A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

A Roadmap for Innovation to Advance Transplant Access and Outcomes: A Position Statement From the National Kidney Foundation.

Over the past 65 years, kidney transplantation has evolved into the optimal treatment for patients with kidney failure, dramatically reducing suffering through improved survival and quality of life. However, access to transplant is still limited by organ supply, opportunities for transplant are inequitably distributed, and lifelong transplant survival remains elusive. To address these persistent needs, the National Kidney Foundation convened an expert panel to define an agenda for future research. The key priorities identified by the panel center on the needs to develop and evaluate strategies to expand living donation, improve waitlist management and transplant readiness, maximize use of available deceased donor organs, and extend allograft longevity. Strategies targeting the critical goal of decreasing organ discard that warrant research investment include educating patients and clinicians about potential benefits of accepting nonstandard organs, use of novel organ assessment technologies and real-time decision support, and approaches to preserve and resuscitate allografts before implantation. The development of personalized strategies to reduce the burden of lifelong immunosuppression and support "one transplant for life" was also identified as a vital priority. The panel noted the specific goal of improving transplant access and graft survival for children with kidney failure. This ambitious agenda will focus research investment to promote greater equity and efficiency in access to transplantation, and help sustain long-term benefits of the gift of life for more patients in need.

Leukocyte transcriptome indicators of development of infection in kidney transplant recipients.

After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation.

Impact of donor obesity on allograft outcomes after kidney transplantation adjusted for kidney donor profile index - a national cohort study.

Obesity in deceased kidney donors is a known risk factor for poor allograft outcomes. The Kidney Donor Profile Index (KDPI) has been introduced to predict graft survival in deceased donor kidney transplantation (DDKT). Obesity, however, is not included in KDPI. We study the impact of donor obesity on DDKT outcomes after adjusting for organ quality by KDPI. The Organ Procurement Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data of DDKT from 2005 to 2017, with donor BMI ≥ 18.5 kg/m2 and weight >80 kg were included. There was a total of 66 382 DDKTs with 10 917 death-censored graft failures. For KDPI ≤ 30%, the 10-year death-censored graft survival (DCGS) rates among donor BMI < 30, 30-35, 35-40, 40-45 and ≥45 kg/m2 groups were 75.9%, 75.4%, 76.1%, 74.9% and 79.6%, respectively. For KDPI > 30%, 10-year DCGS rates were 67.5%, 66.1%, 65.9%, 62.6% and 63.2%, respectively. After adjusting for known confounding factors including KDPI, donor obesity was not independently associated with an increased risk for graft failure. In DDKT with donor weight >80 kg, donor obesity was not associated with a lower long term DCGS compared to non-obesity when KDPI ≤ 30%.

Elective Resection of Symptomatic Arteriovenous Fistulae and Grafts in Patients with Functioning Renal Allografts at A High Volume Transplant Hospital.

OBJECTIVE: Patients with functioning renal allografts may need ligation of pre-existing hemodialysis conduits. Chronic immunosuppression for renal allografts may adversely affect wound healing and perioperative complications following these procedures. We sought to analyze outcomes following elective ligation and resection of symptomatic arteriovenous (AV) access in immunosuppressed patients with renal allografts no longer requiring dialysis at a high-volume renal transplant hospital. METHODS: We retrospectively reviewed procedure codes for hemodialysis access resection and revision from 2014-2020 at a single academic tertiary care hospital. Patients who underwent complete or subtotal dialysis access resection with a functioning renal allograft were included for analysis of preoperative, operative, and postoperative outcomes. We performed descriptive statistics, and student's t-test using Microsoft Excel. RESULTS: Thirty-four patients met inclusion criteria. The majority were male, 56%, and the most common causes of renal failure were hypertension and diabetes, respectively. Ligation and resection of proximal upper extremity access was performed in 68%. The mean operative time was 126 minutes with pain being the most common indication for intervention. Four patients required arterial reconstruction. Mean postoperative follow-up was 13 months. Arm pain and swelling resolved in 100% and 88% of patients following AV access resection, respectively. No impairment in mean postoperative glomerular filtration rates were noted. One patient required hemodialysis and died three months after fistula resection following complications from treatment of a newly diagnosed neuroendocrine tumor and subsequent fungemia, CONCLUSION: Elective operative resection of symptomatic AV access may be performed safely in immunosuppressed patients with functioning renal transplants. The risk of allograft impairment and/or failure as a result of AV access resection in our series was low. Elective ligation and resection can be achieved with low mortality, excellent symptomatic relief, and few wound complications despite chronic immunosuppression.

Mesangial sclerosis in a patient with type 1 diabetes following simultaneous pancreas-kidney transplantation despite maintenance of normoglycemia: a case report.

