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.

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.

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.

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.

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.

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.

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.

Effect of diabetes and acute rejection on liver transplant outcomes: An analysis of the organ procurement and transplantation network/united network for organ sharing database.

The effects of diabetic status and acute rejection (AR) on liver transplant outcomes are largely unknown. We studied 13,736 liver recipients from the United Network for Organ Sharing/Organ Procurement Transplant Network database who underwent transplantation between 2004 and 2007 with a functioning graft for greater than 1 year. The association of pretransplant diabetes mellitus (PDM), new-onset diabetes after transplant (NODAT), and AR rates on allograft failure, all-cause mortality, and cardiovascular mortality were determined. To determine the differential and joint effects of diabetic status and AR on transplant outcomes, recipients were further stratified into 6 groups: neither (reference, n = 6600); NODAT alone (n = 2054); PDM alone (n = 2414); AR alone (n = 1448); NODAT and AR (n = 707); and PDM and AR (n = 513). An analysis with hepatitis C virus (HCV) serostatus was also performed (HCV recipients, n = 6384; and non-HCV recipient, n = 5934). The median follow-up was 2537 days. The prevalence of PDM was 21.3%. At 1 year after transplant, the rates of NODAT and AR were 25.5% and 19.4%, respectively. Overall, PDM, NODAT, and AR were associated with increased risks for graft failure (PDM, hazard ratio [HR] = 1.31, P < 0.01; NODAT, HR = 1.11, P = 0.02; AR, HR = 1.28, P < 0.01). A multivariate Cox regression analysis of the 6 recipient groups demonstrated that NODAT alone was not significantly associated with any study outcomes. The presence of PDM, AR, NODAT and AR, and PDM and AR were associated with higher overall graft failure risk and mortality risk. The presence of PDM was associated with higher cardiovascular mortality risk. The analyses in both HCV-positive and HCV-negative cohorts showed a similar trend as in the overall cohort. In conclusion, PDM and AR, but not NODAT, is associated with increased mortality and liver allograft failure. Liver Transplantation 22 796-804 2016 AASLD.

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.