Allograft Survival In Recipients Research Articles

Donor fat-to-muscle ratio and kidney transplant outcomes: Aproposition of metabolic memory.

The impact of donor abdominal fat-to-muscle ratio (FMR) on kidney transplant (KT) outcomes was assessed. Given the transient nature of the donor's metabolic environment in transplant recipients, this study investigated the capacity of body composition to induce metabolic memory effects. KT patients (n=895) who received allografts from living donors (2003-2013) were included. Donor fat and muscle were quantified using pre-KT abdominal computed tomography scans. Patients were categorised into donor FMR tertiles and followed up for graft outcomes. Additionally, genome-wide DNA methylation analysis was performed on 28 kidney graft samples from KT patients in the low- and high-FMR groups. Mean recipient age was 42.9±11.4years and 60.9% were males. Donor FMR averaged 1.67±0.79. Over a median of 120.9±42.5months, graft failure (n=127) and death-censored graft failure (n=109) were more frequent in the higher FMR tertiles. Adjusted hazard ratios for the highest versus lowest FMR tertile were 1.71 (95% CI, 1.06-2.75) for overall graft failure and 1.90 (95% CI, 1.13-3.20) for death-censored graft failure. Genome-wide DNA methylation analysis identified 58 differentially methylated regions (p<0.05, |Δβ|>0.2) and 35 genes showed differential methylation between the high- (FMR >1.91) and low-FMR (FMR <1.27) groups. Donors with increased fat and reduced muscle composition may negatively impact kidney allograft survival in recipients, possibly through the transmission of epigenetic changes, implying a body-composition-related metabolic memory effect.

Donor noradrenaline use is associated with better allograft survival in recipients of pancreas transplantation.

Outcomes following pancreas transplantation are suboptimal and better donor selection is required to improve this. Vasoactive drugs (VaD) are commonly used to correct the abnormal haemodynamics of organ donors in intensive care units. VaDs can differentially affect insulin secretion positively (dobutamine) or negatively (noradrenaline). The hypothesis was that some VaDs might induce beta-cell stress or rest and therefore impact pancreas transplant outcomes. The aim of the study was to assess relationships between VaD use and pancreas transplant graft survival. Data from the UK Transplant Registry on all pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Univariable- and multivariable-adjusted Cox regression analyses determined risks of graft failure associated with VaD use. In 2,183 pancreas transplants, VaDs were used in the following numbers of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). In multivariable models, adjusted for covariates and the co-administration of other VaDs, noradrenaline use (vs non-use) was a strong predictor of better graft survival (hazard ratio [95% confidence interval] 0.77 [0.64-0.94], p = 0.01). Noradrenaline use was associated with better graft survival in models adjusted for donor and recipient variables - this may be related to inhibition of pancreatic insulin secretion initiating pancreatic beta-cell 'rest'. Further research is required to replicate these findings and establish whether relationships are causal. Identification of alternative methods of inducing beta-cell rest could be valuable in improving graft outcomes.

Fibroblastic reticular cells orchestrate long-term graft survival following recipient treatment with CD40 ligand–targeted costimulatory blockade

Fibroblastic reticular cells (FRCs) maintain the architecture of secondary lymphoid organs, which optimize interactions between antigen-presenting dendritic cells and reactive naive T cells. In this issue of the JCI, Zhao, Jung, and colleagues investigated CD4+FoxP3+ regulatory T cell development and long-term heart allograft survival in recipients treated with peritransplant costimulatory blockade to inhibit CD40/CD40 ligand (CD40L) signaling. Treatment with an anti-CD40L monoclonal antibody (mAb) increased the lymph node (LN) population of Madcam1+ FRCs and altered their transcription profile to express immunoregulatory mediators. Administration of nanoparticles, containing the anti-CD40L mAb and a targeting antibody against high endothelial venules, delivered the treatment into LNs of allograft recipients. Direct LN delivery of the costimulatory blockade allowed decreased dosing and increased the efficacy in extending graft survival. The results provide insights into mechanisms by which FRCs can promote donor-reactive tolerance, and establish a strategy for administering costimulation-blocking reagents that circumvent systemic effects and improve allograft outcomes.

