Pretransplant Treatment to Avoid Recurrent Membranous Nephropathy in a Kidney Transplant Recipient: A Case Report.

Kidney transplant candidates with high anti-M-type phospholipase A2 receptor antibody activity may be at increased risk for early postkidney transplant recurrence and allograft loss. Pretransplant treatment to induce serological remission may be warranted to improve allograft survival. In this case report, a patient seeking their third kidney transplant, who lost 2 prior living donor transplants from early recurrent membranous nephropathy, underwent pretransplant treatment for membranous nephropathy with serological remission and no evidence of recurrent disease.

Novel indications for referral and care for simultaneous liver kidney transplant recipients.

PURPOSE OF REVIEW: Kidney dysfunction is challenging in liver transplant candidates to determine whether it is reversible or not. This review focuses on the pertinent data on how to best approach liver transplant candidates with kidney dysfunction in the current era after implementing the simultaneous liver kidney (SLK) allocation policy and safety net. RECENT FINDINGS: The implementation of the SLK policy inverted the steady rise in SLK transplants and improved the utilization of high-quality kidneys. Access to kidney transplantation following liver transplant alone (LTA) increased with favorable outcomes. Estimating GFR in liver transplant candidates remains challenging, and innovative methods are needed. SLK provided superior patient and graft survival compared to LTA only for patients with advanced CKD and dialysis at least 3 months. SLK can provide immunological protection against kidney rejection in highly sensitized candidates. Post-SLK transplant care is complex, with an increased risk of complications and hospitalization. SUMMARY: The SLK policy improved kidney access and utilization. Transplant centers are encouraged, under the safety net, to reserve SLK for liver transplant candidates with advanced CKD or dialysis at least 3 months while allowing lower thresholds for highly sensitized patients. Herein, we propose a practical approach to liver transplant candidates with kidney dysfunction.

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.

Continuation of immunosuppression vs. immunosuppression weaning in potential repeat kidney transplant candidates: a care management perspective.

Management of immunosuppression in patients with a failing or failed kidney transplant requires a complete assessment of their clinical condition. One of the major considerations in determining immunosuppression is whether or not such an individual is considered a candidate for re-transplantation. Withdrawal of immunosuppression in a re-transplant candidate can result in allosensitization and markedly reduce the chances of a repeat transplant. In this review, we summarize the effects of immunosuppression reduction on HLA sensitization, discuss the impacts of allosensitization in these patients, and explore reduction protocols and future directions. Risks of chronic immunosuppression, medical management of the failing allograft, and the effect of nephrectomy are covered elsewhere in this issue.

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%.

Reduction in Maintenance Immunosuppression in Kidney Transplant Recipients With Stable Donor-Derived Cell-Free DNA Measurements: A Case Series.

Personalization of maintenance immunosuppression in kidney transplant recipients has long remained a goal in the transplant community. The recent addition of donor-derived cell-free DNA assays to detect allograft rejection and monitor allograft health may permit for reductions in maintenance immunosuppression in recipients with stable levels. Herein, we described 5 patients with stable donor-derived cell-free DNA levels who underwent reduction in maintenance immunosuppression without precipitation of clinical rejection, proteinuria, or de novo donor specific antibody formation.

Apheresis of Deceased Donors as a New Source of Mobilized Peripheral Blood Hematopoietic Stem Cells for Transplant Tolerance.

