Incidence, risk factors, treatment, and consequences of antibody-mediated kidney transplant rejection: A systematic review.

BACKGROUND: Antibody-mediated rejection (AMR) is a leading cause of kidney allograft failure, but its incidence, risk factors, and outcomes are not well understood. METHODS: We searched Ovid MEDLINE, Cochrane, EMBASE, and Scopus from January 2000 to January 2020 to identify published cohorts of ≥500 incident adult or 75 pediatric kidney transplant recipients followed for ≥1 year post-transplant. RESULTS: At least two reviewers screened 5061 articles and abstracts; 28 met inclusion criteria. Incidence of acute AMR was 1.1%-21.5%; most studies reported 3%-12% incidence, usually within the first year post-transplant. Few studies reported chronic AMR incidence, from 7.5%-20.1% up to 10 years. Almost all patients with acute or chronic AMR received corticosteroids and intravenous immunoglobulin; most received plasmapheresis, and approximately half with rituximab. Most studies examining death-censored graft failure identified AMR as an independent risk factor. Few reported refractory AMR rates or outcomes, and none examined costs. Most studies were single-center and varied greatly in design. CONCLUSIONS: Cohort studies of kidney transplant recipients demonstrate that AMR is common and associated with increased risk of death-censored graft failure, but studies vary widely regarding populations, definitions, and reported incidence. Gaps remain in our understanding of refractory AMR, its costs, and resulting quality of life.

TpTe and TpTe/QT: novel markers to predict sudden cardiac death in ESRD? / TpTe e TpTe/QT: novos marcadores para prever morte súbita cardíaca na DRT?

ABSTRACT Introduction: Reliable markers to predict sudden cardiac death (SCD) in patients with end stage renal disease (ESRD) remain elusive, but echocardiogram (ECG) parameters may help stratify patients. Given their roles as markers for myocardial dispersion especially in high risk populations such as those with Brugada syndrome, we hypothesized that the Tpeak to Tend (TpTe) interval and TpTe/QT are independent risk factors for SCD in ESRD. Methods: Retrospective chart review was conducted on a cohort of patients with ESRD starting hemodialysis. Patients were US veterans who utilized the Veterans Affairs medical centers for health care. Average age of all participants was 66 years and the majority were males, consistent with a US veteran population. ECGs that were performed within 18 months of dialysis initiation were manually evaluated for TpTe and TpTe/QT. The primary outcomes were SCD and all-cause mortality, and these were assessed up to 5 years following dialysis initiation. Results: After exclusion criteria, 205 patients were identified, of whom 94 had a prolonged TpTe, and 61 had a prolonged TpTe/QT interval (not mutually exclusive). Overall mortality was 70.2% at 5 years and SCD was 15.2%. No significant difference was observed in the primary outcomes when examining TpTe (SCD: prolonged 16.0% vs. normal 14.4%, p=0.73; all-cause mortality: prolonged 55.3% vs. normal 47.7%, p=0.43). Likewise, no significant difference was found for TpTe/QT (SCD: prolonged 15.4% vs. normal 15.0%, p=0.51; all-cause mortality: prolonged 80.7% vs. normal 66.7%, p=0.39). Conclusions: In ESRD patients on hemodialysis, prolonged TpTe or TpTe/QT was not associated with a significant increase in SCD or all-cause mortality.

RESUMO Introdução: Marcadores confiáveis para predizer morte súbita cardíaca (MSC) em pacientes com doença renal terminal (DRT) permanecem elusivos, mas os parâmetros do ecocardiograma (ECG) podem ajudar a estratificar os pacientes. Devido a seus papéis como marcadores para a dispersão miocárdica, especialmente em populações de alto risco, como aquelas com síndrome de Brugada, nós hipotetizamos que o intervalo pico da onda T ao final da onda T (TpTe) e TpTe/QT são fatores de risco independentes para MSC na DRT. Métodos: Revisão retrospectiva do prontuário foi realizada em uma coorte de pacientes com DRT iniciando a hemodiálise. Os pacientes eram veteranos de guerra americanos que utilizavam os centros médicos do Veterans Affairs para atendimento médico. A idade média de todos os participantes foi de 66 anos e a maioria era do sexo masculino, consistente com uma população veterana dos EUA. ECGs que foram realizados dentro de 18 meses após o início da diálise, e foram avaliados manualmente para TpTe e TpTe/QT. Os desfechos primários foram MSC e mortalidade por todas as causas, e estes foram avaliados até 5 anos após o início da diálise. Resultados: Após o critério de exclusão, foram identificados 205 pacientes, dos quais 94 com TpTe prolongado e 61 com intervalo TpTe/QT prolongado (não mutuamente exclusivo). A mortalidade geral foi de 70,2% em 5 anos e a MSC foi de 15,2%. Nenhuma diferença significativa foi observada nos desfechos primários ao se avaliar o TpTe (MSC: prolongado 16,0% versus normal 14,4%, p = 0,73; mortalidade por todas as causas: prolongado 55,3% vs. normal 47,7%, p = 0,43). Da mesma forma, nenhuma diferença significativa foi encontrada para TpTe/QT (MSC: prolongado 15,4% vs. normal 15,0%, p = 0,51; mortalidade por todas as causas: prolongado 80,7% vs. normal 66,7%, p = 0,39). Conclusões: Em pacientes com insuficiência renal terminal em hemodiálise, TpTe ou TpTe/QT prolongados não foram associados a um aumento significativo da morte súbita ou mortalidade por todas as causas.

