-year post-transplant period (9 patients) or later (13 patients) (log rank p < .001 and p < .001, respectively). One dnDSA+/AAD-, 7 dnDSA+/AAD+, and 5 dnDSA- patients lost their allograft. Allograft survival was shorter in dnDSA+/AAD+ patients compared with the 16 dnDSA-/AAD+ patients (log rank p < .001) but did not differ between dnDSA+/AAD- and dnDSA-/AAD- patients (log rank p = .157). dnDSA+/AAD+ and dnDSA-/AAD+ patients presented higher risk of allograft failure compared with the other patient groups after adjustment for recipient age at KTx, donor type, and incidence of delayed graft function (HR 11.322, 95% CI 3.094-41.429, p < .001). Concurrent MFI-sum >10 000 and multiple dnDSA specificities were more significantly associated with AAD, compared with each factor separately (p < .001). CONCLUSIONS: In pediatric KTx, AAD shortens allograft survival in dnDSA+ patients, regardless of dnDSA time detection, and is commonly observed when high MFI-sum concurs with multiple dnDSA specificities. dnDSA without AAD incidence does not determinately affect allograft survival.

Impact of Post-Transplantation Hypomagnesemia on Long-Term Graft and Patient Survival after Transplantation.

BACKGROUND: Post-transplant hypomagnesemia is commonly observed among patients prescribed calcineurin inhibitor (CNIs). METHODS: We conducted a retrospective single-center analysis (2000-2013, N = 726) to examine the association of hypomagnesemia with long-term patient and allograft outcomes in kidney transplant recipients. A median serum magnesium (Mg) level of all measured Mg levels from 1 month to 1 year posttransplant was calculated. RESULTS: For every increase in Mg of 0.1 mg/dL, the risk for either graft loss or death, overall mortality, and death with a functioning graft increased by 11%, 14%, and 12%, respectively (p < 0.01). In a multivariate model, patients with median Mg level ≥1.7 mg/dL had a reduced overall survival rate (HR 1.57, 95% CI: 1.04-2.38, p = 0.033) compared to those with median Mg level <1.7 mg/dL. This association was observed in subgroups of patients above 60 years old, in those who had a slow graft function (SGF) and in females. CONCLUSIONS: Posttransplant hypomagnesemia is associated with better patient and allograft survival up to 10 years posttransplant. This relationship remained significant after accounting for baseline allograft function, presence of SGF and CNI trough levels.

Vesicoureteral reflux treatment following kidney transplantation potentially prevents graft function deterioration and allows long-term graft survival.

OBJECTIVES: The impact of vesicoureteral reflux post-kidney transplantation on graft survival remains unclear, and guidelines on appropriate vesicoureteral reflux management post-kidney transplantation are lacking. For this reason, we conducted a retrospective study on the impact of vesicoureteral reflux and its treatment on graft survival. METHODS: We evaluated 347 consecutive kidney transplantation recipients, who also underwent a ureteroneocystostomy, between 1996 and 2012. RESULTS: Vesicoureteral reflux was diagnosed in 55 cases (15.9%), with a median post-kidney transplantation duration of 50 months (range 0-172 months). Among these, 22 were monitored, 17 underwent transurethral collagen injections, and 16 received a ureteroneocystostomy. The 10-year graft survival rate was significantly lower in recipients with vesicoureteral reflux (68.9%) than in those without vesicoureteral reflux (84.4%) (P = 0.0165). Moreover, among the vesicoureteral reflux recipients, the 10-year graft survival rate was significantly higher in those whose vesicoureteral reflux was cured (80.1%) than in those whose vesicoureteral reflux persisted (53.6%) (P = 0.0062). Multivariate analysis showed that vesicoureteral reflux was significantly associated with both overall and death-censored graft loss (odds ratio 3.737 and 3.685; P = 0.0015 and P = 0.0052, respectively). Lastly, the incidence of interstitial fibrosis and tubular atrophy was higher in recipients with vesicoureteral reflux than in those without vesicoureteral reflux (P = 0.0009). CONCLUSIONS: Post-kidney transplantation vesicoureteral reflux has a negative impact on long-term graft survival, and that treatment prevents graft deterioration. From the perspective of maintaining long-term graft function in kidney recipients, vesicoureteral reflux may be one of the most important complications to be addressed.

Allograft Vesicoureteral Reflux after Kidney Transplantation.

