Outcomes of Older Patients in the Recent Era of Heart Kidney Transplantation.

BACKGROUND AND OBJECTIVE: Variable age thresholds are often used at transplant centers for simultaneous heart and kidney transplantation (HKT). We hypothesize that selected older recipients enjoy comparable outcome to younger recipients in the current era of HKT. METHODS: We performed a retrospective analysis of HKT outcomes in the United Network for Organ Sharing (UNOS) registry from 2006 to 2018, classifying patients by age at transplant as ≥ 65 or < 65 years. The primary outcome was patient death. Secondary outcomes included all-cause kidney graft failure and death-censored kidney allograft failure. RESULTS: Of 973 patients, 774 (80%) were younger than 65 years (mean 52 ± 10 years) and 199 (20%) were 65 years or older (mean 67 ± 2 years). The older HKT cohort had fewer blacks (22% vs 35%, P = .01) and women (12 vs 18%, P = .04). Fewer older patients received dialysis (30% vs 54%, P < .001) and mechanical support (36% vs 45%, P = .03) before HKT. Older recipients received organs from slightly older donors. The median follow-up time was shorter for patients 65 years or older than for the younger group (2.3 vs 3.3 years, P < .001). Patient survival was similar between the groups (mean 8.8 vs 9.8 years, P = .3), with the most common causes of death being cardiovascular (29%) and infectious complications (28%). There was no difference in all-cause kidney graft survival (mean 8.7 vs 9.3 years, P = .8). Most commonly, recipients died with a functional renal allograft (59.8%), and this occurred more commonly in older patients (81.4% vs 54.8%, P = .001). Cox proportional hazard modeling showed that higher donor age (hazard ratio [HR] 1.015, P = .01; HR 1.022, P = .02) and use of pre-transplant dialysis (HR 1.5, P = .004; HR 1.8, P = .006) increased the risk for both all-cause and death-censored kidney allograft failure, respectively. CONCLUSIONS: Our study showed that carefully selected older patients have outcomes similar to those of a younger cohort and argues for comprehensive evaluation of the recipients with age as part of comorbidity assessment rather than use of an arbitrary age threshold for candidacy.

Lack of Benefit and Potential Harm of Induction Therapy in Simultaneous Liver-Kidney Transplants.

The number of simultaneous liver-kidney transplantations (SLKTs) and use of induction therapy for SLKT have increased recently, without much published evidence, especially in the context of maintenance immunosuppression containing tacrolimus (TAC) and mycophenolic acid (MPA). We queried the Organ Procurement and Transplant Network registry for SLKT recipients maintained on TAC/MPA at discharge in the United States for 2002-2016. The cohort was divided into 3 groups on the basis of induction type: rabbit antithymocyte globulin (r-ATG; n = 831), interleukin 2 receptor antagonist (IL2RA; n = 1558), and no induction (n = 2333). Primary outcomes were posttransplant all-cause mortality and acute rejection rates in kidney and liver allografts at 12 months. Survival rates were analyzed by the Kaplan-Meier method. A propensity score analysis was used to control potential selection bias. Multivariate inverse probability weighted Cox proportional hazard and logistic regression models were used to estimate the hazard ratios (HRs) and odds ratios. Among SLKT recipients, survival estimates at 3 years were lower for recipients receiving r-ATG (P = 0.05). Compared with no induction, the multivariate analyses showed an increased mortality risk with r-ATG (HR, 1.29; 95% confidence interval [CI], 1.10-1.52; P = 0.002) and no difference in acute liver or kidney rejection rates at 12 months across all induction categories. No difference in outcomes was noted with IL2RA induction over the no induction category. In conclusion, there appears to be no survival benefit nor reduction in rejection rates for SLKT recipients who receive induction therapy, and r-ATG appears to increase mortality risk compared with no induction.

Induction regimen and survival in simultaneous heart-kidney transplant recipients.

