Long-term Renal Allograft Survival Research Articles

The association between activation of the ERK1/2-NF-κB signaling pathway by TIMP2 expression and chronic renal allograft dysfunction in the CRAD rat model

PurposeThe tissue inhibitor of metalloproteinase 2 (TIMP2), a natural inhibitor of matrix metalloproteinase (MMP), regulates inflammation, fibrosis, and cell proliferation. Chronic renal allograft dysfunction (CRAD) is a primary factor affecting the long-term survival of renal allografts. We assessed whether up-regulation of TIMP2 expression may affect the ERK1/2-NF-κB signaling pathway and CRAD development. MethodsLewis rats received orthotopic F344 kidney allografts to establish the classical CRAD model. The treatment group was injected with a lentivirus encoding a TIMP2-targeting small hairpin (sh)RNA (LTS) at 5 × 108 TU/ml monthly after kidney transplantation. A second CRAD group was injected with a lentivirus TIMP2-control vector (LTC). After 12 weeks, blood, urine, and kidney tissue were harvested to evaluate renal function and pathological examinations. Hematoxylin and eosin staining, Masson staining, and Periodic acid–Schiff staining were performed for renal histopathological evaluation according to the Banff criteria. TIMP2, phospho (p)-ERK1/2, p-p65 (NF-κB) expression levels were measured via immunohistochemical and Western blot analyses. ResultsCompared to the F344 and Lewis control groups, the expression of TIMP2, p-ERK1/2, and p-p65 were significantly higher in the CRAD and CRAD+LTC renal tissues (p < 0.05). There were also increased levels of serum creatinine, nitrogen, and 24 h urinary protein in these two groups (p < 0.05). Typical histopathological changes of CRAD were observed in the CRAD and CRAD+LTC groups. Administration of LTS effectively decreased the expression of TIMP2, p-ERK1/2, and p-P65, and reduced interstitial fibrosis and macrophage infiltration in the treatment group (p < 0.05). Additionally, MCP1 and ICAM-1, which are downstream cytokines of the NF-κB pathway, were also inhibited in the renal rat kidney from the LTS group (p < 0.05). Furthermore, renal function was well preserved in the LTS group compared to the CRAD group and CRAD+LTC group. ConclusionA decrease of TIMP2 can alleviate the progression of inflammation in CRAD via inhibition of the ERK1/2-NF-κB signaling pathway.

Sirolimus in combination with low-dose extended-release tacrolimus in kidney transplant recipients.

Many challenges remain for long-term survival of renal allografts. Once-daily sirolimus (SRL) combined with low-dose extended-release tacrolimus (LER-TAC) may improve medication adherence and reduce the potential nephrotoxicity of calcineurin inhibitors (CNI) compared with standard immunosuppression regimens, thus potentially improving long-term graft survival. This retrospective, observational, single-center, propensity score matching (PSM) study compared conversion to SRL combined with low-dose ER-TAC and mycophenolic acid (MPA) combined with standard-dose TAC in kidney transplant recipients. After PSM, there were 56 patients in each group. Efficacy, safety, and medication adherence were evaluated over 12 months. There was no significant difference between the two groups in terms of graft and recipient survival and incidence of biopsy-proven acute rejection (p = 1.000), and none of the recipients developed dnDSA after conversion. The mean eGFR improved in SRL + LER-TAC group after conversion compared to before conversion (51.12 ± 20.1 ml/min/1.73 m2 vs. 56.97 ± 19.23 ml/min/1.73 m2, p < 0.05). The medication adherence at 12 months after conversion was superior to before conversion (p = 0.002). Our findings suggest that an immunosuppressive regimen of SRL combined with low-dose ER-TAC is no less effective and safe than standard immunosuppressive regimens for renal transplant recipients and may improve graft renal function and medication adherence.

