Glomerular and tubular effects of dapagliflozin, eplerenone and their combination in patients with chronic kidney disease: A post-hoc analysis of the ROTATE-3 study.

AIM: Sodium-glucose co-transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function. METHODS: This post-hoc analysis utilized data of the ROTATE-3 study, a randomized cross-over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro-hormonal markers and tubular sodium handling were assessed with mixed repeated measures models. RESULTS: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin-eplerenone was -34.8% (95% CI -52.2, -10.9), -5.9% (95% CI -32.5, 31.3) and -28.1% (95% CI -48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin-eplerenone [32.2% (95% CI -1.5, 77.4)], compared with dapagliflozin [-12.5% (95% CI -35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin-eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI -10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI -879.2, -32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI -926.1, -120.0). Dapagliflozin-eplerenone decreased proximal absolute sodium reabsorption [-971.0 mmol/min (95% CI -1411.0, -531.0)], but did not affect distal absolute sodium reabsorption [-9.2 mmol/min (95% CI -402.0, 383.6)]. CONCLUSIONS: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects.

Study of oxidative stress in patients with advanced renal disease and undergoing either hemodialysis or peritoneal dialysis.

Oxidative stress (OS) is directly involved in the formation of atheroma plaque and has been shown to be present since the early stages of Chronic Kidney Disease (CKD); however, the net role that dialytica techniques may play in OS process is yet to be determined. We studied three groups: hemodialysis (HD, n = 30), peritoneal dialysis (PD, n = 31), predialysis (pre-D, n = 32), and one control group (C, n = 67). Using highresolution liquid chromatography columns (HPLC), the superoxide dismutase (SOD), glutathione oxidized/reduced ratio (GSSG/GSH), and nuclear, as well as mitochondrial 8-oxo-dG (8-oxo-dG mit) were measured in lymphocytes. Protein carbonyls and F2-isoprostanes were measured in plasma. The antioxidant enzyme activity was evaluated by a spectrophotometric assay of catalase, glutathione peroxidase (GPX), glutathione reductase (GSR), and superoxide dismutase (SOD). Compared to the control group, all groups had significantly higher levels of products derived from molecular oxidation with a significant decrease in antioxidant enzymes. Patients in the pre-D group showed higher values for most of the oxidized molecules. The PD group showed a better oxidative balance, with no significant differences in levels of mitochondrial 8-oxo-dG when compared to the control group. We speculated that the better control of OS observed in patients receiving PD might be explained by the fact that this technique is more biocompatible, and this might help reduce the risk of cardiovascular events.

Disorders in bone-mineral parameters and the risk of death in persons with chronic kidney disease stages 4 and 5: the PECERA study.

BACKGROUND: Abnormalities of bone mineral parameters are associated with increased mortality in patients on dialysis, but their effects and the optimal range of these biomarkers are less well characterized in non-dialysis chronic kidney disease (CKD). METHODS: PECERA (Collaborative Study Project in Patients with Advanced CKD) is a 3-year, prospective multicenter, open-cohort study of 966 adult patients with non-dialyzed CKD stages 4-5 enrolled from 12 centers in Spain. Associations between levels of serum calcium (Ca) (corrected for albumin), phosphate (P), and intact parathyroid hormone (iPTH) with all-cause mortality (primary outcome) and cardiovascular mortality (secondary outcome) were examined using time-dependent Cox proportional hazards models and penalized splines analysis adjusted by demographics and comorbidities, treatments and biochemical values collected every 6 months for 3 years. RESULTS: After a median follow-up of 29 months (IQR: 13-36 months) there were 181 deaths (19%). The association of calcium with all-cause mortality was J-shaped, with an increased risk for all-cause mortality at levels > 10.5 mg/dL. For phosphate and iPTH levels, the association was U-shaped. The serum values associated with the minimum risk of mortality were 3.8 mg/dL for phosphate and 70 pg/mL for iPTH, being the lowest risk ranges between 2.8 and 5.0 mg/dL, and between 38 and 112 pg/mL for phosphate and iPTH, respectively. CONCLUSIONS: Our study provides evidence on the non-linear association of serum calcium, phosphate and iPTH levels with mortality in stage 4 and 5 CKD patients, and suggests potential survival benefits for controlling bone mineral parameters in this population, as previously reported for dialysis patients.

