Emerging Evidence on Coronary Heart Disease Screening in Kidney and Liver Transplantation Candidates: A Scientific Statement From the American Heart Association: Endorsed by the American Society of Transplantation.

Coronary heart disease is an important source of mortality and morbidity among kidney transplantation and liver transplantation candidates and recipients and is driven by traditional and nontraditional risk factors related to end-stage organ disease. In this scientific statement, we review evidence from the past decade related to coronary heart disease screening and management for kidney and liver transplantation candidates. Coronary heart disease screening in asymptomatic kidney and liver transplantation candidates has not been demonstrated to improve outcomes but is common in practice. Risk stratification algorithms based on the presence or absence of clinical risk factors and physical performance have been proposed, but a high proportion of candidates still meet criteria for screening tests. We suggest new approaches to pretransplantation evaluation grounded on the presence or absence of known coronary heart disease and cardiac symptoms and emphasize multidisciplinary engagement, including involvement of a dedicated cardiologist. Noninvasive functional screening methods such as stress echocardiography and myocardial perfusion scintigraphy have limited accuracy, and newer noninvasive modalities, especially cardiac computed tomography-based tests, are promising alternatives. Emerging evidence such as results of the 2020 International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease trial emphasizes the vital importance of guideline-directed medical therapy in managing diagnosed coronary heart disease and further questions the value of revascularization among asymptomatic kidney transplantation candidates. Optimizing strategies to disseminate and implement best practices for medical management in the broader end-stage organ disease population should be prioritized to improve cardiovascular outcomes in these populations.

Recurrence of IgA Nephropathy after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

Performance versus Risk Factor-Based Approaches to Coronary Artery Disease Screening in Waitlisted Kidney Transplant Candidates.

INTRODUCTION: Current screening algorithms for coronary artery disease (CAD) before kidney transplantation result in many tests but few interventions. OBJECTIVE: The aim of this study was to study the utility of 6-minute walk test (6MWT), an office-based test of cardiorespiratory fitness, for risk stratification in this setting. METHODS: We enrolled 360 patients who are near the top of the kidney transplant waitlist at our institution. All patients underwent CAD evaluation irrespective of 6MWT results. We examined the association between 6MWT and time to CAD-related events (defined as cardiac death, revascularization, nonfatal myocardial infarction, and removal from the waitlist for CAD), treating noncardiac death and waitlist removal for non-CAD reasons as competing events. RESULTS: The 6MWT-based approach designated approximately 45% of patients as "low risk," whereas a risk factor- or symptom-based approach designated 14 and 81% of patients as "low risk," respectively. The 6MWT-based approach was not significantly associated with CAD-related events within 1 year (subproportional hazard ratio [sHR] 1.00 [0.90-1.11] per 50 m) but was significantly associated with competing events (sHR 0.70 [0.66-0.75] per 50 m). In a companion analysis, removing waitlist status from consideration, 6MWT result was associated with the development of CAD-related events (sHR 0.92 [0.84-1.00] per 50 m). CONCLUSIONS: The 6MWT designates fewer patients as high risk and in need of further testing (compared to risk factor-based approaches), but its utility as a pure CAD risk stratification tool is modulated by the background waitlist removal rate. CAD screening before kidney transplant should be tailored according to a patient's actual chance of receiving a transplant.

Histologic Case Definition of an Atypical Glomerular Immune-Complex Deposition Following Kidney Transplantation.

INTRODUCTION: Immune-complex deposition in the transplanted kidney can present as well-phenotyped recurrent or de novo glomerular disease. However, a subset, herein termed immune-complex glomerulopathy not otherwise specified (ICG-NOS), defies classification. We quantified, categorized, and characterized cases of transplant ICG-NOS occurring at a single US academic medical center. METHODS: We retrospectively reviewed our single-institution pathology database (July 2007-July 2018) to identify and categorize all cases of immune-complex deposition in kidney allografts (based on immunofluorescence microscopy). We extracted clinicopathologic and outcome data for ICG-NOS (i.e., immune complex deposition not conforming to any well-characterized glomerular disease entity). RESULTS: Of 104 patients with significant immune deposits, 28 (27%) were classified as ICG-NOS. We created 5 mutually exclusive ICG-NOS categories: Full-house, Quasi-full-house, IgA-rich, C1q-rich, and C1q-poor. Overall, 16 (57%) patients met criteria for definite or possible allograft rejection, including 9 (32%) with antibody-mediated rejection (ABMR), 3 (11%) suspicious for ABMR, 1 (4%) with T-cell-mediated rejection (TCMR), and 9 (32%) with borderline TCMR. After a median follow-up of 2.3 (range, 0.1-14.0) years after biopsy, 7 (25%) allografts had failed and an additional 8 (29%) had persistent renal dysfunction (hematuria, 14%; proteinuria, 21%; and estimated glomerular filtration rate <60 ml/min per 1.73 m2, 11%). CONCLUSION: In contrast to prior studies, our findings suggest that ICG-NOS is not necessarily a benign glomerular process and that there may be an association between ICG-NOS and alloimmunity. Our immunofluorescence-based classification provides a framework for future studies aiming to further elucidate ICG-NOS pathogenesis and prognosis.