Long-standing donor diabetes and pathologic findings are associated with shorter allograft survival in recipients of kidney transplants from diabetic donors

Approximately 6% of deceased kidney donors (DKDs) are diabetic; their kidneys may be associated with worse allograft survival, but published studies suggest that recipient diabetes status has a greater impact on mortality and survival. Since biopsy findings are the most common reason for organ discard, we sought to understand histologic and clinical factors that influence graft survival in patients who receive a kidney from a diabetic DKD. We retrospectively reviewed our institutional experience from 2005 to 2019, and re-evaluated pre-implantation and earliest post-transplant biopsies. Histologic findings were compared against a control cohort of non-diabetic DKD. Of 829 adult DKD transplants, 37 (4.5%) came from diabetic donors. There was no significant difference in diabetic vs. non-diabetic DKD graft survival for all-comers; however, when stratified by duration of donor diabetes, donor diabetes ≥6 years was associated with graft failure. In 25 patients with post-transplant biopsies available, diabetic DKD allografts had significantly greater non-glomerular chronic injury than non-diabetic DKD allografts. Moderate arteriolar hyalinosis (in 24%), moderate tubular atrophy and interstitial fibrosis (IFTA, in 36%), and diabetic glomerulopathy (in 24%) on early post-transplant biopsy were associated with allograft failure. Pre-implantation frozen section discrepancies were more common in long-standing donor diabetes, and arteriolar hyalinosis and IFTA scores on frozen accurately prognosticated graft loss. There was no morphologic improvement in lesions of diabetic nephropathy on short-term follow-up. In conclusion, donor diabetes ≥6 years, and histologic findings on frozen section and early post-transplant biopsy are associated with diabetic DKD allograft loss.

Fractionated Infusion of Hematopoietic Progenitor Cells Does Not Improve Neutrophil Recovery or Survival in Allograft Recipients

Allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy in patients with hematologic malignancies; however, nonrelapse mortality (NRM) remains a concern. Strategies to improve neutrophil recovery and immune reconstitution are needed to decrease NRM. Murine models of allogeneic HCT suggest that fractionated hematopoietic progenitor cell (HPC) infusion may improve engraftment through improved access of HPCs to a viable hematopoietic niche. The primary objective of the present study was to determine the impact of fractionated infusion versus unfractionated (bulk) infusion of HPCs on the time to achieve neutrophil engraftment. Secondary objectives included the effect of fractionated versus bulk infusion of HPCs on platelet engraftment, immune reconstitution, the incidence of acute graft-versus-host disease (GVHD) grade II-IV, NRM, and overall survival (OS). In this randomized phase 2 study, patients with hematologic malignancies undergoing allogeneic HCT were randomized to receive HPC infusion as a bulk (bulk arm) or in fractions (fractionated arm): 4×106 CD34+ cells/kg recipient weight infused on day 0, with the remaining HPCs CD34+ cell-selected then infused in equally distributed aliquots on days 2, 4, and 6 post-HCT. Randomization was stratified by type of transplant, unmodified (i.e. T cell-replete graft) versus CD34+ cell-selected (T cell-depleted graft). Patients whose donor failed to collect at least 7×106 CD34+ cells/kg of recipient weight received bulk HPC infusions regardless of randomization, for safety. These patients continued the HCT process on study but were replaced until each arm reached the prespecified accrual target. Per protocol, these patients were not included in this modified intention-to-treat analysis. A total of 116 patients were enrolled. Donors of 42 patients failed to mobilize the minimum CD34+ cell dose (7×106 cells/kg recipient weight) and were excluded from the analysis. The 74 evaluable patients included 38 randomized to the bulk arm and 36 randomized to the fractionated arm. All patients engrafted. The median time to an absolute neutrophil count of ≥0.5×109/L was 11 days on both arms. The day +180 median CD4+ cell count was 179 cells/µL in the bulk arm and 111 cells/µL in the fractionated arm (P=.779). The cumulative incidence of grade II-IV acute GVHD on post-transplant day +100 was 32% in the bulk arm and 17% in the fractionated arm (P=.131). Two patients in the bulk arm, but none in the fractionated arm, experienced grade III-IV GVHD. The 4-year OS was 60% in the bulk arm and 62% in the fractionated arm (P=.414), whereas the 4-year cumulative incidences of NRM and relapse were similar in the 2 arms. Fractionated infusion of HPCs in allogeneic HCT recipients did not impact neutrophil or CD4+ cell recovery, NRM, relapse, or OS when compared with bulk HPC infusion. We also observed that with current mobilization techniques, it was unlikely that more than 60% of healthy donors would be able to collect >7×106 CD34+ cells/kg recipient weight for adult recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

