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.

Determinants of thromboxane biosynthesis in patients with moderate to severe chronic kidney disease.

BACKGROUND: Mechanisms of accelerated atherothrombosis in patients with chronic kidney disease (CKD) are only partly characterized. The aims of this study were to evaluate the extent of thromboxane (TX)-dependent platelet activation in patients with CKD, and to characterize the determinants of altered TX biosynthesis in this setting, with particular reference to enhanced lipid peroxidation, low grade inflammation and CKD-related anemia. PATIENTS AND METHODS: A cross sectional comparison between urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, was performed in 115 patients with stage 1-4 CKD. RESULTS: Levels of both urinary 11-dehydro-TXB2 and 8-iso-PGF2α increased sequentially across the four CKD stages (P<0.0001, Kruskal-Wallis test). Both urinary prostanoids were inversely associated with either estimated glomerular filtration rate (eGFR, P<0.0001) or hemoglobin levels (P<0.0001). A significant direct correlation was also observed between urinary 11-dehydro-TXB2 and 8-iso-PGF2α (Rho=0.620, P<0.0001). On multivariate analysis, urinary 8-iso-PGF2α (ß=0.459, P<0.0001), hemoglobin levels (ß=- 0.261, P=0.002) and eGFR (ß=-0.172, P=0.032) were independent predictors of urinary 11-dehydro-TXB2 (adjusted R(2)=0.488). CONCLUSIONS: This study provides biochemical evidence of persistent platelet activation in patients with CKD. This condition occurs early in the natural history of the disease and is related to kidney function and oxidative stress. Moreover, we found an independent inverse relationship between hemoglobin levels and TX-dependent platelet activation. This finding may provide a mechanistic link between CKD-related anemia and increased cardiovascular risk.

Postdialysis Hypertension: Associated Factors, Patient Profiles, and Cardiovascular Mortality.

BACKGROUND AND OBJECTIVES: A postdialytic increase in blood pressure (BP) is a recognized but often an overlooked complication. The epidemiology and predisposing factors are still not well defined. We studied a large sample of Italian dialysis patients to assess the prevalence of postdialysis hypertension (PDHYPER), defined as any increase of systolic BP (SBP) >10mm, Hg above the predialysis value, the associated factors and its role in cardiovascular (CV) mortality. PATIENTS AND METHODS: In this observational study, we assessed dialysis associated changes in BP in 4,292 hemodialysis (HD) patients over 1 month (51,504 sessions). We compared the clinical characteristics of the patients with stable BP values during the HD session with those with PDHYPER. We also assessed the impact of PDHYPER on CV mortality. RESULTS: A total of 994 (23.1%) patients had PDHYPER. Patients with PDHYPER were more likely to be hypertesive, older, have a shorter dialysis vintage, be male, have lower SBP, lower changes in weight during HD, and receive more antihypertensive medications. These predictive factors were shown to be associated with an interaction between weight loss and dialysis, suggesting a volume-related mechanism in its pathogenesis. PDHYPER was also associated with CV mortality. CONCLUSIONS: In our study on a large Italian cohort of dialysis patients, the prevalence of PDHYPER was higher than what was previously reported and is a significant risk factor for CV mortality in dialysis patients. The pathogenesis is multifactorial but hypertensive state, antihypertensive medications, and extracellular volume expansion appear to play a major role.

Post-dilution hemodiafiltration with a heparin-grafted polyacrylonitrile membrane.

The aim of this multicenter, prospective study was to explore the possibility of carrying out routine sessions of post-dilution hemodiafiltration with a polyacrylonitrile membrane grafted with heparin (HeprAN) and reduced anticoagulation. Forty-four patients from eight centers were included in the study and treated by means of post-dilution on-line hemodiafiltration with automatic control of TMP, according to three different modalities tested consecutively: phase 1, polyethersulfone filter primed with heparinized saline and anticoagulated with continuous infusion of unfractionated heparin 1000/h; phase 2, HeprAN membrane filter primed with saline without heparin. Anticoagulation: a 1000-unit bolus of unfractionated heparin at the start of session followed by a second one at the end of the second dialysis hour; phase 3, same filter and priming procedure as in phase 2; anticoagulation with nadroparin calcium at the beginning of treatment. Partial or massive clotting of the dialyzer occurred in less than 1% of sessions in phase 1; 10% and 7% in phase 2; and 1% and 2% in phase 3. Clotting limited to the drip chambers was observed in 13%, 34% and 12%, respectively. The study of coagulation parameters showed a better profile when low-molecular weight heparin (LMWH) was used in association with HeprAN membrane, while the generation of TAT complexes did not differ from that observed with the standard anticoagulation modality used in phase 1. Our results suggest that the HeprAN membrane can be used safely in routine post-dilution hemodiafiltration with reduced doses of LMWH.

