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.

Evaluation of Renal Disease in Patients With Cirrhosis.

Renal dysfunction in cirrhosis is common and is associated with increased mortality. Identifying and treating reversible causes of renal disease can significantly improve outcomes. The etiology, approach, and evaluation of renal disease in this group of patients is similar to the noncirrhosis patient, with a few specific caveats. Renal disease may be unrelated to the cause of cirrhosis (eg, prerenal acute kidney injury, acute tubular necrosis), occur as a manifestation of the same systemic disease responsible for the liver disease (eg, chronic viral hepatitis B and C infection) or as a consequence of cirrhosis (hepatorenal syndrome). Kidney impairment may be underrecognized in patients with cirrhosis due to over-reliance on creatinine-based glomerular filtration rate equations used in clinical practice. The first steps of evaluation for the renal disease include a thorough medical history to identify the underlying cause of cirrhosis and any potential trigger for renal dysfunction, physical examination, and review of prior laboratory records for baseline renal function. Renal imaging and urinalysis should be performed on all cirrhotic patients with renal dysfunction to establish the presence of urinary obstruction, chronicity and intrinsic renal disease.

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.

Current Status of Simultaneous Liver-Kidney Transplantation in the United States.

On August 10, 2017, a formal policy was enacted in the United States that defined listing criteria for simultaneous liver-kidney transplantation and priority for patients who received a liver transplantation (LT) and subsequently developed significant kidney disease after LT. This article reviews and summarizes the rationale for such policies, the policies themselves, and the potential impact on LT candidates.

Current opinions in nephrology and hypertension: kidney transplantation in patients with plasma cell dyscrasias.

PURPOSE OF REVIEW: Plasma cell dyscrasias encompass a group of hematological disorders characterized by increased production of immunoglobulins by clonal B cells. Kidney involvement is common. Significant advances in the treatment of plasma cell dyscrasias have resulted in improved survival and may permit kidney transplantation in candidates previously denied transplantation. Treatments may also have effects on kidney transplant recipients who develop plasma cell dyscrasias post transplantation. RECENT FINDING: The available evidence suggests that transplantation of candidates with nonmultiple myeloma plasma cell dyscrasias provides good outcome with low recurrence rates, so long as the disease has been treated with a complete or good partial response prior to transplantation. Candidates with a history untreated MGRS or a history of multiple myeloma have a high rate of recurrence posttransplant. Kidney transplant recipients who develop plasma cell dyscrasias post transplantation have an increased risk of death and thalidomide-based regimens may increase the risk of rejection. SUMMARY: Transplant candidates with a history of plasma cell dyscrasia who are in remission should not be excluded from transplantation. Individuals with multiple myeloma have a high rate of recurrence and myeloma post kidney transplant must be managed carefully.

Association of Citizenship Status With Kidney Transplantation in Medicaid Patients.

BACKGROUND: Although individuals classified as nonresident aliens, including undocumented immigrants, are entitled to receive emergency dialysis in the United States regardless of their ability to pay, most states do not provide them with subsidized care for maintenance dialysis or kidney transplantation. We explored whether nonresident aliens have similar outcomes to US citizens after receiving kidney transplants covered by Medicaid, a joint federal and state health insurance program. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: All adult Medicaid patients in the US Renal Data System who received their first kidney transplant from 1990 to 2011. PREDICTOR: Citizenship status, categorized as US citizen, nonresident alien, or permanent resident. OUTCOME: All-cause transplant loss. MEASUREMENTS: HRs and 95% CIs estimated by applying Cox proportional hazards frailty models with transplantation center as a random effect. RESULTS: Of 10,495 patients, 8,660 (82%) were US citizens, 1,489 (14%) were permanent residents, and 346 (3%) were nonresident aliens, whom we assumed were undocumented immigrants. Nonresident aliens were younger, healthier, receiving dialysis longer, and more likely to have had a living donor. 71% underwent transplantation in California, and 61% underwent transplantation after 2005. Nonresident aliens had a lower unadjusted risk for transplant loss compared with US citizens (HR, 0.48; 95% CI, 0.35-0.65). Results were attenuated but still significant when adjusted for demographics, comorbid conditions, dialysis, and transplant-related factors (HR, 0.67; 95% CI, 0.46-0.94). LIMITATIONS: Citizenship status was self-reported, possible residual confounding. CONCLUSIONS: Our study suggests that the select group of insured nonresident aliens who undergo transplantation with Medicaid do just as well as US citizens with Medicaid. Policymakers should consider expanding coverage for kidney transplantation in nonresident aliens, including undocumented immigrants, given the associated high-quality outcomes in these patients.