OLDER LIVERS SHOULD NOT BE UTILIZED IN PEDIATRIC LIVER TRANSPLANTATION

Introduction: Organ scarcity in liver transplantation has required expansion of the acceptable criteria used for donor selection. The utilization of older donors (>60 years) has become common practice in adult liver transplantation. We examined outcomes in pediatric liver transplantation where recipients received a liver from a donor >60 years in age. Methods: The UNOS database was used to identify all pediatric liver transplant recipients (<18 years) transplanted between 1987—2018. Only recipients of solitary, deceased donor organs were included. Pediatric recipients were grouped according to donor age; <60 years (YOUNG) and >60 years (OLD). Donor and recipient demographic data were examined, as were survival and outcomes. A p-value of <0.05 was considered to be significant. Results: Of 15,448 pediatric transplants, 71 received an OLD liver while 15,377 received a YOUNG liver. Donors were significantly older in the OLD group (67.3 vs. 11.7 years), with higher BMI (24.1 vs. 19.5 kg/m2), more frequently Caucasian (85.9% vs. 62.6%) and female (62.0% vs. 41.2%) compared with YOUNG donors. Cause of death was frequently a cerebrovascular accident (85.9% vs. 12.5%) in OLD donors. There were no differences in cold ischemia time, biopsy fat content, or transaminases. OLD donors were not donation after cardiac death (DCD) donors. Recipients of OLD livers were significantly older (11.3 vs. 5.1 years), had a shorter wait time (23.5 vs. 148.5 days), increased BMI (21.1 vs. 18.3 kg/m2), and higher initial and final PELD/MELD scores (34 vs. 12 initial; 31 vs. 14 final). OLD donors were more likely to have used in treatment of fulminant hepatic failure (FHF, 74.7% vs. 35.1%). In addition, recipients of older livers were more likely to be on life support (62.0% vs. 16.6%) or the ventilator (57.8% vs. 13.8%), have had dialysis in the week prior to transplant (9.9% vs. 5.0%) and to have had a previous liver transplant (23.4% vs. 13.8%). Importantly, allograft survival in recipients of OLD livers were found to be significantly diminished when compared to YOUNG livers (Figure 1).Conclusions: Pediatric recipients of older liver allografts are significantly sicker than those who receive younger allografts. Allograft survival, however, was greatly reduced when compared to younger allografts. Use of older liver donors should be avoided, especially in younger or fulminant recipients.