Echocardiographic impact of hydration status in dialysis patients.

INTRODUCTION: Cardiovascular disease is the main cause of death in Chronic Kidney Disease patients. Left ventricular hypertrophy is the most common manifestation and it is linked to arterial hypertension and overhydration. The goal of this paper is to stratify dialyzed patients according to hydration status and to make an evaluation about the possible echocardiography alterations of the different groups. METHODS: A transversal study was carried out with 117 patients: 65 were on hemodialysis and 52 on peritoneal dialysis. We performed the following tests: multifrequency bioimpedance with the BCM-Body Composition Freesenius' Monitor system, transthoracic echocardiography, and blood tests. If ECW/TBW (extracellular water vs total body water) normalization ratio for age and gender was > 2.5% SD, the patient was considered overhydrated. RESULTS: HD patients are significantly overhydrated before HD (67.1%) compared to DP patients (46.1%), and almost half of the overhydrated population presents arterial hypertension. However, after an HD session, a better control of the hydration status is reached (26.1%). DP patients frequently present high arterial pressure and/or are under antihypertensive treatment (DP 76.9% vs HD 49.2%). Left ventricular hypertrophy is much more common in HD overhydrated patients, eccentric LVH being more prevalent. Overhydrated patients present significantly high values of LAVI, ILVM, OH/ECW. CONCLUSIONS: Bioimpedance technique allows for the detection of a large number of overhydrated patients. Echocardiographic alterations in dialyzed patients show a high correlation between the hydration stage by ECW/TBW normalized ratio for age and gender and the LAVI and ILVM.

Estimated Glomerular Filtration Rate in Short-Risk Stratification in Acute Myocardial Infarction.

BACKGROUND/AIMS: Renal dysfunction is associated with a higher risk of cardiovascular disease in patients with acute myocardial infarction (AMI). The aim of this study was to investigate the independent prognostic value of renal dysfunction and its incremental predictability risk after adjusting for well-known clinical factors in patients with AMI. METHODS: 751 consecutive patients with AMI admitted to the Coronary Care Unit (CCU) were included. Patients were grouped into 2 categories according to the baseline estimated glomerular filtration rate (eGFR) on admission (eGFR <60 vs. eGFR ≧60 ml/min/1.73 m2). C-reactive protein and white blood cell count (WBC) as well as clinical prognostic variables were assessed. The endpoint was mortality during CCU stay. The discriminatory power was estimated by the C-index. RESULTS: The patient group with an eGFR <60 ml/min/1.73 m2 was older, had more cardiovascular risk factors, a lower left ventricular ejection fraction and higher cardiovascular mortality during CCU stay (13 vs. 3%). Logistic regression analysis revealed the following predictors of mortality: degree of renal impairment (eGFR <60 ml/min/1.73 m2), hazard ratio (HR) = 2.2 (95% CI 1.1-4.3; p = 0.028); WBC >11,000 × 106/l, HR = 2.3 (95% CI 1.2-4.5; p = 0.017); Killip class on admission, HR = 3.8 (95% CI 1.7-8.5; p = 0.001), and New York Heart Association Functional Classification, HR = 3.6 (95% CI 1.7-7.4; p = 0.001). The adjusted C-index was 0.78 for baseline clinical variables and 0.84 for eGFR. CONCLUSIONS: In patients with AMI, decreased eGFR is an important prognostic factor for impaired cardiac function and mortality in the short-term follow-up. The eGFR may be reliably used in the risk stratification of patients with AMI.