Allograft vesicoureteral reflux (VUR) is a leading urological complication of kidney transplantation. Despite the relatively high incidence, there is a lack of consensus regarding VUR risk factors, impact on renal function, and management. Dialysis vintage and atrophic bladder have been recognized as the most relevant recipient-related determinants of post-transplant VUR, whilst possible relationships with sex, age, and ureteral implantation technique remain debated. Clinical manifestations vary from an asymptomatic condition to persistent or recurrent urinary tract infections (UTIs). Voiding cystourethrography is widely accepted as the gold standard diagnostic modality, and the reflux is generally graded following the International Reflux Study Committee Scale. Long-term transplant outcomes of recipients with asymptomatic grade I-III VUR are yet to be clarified. On the contrary, available data suggest that symptomatic grade IV-V VUR may lead to progressive allograft dysfunction and premature transplant loss. Therapeutic options include watchful waiting, prolonged antibiotic suppression, sub-mucosal endoscopic injection of dextranomer/hyaluronic acid copolymer at the site of the ureteral anastomosis, and surgery. Indication for specific treatments depends on recipient's characteristics (age, frailty, compliance with antibiotics), renal function (serum creatinine concentration < 2.5 vs. ≥ 2.5 mg/dL), severity of UTIs, and VUR grading (grade I-III vs. IV-V). Current evidence supporting surgical referral over more conservative strategies is weak. Therefore, a tailored approach should be preferred. Properly designed studies, with adequate sample size and follow-up, are warranted to clarify those unresolved issues.

Peritoneal Dialysis for Potential Kidney Transplant Recipients: Pride or Prejudice?

Kidney transplantation (KT) is recognized as the gold-standard of treatment for patients with end-stage renal disease. Additionally, it has been demonstrated that receiving a pre-emptive KT ensures the best recipient and graft survivals. However, due to an overwhelming discrepancy between the organs available and the patients on the transplant waiting list, the vast majority of transplant candidates require prolonged periods of dialysis before being transplanted. For many years, peritoneal dialysis (PD) and hemodialysis (HD) have been considered competitive renal replacement therapies (RRT). This dualistic vision has recently been questioned by evidence suggesting that an individualized and flexible approach may be more appropriate. In fact, tailored and cleverly planned changes between different RRT modalities, according to the patient's needs and characteristics, are often needed in order to achieve the best results. While home HD is still under scrutiny in this particular setting, current data seems to favor the use of PD over in-center HD in patients awaiting a KT. In this specific population, the demonstrated advantages of PD are superior quality of life, longer preservation of residual renal function, lower incidence of delayed graft function, better recipient survival, and reduced cost.

Can uric acid blood levels in renal transplant recipients predict allograft outcome?

BACKGROUND: Hyperuricemia is common after renal transplantation, especially in those receiving calcineurin inhibitors. Little, however, is known about the relationship between uric acid (UA) levels and allograft outcome. METHODS: We conducted a retrospective single-center analysis (N = 368) in order to assess UA blood levels post-transplant association with allograft outcome. For this study, a median serum UA level of all measured UA levels from 1 month to 1 year post renal transplantation was calculated. RESULTS: Patients were divided into 2 groups based on the median UA level measured between 1 and 12 months post-transplant. Those with median UA level ≥ 7 and ≥ 6 mg/dL (N = 164) versus median UA level < 7 and < 6 mg/dL for men and women respectively (N = 204) had lower GFR values at 1, 3 and 5 years posttransplant (mean GFR ± SD of 43.4 ± 20.6 and 58 ± 19.9 at 3 years post-transplant, p < 0.001). In multivariate models, UA levels were no longer significantly associated with renal allograft function. In a multivariate cox proportional hazard model, UA level was found to be independently associated with increased risk for death-censored graft loss (HR of 1.3, 95% CI 1.0-1.7, p < 0.05 for every increase of 1 mg/dL in UA level). CONCLUSION: Hyperuricemia was found to be associated with increased death- censored graft loss but not with allograft function. Increased UA levels were not found to be an independent predictor of long-term allograft function despite the known association of hyperuricemia with the progression of cardiovascular and renal disease.

Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis.

Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival.

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%LCL aHR95%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 1.53 2.203.17 ; LD-KA: aHR 1.29 1.872.71 ) and death (DD-KA: aHR 2.12 3.255.00 ; LD-KA: aHR 1.54 2.353.59 ). SPK,P- recipients had significantly higher risk of death (aHR 1.68 3.306.50 ). 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.

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

RATIONALE & OBJECTIVES: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING & PARTICIPANTS: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.