Histopathological diagnoses revealed by indication-based renal allograft biopsies: a retrospective analysis

Objectives: Although there have been several advances in post-solid organ transplantation immunosuppression medications over the last two decades, the long-term survival of renal allografts did not significantly improve. Renal allograft biopsy is a helpful tool for determining the cause of graft dysfunction and adjusting patient management. Methods: Patients who received kidney transplantation and underwent allograft biopsy in Istinye University Hospital between January 2017 and January 2023 constituted the target population of this study. Demographic parameters, clinical data and biopsy indications, and histopathological assessment results of the patients were retrospectively analyzed. Results: Overall, 74 patients were included. The histopathology results included acute T-Cell mediated rejection (TCMR) (n = 15, 20%), tubular atrophy/chronic allograft nephropathy (IFTA) (n = 11, 15%), calcineurin inhibitor (CNI) toxicity (n = 2, 3%), chronic antibody-mediated rejection (ABMR) (n = 2, 3%), borderline pathology (n = 10, 13.5%), normal histology (n = 5, 6.5%), transplant glomerulopathy (TG) (n = 5, 6.5%), acute ABMR (n = 4, 5%), acute tubular necrosis (n = 7, 9%), polyomavirus nephropathy (n = 3, 4%) and non-specific changes (n = 10, 13.5%). The C4d was positive in 12% (n = 9) of the graft biopsies. In 73% (n = 54) of cases, the treatment strategy was changed based on biopsy results. Among all patients, 19 (25.6%) lost their grafts during follow-up. Conclusions: According to the histopathological analysis results, acute TCMR, IFTA, and borderline pathology were the most common causes of renal graft dysfunction. Renal allograft biopsy led to a remarkable change in treatment strategies in a significant number of cases.

Discussion on two common problems in renal transplantation donor-specificity discrimination of anti-human leukocyte antigen antibody

Antibody-mediated rejection (AMR) is a key factor affecting the long-term survival of renal allografts. Donor-specific antibody (DSA) is the etiology of AMR. So it is very important to accurately detect DSA. The single antigen bead (SAB) method, which is widely used in clinical practice, is prone to miss DSA detection and underestimate its mean fluorescence intensity (MFI). In this paper, the probability of missed detection of two SAB reagents was calculated by comparing common HLA alleles in China population, and the in vitro effect of antibody cross reaction on MFI value of DSA was revealed. The authors emphasized the clinical significance of the above two problems, tried to manage them by using functional epitope (eplet) analysis and give some clinical examples. Finally, the limitations of this correction method were analyzed.

Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion.

Costimulation blockade targeting the CD28 pathway provides improved long-term renal allograft survival compared to calcineurin inhibitors but may be limited as CTLA-4-Ig (abatacept, belatacept) blocks both CD28 costimulation and CTLA-4 coinhibition. Directly targeting CD28 while leaving CTLA-4 intact may provide a mechanistic advantage. Fc-silent non-crosslinking CD28 antagonizing domain antibodies (dAb) are currently in clinical trials for renal transplantation. Given the current standard of care in renal transplantation at most US centers, it is likely that lymphodepletion via thymoglobulin induction therapy could be used in patients treated with CD28 antagonists. Thus, we investigated the impact of T cell depletion (TCD) on T cell phenotype following homeostatic reconstitution in a murine model of skin transplantation treated with anti-CD28dAb. Skin from BALB/cJ donors was grafted onto C56BL/6 recipients which were treated with or without 0.2mg anti-CD4 and 10μg anti-CD8 one day prior to transplant and with or without 100μg anti-CD28dAb on days 0, 2, 4, 6, and weekly thereafter. Mice were euthanized six weeks post-transplant and lymphoid cells were analyzed by flow cytometry. Anti-CD28dAb reversed lymphopenia-induced differentiation of memory CD4+ T cells in the spleen and lymph node compared to TCD alone. Mice treated with TCD+anti-CD28dAb exhibited significantly improved skin graft survival compared to anti-CD28dAb alone, which was also improved compared to no treatment. In addition, the expression of CD69 was reduced on CD4+ and CD8+ T cells in the spleen and lymph node from mice that received TCD+anti-CD28dAb compared to TCD alone. While a reduced frequency of CD4+FoxP3+ T cells was observed in anti-CD28dAb treated mice relative to untreated controls, this was balanced by an increased frequency of CD8+Foxp3+ T cells that was observed in the blood and kidney of mice given TCD+anti-CD28dAb compared to TCD alone. These data demonstrate that CD28 signaling impacts the differentiation of both CD4+ and CD8+ T cells during homeostatic reconstitution following lymphodepletion, resulting in a shift towards fewer activated memory T cells and more CD8+FoxP3+ T cells, a profile that may underpin the observed prolongation in allograft survival.