Renal allograft survival in transplant recipients with focal segmental glomerulosclerosis

Introduction: The frequency that idiopathic focal segmental glomerulosclerosis (FSGS) recurs in renal allografts is reportedly 20-50%, but the epidemiology of secondary FSGS in this setting has scarcely been addressed. Objectives: The aim of this study was to examine the incidence, etiology, and subtypes of FSGS in renal allograft recipients and allograft survival in recipients with FSGS. Patients and Methods: As a retrospective review, we examined medical records of 359 consecutive renal allograft recipients (living donors, 329; cadaveric donors, 30). In 121 of these patients, allograft dysfunction or proteinuria prompted biopsies. We compared allograft survival in recipients with and without FSGS. We then determined histologic subtypes of FSGS using the Columbia classification and categorized FSGS as recurrent or de novo, and idiopathic or secondary. Results: Of 121 subjects who were biopsied, six with inadequate specimens (&lt;10 glomeruli) were excluded. Only 17 of those remaining (n=115) were diagnosed as secondary FSGS. Renal allograft survival did not differ significantly in patients with or without FSGS (P=0.953). Subtypes of FSGS were as follows; not otherwise specified (NOS; n=8), collapsing (n=5), cellular (n=2), and perihilar (n=2). Conclusion: Secondary FSGS was observed in 14.5% of biopsies of renal allograft recipients and seemed no significant impact on allograft survival.

Influence of mildly and moderately elevated pulmonary artery systolic pressure on post-renal transplantation survival and graft function.

Severe pulmonary hypertension (PH) has been associated with decreased post-kidney transplant survival and increased rate of long-term cardiovascular complications. Despite a high prevalence of PH in patients with end-stage renal disease, data on post-transplant renal allograft survival in recipients with pre-existing mild-to-moderate PH are limited. The single-center retrospective study cohort consisted of 192 consecutive (2008-2015) renal transplant recipients with documented pretransplantation transthoracic echocardiogram (TTE) pulmonary artery systolic pressure (PASP). Mean age was 50.9±12.4years, 36.5% were females, and 81.25% were Caucasians. Elevated PASP≥37mmHg was present in 51 patients. Elevated PASP was more common in patients with decreased <50% left ventricular ejection fraction (13.73% vs 3.55%, P=0.010); otherwise, there were no significant differences in baseline demographic (age, ethnicity, gender, and donor status) and clinical parameters between patients with normal and elevated PASP. Four-year mortality (5.7%) was not significantly affected by elevated PASP. However, elevated PASP was associated with significantly decreased estimated glomerular filtration rate (eGFR) at 1year (52.26 vs 60.13mL/min, P=0.019) and 2years (51.04 vs 60.28mL/min, P=0.006) post-transplant. Mild and moderately elevated pre-kidney transplant PASP does not affect 4-year post-transplant mortality or graft loss. However, elevated pretransplant PASP is significantly associated with decreased 1year and 2years post-transplant eGFR. Preoperative echocardiographic evaluation for PH may be useful in predicting the probability of short-term renal graft and long-term graft dysfunction in these patients.

Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function.

Allograft rejection is the major cause of corneal allograft failure. Rapamycin (RAPA) has been reported as an effective and novel immunosuppressive agent for patients undergoing corneal transplantation. However, its high water insolubility and low bioavailability have strongly constrained its clinical application. In this study, we successfully developed a RAPA nano-micelle ophthalmic solution and found that corneal allograft survival in recipients treated with RAPA nano-micelle ophthalmic solution was significantly prolonged for more than 2 months, with less inflammatory infiltration, decreased production of pro-inflammatory factors, and elevated recruitment of myeloid-derived suppressor cells (MDSCs). MDSCs from mice treated with RAPA nano-micelle ophthalmic solution could significantly inhibit the proliferation of CD4+T cells through increased expressions of inducible nitric oxidase (iNOS) and arginase-1 (Arg-1). The activity blockade of Arg-1 and iNOS pharmacologically reversed their immunosuppressive ability. Moreover, the effects of RAPA were antagonized by the administration of anti-Gr-1 antibody or by inhibiting the activity of iNOS pharmacologically. In addition, RAPA nano-micelle also effectively alleviated allograft rejection in high-risk rabbit penetrating keratoplasty (PKP) models with corneal vascularization. Collectively, our results demonstrate that RAPA nano-micelle ophthalmic solution could improve the immunosuppressive activity of MDSCs through elevated expression of Arg-1 and iNOS, which highlights the possible therapeutic applications of RAPA against corneal allograft rejection.

