Physical Frailty Predicts Outcomes in Patients Undergoing Evaluation for Kidney Transplantation.

INTRODUCTION: An increasing number of older patients are undergoing evaluation for kidney transplantation; however, older patients experience increased rates of complications compared with younger patients, leading to the study of frailty assessments. Although many centers have evaluated the Fried Frailty Phenotype (FFP), less is known about the ability of the Short Performance Physical Battery (SPPB) to predict outcomes. METHODS: Frailty assessment by FFP and SPPB was introduced into routine outpatient evaluation for patients aged 55 years and older referred for transplantation. Transplant rate, length of stay, readmission up to 3 months posttransplant, and death were reviewed. Patients were evaluated in an initial cohort followed by a validation cohort by FFP and SPPB. Multivariate analysis correcting for demographic characteristics was applied. RESULTS: Patient cohorts reflected the racial and ethnic diversity of our population, including approximately 40% Hispanic patients. The first cohort of 514 patients demonstrated a significant association between frailty as measured by SPPB and transplantation (odds ratio [OR], 2.27; 95% CI, 1.38-3.83; p = .002). The second cohort of 1408 patients validated the association between frailty measured by SPPB and transplantation (OR, 2.81; 95% CI, 1.83-4.48; p < .001). In addition, there was a significant association between nonfrail status measured by SPPB and death (OR, 0.16; 95% CI, 0.04-0.62; p = .006). CONCLUSIONS: Frailty assessment is a potentially useful approach for the assessment of transplant candidates. Our real-world study examined the performance of 2 methods of frailty evaluation methods in a diverse population, demonstrating that SPPB but not FFP was predictive of clinical outcomes. Incorporation of frailty assessments into transplant evaluation may improve risk stratification and optimize outcomes for older patients.

Deceased Donor Kidney Nonuse: A Systematic Approach to Improvement.

A large number of procured kidneys continue not to be transplanted, while the waiting list remains high. Methods: We analyzed donor characteristics for unutilized kidneys in our large organ procurement organization (OPO) service area in a single year to determine the reasonableness of their nonuse and to identify how we might increase the transplant rate of these kidneys. Five experienced local transplant physicians independently reviewed unutilized kidneys to identify which kidneys they would consider transplanting in the future. Biopsy results, donor age, kidney donor profile index, positive serologies, diabetes, and hypertension were risk factors for nonuse. Results: Two-thirds of nonused kidneys had biopsies with high degree of glomerulosclerosis and interstitial fibrosis. Reviewers identified 33 kidneys as potentially transplantable (12%). Conclusions: Reducing the rate of unutilized kidneys in this OPO service area will be achieved by setting acceptable expanded donor characteristics, identifying suitable well-informed recipients, defining acceptable outcomes, and systematically evaluating the results of these transplants. Because the improvement opportunity will vary by region, to achieve a significant impact on improving the national nonuse rate, it would be useful for all OPOs, in collaboration with their transplant centers, to conduct a similar analysis.

Preservation of Antiviral Immunologic Efficacy Without Alloimmunity After Switch to Belatacept in Calcineurin Inhibitor-Intolerant Patients.

Introduction: Belatacept has shown potential for prevention of rejection after kidney transplantation, given its demonstration of reduced nephrotoxicity in combination with absence of significant incidence of rejection. However, concerns have been raised regarding increased risk of viral infection. Methods: We set out to explore the impact of the switch to belatacept on alloimmune and antiviral immunity through the study of patients switched from calcineurin inhibitor (CNI) to belatacept within 3 months of kidney transplantation compared with a matched cohort of control patients on a CNI-based regimen. Results: After the switch to belatacept, immune phenotyping demonstrated a decrease in naive and an increase in terminally differentiated effector memory (TMRA) T cells, with no significant difference compared with control patients. Donor-specific immune response, measured by intracellular cytokine staining (ICS), did not change significantly either by single or double cytokine secretion, but it was associated with the appearance of donor-specific antibody (DSA) in the control but not the belatacept cohort (P = 0.039 for naive and P = 0.002 for TMRA subtypes). Increased incidence of de novo DSA development was observed in the control group (P = 0.035). Virus-specific immune response, as measured by ICS in response to cytomegalovirus (CMV) or Epstein-Barr virus (EBV), was similar in both groups and stable over time. Conclusion: We found that belatacept use was associated with an absence of alloreactivity without impact on immune phenotype, while preserving the antiviral immune response, for patients switched from a CNI-based regimen. In parallel, the antiviral immune response against CMV and EBV was preserved after the belatacept switch (clinicaltrials.gov: NCT01953120).

Cold Ischemia Time, Kidney Donor Profile Index, and Kidney Transplant Outcomes: A Cohort Study.