246.6: Long-term Rejection Free Renal Allograft Survival With Fc-Modified Anti-CD154 Antibody Monotherapy in Nonhuman Primates

Belatacept is currently an only FDA approved costimulatory blockade (CB) used as an alternative to calcineurin inhibitors in kidney transplantation. However, it has been associated with higher rates of acute cellular rejection (ACR) and more effective CB has been sought. Blockade of the CD154/CD40 pathway with anti-CD154 antibody (aCD154) has been shown to be more effective in inhibiting alloimmune responses than CTLA4Ig. Unfortunately, clinical application of aCD154 has been abandoned due to its thrombophilic property which appears to be mediated by FcγRIIA receptor–dependent platelet activation. To address this problem, an Fc-modified aCD154 (TNX-1500), in which Fc was engineered to decrease binding to Fcγ RII, has been developed. In the current study, we have evaluated TNX-1500 for its efficacy to prevent kidney allograft rejection in NHPs. Twelve cynomolgus macaques received MHC mismatched kidney allografts with either TNX-1500 monotherapy (20mg/kg weekly) (Group A) or combined with daily mycophenolate mofetil (MMF) (TNX-1500 weekly for 6 weeks followed by every 2 weeks) (Group B). The results were compared with our historic results of no immunosuppression (No IS, n=5) or conventional immunosuppression (I.S.) with tacrolimus (Tac), MMF and methylprednisolone (Pred). (Conventional IS, n=20). Without any prophylaxis, no thromboembolic complication was observed in all nine recipients of TNX-1500. Renal allograft survival at 6 month was 80% in Group A (n=6). Histopathology at 6 months of 5/6 recipients showed no evidence of rejection (g0,i0,t0,v0,ptc0,cg0,ci0,ct0,cv0, C4d0). One recipient lost on day 28 with ACR2b. Six recipients have so far have been tested in Group B. Two recipients developed rejection on day 36 and 48 while they were still treated with weekly TNX-1500. Another recipient had to be euthanized on day 111 post-transplant due to complications from MMF. The three other recipients in this group are currently in progress with normal kidney function at days >180, >84 and >42. Renal allograft survival at four months in Conventional I.S. was 52% (p=0.33 vs. Group A) and all five recipients without I.S. rejected their kidney allografts by day 11 (p=0.0018 vs. Group A). Excellent renal allograft survival was achieved with TNX-1500 monotherapy without thromboembolic complications. Combination with MMF resulted in inferior allograft survival.Financial support from NIH Grants 1R21AI163806-01, 5T32AI007529-22 & Tonix Pharmaceuticals.

Posttransplant-Alloantibodies Against MICA Antigens Associated With Decreased Long-Term Allograft Survival of Kidney Transplant Recipients

Previous evidence showed that antibodies against major histocompatibility complex class I-related chain A (MICA) could lead to antibody-mediated rejection in kidney transplantation in case where the patients had no alloantibodies against HLA. However, the effects of posttransplant anti-MICA antibodies on long-term renal allograft survival and function remained unsettled. We tested the posttransplant anti-MICA antibodies in 150 kidney transplant patients. The aim of this study was to compare the long-term graft survival and function between patients who were MICA positive and those who were negative. The posttransplant serum samples from 150 patients receiving kidney transplantation in our center from 2012 to 2013 were tested for MICA antibodies and HLA antibodies by Luminex single antigen array technology. Graft survival and function were followed up for a mean time of 74.2 months. The research was conducted in accordance with the Helsinki Congress and the Declaration of Istanbul. Of the 150 patients, 38 (25.3%) were sensitized against MICA after transplantation. The anti-MICA antibodies-positive (anti-MICA+) group had a worse long-term renal allograft survival than that of anti-MICA-negative (anti-MICA-) group (P = .029), even when stratified by posttransplant HLA sensitization status or donor source. Anti-MICA antibodies also had a detrimental impact on renal allograft function, but only at 1 year posttransplantation (estimated glomerular filtration rates at 1 year: anti-MICA+ 66.6 mL/min/1.73 m2 vs anti-MICA- 78.7 mL/min/1.73 m2; P = .023). Posttransplant anti-MICA antibodies were associated with decreased long-term renal allograft survival and short-term renal allograft function.

A Rat Orthotopic Renal Transplantation Model for Renal Allograft Rejection.