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.

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.

Balancing the Evidence: How to Reconcile the Results of Observational Studies vs. Randomized Clinical Trials in Dialysis.

Because large randomized clinical trials (RCTs) in dialysis have been relatively scarce, evidence-based dialysis care has depended heavily on the results of observational studies. However, when results from RCTs appear to contradict the findings of observational studies, nephrologists are left to wonder which type of study they should believe. In this editorial, we explore the key differences between observational studies and RCTs in the context of such seemingly conflicting studies in dialysis. Confounding is the major limitation of observational studies, whereas low statistical power and problems with external validity are more likely to limit the findings of RCTs. Differences in the specification of the population, exposure, and outcomes can also contribute to different results among RCTs and observational studies. Rigorous methods are required regardless of what type of study is conducted, and readers should not automatically assume that one type of study design is superior to the other. Ultimately, dialysis care requires both well-designed, well-conducted observational studies and RCTs to move the field forward.

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.

A2/A2B Deceased Donor Kidney Transplantation Using A2 Titers Improves Access to Kidney Transplantation: A Single-Center Study.

Rationale & Objective: The option for A2/A2B deceased donor kidney transplantation was integrated into the kidney allocation system in 2014 to improve access for B blood group waitlist candidates. Despite excellent reported outcomes, center uptake has remained low across the United States. Here, we examined the effect of implementing an A2/A2B protocol using a cutoff titer of ≤1:8 for IgG and ≤1:16 for IgM on blood group B kidney transplant recipients at a single center. Study Design: Retrospective observational study. Setting & Participants: Blood group B recipients of deceased donor kidney transplants at a single center from January 1, 2019, to December 2022. Exposure: Recipients of deceased donor kidney transplants were analyzed based on donor blood type with comparisons of A2/A2B versus blood group compatible. Outcomes: One-year patient survival, death-censored allograft function, primary nonfunction, delayed graft function, allograft function as measured using serum creatinine levels and estimated glomerular filtration rate at 1 year, biopsy-proven rejection, and need for plasmapheresis. Analytical Approach: Comparison between the A2/A2B and compatible groups were performed using the Fisher test or the χ2 test for categorical variables and the nonparametric Wilcoxon rank-sum test for continuous variables. Results: A total of 104 blood type B patients received a deceased donor kidney transplant at our center during the study period, 49 (47.1%) of whom received an A2/A2B transplant. Waiting time was lower in A2/A2B recipients compared with blood group compatible recipients (57.9 months vs 74.7 months, P = 0.01). A2/A2B recipients were more likely to receive a donor after cardiac death (24.5% vs 1.8%, P < 0.05) and experience delayed graft function (65.3% vs 41.8%). There were no observed differences in the average serum creatinine level or estimated glomerular filtration rate at 1 month, 3 months, and 1 year post kidney transplantation, acute rejection, or primary nonfunction. Limitations: Single-center study. Small cohort size limiting outcome analysis. Conclusions: Implementation of an A2/A2B protocol increased transplant volumes of blood group B waitlisted patients by 83.6% and decreased the waiting time for transplantation by 22.5% with similar transplant outcomes.

Recipient blood type is one of the main determinants of waiting time to receive a deceased donor kidney transplant. Patients with blood type B have some of the longest waiting times for a kidney in the United States. Minorities comprise a large percentage of blood group B waitlist patients, contributing to observed racial differences in kidney transplantation rates. In this study, accepting an A2/A2B incompatible kidney resulted in receiving a kidney transplant almost 18 months earlier compared with receiving a blood group compatible kidney. No differences in outcomes were seen by accepting A2/A2B kidneys.

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.

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.

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.