BACKGROUND: Solid organ transplantation is the therapy of choice for many patients with end-stage organ failure; however, recipients must remain on lifelong immunosuppression, leaving them susceptible to infections and cancer. The study of transplant tolerance to prolong graft survival in the absence of immunosuppression has been restricted to recipients of living donor allografts; however, deceased donors significantly outnumber living donors. Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to peripheral blood (PB) could allow PB-HSCs to be used to induce tolerance in deceased donor kidney recipients; however, a major concern is the well-known concomitant mobilization of immune cells into the liver. METHODS: We mobilized HSCs to the PD using a protocol of 2 doses of granulocyte colony-stimulating factor and 1 dose of plerixafor, followed by the collection of mobilized cells via apheresis in 3 deceased donors. The physiological, laboratory, and radiographic parameters were monitored throughout the procedure. Longitudinal biopsies were performed to assess the potential for ectopic liver mobilization. RESULTS: The use of both agents led to the successful mobilization of peripheral blood CD34+ cells, demonstrating the potential for use in transplant tolerance protocols. Increased immune cell trafficking into the liver was not observed, and apheresis of mobilized cells resulted in a uniform decrease in all liver leukocyte subsets. CONCLUSIONS: HSCs can be mobilized and collected from the PB of brain-dead donors. This new approach may facilitate the dissemination of immune tolerance trials beyond living-donor kidney transplantation to deceased-donor transplantation, without sacrificing the transplantability of the liver.

Impact of solid organ transplant status on outcomes of hospitalized patients with COVID-19 infection.

BACKGROUND: The COVID-19 pandemic has caused significant morbidity and mortality in solid organ transplant (SOT) recipients. However, it remains unclear whether the risk factor for SOT patients is the immunosuppression inherent to transplantation versus patient comorbidities. METHODS: We reviewed outcomes in a cohort of SOT (n = 129) and non-SOT (NSOT) patients (n = 708) admitted to the University of California, Los Angeles for COVID-19 infection. Data analyses utilized multivariate logistic regression to evaluate the impact of patient demographics, comorbidities, and transplant status on outcomes. SOT patients were analyzed by kidney SOT (KSOT) versus nonkidney SOT (NKSOT) groups. RESULTS: SOT and NSOT patients with COVID-19 infection differed in terms of patient age, ethnicity, and comorbidities. NKSOT patients were the most likely to experience death, with a mortality rate of 16.2% compared with 1.8% for KSOT and 8.3% for NSOT patients (p = .013). Multivariable analysis of hospitalized patients revealed that patient age (odds ratio [OR] 2.79, p = .001) and neurologic condition (OR 2.66, p < .001) were significantly associated with mortality. Analysis of ICU patients revealed a 2.98-fold increased odds of death in NKSOT compared with NSOT patients (p = .013). CONCLUSIONS: This study demonstrates the importance of transplant status in predicting adverse clinical outcomes in patients hospitalized or admitted to the ICU with COVID-19, especially for NKSOT patients. Transplant status and comorbidities, including age, could be used to risk stratify patients with COVID-19. This data suggests that immunosuppression contributes to COVID-19 disease severity and mortality and may have implications for managing immunosuppression, especially for critically ill patients admitted to the ICU.

Outcomes of small pediatric donor kidney transplants according to donor weight.

A small pediatric deceased donor (SPD) weight cutoff whether to transplant as en bloc (EB) or single pediatric (SP) kidney is uncertain. Using UNOS/OPTN data (2000-2019), 27 875 SPDs were divided by (i) EB (11.4%) or SP (88.6%) and (ii) donor weight [≤10 (5.4%), >10-15 (8.3%), >15-18 (3.7%), >18-20 (2.9%), and >20 kg (79.7%)]. SP >20 kg and adult deceased donors (grouped by Kidney Donor Profile Index, KDPI, <30, 30-85, and >85) were used as references. The primary outcome was 10-year graft failure. In SP <10 kg, the hazard ratio (HR) for overall graft failure was 1.64 (1.38-2.20) compared with EB <10 kg, and 1.45 (1.18-1.80) compared with SP >20 kg. In SP >10-15 kg, HR was 1.31 (1.12-1.54) compared with EB >10-15 kg, and 1.04 (0.91-1.18) compared with SP >20 kg. In SP >15 kg, the risk was the same as SP >20 kg. Ten-year overall graft survival of SP 12 kg was comparable to SP >20 kg (62% vs. 57%). Ten-year death censored graft failure of SP >10-15 kg (70%) and SP >15-18 kg (70%) was like the adult donors with KDPI 30-85 (67%). In conclusion, we recommend single kidney transplants from SPDs with weight >12 kg to adult recipients in centers with experience in SPD transplants to optimize organ utilization.