An overview of frailty in kidney transplantation: measurement, management and future considerations.

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

Native kidney cytomegalovirus nephritis and cytomegalovirus prostatitis in a kidney transplant recipient.

We present a case of cytomegalovirus (CMV) native kidney nephritis and prostatitis in a CMV D+/R- kidney transplant recipient who had completed six months of CMV prophylaxis four weeks prior to the diagnosis of genitourinary CMV disease. The patient had a history of benign prostatic hypertrophy and urinary retention that required self-catheterization to relieve high post-voiding residual volumes. At 7 months post-transplant, he was found to have a urinary tract infection, moderate hydronephrosis of the transplanted kidney, and severe hydroureteronephrosis of the native left kidney and ureter, and underwent native left nephrectomy and transurethral resection of the prostate. Histopathologic examination of kidney and prostate tissue revealed CMV inclusions consistent with invasive CMV disease. This case highlights that CMV may extend beyond the kidney allograft to involve other parts of the genitourinary tract, including the native kidneys and prostate. Furthermore, we highlight the tissue-specific risk factors that preceded CMV tissue invasion. In addition to concurrent diagnoses, health care providers should have a low threshold for considering late-onset CMV disease in high-risk solid organ transplant recipients presenting with signs and symptoms of genitourinary tract pathology.

A large, international study on post-transplant glomerular diseases: the TANGO project.

BACKGROUND: Long-term outcomes in kidney transplantation (KT) have not significantly improved during the past twenty years. Despite being a leading cause of graft failure, glomerular disease (GD) recurrence remains poorly understood, due to heterogeneity in disease pathogenesis and clinical presentation, reliance on histopathology to confirm disease recurrence, and the low incidence of individual GD subtypes. Large, international cohorts of patients with GD are urgently needed to better understand the disease pathophysiology, predictors of recurrence, and response to therapy. METHODS: The Post-TrANsplant GlOmerular Disease (TANGO) study is an observational, multicenter cohort study initiated in January 2017 that aims to: 1) characterize the natural history of GD after KT, 2) create a biorepository of saliva, blood, urine, stools and kidney tissue samples, and 3) establish a network of patients and centers to support novel therapeutic trials. The study includes 15 centers in America and Europe. Enrollment is open to patients with biopsy-proven GD prior to transplantation, including IgA nephropathy, membranous nephropathy, focal and segmental glomerulosclerosis, atypical hemolytic uremic syndrome, dense-deposit disease, C3 glomerulopathy, complement- and IgG-positive membranoproliferative glomerulonephritis or membranoproliferative glomerulonephritis type I-III (old classification). During phase 1, patient data will be collected in an online database. The biorepository (phase 2) will involve collection of samples from patients for identification of predictors of recurrence, biomarkers of disease activity or response to therapy, and novel pathogenic mechanisms. Finally, through phase 3, we will use our multicenter network of patients and centers to launch interventional studies. DISCUSSION: Most prior studies of post-transplant GD recurrence are single-center and retrospective, or rely upon registry data that frequently misclassify the cause of kidney disease. Systematically determining GD recurrence rates and predictors of clinical outcomes is essential to improving post-transplant outcomes. Furthermore, accurate molecular phenotyping and biomarker development will allow better understanding of individual GD pathogenesis, and potentially identify novel drug targets for GD in both native and transplanted kidneys. The TANGO study has the potential to tackle GD recurrence through a multicenter design and a comprehensive biorepository.

Inhibitory interactions between BK and JC virus among kidney transplant recipients.

BK and JC polyomaviruses can reactivate after transplantation, causing renal dysfunction and graft loss. The incidence of JC reactivation after renal transplant is not well understood. Here, we characterized JC reactivation using samples collected during the first year after transplantation from 200 kidney recipients. We detected BK and JC viruses in the urine of 35 and 16% of transplant recipients, respectively. The median viral load in the urine was 400 times higher for BK virus than JC virus. The presence of BK viruria made concurrent JC viruria less likely: JC viruria was detected in 22% of non-BK viruric recipients compared with 4% of BK viruric recipients (P=0.001). The co-detection rate was 1.5%, which is less than the expected 5.6% if reactivation of each virus was independent (P=0.001). We did not observe JC viremia, JC nephropathy, or progressive multifocal leukoencephalopathy. The onset of JC viruria was associated with donor, but not recipient, JC-specific antibody in a titer-dependent fashion and inversely associated with donor and recipient BK-specific antibody. Donor and recipient JC seropositivity did not predict BK viruria or viremia. In conclusion, among renal transplant recipients, infection with one polyomavirus inversely associates with infection with the other.