BACKGROUND: Simultaneous pancreas-kidney transplantation is considered a curative treatment for type 1 diabetes complicated by end-stage kidney disease. We report herein a case of mesangial sclerosis in a patient who underwent successful kidney-pancreas transplantation despite well-controlled glucose and excellent pancreatic allograft function. CASE PRESENTATION: A 76-year-old type 1 diabetic man who underwent a simultaneous pancreas-kidney transplantation 19 years prior presented with persistent nephrotic range proteinuria although creatinine was at his baseline (normal) level. Hemoglobin A1c and fasting glucose were well controlled without the use of insulin or oral antihyperglycemic agents. Serum lipase and amylase were within the reference range and there was no evidence of donor-specific antibodies. Kidney allograft biopsy was performed to evaluate proteinuria and showed diffuse capillary loop thickening and diffuse moderate to severe mesangial sclerosis resembling diabetic nephropathy. CONCLUSIONS: This case demonstrates a case of mesangial sclerosis resembling diabetic nephropathy in a patient with good glucose control after simultaneous pancreas-kidney transplantation with excellent pancreatic allograft function.

Novel options for failing allograft in kidney transplanted patients to avoid or defer dialysis therapy.

PURPOSE OF REVIEW: Despite improvement in short-term renal allograft survival in recent years, renal transplant recipients (RTR) have poorer long-term allograft outcomes. Allograft function slowly declines with periods of stable function similar to natural progression of chronic kidney disease in nontransplant population. Nearly all RTR transitions to failing renal allograft (FRG) period and require transition to dialysis. Conservative chronic kidney disease management before transition to end-stage renal disease is an increasingly important topic; however, there is limited data in RTR regarding how to delay dialysis initiation with conservative management. RECENT FINDINGS: Since immunological and nonimmunological factors unique to RTR contribute to decline in allograft function, therapies to slow progression of FRG should take both sets of factors into account. Renal replacement therapy either incremental dialysis or rekidney transplantation should be explored. This required taking benefits and risks of continuing immunosuppressive medications into account when allograft nephrectomy may be necessary. SUMMARY: FRG may benefit from various interventions to slow progression of worsening allograft function. Until there are stronger evidence to guide interventions to preserve renal function, extrapolating evidence from nontransplant patients and clinical judgment are necessary. The goal is to provide individualized care for conservative management of RTR with FRG.

Factors predicting kidney delayed graft function among recipients of simultaneous liver-kidney transplantation: A single-center experience.

BACKGROUND: Kidney delayed graft function (kDGF) remains a challenging problem following simultaneous liver and kidney transplantation (SLKT) with a reported incidence up to 40%. Given the scarcity of renal allografts, it is crucial to minimize the development of kDGF among SLKT recipients to improve patient and graft outcomes. We sought to assess the role of preoperative recipient and donor/graft factors on developing kDGF among recipients of SLKT. METHODS: A retrospective review of 194 patients who received SLKT in the period from January 2004 to March 2017 in a single center was performed to assess the effect of preoperative factors on the development of kDGF. RESULTS: Kidney delayed graft function was observed in 95 patients (49%). Multivariate analysis revealed that donor history of hypertension, cold static preservation of kidney grafts [versus using hypothermic pulsatile machine perfusion (HPMP)], donor final creatinine, physiologic MELD, and duration of delay of kidney transplantation after liver transplantation were significant independent predictors for kDGF. kDGF is associated with worse graft function and patient and graft survival. CONCLUSIONS: Kidney delayed graft function has detrimental effects on graft function and graft survival. Understanding the risks and combining careful perioperative patient management, proper recipient selection and donor matching, and graft preservation using HPMP would decrease kDGF among SLKT recipients.

Combined Dual-Kidney Liver Transplantation in the United States: A Review of United Network for Organ Sharing/Organ Procurement and Transplantation Network Data Between 2002 and 2012.

In kidney-alone recipients, dual-kidney transplantation using "higher-risk" donor organs has shown outcomes comparable to those of single-kidney transplantation using extended criteria donor (ECD) organs. To investigate the feasibility of a similar approach with combined kidney-liver transplantation, we identified 22 dual-kidney liver transplantations (DKLTs) and 3044 single-kidney liver transplantations (SKLTs) performed in the United States between 2002 and 2012 using United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data. We compared donor/recipient characteristics as well as graft/recipient survival between DKLT recipients and SKLT recipients of "higher-risk" kidneys (ECD and high kidney donor profile index [KDPI; >85%] donors). Despite having overall similar donor and recipient characteristics compared with both "higher-risk" donor groups, recipient survival in the DKLT group at 36 months was markedly inferior at 40.9% (compared with 67.5% for ECD SKLT recipients and 64.5% for high-KDPI SKLT recipients); nondeath-censored graft survival did not differ. Death was the most common cause of graft loss in all groups. Contrary to dual-kidney transplantation data in kidney-alone recipients, DKLT recipients in our study had inferior survival when compared with SKLT recipients of "higher-risk" donor kidneys. These findings would suggest that dual kidney-liver transplantation has an uncertain role as a strategy to expand the existing kidney donor pool in combined transplantation.