Extremely High Cell-free DNA Levels Observed in Renal Allograft Patient With SARS-CoV-2 Infection.

Beyond its widely recognized morbidity and mortality, coronavirus disease 2019 poses an additional health risk to renal allograft recipients. Detection and measurement of donor-derived cell-free DNA (dd-cfDNA), expressed as a fraction of the total cell-free DNA (cfDNA), has emerged as a noninvasive biomarker for allograft rejection. Here, we present a case report of a patient who was infected with severe acute respiratory syndrome coronavirus 2, 11 mo post-kidney transplant. The patient was serially monitored using an analytically and clinically validated massively multiplex PCR-based dd-cfDNA assay to assess allograft injury and risk for rejection. Over the course of infection, low dd-cfDNA fractions were observed (below the 1% cutoff) and were accompanied by unusually highly elevated levels of total cfDNA, which gradually declined as the infection resolved. The case study highlights the variability in total cfDNA levels during and after viral infection, and the need to consider both total and dd-cfDNA levels when clinically interpreting the results for allograft rejection. Furthermore, the study highlights the importance of serial testing, wherein an interplay between total cfDNA and dd-cfDNA can inform the optimization of a patient's immunosuppressive treatment regimen in response to infection.

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.

Early cytomegalovirus DNAemia and antiviral dose adjustment in high vs intermediate risk kidney transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection continues to negatively affect outcomes for solid organ transplant recipients, despite the advent of strategies for preemptive surveillance and prophylaxis. The impact is especially great for CMV seronegative recipients of donor seropositive organs, who typically lack the ability to control CMV infection at the time of transplantation. METHODS: We reviewed episodes of CMV DNAemia in a modern cohort of kidney transplant recipients over a 3-year period at a high-volume transplant center to investigate the frequency of DNAemia during antiviral prophylaxis. RESULTS: Despite receipt of antiviral prophylaxis per current guidelines, 75 cases of CMV DNAemia were observed in the first 100 days after transplantation. For high risk patients, median time to DNAemia was 75 days after transplantation, and the majority of patients had experienced dose-reduction of valganciclovir due to renal insufficiency. Review of CMV seropositive intermediate risk patients demonstrated DNAemia occurring earlier after transplantation compared with high risk patients with a median time of 64 days (P = .029). The impact of valganciclovir dose adjustment was less notable in the intermediate risk group. CONCLUSIONS: Guidelines recommend beginning routine surveillance for CMV after the completion of antiviral prophylaxis. Our findings suggest that closer monitoring may be beneficial, especially for high risk patients at risk for DNAemia. Patients requiring dose adjustment of valganciclovir due to renal insufficiency may be at increased risk for CMV DNAemia. Improved methods for CMV prophylaxis and evaluation of immunologic risk for CMV DNAemia and disease are needed to improve patient outcomes after kidney transplantation.

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.

DNA Methylation Age Is More Closely Associated With Infection Risk Than Chronological Age in Kidney Transplant Recipients.

Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age. METHODS: DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age. RESULTS: Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection. CONCLUSIONS: Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.

Spectrum of Coronavirus Disease 2019 Outcomes in Kidney Transplant Recipients: A Single-Center Experience.