Impact of Sofosbuvir-Based Therapy on Liver Transplant Candidates with Hepatitis C Virus Infection.

BACKGROUND: Sofosbuvir use in patients with decompensated cirrhosis may be associated with reduced liver transplant waitlist mortality and reduced need for transplant. METHODS: Data from the Scientific Registry of Transplant Recipients were linked with a national database of pharmacy claims. All adult patients on the liver transplant waitlist on January 1, 2014, or added to the list during 2014, with hepatitis C virus as reason for listing were identified (2009 patients). A subgroup of 1093 unique patients had consistent pharmacy claim capture and observations. We compared patients who were and were not treated with all sofosbuvir-based regimens. RESULTS: During the study period, 154 patients received sofosbuvir-based regimens. These patients had lower model for end-stage liver disease scores and significantly longer waiting times. We found a trend toward significance for more sofosbuvir-treated than untreated patients being removed from the waitlist due to improved condition (4.54% vs 3.19%, p=0.03). In a propensity score-adjusted analysis, sofosbuvir-treated patients were less likely to undergo transplant (hazard ratio 0.57, 95% confidence interval 0.37-0.89, p=0.01). CONCLUSION: During the study period reflecting early sofosbuvir use, few liver transplant candidates received sofosbuvir. Use was associated with lower incidence of transplant and a trend toward more waitlist removals due to improved condition.

TpTe and TpTe/QT: novel markers to predict sudden cardiac death in ESRD?

INTRODUCTION: Reliable markers to predict sudden cardiac death (SCD) in patients with end stage renal disease (ESRD) remain elusive, but electrocardiogram (ECG) parameters may help stratify patients. Given their roles as markers for myocardial dispersion especially in high risk populations such as those with Brugada syndrome, we hypothesized that the Tpeak to Tend (TpTe) interval and TpTe/QT are independent risk factors for SCD in ESRD. METHODS: Retrospective chart review was conducted on a cohort of patients with ESRD starting hemodialysis. Patients were US veterans who utilized the Veterans Affairs medical centers for health care. Average age of all participants was 66 years and the majority were males, consistent with a US veteran population. ECGs that were performed within 18 months of dialysis initiation were manually evaluated for TpTe and TpTe/QT. The primary outcomes were SCD and all-cause mortality, and these were assessed up to 5 years following dialysis initiation. RESULTS: After exclusion criteria, 205 patients were identified, of whom 94 had a prolonged TpTe, and 61 had a prolonged TpTe/QT interval (not mutually exclusive). Overall mortality was 70.2% at 5 years and SCD was 15.2%. No significant difference was observed in the primary outcomes when examining TpTe (SCD: prolonged 16.0% vs. normal 14.4%, p=0.73; all-cause mortality: prolonged 55.3% vs. normal 47.7%, p=0.43). Likewise, no significant difference was found for TpTe/QT (SCD: prolonged 15.4% vs. normal 15.0%, p=0.51; all-cause mortality: prolonged 80.7% vs. normal 66.7%, p=0.39). CONCLUSIONS: In ESRD patients on hemodialysis, prolonged TpTe or TpTe/QT was not associated with a significant increase in SCD or all-cause mortality.

Current Status of Kidney Transplant Outcomes: Dying to Survive.

Kidney transplantation is associated with improved survival compared with maintenance dialysis. In the United States, post-transplant outcomes have steadily improved over the last several decades, with current 1-year allograft and patient survival rates well over 90%. Although short-term outcomes are similar to those in the international community, long-term outcomes appear to be inferior to those reported by other countries. Differences in recipient case mix, allocation polices, and health care coverage contribute to the long-term outcome disparity. This review presents the current status of kidney transplant outcomes in the United States and compares them with the most recent outcomes from Australia and New Zealand, Europe, and Canada. In addition, early trends after implementation of the new kidney allocation system in the United States and its potential impact on post-transplant outcomes are discussed.

Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial.

Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, and prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin in patients with established coronary heart disease. Here we conducted a post hoc analysis of the AIM-HIGH trial examining whether participants derived cardiovascular or renal benefits when stratified by renal function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among the CKD subset, demographics and cardiovascular disease (CVD) risk factors were well balanced in the ERN and placebo arms. Compared with placebo, CKD participants receiving ERN had a significant decrease in triglycerides by a median of 59.0 mg/dl, and high-density lipoprotein cholesterol significantly increased by a mean of 11.3 mg/dl over a mean follow-up of 3 years. CVD events were similar between CKD participants in both arms. However, all-cause mortality was significantly higher in the ERN group (hazard ratio of 1.73). Mean change in eGFR among ERN-treated CKD participants was not significantly different between study arms. Thus, among AIM-HIGH participants with CKD, the addition of ERN to simvastatin for secondary prevention of CVD improved triglyceride and high-density lipoprotein-cholesterol concentrations but did not improve cardiovascular outcomes or kidney function, and was associated with higher all-cause mortality.

Analytical approaches to metabolomics and applications to systems biology.

Phenotypic expression of renal diseases encompasses a complex interaction between genetic, environmental, and local tissue factors. The level of complexity requires integrated understanding of perturbations in the network of genes, proteins, and metabolites. Metabolomics attempts to systematically identify and quantitate metabolites from biological samples. The small molecules represent the end result of complexity of biological processes in a given cell, tissue, or organ, and thus form attractive candidates to understand disease phenotypes. Metabolites represent a diverse group of low-molecular-weight structures including lipids, amino acids, peptides, nucleic acids, and organic acids, which makes comprehensive analysis a difficult analytical challenge. The recent rapid development of a variety of analytical platforms based on mass spectrometry and nuclear magnetic resonance have enabled separation, characterization, detection, and quantification of such chemically diverse structures. Continued development of bioinformatics and analytical strategies will accelerate widespread use and integration of metabolomics into systems biology. Here, we will discuss analytical and bioinformatic techniques and highlight recent studies that use metabolomics in understanding pathophysiology of disease processes.

Screening and management of pretransplant cardiovascular disease.

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death in kidney transplant recipients. Hence, accurate cardiac risk assessment in potential candidates is an important issue. The purpose of this review is to examine the existing research on the screening and management of pretransplant cardiovascular disease, with an emphasis on defining the optimal approach for asymptomatic high-risk candidates. RECENT FINDINGS: Randomized controlled trials (RCTs) in the general population demonstrate that prophylactic revascularization in stable patients prior to major noncardiac surgery does not reduce cardiac events or improve survival postoperatively. The benefit of noninvasive stress testing in this population is doubtful based on smaller RCTs and observational studies. Perioperative beta-blockade in intermediate-risk or high-risk candidates appears to be beneficial but acute administration is harmful. SUMMARY: Investigation for coronary artery disease is warranted for kidney transplant candidates with symptoms of myocardial ischemia. However, there is insufficient evidence to support routine cardiovascular screening in asymptomatic candidates regardless of their cardiac risk factor status. RCTs specifically looking at this issue in renal transplant candidates are a research priority.

The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus.

Individuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor gamma agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters, and disease activity in the lupus-prone murine model New Zealand Black/New Zealand White (NZB x NZW)F(1). Ten-week-old prenephritic female NZB/NZW F(1) mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 wk. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone marrow-derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine, and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration, and intrarenal synthesis of TNF-alpha, IL-1beta, and VCAM-1. These results indicate that peroxisome proliferator-activated receptor gamma agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE.

Mass spectrometric quantification of amino acid oxidation products identifies oxidative mechanisms of diabetic end-organ damage.

Diabetes mellitus is increasingly prevalent worldwide. Diabetic individuals are at markedly increased risk for premature death due to cardiovascular disease. Furthermore, substantial morbidity results from microvascular complications which include retinopathy, nephropathy, and neuropathy. Clinical studies involving diabetic patients have suggested that degree of diabetic hyperglycemia correlates with risk of complications. Recent evidence implicates a central role for oxidative stress and vascular inflammation in all forms of insulin resistance, obesity, diabetes and its complications. Although, glucose promotes glycoxidation reactions in vitro and products of glycoxidation and lipoxidation are elevated in plasma and tissue in diabetics, the exact relationships among hyperglycemia, the diabetic state, and oxidative stress are not well-understood. Using a combination of in vitro and in vivo experiments, we have identified amino acid oxidation markers that serve as molecular fingerprints of specific oxidative pathways. Quantification of these products utilizing highly sensitive and specific gas chromatography/mass spectrometry in animal models of diabetic complications and in humans has provided insights in oxidative pathways that result in diabetic complications. Our studies strongly support the hypothesis that unique oxidants are generated in the microenvironment of tissues vulnerable to diabetic damage. Potential therapies interrupting these reactive pathways in target tissue are likely to be beneficial in preventing diabetic complications.