Rationale & Objective: An average of 3,280 recovered deceased donor kidneys are discarded annually in the United States. Increased cold ischemia time is associated with an increased rate of organ decline and subsequent discard. Here we examined the effect of prolonged cold ischemia time on kidney transplant outcomes. Study Design: Retrospective observational study. Setting & Participants: Recipients of deceased donor kidney transplants in the United States from 2000 to 2018. Exposure: Recipients of deceased donor kidneys were divided based on documented cold ischemia time: ≤16, 16-24, 24-32, 32-40, and >40 hours. Outcomes: The incidence of delayed graft function, primary nonfunction, and 10-year death-censored graft survival. Analytical Approach: The Kaplan-Meier method was used to generate survival curves, and the log rank test was used to compare graft survival. Results: The rate of observed delayed graft function increased with cold ischemia time (20.9%, 28.1%, 32.4%, 37.5%, and 35.8%). Primary nonfunction also showed a similar increase with cold ischemia time (0.6%, 0.9%, 1.3%, 2.1%, and 2.3%), During a median follow-up time of 4.6 years, 37,301 recipients experienced death-censored graft failure. Analysis based on kidney donor profile index (KDPI) demonstrated significant differences in 10-year death-censored graft survival, with a death-censored graft survival in recipients of a kidney with a KDPI <85% of 71.0% (95% CI, 70.5%-71.5%), 70.5% (95% CI, 69.9%-71.0%), 69.6% (95% CI, 68.7%-70.4%), 65.5% (95% CI, 63.7%-67.3%), and 67.2% (95% CI, 64.6%-69.6%), compared to 53.5% (95% CI, 51.1%-55.8%), 50.7% (95% CI, 48.3%-53.1%), 50.3% (95% CI, 46.6%-53.8%), 50.7% (95% CI, 45.1%-56.1%), and 48.3% (95% CI, 40.0%-56.1%), for recipients of a kidney with a KDPI >85%. Limitations: Heterogeneity of acceptance patterns among transplant centers, presence of confounding variables leading to acceptance of kidneys with prolonged cold ischemia times. Conclusions: Cold ischemia time was associated with an increased risk of delayed graft function and primary nonfunction. However, the effect of increased cold ischemia time is modest and has less impact than the KDPI. Transplant programs should not consider prolonged cold ischemia time alone as a predominant reason to decline an organ, especially with a KDPI <85%.

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.

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.

Voucher-Based Kidney Donation and Redemption for Future Transplant.

Importance: Policy makers, transplant professionals, and patient organizations agree that there is a need to increase the number of kidney transplants by facilitating living donation. Vouchers for future transplant provide a means of overcoming the chronological incompatibility that occurs when the ideal time for living donation differs from the time at which the intended recipient actually needs a transplant. However, uncertainty remains regarding the actual change in the number of living kidney donors associated with voucher programs and the capability of voucher redemptions to produce timely transplants. Objective: To examine the consequences of voucher-based kidney donation and the capability of voucher redemptions to provide timely kidney allografts. Design, Setting, and Participants: This multicenter cohort study of 79 transplant centers across the US used data from the National Kidney Registry from January 1, 2014, to January 31, 2021, to identify all family vouchers and patterns in downstream kidney-paired donations. The analysis included living kidney donors and recipients participating in the National Kidney Registry family voucher program. Exposures: A voucher was provided to the intended recipient at the time of donation. Vouchers had no cash value and could not be sold, bartered, or transferred to another person. When a voucher was redeemed, a living donation chain was used to return a kidney to the voucher holder. Main Outcomes and Measures: Deidentified demographic and clinical data from each kidney donation were evaluated, including the downstream patterns in kidney-paired donation. Voucher redemptions were separately evaluated and analyzed. Results: Between 2014 and 2021, 250 family voucher-based donations were facilitated. Each donation precipitated a transplant chain with a mean (SD) length of 2.3 (1.6) downstream kidney transplants, facilitating 573 total transplants. Of those, 111 transplants (19.4%) were performed in highly sensitized recipients. Among 250 voucher donors, the median age was 46 years (range, 19-78 years), and 157 donors (62.8%) were female, 241 (96.4%) were White, and 104 (41.6%) had blood type O. Over a 7-year period, the waiting time for those in the National Kidney Registry exchange pool decreased by more than 3 months. Six vouchers were redeemed, and 3 of those redemptions were among individuals with blood type O. The time from voucher redemption to kidney transplant ranged from 36 to 155 days. Conclusions and Relevance: In this study, the family voucher program appeared to mitigate a major disincentive to living kidney donation, namely the reluctance to donate a kidney in the present that could be redeemed in the future if needed. The program facilitated kidney donations that may not otherwise have occurred. All 6 of the redeemed vouchers produced timely kidney transplants, indicating the capability of the voucher program.

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.

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%.

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.