BACKGROUND: Induction therapy in simultaneous heart-kidney transplantation (SHKT) is not well studied in the setting of contemporary maintenance immunosuppression consisting of tacrolimus (TAC), mycophenolic acid (MPA), and prednisone (PRED). METHODS: We analyzed the Organ Procurement and Transplant Network registry from January 1, 2000, to March 3, 2015, for recipients of SHKT (N = 623) maintained on TAC/MPA/PRED at hospital discharge. The study cohort was further stratified into 3 groups by induction choice: induction (n = 232), rabbit anti-thymoglobulin (r-ATG; n = 204), and interleukin-2 receptor-α (n = 187) antagonists. Survival rates were estimated using the Kaplan-Meier estimator. Multivariable inverse probability weighted Cox proportional hazard regression models were used to assess hazard ratios associated with post-transplant mortality as the primary outcome. The study cohort was censored on March 4, 2016, to allow at least 1-year of follow-up. RESULTS: During the study period, the number of SHKTs increased nearly 5-fold. The Kaplan-Meier survival curve showed superior outcomes with r-ATG compared with no induction or interleukin-2 receptor-α induction. Compared with the no-induction group, an inverse probability weighted Cox proportional hazard model showed no independent association of induction therapy with the primary outcome. In sub-group analysis, r-ATG appeared to lower mortality in sensitized patients with panel reactive antibody of 10% or higher (hazard ratio, 0.19; 95% confidence interval, 0.05-0.71). CONCLUSION: r-ATG may provide a survival benefit in SHKT, especially in sensitized patients maintained on TAC/MPA/PRED at hospital discharge.

Kidney Diseases Associated With Alternative Complement Pathway Dysregulation and Potential Treatment Options.

Atypical hemolytic uremic syndrome and C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) are characterized as inappropriate activation of the alternative complement pathway. Genetic mutations affecting the alternative complement pathway regulating proteins (complement factor H, I, membrane cofactor protein and complement factor H-related proteins) and triggers (such as infection, surgery, pregnancy and autoimmune disease flares) result in the clinical manifestation of these diseases. A decade ago, prognosis of these disease states was quite poor, with most patients developing end-stage renal disease. Furthermore, renal transplantation in these conditions was associated with poor outcomes due to graft loss to recurrent disease. Recent advances in targeted complement inhibitor therapy resulted in significant improvement in disease remission, renal recovery, health-related quality of life and allograft survival.

Transplant Professionals' Perceptions of Long-Term Care Residents' Candidacy for Kidney Transplantation.

CONTEXT: Given the aging end-stage renal disease (ESRD) population, kidney transplant (KTx) centers may experience an increase in referrals of patients living in long-term care (LTC) settings (eg, skilled nursing facilities, assisted living facilities, group homes, and boarding homes). OBJECTIVE: To identify best practices among KTx professionals when considering individuals in LTC settings for transplantation. DESIGN AND SETTING: A cross-sectional survey administered online to US transplant professionals via e-mail LISTSERVs and other professional networks. PARTICIPANTS: One hundred twenty-six KTx professionals working in the United States. MAIN OUTCOME MEASURES: The survey was composed of demographic questions and 6 hypothetical scenarios. These scenarios asked participants to assess transplant candidacy of patients with ESRD living in LTC settings based on the information provided in the scenario. Each scenario presented a different variable that necessitated LTC placement, including lack of social support, moderate intellectual disability, stable neurological condition, mild dementia, a psychiatric condition controlled on medications, and limited mobility. RESULTS: The only scenario that elicited an overwhelmingly negative response was mild dementia with 73.9% of participants unwilling to consider such patients for KTx. By contrast, the proportion of KTx professionals reluctant to proceed with KTx in the remaining scenarios ranged between 40.0% and 50.6%. CONCLUSIONS: This survey of a large number of KTx professionals suggests that there is presently no best practice consensus regarding offering KTx to patients living in LTC settings. Further research should include a broader range of KTx professionals and should also include a study of outcomes with KTx in this particular patient population.

Renal Transplantation in Advanced Chronic Kidney Disease Patients.

Kidney transplantation is the best option for patients with end-stage kidney disease. It is associated with better quality of life, lower medical costs, less hospitalization, and improved survival compared with wait-listed patients who remain on dialysis. Timely referral for transplantation is essential to reap the maximal benefit and should begin in the advanced chronic kidney disease stage prior to starting dialysis. Shortage of donor organs remains the biggest challenge to transplantation. With the improved success of kidney transplantation, candidate acceptance criteria continue to broaden. This article provides an overview of the pretransplantation multidisciplinary evaluation process detailing the factors that determine transplant candidacy.