Renal allograft rejection limits the long-term survival of patients after renal transplantation. Rat orthotopic renal transplantation is an essential model to investigate the mechanism of renal allograft rejection in pre-clinical studies and could aid in the development of novel approaches to improve the long-term survival of renal allografts. Donor kidney implantation in rat orthotopic renal transplantation is commonly performed by end-to-side anastomosis to recipients' aorta and inferior vena cava. In this model, the donor's kidney was implanted using end-to-end anastomosis to the recipients' renal artery and renal vein. The donor's ureter was anastomosed to the recipient's bladder in an end-to-side 'tunnel' method. This model contributes to better healing of ureter-bladder anastomosis and increases the recipients' survival by avoiding interference with blood supply and venous reflux of the lower body. This model can be used to investigate the mechanisms of acute and chronic immune and pathologic rejection of renal allografts. Here, the study describes the detailed protocols of this orthotopic renal transplantation between rats.

Death With Function and Graft Failure After Kidney Transplantation: Risk Factors at Baseline Suggest New Approaches to Management.

Improving both patient and graft survival after kidney transplantation are major unmet needs. The goal of this study was to assess risk factors for specific causes of graft loss to determine to what extent patients who develop either death with a functioning graft (DWFG) or graft failure (GF) have similar baseline risk factors for graft loss. We retrospectively studied all solitary renal transplants performed between January 1, 2006, and December 31, 2018, at 3 centers and determined the specific causes of DWFG and GF. We examined outcomes in different subgroups using competing risk estimates and cause-specific Cox models. Of the 5752 kidney transplants, graft loss occurred in 21.6% (1244) patients, including 12.0% (691) DWFG and 9.6% (553) GF. DWFG was most commonly due to malignancy (20.0%), infection (19.7%), cardiac disease (12.6%) with risk factors of older age and pretransplant dialysis, and diabetes as the cause of renal failure. For GF, alloimmunity (38.7%), glomerular diseases (18.6%), and tubular injury (13.9%) were the major causes. Competing risk incidence models identified diabetes and older recipients with higher rates of both DWFG and nonalloimmune GF. These data suggest that at baseline, 2 distinct populations can be identified who are at high risk for renal allograft loss: a younger, nondiabetic patient group who develops GF due to alloimmunity and an older, more commonly diabetic population who develops DWFG and GF due to a mixture of causes-many nonalloimmune. Individualized management is needed to improve long-term renal allograft survival in the latter group.

Poor Long-Term Renal Allograft Survival in Patients with Chronic Antibody-Mediated Rejection, Irrespective of Treatment—A Single Center Retrospective Study

The Banff 2017 report permits the diagnosis of pure chronic antibody-mediated rejection (cAMR) in absence of microcirculation inflammation. We retrospectively investigated renal allograft function and long-term outcomes of 67 patients with cAMR, and compared patients who received antihumoral therapy (cAMR-AHT, n = 21) with patients without treatment (cAMRwo, n = 46). At baseline, the cAMR-AHT group had more concomitant T-cell-mediated rejection (9/46 (19.2%) vs. 10/21 (47.6%); p = 0.04), a higher g-lesion score (0.4 ± 0.5 versus 0.1 ± 0.3; p = 0.01) and a higher median eGFR decline in the six months prior to biopsy (6.6 vs. 3.0 mL/min; p = 0.04). The median eGFR decline six months after biopsy was comparable (2.6 vs. 4.9 mL/min, p = 0.61) between both groups, and three-year graft survival after biopsy was statistically lower in the cAMR-AHT group (35.0% vs. 61.0%, p = 0.03). Patients who received AHT had more infections (0.38 vs. 0.20 infections/patient; p = 0.04). Currently, antihumoral therapy is more often administered to patients with cAMR and rapidly deteriorating renal function or concomitant TCMR. However, long-term graft outcomes remain poor, despite treatment.