Depletion of macrophages from Cytomegalovirus (CMV) latently infected donor allografts decreases CMV mediated immunopathology and prevents CMV-accelerated chronic rejection

Abstract Cytomegalovirus (CMV), a ubiquitous β-herpesvirus, is linked to acceleration of solid organ transplant vascular sclerosis (TVS) and chronic rejection (CR). Latent CMV infection increases cardiac-resident macrophages and T cells that may increase inflammation and promote allograft rejection. To investigate the role of cardiac macrophages in CMV mediated TVS/CR, macrophages were depleted from CMV+ donor allografts prior to transplantation using clodronate liposomes (clod) in our rat heart transplant model. Latently rat CMV infected donor F344 rats were treated with clod or PBS or control liposomes 3 days prior to heterotopic cardiac transplant into CMV-naïve Lewis rats and macrophage depletion was validated. Donor hearts were transplanted and monitored daily for rejection. Clod treatment significantly increased graft survival from 61 days post-transplant to 84 days. The severity of graft vessel disease was decreased compared to controls. Clod treatment significant decreased macrophage and T cell infiltration into allograft tissue versus controls. Clod treatment also altered allograft tissue protein and gene expression cytokine/chemokine profiles toward a phenotype that promotes graft survival by reducing the allograft inflammation. Clod treatment did not prevent CMV reactivation since all recipients seroconverted and CMV DNA was detectable in recipient salivary glands. Depletion of donor macrophages prior to transplant represents a novel method to modulate allograft rejection immunity and prevent the negative impact of CMV on allograft recipient survival.

Importance of B cells to development of regulatory T cells and prolongation of tissue allograft survival in recipients receiving autologous bone marrow transplantation.

We previously showed that congenic bone marrow transplantation (BMTx) post myeloablation augmented tissue allograft survival in association with increased regulatory T (Treg) cells of both host and bone marrow donor origin. Regulatory B (Breg) cells can also modulate T-cell immunity and B cells may be implicated in the development of Treg cells. Accordingly, we explored the effect of B-cell depletion invivo on augmented graft survival post BMTx. C57BL/6 mice received BALB/c skin allografts followed 7days later by myeloablation using cyclophosphamide and busulphan. Mice then received T-cell-depleted bone marrow from CD45.1 congenic donors, and ongoing immunosuppression with rapamycin (to day 28 after BMTx). Control mice received cyclophosphamide and busulphan followed by rapamycin, but not congenic bone marrow. At different times post BMTx, mice received B-cell-depleting antibody treatment, and the effect on both skin graft survival, and induction of Treg cells was assessed. BMTx resulted in significantly prolonged skin graft survival versus control mice, in association with attenuated donor-specific alloreactivity relative to controls, increased splenic Treg cells and significantly diminished anti-donor IgG. In mice receiving infusion of B-depleting antibodies for 12days from day 15 post BMTx, both graft survival and Treg cell activity were diminished, particularly for functional Treg cells of donor origin. Adoptive transfer of Breg cells from mice harvested at 15days post BMTx prolonged survival in naive transplanted mice and increased Treg cell levels. Thus, autologous BMTx augmentation of graft survival is dependent in part upon a population of Breg cells that can modulate the function of donor-derived Treg cells.

Patient and Kidney Allograft Survival in Recipients With End-Stage Renal Disease From Amyloidosis.