PURPOSE: We reviewed the clinical experience of kidney transplant recipients diagnosed with severe acute respiratory syndrome coronavirus 2 infection in order to understand the impact of the current coronavirus disease 2019 (COVID-19) pandemic infection on transplant recipients. Given that early reports from heavily affected areas demonstrated a very high mortality rate amongst kidney transplant recipients, ranging between 30% and 40%, we sought to evaluate outcomes at a center with a high burden of cases but not experiencing acute crisis due to COVID-19. PROCEDURES: In this single center retrospective observational study, medical records of all kidney transplant recipients at the UCLA Medical Center were reviewed for a diagnosis of COVID-19 by polymerase chain reaction, followed by chart review to determine kidney transplant characteristics and clinical course. MAIN FINDINGS: A total of 41 kidney transplant recipients were identified with COVID-19 positive polymerase chain reaction. Recipients had been transplanted for a median of 47 months before diagnosis. The large proportion of infected individuals were minorities (Hispanic 65.9%, black 14.6%), on prednisone, tacrolimus, and mycophenolate mofetil (95.1%, 87.8%, and 87.8%, respectively), and had excellent allograft function (median 1.25 mg/dL). The most common presenting symptoms were fever, dyspnea, or cough. Most patients were hospitalized (63.4%); mortality was 9.8% and occurred only in patients in the intensive care unit. The most common treatment was reduction or removal of antimetabolite (77.8%). Approximately 26.9% presented with AKI. CONCLUSIONS: COVID-19 infection in kidney transplant recipients results in a higher rate of hospitalization and mortality than in the general population. In an area with a high number of infections, the mortality rate was lower compared with earlier reports from areas experiencing early surge and strain on the medical system. Minorities were disproportionately affected. Future studies are needed to determine optimal approach to treatment and management of immunosuppression in kidney transplant recipients with COVID-19 infection.

Time to second kidney transplantation in young adults after failed pediatric kidney transplant.

BACKGROUND: Under the current kidney allocation system, pediatric candidates listed prior to age 18 receive priority for high-quality deceased donor organs. This has resulted in a decline in living donor transplantation in pediatrics, despite superior outcomes of living donor transplantation. Due to a young age at transplantation, most pediatric kidney transplant recipients require re-transplantation. The effects of a previously failed deceased donor vs a previously failed living donor on re-transplant candidates are unknown. METHODS: Using the United Network for Organ Sharing database, we examined 2772 re-transplant recipients aged 18-30 years at time of relisting for second KT from 2000 to 2018 with history of prior pediatric KT (age ≤ 18 years). RESULTS: PFLDKT recipients compared to those with PFDDKT had shorter median waiting times and dialysis time regardless of their second donor type (14.0 vs 20.3 months, and 19.1 vs 34.5 months, respectively). PFLDKT recipients had higher re-transplant rates (adjusted HR 1.17, 95% CI 1.09-1.27, and adjusted HR 1.05, 95% CI 0.95-1.15 when calculating from time of relisting and time of returning to dialysis, respectively). PFDDKT recipients were more likely to have higher median PRA levels (90% vs 73%). CONCLUSIONS: Re-transplant candidates who received a previous deceased donor as a child had a higher level of sensitization, longer waiting time, and dialysis exposure compared to those with PFLDKT. Among primary pediatric kidney transplant candidates, consideration should be considered for living donor transplantation, despite the priority for deceased donor organs, to avoid increased sensitization and longer waiting times for with re-transplantation.

Listing Malignant Melanoma Patients for Renal Transplantation.

BACKGROUND: Melanoma is an immune responsive malignancy and the need for immunosuppression for successful transplantation may lead to recurrent disease. The recommended waiting time is unknown with various groups recommending anywhere from no wait to 5 years. METHODS: In this single-center, retrospective observational study all kidney transplant recipients' charts from 1991 to 2015 were reviewed for a diagnosis of melanoma before transplantation. The charts were reviewed for the clinical characteristics of melanoma pre transplantation, induction immunosuppression, maintenance immunosuppression, graft function, death, and recurrence of melanoma. RESULTS: Thirteen patients with a history of melanoma underwent kidney transplantation during this period. Recipients had been in remission for an average of 7.0 years (range, 10 months to 20 years, median 6 years). Approximately 61.5% received a living donor transplant, antithymocyte globulin was administered in 23.1% of recipients, and the remaining 76.9% received basiliximab. Melanoma recurred in 1 patient (7.7%). Maintenance immunosuppression varied, but only 2 patients remained on standard triple therapy with prednisone, calcineurin inhibitor, and antimetabolite therapy. Average follow-up time since transplant was 7.5 years, with 1 patient death 9 years post transplant from sepsis. CONCLUSION: In conclusion, with our center demonstrates safety of kidney transplantation in patients with a prior history of localized melanoma and shorter waiting time. In malignant melanoma stage 0 and 1, waiting the recommended 5 years from the time of remission to kidney transplantation should be reconsidered.