Clinical and Pathologic Feature of Patients With Early Versus Late Active Antibody-Mediated Rejection After Kidney Transplantation: A Single-Center Experience

ObjectiveActive antibody-mediated rejection (aABMR), particularly late aABMR, remains a major challenge for long-term renal allograft survival. This single-center retrospective study aimed to compare clinical features between early vs late aABMR and to identify risk factors for allograft failure among patients with aABMR. MethodForty-one patients diagnosed with aABMR at our hospital were included and were divided into 2 groups: early aABMR (≤6 months; n = 10) vs late aABMR (>6 months; n = 31) based on the time from transplant to diagnosis. Their clinical and pathologic data were compared. This study was performed in compliance with the Helsinki Congress and the Declaration of Istanbul. ResultsOf 10 patients with early aABMR, none had allograft failure, whereas 8 of 31 patients with late aABMR had developed allograft failure at the time of follow-up (25.8%). At the time of biopsy, patients with early aABMR had higher positive grade in urine occult blood test than patients with late aABMR (P = .01); however, the late aABMR group displayed more intensive interstitial fibrosis and tubular atrophy (P = .03) and more frequent HLA-DQ-type donor-specific antibodies. Interestingly, donor-specific antibody conversion from positive to negative was not associated with C4d grade but was correlated with time from transplant to biopsy. Multivariate Cox regression analysis indicated that high levels of serum creatinine or proteinuria and concomitant T-cell-mediated rejection were independent risk factors for allograft failure in patients with aABMR. ConclusionThese data not only confirm that early aABMR has better clinical outcomes than late aABMR but highlight the importance of early diagnostic biopsy and early therapeutic interventions in ABMR, particularly in patients with high levels of serum creatinine or proteinuria in the early posttransplant phase.

Early Post-transplant Renal Functions Predict Incidence of Acute Rejection in Kidney Transplantation

Objectives: After renal transplantation, a remarkable improvement of impaired patient’s kidney function is often observed. Preserving improved kidney function ensures long-term renal allograft survival. However, there are different risk factors; the acute rejection is the major risk factor. Therefore, the aim of the present study was to examine renal function within the first six months as independent variables in predicting long-term survival and incidence of acute rejection.&#x0D; Methods: Fifty-three patients who underwent kidney transplantation in 2016 and 2017 in King Abdulaziz Medical City- National Guard were evaluated consecutively1 and 2-month pre-transplant up to six months’ post-transplant. Time course of changes in kidney functions; measurements of serum creatinine (Scr), blood urea nitrogen(BUN), albumin, calcium, sodium and potassium were recorded. Estimated glomerular filtration rate (eGFR) and anion gap (AGAP) were also reported. In addition, age, anthropometric factors and causes of ESRD were analyzed.&#x0D; Results: Lower level of calcium was observed in 40% of patient’s two-month pre-transplantation and 69% of patients one month before. Normalization of calcium was achieved in all patients starting from second month post-transplantation. All patients presented elevated serum potassium level in pre-transplant months, however, renal transplant normalize potassium level starting from first month. A remarkable higher level of serum BUN was observed in all pre-transplant patients followed by dramatically decreased after renal transplant for first four months and remain in normal level starting from month 5. Likewise, serum creatinine was highly elevated in all pre-transplant patients. A profound reduction in serum creatinine started from month 1 post-transplant and normalizes at month 4. Moreover, both eGFR and AGAP were kept in normal level immediately after renal transplantation. All patients with early acute rejection during mean follow-up period have a remarkable elevated level of serum creatinine and profound decrease in eGFR starting from first month. While a significant higher level of serum BUN observed in fifth month only and serum albumin in third month.&#x0D; Conclusion: Significant elevation of serum creatinine and reduction in eGFR starting from first month were associated with post-transplanted patients with early acute rejection. The clinical use of eGFR and serum creatinine may aid in predicting incidence of early acute rejection.

Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats.

Chronic renal allograft dysfunction (CRAD) is a major condition that impedes the long-term survival of renal allografts. However, the mechanism of CRAD is obscure, and the effective strategies for controlling the progression of CRAD are lacking. The present study used a CRAD rat model to assess the effect of glycogen synthase kinase 3β (GSK-3β) inhibition on the development of CRAD. A classical F334-to-LEW orthotopic renal transplantation was performed on the CRAD group. The treatment group was treated with the GSK-3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione for 12 consecutive weeks following renal transplantation. The study included uninephrectomized F344 and Lewis rats as control subjects. Twelve weeks post surgery, the rats were retrieved for analysis of renal function, urine protein levels, histological, immunohistochemical, and molecular biological parameters. Administration of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione inactivated GSK-3β and thereby improved renal function, attenuated proteinuria, and reduced renal tissue damage in CRAD rats. Besides, inactivation of GSK-3β inhibited nuclear factor-κB activation, macrophage infiltration, and expression of multiple proinflammatory cytokines/chemokines. Inhibition of GSK-3β also decreased the levels of malondialdehyde, increased superoxide dismutase levels, upregulated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, and enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 in the kidneys of CRAD rats. Inhibition of GSK-3β attenuates the development of CRAD by inhibiting inflammation and oxidant stress. Thus, GSK-3β inhibition may represent a potential therapeutic strategy for the prevention and treatment of CRAD.