Outcomes after kidney transplantation for patients with amyloidosis-associated end-stage renal disease (ESRD) have not been well characterized. We performed a retrospective propensity score matched cohort study with Cox proportional hazards modeling using data from the United Network of Organ Sharing including patients transplanted from 1987 to 2015 (N = 310 629). Amyloidosis patients (N = 576) had higher rates of death (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.28-1.95) and graft loss (HR, 1.49; 95% CI, 1.19-1.87) compared with nonamyloidosis patients. The results were similar when the cohort was restricted to patients transplanted on or after 2001 (HR, 1.72; 95% CI, 1.31-2.26 for death; HR, 1.77; 95% CI, 1.35-2.33 for graft loss). However, there was no significant difference in risk of death or graft loss when amyloidosis patients were compared with those with diabetes-associated ESRD (mortality: HR, 0.99; 95% CI, 0.84-1.17; allograft loss: HR, 1.00; 95% CI, 0.84-1.20), or when compared with elderly patients (age, >65 years at the time of transplant) (mortality: HR, 0.99; 95% CI, 0.81-1.21; graft loss: HR, 1.02; 95% CI, 0.82-1.26). For patients with amyloidosis-associated ESRD deemed suitable for transplantation, patient and graft survivals are diminished compared to kidney transplant recipients overall, but are comparable to other high-risk subgroups.

Polymorphism in programmed cell death 1 gene is strongly associated with lung and kidney allograft survival in recipients from CMV-positive donors

Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A). We performed a retrospective study to assess the impact of PD-1.3 on graft outcome in donor CMV seropositive (D+) and donor CMV seronegative (D-) KTx and LTx. We also performed a case-control study to evaluate the anti-CMVpp65 response according to genotype. PD-1.3 was determined in 1,119 KTx and 181 LTx. In 481 D+ KTx, A allele carriers (24%) experienced significantly less graft failure compared with GG carriers (p = 0.001). Multivariate analysis showed that this association was independent of donor and recipient age, acute rejection episodes, and number of human leukocyte antigen mismatches (hazard ratio, 0.381; 95% confidence interval, 0.209-0.696; p = 0.002). Analysis in 85 D+ LTx showed similar results: A allele carriers had better survival (hazard ratio, 0.302; 95% confidence interval, 0.128-0.716; p = 0.006) and greater 6-month forced expiratory volume (71% ± 17% vs 54% ± 16%, p = 0.001). In D- recipients, PD-1.3 did not affect KTx or LTx outcome. Finally, AA recipients had a stronger anti-CMVpp65 T-cell response than matched GG recipients (p = 0.003). The A variant allele in PD-1.3 single nucleotide polymorphism improved graft survival in kidney and lung transplant recipients receiving grafts from CMV-positive donors.

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors. The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed. Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant. Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Apolipoprotein L1 Gene Variants in Deceased Organ Donors Are Associated With Renal Allograft Failure

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.

B Cell Activating Factor (BAFF) and a Proliferation Inducing Ligand (APRIL) Mediate CD40-Independent Help by Memory CD4 T Cells

Donor-reactive memory T cells undermine organ transplant survival and are poorly controlled by immunosuppression or costimulatory blockade. Memory CD4 T cells provide CD40-independent help for the generation of donor-reactive effector CD8 T cells and alloantibodies (alloAbs) that rapidly mediate allograft rejection. The goal of this study was to investigate the role of B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in alloresponses driven by memory CD4 T cells. The short-term neutralization of BAFF alone or BAFF plus APRIL synergized with anti-CD154 mAb to prolong heart allograft survival in recipients containing donor-reactive memory CD4 T cells. The prolongation was associated with reduction in antidonor alloAb responses and with inhibited reactivation and helper functions of memory CD4 T cells. Additional depletion of CD8 T cells did not enhance the prolonged allograft survival suggesting that donor-reactive alloAbs mediate late graft rejection in these recipients. This is the first report that targeting the BAFF cytokine network inhibits both humoral and cellular immune responses induced by memory CD4 T cells. Our results suggest that reagents neutralizing BAFF and APRIL may be used to enhance the efficacy of CD40/CD154 costimulatory blockade and improve allograft survival in T cell-sensitized recipients.

