Pre-transplant serum Beta Trace Protein indicates risk for post-transplant major cardiac adverse events.

BACKGROUND: Beta Trace Protein (BTP) is a biomarker for residual kidney function which has been linked to cardiovascular and all-cause mortality in haemodialysis patients. Following renal transplantation, recipients remain at increased risk for cardiovascular events compared with the general population. We aimed to determine the relationship of pre-transplant BTP to major adverse cardiac events (MACE) in patients following kidney transplantation. METHODS: We included 384 patients with end-stage renal disease who received a kidney transplant. MACE was defined as myocardial infarction (ST-segment elevation or non-ST-segment elevation, stroke or transient ischemic attack), coronary artery disease requiring intervention or bypass or death for cardiovascular reason. The association between pre-transplant serum BTP concentration and post-transplant MACE was evaluated by Kaplan-Meier and Cox regression analyses. RESULTS: Post-transplant MACE occurred in 70/384 patients. Pre-transplant BTP was significantly higher in patients with post-transplant MACE (14.36 ± 5.73 mg/l vs. 11.26 ± 5.11 mg/l; p < .01). Next to smoking (HR 1.81), age > 56.38 years (HR 1.97) and pre-existing coronary heart disease (HR 8.23), BTP above the cut off value of 12.7 mg/l was confirmed as independent risk factor for MACE (HR 2.02, all p < .05). MACE-free survival inversely correlated with pre-transplant BTP levels. CONCLUSIONS: Pre-transplant serum BTP concentration may identify renal transplant recipients with higher risk of post-transplant MACE.

Beta-trace protein as a potential biomarker of residual renal function in patients undergoing peritoneal dialysis.

BACKGROUND: Residual renal function is closely linked to quality of life, morbidity and mortality in dialysis patients. Beta-trace protein (BTP), a low molecular weight protein, has been suggested as marker of residual renal function, in particular in patients on hemodialysis. We hypothesized that BTP also serves as a marker of residual renal function in pertioneal dialysis patients. METHODS: In this study 34 adult patients on peritoneal dialysis were included. BTP, creatinine, cystatin C and urea concentrations were analyzed simultaneously in serum and dialysate to calculate renal and peritoneal removal of the analytes. RESULTS: In peritoneal dialysis patients with residual diuresis, mean serum BTP was 8.16 mg/l (SD ± 4.75 mg/l). BTP correlated inversely with residual diuresis (rs = - 0.58, p < 0.001), residual creatinine clearance (ClCr) (rs = - 0.69, p < 0.001) and total urea clearance (Clurea) (rs = - 0.56, p < 0.001). Mean peritoneal removal of BTP was 3.36 L/week/1.73m2 (SD ± 1.38) and mean renal removal 15.14 L/week/1.73m2 (SD ± 12.65) demonstrating a significant renal contribution to the total removal. Finally, serum BTP inversely correlated with alterations in residual diuresis (r = - 0.41, p = 0.035) and renal creatinine clearance over time (r = - 0.79, p = p < 0.001). CONCLUSION: BTP measurement in the serum may be a simple tool to assess residual renal function in peritoneal dialysis patients.

Association of lactate dehydrogenase with mortality in incident hemodialysis patients.

BACKGROUND: Lactate dehydrogenase (LDH) plays a role in the glucose metabolism of the human body. Higher LDH levels have been linked to mortality in various cancer types; however, the relationship between LDH and survival in incident hemodialysis (HD) patients has not yet been examined. We hypothesized that higher LDH level is associated with higher death risk in these patients. METHODS: We examined the association of baseline and time-varying serum LDH with all-cause, cardiovascular and infection-related mortality among 109 632 adult incident HD patients receiving care from a large dialysis organization in the USA during January 2007 to December 2011. Baseline and time-varying survival models were adjusted for demographic variables and available clinical and laboratory surrogates of malnutrition-inflammation complex syndrome. RESULTS: There was a linear association between baseline serum LDH levels and all-cause, cardiovascular and infection-related mortality in both baseline and time-varying models, except for time-varying infection-related mortality. Adjustment for markers of inflammation and malnutrition attenuated the association in all models. In fully adjusted models, baseline LDH levels ≥360 U/L were associated with the highest risk of all-cause mortality (hazard ratios = 1.19, 95% confidence interval 1.14-1.25). In time-varying models, LDH >280 U/L was associated with higher death risk in all three hierarchical models for all-cause and cardiovascular mortality. CONCLUSIONS: Higher LDH level >280 U/L was incrementally associated with higher all-cause and cardiovascular mortality in incident dialysis patients, whereas LDH <240 U/L was associated with better survival. These findings suggest that the assessment of metabolic functions and monitoring for comorbidities may confer survival benefit to dialysis patients.

TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor.

Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.

Obesity Paradox in Advanced Kidney Disease: From Bedside to the Bench.

While obesity is associated with a variety of complications including diabetes, hypertension, cardiovascular disease and premature death, observational studies have also found that obesity and increasing body mass index (BMI) can be linked with improved survival in certain patient populations, including those with conditions marked by protein-energy wasting and dysmetabolism that ultimately lead to cachexia. The latter observations have been reported in various clinical settings including end-stage renal disease (ESRD) and have been described as the "obesity paradox" or "reverse epidemiology", engendering controversy. While some have attributed the obesity paradox to residual confounding in an effort to "debunk" these observations, recent experimental discoveries provide biologically plausible mechanisms in which higher BMI can be linked to longevity in certain groups of patients. In addition, sophisticated epidemiologic methods that extensively adjusted for confounding have found that the obesity paradox remains robust in ESRD. Furthermore, novel hypotheses suggest that weight loss and cachexia can be linked to adverse outcomes including cardiomyopathy, arrhythmias, sudden death and poor outcomes. Therefore, the survival benefit observed in obese ESRD patients can at least partly be derived from mechanisms that protect against inefficient energy utilization, cachexia and protein-energy wasting. Given that in ESRD patients, treatment of traditional risk factors has failed to alter outcomes, detailed translational studies of the obesity paradox may help identify innovative pathways that can be targeted to improve survival. We have reviewed recent clinical evidence detailing the association of BMI with outcomes in patients with chronic kidney disease, including ESRD, and discuss potential mechanisms underlying the obesity paradox with potential for clinical applicability.