Blood pressure and cardiovascular mortality in dialysis patients with left ventricular systolic dysfunction.

BACKGROUND: In patients chronically treated with hemodialysis, the prevalence of heart failure is high with a consequently poor prognosis. The role played by blood pressure (BP) on cardiovascular (CV) mortality of these patients has not been clearly defined. METHODS: In this follow-up study, we investigated the relationship of pre- and postdialysis measurements of BP with CV and all-cause mortality in a cohort of 557 dialysis patients with a left ventricular (LV) ejection fraction <50%. RESULTS: During the follow-up (mean = 21.6 ± 8.8 months), 179 deaths were recorded. Ninety-eight patients died from CV causes. By the Cox multivariable analysis, we constructed a predictive model of CV mortality including age, duration on dialysis, diabetes, serum albumin, diffusive dialysis technique, predialysis mean arterial pressure (MAP) (hazard ratio (HR) = 0.978; 95% confidence interval (CI) = 0.956-0.999), and postdialysis MAP (HR = 1.035; 95% CI = 1.010-1.061). The relationship with mortality was inverse for predialysis MAP and direct for postdialysis MAP. In a subsequent analysis, we found that pre- and postdialysis systolic BP, but not diastolic BP, were predictive of CV mortality. Predialysis MAP was in a direct relationship with body mass index. Postdialysis MAP had an inverse relationship with weight loss during dialysis session. CONCLUSIONS: CV mortality in dialysis patients with LV dysfunction is associated with both pre- and postdialysis BP interacting in a complex relationship. Nutritional state and fluid balance and removal are possible clues to this relationship.

Peritoneal ultrafiltration in patients with advanced decompensated heart failure.

The aim of the Best Practice guidelines on peritoneal ultrafiltration (UF) in patients with treatment-resistant advanced decompensated heart failure (TR-AHDF) is to achieve a common approach to the management of decompensated heart failure in those situations in which all conventional treatment options have been unsuccessful, and to stimulate a closer cooperation between nephrologists and cardiologists. The standardization of the case series of different centers would allow a better definition of the results published in the literature, without which they are nothing more than anecdotes. TR-AHDF is characterized by the persistence of severe symptoms even when all possible pharmacological and surgical options have been exhausted. These patients are often treated with methods that allow extracorporeal UF - slow continuous ultrafiltration (SCUF) and continuous renal replacement therapy (CRRT) - which have to be performed in hospital facilities. Peritoneal ultrafiltration (PUF) can be considered a treatment option in patients with TR-AHDF when, despite the fact that all treatment options have been used, patients meet the following criteria: • stage D decompensated heart failure (ACC/AHA classification); • INTERMACS level 4 decompensated heart failure; • INTERMACS frequent flyer profile; • chronic renal failure (estimated glomerular filtration rate <50 ml/min per 1.73 m2: KDOQI classification stage 3 chronic kidney disease); • no obvious contraindications to peritoneal UF. PUF treatment modes are derived from the treatment regimens proposed by various authors to obtain systemic UF in patients with severe decompensated heart failure, using manual and automated incremental peritoneal dialysis involving various glucose concentrations in addition to the single icodextrin exchange. These guidelines also identify a minimum set of tests and procedures for the follow-up phase, to be supplemented, according to the center's resources and policy, with other tests that are less routine or more complex also from a logistic/organizational standpoint, emphasizing the need for the patient's clinical and treatment program to involve both the nephrologist and the cardiologist. The pathophysiological aspects of a deterioration in kidney function in patients with decompensated heart failure are also considered, and the results of PUF in patients with decompensated heart failure reported in the various case series are reviewed.

Effect of an L-carnitine-containing peritoneal dialysate on insulin sensitivity in patients treated with CAPD: a 4-month, prospective, multicenter randomized trial.