Transient Lymphopenia Breaks Costimulatory Blockade-Based Peripheral Tolerance and Initiates Cardiac Allograft Rejection

Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long-term graft acceptance. After vascularized MHC-mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti-CD4 plus anti-CD8 mAb. Long-term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44high effector/memory T cells in lymphatic organs and strong recovery of donor-reactive T cell responses, indicating lymphopenia-induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4+ Foxp3+) cell and B cell numbers as well as donor-specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor-reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.

Late, Severe, Noninfectious Diarrhea After Renal Transplantation: High-Risk Factors, Therapy, and Prognosis

ObjectiveLate severe noninfectious diarrhea in renal transplant recipients can lead to malnutrition and even graft loss. The purpose of this study was to evaluate risk factors associated with this condition and summarize therapy for these patients. MethodsFor more than 36 months we observed a cohort of 541 recipients who underwent kidney transplantation from January 2001 to June 2007. They were provided a calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF). The four group includes a continuous cyclosporine (CsA); a preconversion to tacrolimus and a postconversion group as well as a continuous tacrolimus group. The rate of severe late noninfectious diarrhea was compared among the four groups. Risk factors were analyzed between the diarrhea and nondiarrhea cohorts. Clinical characteristics, efficacy, and safety were observed after modifying the immunosuppressive protocol for late severe noninfectious diarrhea recipients. ResultsTwenty-eight recipients presented with late sever noninfectious diarrhea. No patients displayed chronic diarrhea in the CsA (n = 145) or preconversion group (n = 95). The rate of diarrhea was 7.31% in the postconversion and 7.35% in the tacrolimus group. Using multivariate Cox proportional hazards analysis, factors associated with an increased risk of noninfectious diarrhea were cytochrome P450(CYP)3A5 *3/*3 type, chronic renal allograft dysfunction, and patient ingestion of Tripterygium wilfordii Hook F. All diarrheal recipients experienced weight loss, hypoalbuminia, and an increased serum creatinine. All affected patients underwent adjustment of the immunosuppressive regimen to achieve remission. Renal allograft survival in recipients with diarrhea was worse than that in nondiarrheal recipients receiving tacrolimus combined with MMF. ConclusionTacrolimus with MMF increased the risk of late severe noninfectious diarrhea among renal transplant recipients compared with hosts treats with CsA plus MMF. The CYP3A5 *3/*3 type, chronic renal allograft dysfunction, and T wilfordii supplementation were high-risk factors for late diarrhea. Prompt adjustment of immunosuppression was an effective, feasible therapy for these patients.

Galectin-9-Mediated Protection from Allo-Specific T Cells as a Mechanism of Immune Privilege of Corneal Allografts

The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti-Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea.

Long-term Outcome of Renal Transplantation Patients with Henoch-Schönlein Purpura

Although Henoch-Schönlein purpura (HSP) is the most common form of renal vasculitis in childhood, progression to ESRD is rare, and there are few data on outcomes of renal transplantation in patients with HSP. This is a matched retrospective cohort study of renal allografts using the United Network of Organ Sharing database (1987 to 2005). Of the 189,211 primary renal allografts, there were 339 with a diagnosis of HSP. The primary end point was allograft survival. Compared with the remainder of the database, the HSP population was younger (25 years versus 46 years), and had a higher proportion of women (47% versus 40%), live donors (50% versus 35%), and Caucasians (77% versus 60%). Controlling for age, gender, donor source, ethnicity, and year of transplantation, death-censored graft survival for patients with HSP was 80.0% at 5 years and 58.8% at 10 years compared with 79.0% at 5 years and 55.4% at 10 years in the non-HSP population. Among patients with reported causes of graft loss, failure from recurrent disease occurred in 13.6% of patients with HSP, compared with 6.6% in the non-HSP population. When analyzing allograft survival in recipients with HSP compared with those with IgA nephropathy, there was no difference in 10-year allograft survival (58.4% and 59.3%, respectively). These data indicate that although there is an increased risk of graft failure attributable to recurrent disease in patients with HSP, a diagnosis of HSP has little effect on overall renal allograft survival.