Long-Term Functional Recovery, Quality of Life, and Pregnancy After Solid Organ Transplantation.

This article reviews the salient features of functional recovery, health-related quality of life (HR-QOL), and reproductive health, with special emphasis on pregnancy outcomes in kidney and liver recipients. Transplantation results in improved functional status and HR-QOL. Addressing factors that limit the optimal rehabilitation of transplant recipients can improve transplant outcomes. After successful transplantation, there is a rapid return of fertility, warranting counseling regarding contraception. Practitioners should be aware of the teratogenic potential of mycophenolic acid products. Posttransplant pregnancies are high risk, with increased incidences of hypertension, preeclampsia, and prematurity. Most pregnancies in kidney and liver recipients have successful maternal and newborn outcomes.

Pathophysiologic and treatment strategies for cardiovascular disease in end-stage renal disease and kidney transplantations.

The inextricable link between the heart and the kidneys predestines that significant cardiovascular disease ensues in the face of end-stage renal disease (ESRD). As a point of fact, the leading cause of mortality of patients on dialysis is still from cardiovascular etiologies, albeit differing in particular types of disease from the general population. For example, sudden cardiac death outnumbers coronary artery disease in patients with ESRD, which is the reverse for the general population. In this review, we will focus on the pathophysiology and treatment options of important traditional and nontraditional risk factors for cardiovascular disease in ESRD patients such as hypertension, anemia, vascular calcification, hyperparathyroidism, uremia, and oxidative stress. The evidence of erythropoietin-stimulating agents, phosphate binders, calcimimetics, and dialysis modalities will be presented. We will then discuss how these risk factors may be changed and perhaps exacerbated after renal transplantation. This is largely due to the immunosuppressive agents that are both crucial yet potentially detrimental in the posttransplant state. Calcineurin inhibitors, corticosteroids, and mammalian target of rapamycin inhibitors, the mainstay of transplant immunosuppression, are all known to increase the risks of developing new onset diabetes as well as the metabolic syndrome. Thus, we need to carefully negotiate between patients' cardiovascular profile and their risks of rejection. Finally, we end by considering strategies by which we may minimize cardiovascular disease in the transplant population, as this modality still confers the highest chance of survival in patients with ESRD.

Impact of Donor Specific HLA Antibody Monitoring After Kidney Transplantation.

Kidney transplantation (KT) recipients with donor specific HLA antibodies (DSA) encounter higher rates of acute rejection and inferior allograft survival. We report our single center experience with prospective DSA monitoring and provide details of treatments utilized to overcome the potential impact of DSA in a cohort of predominantly African American adult KT recipients. Seventy-five flow crossmatch negative KT recipients underwent periodic screening for DSA utilizing the single antigen bead assay at 3, 6, 9, and 12 months post-transplant. Allograft biopsies were performed in the presence of DSA and/or evidence of graft dysfunction. The incidence of DSA was 23%, with a predominance of Class II antibodies. The rate of rejection was 6 times higher in DSA positive KT recipients compared to DSA negative patients (41% versus 7%, p = 0.004). In the DSA positive group, rejections occurred exclusively in the presence of de novo DSA and were predominantly antibody-mediated or mixed rejections. Despite a higher incidence of rejection in KT recipients with DSA, there were no significant differences in serum creatinine, graft survival, and patient survival between DSA positive and negative recipients at median follow-up of 18 months. DSA positive patients had significantly higher proteinuria compared to DSA negative recipients at 6 months, 1 year, and 3 years of follow-up. In conclusion, the detrimental effects of DSA on allograft function could be mitigated by serial DSA surveillance, protocol biopsies, and alterations in immunosuppression. With these measures, the improvement in graft survival in DSA positive KT recipients, at least at short-term, is encouraging.

Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study.

BACKGROUND: Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy. METHODOLOGY/PRINCIPAL FINDINGS: Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = -0.48, p<0.0001) and eGFR (rho = -0.33, p = 0.005). CONCLUSIONS/SIGNIFICANCE: These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets.

Results of repeat renal transplantation after graft loss from BK virus nephropathy.

