Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. RESULTS: At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m2; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. CONCLUSIONS: Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.

Acute effect of a peritoneal dialysis exchange on electrolyte concentration and QT interval in uraemic patients.

BACKGROUND: Hemodialysis (HD) sessions induce changes in plasma electrolytes that lead to modifications of QT interval, virtually associated with dangerous arrhythmias. It is not known whether such a phenomenon occurs even during peritoneal dialysis (PD). The aim of the study is to analyze the relationship between dialysate and plasma electrolyte modifications and QT interval during a PD exchange. METHODS: In 15 patients, two manual PD 4-h exchanges were performed, using two isotonic solutions with different calcium concentration (Ca++1.25 and Ca1.75++ mmol/L). Dialysate and plasma electrolyte concentration and QT interval (ECG Holter recording) were monitored hourly. A computational model simulating the ventricular action potential during the exchange was also performed. RESULTS: Dialysis exchange induced a significant plasma alkalizing effect (p < 0.001). Plasma K+ significantly decreased at the third hour (p < 0.05). Plasma Na+ significantly decreased (p < 0.001), while plasma Ca++ slightly increased only when using the Ca 1.75++ mmol/L solution (p < 0.01). The PD exchange did not induce modifications of clinical relevance in the QT interval, while a significant decrease in heart rate (p < 0.001) was observed. The changes in plasma K+ values were significantly inversely correlated to QT interval modifications (p < 0.001), indicating that even small decreases of K+ were consistently paralleled by small QT prolongations. These results were perfectly confirmed by the computational model. CONCLUSIONS: The PD exchange guarantees a greater cardiac electrical stability compared to the HD session and should be preferred in patients with a higher arrhythmic risk. Moreover, our study shows that ventricular repolarization is extremely sensitive to plasma K+ changes, also in normal range.

Inequalities in transplant waiting list activation across Italian dialysis centers.

BACKGROUND: The demand for kidney transplant exceeds organ supply; therefore, understanding patient-related and contextual factors associated with waiting list activation is key in ensuring that organ allocation is efficient and equitable. We sought to assess whether inequalities in wait-listing probability exist across centers and evaluate correlates of wait-listing in Italy. METHODS: We linked the MigliorDialisi dataset (1,238 patients enrolled in 54 Italian hemodialysis centers) to administrative data concerning the activity of each participating center and contextual information abstracted from the Italian Institute of Statistics. We modeled the odds of waiting list activation for patients on dialysis by the subjects' sociodemographic, biomedical and psychosocial factors along with center-related and contextual factors. RESULTS: The crude enlistment rate was 26% (95% CI 9-54) distributed as follows: 21, 34 and 33% in northern, central, and southern Italy, respectively (p < 0.01). Older patients with poorer health conditions and lower expectations toward transplantation outcomes were less likely to be wait-listed in multilevel multivariable logistic regression. In the fully adjusted model there was not a statistically significant variation in wait-listing across northern, central, and southern regions. However, the variance explained by center-related factors accounted for 12% (p < 0.01) of total variability in enlistment likelihood (20% in patients >65 years, p < 0.01). CONCLUSIONS: Our results showed that inter-center variation exists after adjusting for case mix. Additionally, we identified individual modifiable factors associated with wait-listing inequalities.

Morpho-functional study of peritoneum in peritoneal dialysis patients.

BACKGROUND: Structure and function of the peritoneal membrane (PM) are impaired on peritoneal dialysis (PD). The aim of this study was to examine the relationship between dialytic parameters and histological and functional characteristics of the peritoneum of PD patients. METHODS: A peritoneal biopsy (PB) was performed on 31 PD patients during catheter removal due to malfunction or after drop-out from treatment. PB was performed at least 5 cm from the catheter insertion. For each patient PM transport was evaluated by the last peritoneal equilibration test (PET) before PB. Each daily glucose load was calculated. Tissue was formalin-embedded and stained for histological and immunohistochemical studies. RESULTS: (1) Duration of treatment was longer in patients with mesothelial impairment. (2) Patients showing sub-mesothelial sclerosis (SS) and those with impairment of submesothelial basement membrane and subendothelial vascular membrane (SVM) were submitted to a larger daily glucose load. (3) SS exceeding 50 mm was more frequent among high transporters, who were exposed to larger daily glucose load compared to medium-high transporters. (4) Mesothelial loss correlated to SS and vascular alterations. (5) SS was related to vascular injuries but not to inflammatory infiltrate. CONCLUSIONS: SS is not constant in PD patients and is not a prominent factor in treatment drop-out. Mesothelial impairment seems to be mainly related to duration of PD treatment. Glucose load seems to mainly damage the sub-mesothelial layer.