TREX1 Mutation Causing Autosomal Dominant Thrombotic Microangiopathy and CKD-A Novel Presentation.

Renal thrombotic microangiopathy (TMA) involves diverse causes and clinical presentations. Genetic determinants causing alternate pathway complement dysregulation underlie a substantial proportion of cases. In a significant proportion of TMAs, no defect in complement regulation is identified. Mutations in the major mammalian 3' DNA repair exonuclease 1 (TREX1) have been associated with autoimmune and cerebroretinal vasculopathy syndromes. Carboxy-terminal TREX1 mutations that result in only altered localization of the exonuclease protein with preserved catalytic function cause microangiopathy of the brain and retina, termed retinal vasculopathy and cerebral leukodystrophy (RVCL). Kidney involvement reported with RVCL usually accompanies significant brain and retinal microangiopathy. We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.

PD 1 checkpoint inhibition in solid organ transplants: 2 sides of a coin - case report.

BACKGROUND: The management of malignancy post kidney transplantation includes reduction in immunosuppression and referral to an oncologist management of their malignancy. Recent advances in oncology have resulted in the approval of several classes of drugs with immune-modulatory activity. However, activation of the immune system against malignant cells may precipitate allograft rejection in solid organ transplant recipients. CASE PRESENTATION: Herein we present a case of acute kidney allograft rejection in a 50 year old man following administration of the novel immune-modulatory agent nivolumab for the treatment of metastatic squamous cell carcinoma. CONCLUSION: The management of malignancy in solid organ transplant recipients requires a heightened awareness of the potential for allograft rejection in this new era of cancer therapeutics.

Avoiding Futility in Simultaneous Liver-kidney Transplantation: Analysis of 331 Consecutive Patients Listed for Dual Organ Replacement.

OBJECTIVE: We sought to evaluate outcomes and predictors of renal allograft futility (RAF-patient death or need for renal replacement therapy at 3 months) after simultaneous liver-kidney transplantation (SLKT). BACKGROUND: Model for End-Stage Liver Disease (MELD) prioritization of liver recipients with renal dysfunction has significantly increased utilization of SLKT. Data on renal outcomes after SLKT in the highest MELD recipients are scarce, as are accurate predictors of recovery of native kidney function. Without well-established listing guidelines, SLKT potentially wastes renal allografts in both high-acuity liver recipients at risk for early mortality and recipients who may regain native kidney function. METHODS: A retrospective single-center multivariate regression analysis was performed for adult patients undergoing SLKT (January 2004 to August 2014) to identify predictors of RAF. RESULTS: Of 331 patients dual-listed for SLKT, 171 (52%) expired awaiting transplant, 145 (44%) underwent SLKT, and 15 (5%) underwent liver transplantation alone. After SLKT, 39% experienced delayed graft function and 20.7% had RAF. Compared with patients without RAF, RAF recipients had greater MELD scores, length of hospitalization, intraoperative base deficit, incidence of female donors, kidney and liver donor risk indices, kidney cold ischemia, and inferior overall survival. Multivariate predictors of RAF included pretransplant dialysis duration, kidney cold ischemia, kidney donor risk index, and recipient hyperlipidemia. CONCLUSIONS: With 20% short-term loss of transplanted kidneys after SLKT, our data strongly suggest that renal transplantation should be deferred in liver recipients at high risk for RAF. Consideration for a kidney allocation variance to allow for delayed renal transplantation after liver transplantation may prevent loss of scarce renal allografts.

Acute Kidney Allograft Rejection Precipitated by Lenalidomide Treatment for Multiple Myeloma.

Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.

Banking on Living Kidney Donors-A New Way to Facilitate Donation without Compromising on Ethical Values.

Public surveys conducted in many countries report widespread willingness of individuals to donate a kidney while alive to a family member or close friend, yet thousands suffer and many die each year while waiting for a kidney transplant. Advocates of financial incentive programs or "regulated markets" in kidneys present the problem of the kidney shortage as one of insufficient public motivation to donate, arguing that incentives will increase the number of donors. Others believe the solutions lie-at least in part-in facilitating so-called "altruistic donation;" harnessing the willingness of relatives and friends to donate by addressing the many barriers which serve as disincentives to living donation. Strategies designed to minimize financial barriers to donation and the use of paired kidney exchange programs are increasingly enabling donation, and now, an innovative program designed to address what has been termed "chronologically incompatible donation" is being piloted at the University of California, Los Angeles, and elsewhere in the United States. In this program, a person whose kidney is not currently required for transplantation in a specific recipient may instead donate to the paired exchange program; in return, a commitment is made to the specified recipient that priority access for a living-donor transplant in a paired exchange program will be offered when or if the need arises in the future. We address here potential ethical concerns related to this form of organ "banking" from living donors, and argue that it offers significant benefits without undermining the well-established ethical principles and values currently underpinning living donation programs.