BACKGROUND: BK virus nephropathy (BKVN) is an important cause of renal graft loss in recent years. The aims of this study are to (1) describe the management of patients undergoing retransplantation after allograft loss in the setting of BKVN and (2) to identify risk factors for BK virus replication in the retransplant. METHODS: This retrospective study compiled data on adult patients undergoing repeat transplantation after previous loss of allograft to BKVN from six U.S. centers. Clinical, laboratory, and histopathologic data for both the transplant that failed because of BKVN and the retransplant were abstracted and reviewed. RESULTS: A total of 31 patients underwent retransplantation after a median of 6 months after failure of the first allograft, with 10 of 31 undergoing preemptive retransplantation. Twenty-six patients had documented clearance of viremia and 13 underwent transplant nephrectomy before the retransplant. Two of six centers had changed immunosuppression protocols for the retransplants. After repeat transplant, 11 (35%) had BKV replication in urine and plasma with two patients experiencing BKVN. Seven had acute rejection. In univariate analysis, documented viremia clearance after BKVN in the initial transplant was significantly associated with the absence of BKV replication after repeat transplantation. Serum creatinine was significantly higher at 1 year in patients with BKV replication. One graft loss occurred due to rejection. CONCLUSIONS: Retransplantation is safe and effective for patients with previous graft loss due to BKVN preferably post-BK viral clearance.

Pancreas transplantation: lessons learned from a decade of experience at Wake Forest Baptist Medical Center.

This article reviews the outcome of pancreas transplantations in diabetic recipients according to risk factors, surgical techniques, and immunosuppression management that evolved over the course of a decade at Wake Forest Baptist Medical Center. A randomized trial of alemtuzumab versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous kidney-pancreas transplantation (SKPT) at our institution demonstrated lower rates of acute rejection and infection in the alemtuzumab group. Consequently, alemtuzumab induction has been used exclusively in all pancreas transplantations since February 2009. Early steroid elimination has been feasible in the majority of patients. Extensive experience with surveillance pancreas biopsies in solitary pancreas transplantation (SPT) is described. Surveillance pancreas biopsy-directed immunosuppression has contributed to equivalent long-term pancreas graft survival rates in SKPT and SPT recipients at our center, in contrast to recent registry reports of persistently higher rates of immunologic pancreas graft loss in SPT. Furthermore, the impact of donor and recipient selection on outcomes is explored. Excellent results have been achieved with older (extended) donors and recipients, in recipients of organs from donation after cardiac death donors managed with extracorporeal support, and in African-American patients. Type 2 diabetics with detectable C-peptide levels have been transplanted successfully with outcomes comparable to those of insulinopenic diabetics. Our experiences are discussed in the light of findings reported in the literature.

Collapsing glomerulopathy in a renal transplant recipient: potential molecular mechanisms.

BACKGROUND: In this case report, we describe a predisposed renal transplant patient who developed FSGS with cellular and collapsing features after sirolimus exposure and discuss the potential molecular mechanisms. CASE REPORT: A 35-year old African American female with end stage renal disease due to lupus nephritis received a living related renal transplant from a brother. She had immediate function achieved serum creatinine level of 1.7 mg/dl post day 4. Following a slow rise in the creatinine, first renal allograft biopsy performed on post op day 14 that showed thrombotic microangiopathy (TMA) involving arterioles and glomerular capillaries without any sign of rejection. The serological work up was negative for donor specific and antiphospholipid antibodies. The TMA was attributed to tacrolimus which was subsequently discontinued. It was replaced with sirolimus with loading dose of 10mg once and then 5 mg daily maintenance dose at day 21. At day 35, the patient was noted to have nephrotic range proteinuria, 12 gm/24 hrs. A second renal biopsy performed that revealed de novo focal segmental glomerulosclerosis with cellular and collapsing features, mild mesangial proliferative glomerulonephritis with immunoflourescence consistent with early recurrence of lupus nephritis ISN/RPS class 2. The etiology of cellular and collapsing FSGS was thought to be related to sirolimus based on timing of exposure and negative work up for secondary causes of collapsing FSGS. Sirolimus was switched to cyclosporine. At day 105, proteinuria decreased to 1.6 grams/day and serum creatinine leveled off 1.6 mg/dL. CONCLUSIONS: We report a case of possible sirolimus-induced collapsing FSGS in a renal transplant recipient who may have been predisposed to develop a podocytopathy possibly due to TMA and altered WT1 expression resulting from m-TOR exposure.