THE REQUIREMENT OF THYMIC IRRADIATION FOR INDUCTION OF MIXED CHIMERISM AND RENAL ALLOGRAFT TOLERANCE IN NON-HUMAN PRIMATES

Introduction: Thymic irradiation (TI) has been required for consistent induction of allograft tolerance through a mixed chimerism approach in both murine and nonhuman primate (NHP) models. In this study, we investigated the mechanisms of TI requirement in combined kidney (KTx) and bone marrow transplantation (BMT) in NHPs. Materials and Methods: In Group A, 5 recipients received BMT (combined KTx was evaluated in three) from MHC mismatched donors with a conditioning regimen that included total body irradiation (TBI, 1.5Gy), a Bcl-2 inhibitor (venetoclax), ATG and TI (7Gy). After transplant, the recipients were treated with a short course of anti-CD154 monoclonal antibody and a one-month course of cyclosporine. No immunosuppression was given after one month. In Group B, 3 recipients received combined KTx and BMT with the same regimen but without TI. Results: All recipients in Group A (TI) developed significantly higher chimerism than Group B (p < 0.02). Three recipients in Group A with KTx achieved long-term renal allograft survival without rejection (survival days 313, >646,>982 days) while all three Group B (No TI) recipients rejected renal allografts shortly after discontinuation of cyclosporine (97, 100, 163 days; p < 0.025 Groups A vs. B in Kaplan-Meier; Figure 1).Although recent thymic emigrants (RTE; CD4+CD31+CD45RA+) and naïve T cells of Group A were completely depleted after the preconditioning, those of Group B were substantially observed and significantly higher (Figure 2). On the other hand, no difference was observed in memory T cell subsets or regulatory T cells between two groups. Conclusion: Peripheral T cell deletion by the conditioning regimen may result in enhanced thymopoiesis with increased post-transplant RTE and naïve cells if TI is not administered. Higher post-transplant naïve T cells potentially inhibited chimerism and tolerance induction in recipients without TI.

1072 - Predictors of long-term renal allograft survival after second kidney transplantation

1072 - Predictors of long-term renal allograft survival after second kidney transplantation

Predictors of long-term renal allograft survival after second kidney transplantation.

Few studies investigate significant perioperative predictors for long-term renal allograft survival after second kidney transplant (SKT). We compared long-term survival following SKT with primary kidney transplant and determined predictors of renal allograft failure after SKT. Outcomes of all primary or second kidney transplant recipients at a national kidney transplant center between 1993 and 2017 were reviewed. The primary outcomes measurements were renal allograft survival for both first and second kidney transplants. Secondary outcome measurements were incidence of delayed graft function (DGF), incidence of acute rejection (AR), and predictors for renal allograft survival in SKT recipients. In total, there were 392 SKTs and 2748 primary kidney transplants performed between 1993 and 2017. The 1-, 5-, and 10-year death-censored graft survival for deceased-donor recipients was 95.3%, 88.7%, and 78.2% for primary kidney transplant and 94.9%, 87.1%, and 74.9% for SKT (P=.0288). Survival of primary renal allograft <6years (HR 0.6, P=.017), AR episodes (HR 1.6, P=.031), DGF (HR 2.0, P=.005), and HLA-DR MM (HR 1.7, P=.018) was independent predictors of long-term renal allograft failure after SKT. These findings may provide important information on long-term survival outcomes after SKT and for identifying patients at risk for long-term renal allograft failure after SKT.

BK virus infection in renal transplant recipients: an overview

Although BK virus (BKV) was discovered in 1971, it took almost three decades for this virus to be routinely considered as a possibility among a plethora of causes of renal dysfunction in a kidney transplant recipient. BKV infection, an early complication of renal transplant, often presents within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma. More frequent diagnosis of BKV infection over the past 2 decades is a consequence of more potent immunosuppression (aimed to prevent acute rejection episodes and, thereby, improving allograft survival). Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. A routine screening protocol for early recognition of asymptomatic BKV infection has been reported to result in better allograft outcomes. This review is aimed to discuss the most recent evidence addressing the virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection.