BACKGROUND: In peritoneal dialysis, the high glucose load absorbed from dialysis fluid contributes to several metabolic abnormalities, including insulin resistance. We evaluate the efficacy of a peritoneal dialysis solution containing l-carnitine as an additive to improve insulin sensitivity. STUDY DESIGN: Multicenter parallel randomized controlled trial. SETTING & PARTICIPANTS: Nondiabetic uremic patients on continuous ambulatory peritoneal dialysis enrolled in 8 peritoneal dialysis centers. INTERVENTION: Patients were randomly assigned to receive peritoneal dialysis diurnal exchanges with either a standard glucose-based solution (1.5% or 2.5% according to the patient's need) or a glucose-based solution (identical glucose amount) enriched with l-carnitine (0.1%, weight/volume; 2 g/bag) for 4 months, the nocturnal exchange with icodextrin being unmodified. OUTCOMES & MEASUREMENTS: The primary outcome was insulin sensitivity, measured by the magnitude of change from baseline in glucose infusion rate (in milligrams per kilogram of body weight per minute) during a euglycemic hyperinsulinemic clamp. Secondary outcomes were safety and tolerability, body fluid management, peritoneal dialysis efficiency parameters, and biochemistry tests. RESULTS: 35 patients were randomly assigned, whereas 27 patients (standard solution, n=12; experimental solution, n = 15) were analyzed. Adverse events were not attributable to treatment. Glucose infusion rates in the l-carnitine-treated group increased from 3.8 ± 2.0 (SD) mg/kg/min at baseline to 5.0 ± 2.2 mg/kg/min at day 120 (P = 0.03) compared with 4.8 ± 2.4 mg/kg/min at baseline and 4.7 ± 2.4 mg/kg/min at day 120 observed in the control group (P = 0.8). The difference in glucose infusion rates between groups was 1.3 (95% CI, 0.0-2.6) mg/kg/min. In patients treated with l-carnitine-containing solution, urine volume did not change significantly (P = 0.1) compared to a significant diuresis reduction found in the other group (P = 0.02). For peritoneal function, no differences were observed during the observation period. LIMITATIONS: Small sample size. CONCLUSIONS: The use of l-carnitine in dialysis solutions may represent a new approach to improving insulin sensitivity in nondiabetic peritoneal dialysis patients.

Systolic blood pressure and mortality in chronic hemodialysis patients: results of a nationwide italian study.

Studies on the relationship between blood pressure (BP) and mortality among hemodialysis patients have yielded conflicting results. Reports have come mostly from North America and have dealt with dialysis patients as a homogenous population and differed in methods and time of BP measurement and the optimal BP target. In a prospective nationwide study in 3674 unselected Caucasian patients with end-stage renal disease undergoing chronic hemodialysis from 73 dialysis units, the authors sought to examine the relationship between the different measurements of BP and mortality according to antihypertensive treatment. The mean age of patients was 67.2±14.1 years and the prevalence of diabetes was 19.5%. During follow-up (26.5±10.5 months), 977 deaths were recorded. In the whole cohort, BP was not associated with mortality. After grouping the patients according to antihypertensive treatment, the analysis showed that only in patients who did not take antihypertensive medications (1613) was there an inverse relationship between postdialysis systolic BP and mortality. These patients differed from the others in BP, dialysis vintage, prevalence of diabetes, and type of dialysis technique. This study suggests that with respect to the relationship of BP with mortality, dialysis patients are not a homogenous population. Differences in demographic characteristics and in dialysis technique may therefore explain the reported variability of previous results.

Prevalence of hypertension in a large cohort of Italian hemodialysis patients: results of a cross-sectional study.

BACKGROUND: Hypertension is very common among patients receiving hemodialysis; however, little is known about its prevalence and control following the publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations. METHODS: This was a multicenter, observational, prospective, cross-sectional study aimed at evaluating the prevalence of hypertension and its awareness in a large sample of hemodialysis patients in Italy, and assessing possible relationships between high blood pressure (BP) values and traditional and nontraditional cardiovascular risk factors. Predialysis hypertension was defined as systolic BP (SBP) / diastolic BP (DBP) =140/90 mm Hg, and postdialysis hypertension as SBP/DBP =130/80 mm Hg or the use of antihypertensive medications. RESULTS: We collected data for 4,022 patients (men/women 2,478/1,544, mean age 67.14 ± 14.08 years) from 77 dialysis centers. Of these, 2,832 patients (70.3%) were defined as having predialysis hypertension. At logistic regression analysis, diabetes, months on dialysis, serum albumin levels and treatment with erythropoiesis-stimulating agent (ESA) were independent factors predicting predialysis hypertension. Antihypertensive agents were used in 57.7% of the patients, leading to adequate BP control in only 40% of them. Factors independently predicting inadequate BP control were diabetes, ESA therapy, high serum cholesterol and higher Kt/V values. CONCLUSIONS: Hypertension is highly prevalent in this Italian hemodialysis population; achievement of adequate BP control is inadequate. It is unclear whether this may reflect suboptimal diagnosis or treatment of hypertension or, more likely, the allowance of higher predialysis BP values to try to avoid abrupt BP falls during the dialytic session.