An age-independent gene signature for monitoring acute rejection in kidney transplantation.

Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods.Methods: To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository.Results: We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR.Conclusion: We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.

Long-Term Outcomes of Renal Transplant in Patients With End-Stage Renal Failure Due to Systemic Lupus Erythematosus and Granulomatosis With Polyangiitis.

Systemic lupus erythematosus and granulomatosis with polyangiitis are systemic inflammatory conditions associated with renalfailure that can recur after renal transplant. Patients with these conditions are treated with chronic immunosuppression, potentially increasing risk of secondary malignancies. Here, we investigated long-term outcomes in renal transplant recipients with these conditions. Transplant recipients with end-stage kidney disease due to systemic lupus erythematosus and granulomatosis with polyangiitis seen between 1982 and 2016 at a national kidney transplant center were included. Primary outcome variables were long-term allograft survival and incidence of secondary malignancy. Secondary outcome measures were incidence of delayed graft function, primary disease recurrence, and serum creatinine at follow-up. Ninety-eight transplant procedures (90 from deceased donors) in 92 consecutive patients (mean age 42.3 ± 14.4 y) were included: 55 with systemic lupus erythematosus and 37 with granulomatosis with polyangiitis. Follow-up duration was 110.53 ± 81.95 months (range, 1-393 mo). Overall renal allograft survival was 94.7% at 1 year, 85.4% at 5 years, and 75.4% at 10 years posttransplant. Patientswith systemic lupus erythematosus showed overall allograft survival of 91.6% at 1 year, 84.3% at 5 years, and 74.4% at 10 years. There was 1 allograft failure due to recurrence of primary disease in this group. Patients with granulomatosis with polyangiitis showed overall allograft survival of 100% at 1 year, 92.4% at 5 years, and 92.4% at 10 years. There were 21 mortalities, with 5 (23.8%) due to secondary malignancy. In total, 46 malignancies were diagnosed in 31 patients. We found excellent long-term renal allograft survival rates in patients with systemic lupus erythematosus and granulomatosis with polyangiitis, with secondary malignancy rates similar to those shown in recipients without autoimmune diseases. These findings provide clinicians with long-term data on transplant recipients with end-stage renal failure due to systemic inflammatory conditions.

Bcl-2 Inhibition with Venetoclax Promotes Induction of Mixed Chimerism and Renal Allograft Tolerance Without Severe Myelosuppression in Non-human Primates

Abstract Background Specific Bcl-2 inhibition has been shown to promote mixed chimerism and allograft tolerance without myelosuppressive conditioning in murine models. We extended this approach to nonhuman primates in combined kidney and bone marrow transplantation (CKBMT). Methods In Group A, recipients received CKBMT with the regimen including total body irradiation (TBI,3 Gy) thymic irradiation (TI, 7Gy) and ATG, followed by a short course of anti-CD154 antibody and cyclosporine. In Group B, TBI was reduced to 1.5Gy. In Group C, peri-transplant Bcl-2 inhibitor (Venetoclax) was added to Group B regimen. In Group D, Group C regimen without TBI. In Group E, Group C regimen without TI. Results 7/8 recipients in Group A developed transient chimerism and achieved long-term renal allograft survival without immunosuppression. However, these recipients developed transient but severe pancytopenia between days 10–17 post CKBMT. Both recipients in Group B failed to develop chimerism. By adding Venetoclax to Group B regimen, 3/3 Group C recipients developed significantly higher and longer mixed chimerism without severe myelosuppression. These three recipients also achieved long-term immunosuppression free renal allograft survival without rejection (&amp;gt;316, &amp;gt;575, &amp;gt;239 days). In Group D, both recipients failed to develop chimerism and rejected their allografts on days 140 and 120. Although three Group E recipients successfully developed chimerism, all rejected their renal allografts on days 100, 97, 163 with early recovery of CD31+ naive T cells. Conclusion Enhancement of intrinsic apoptosis with Bcl-2 inhibition is a promising strategy to achieve robust mixed chimerism and allograft tolerance with reduced myelosuppressive conditioning.