Ferruccio Conte

Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation

BACKGROUND Oral anticoagulation therapy (OAT) is the choice treatment for thromboembolism prevention in atrial fibrillation (AF), although data about OAT use in haemodialysis (HD) patients with AF are contradictory. METHODS The effect of OAT on the risk of mortality, stroke and bleeding was prospectively evaluated in a population of HD patients with AF. All the patients of 10 HD Italian centres alive on 31 October 2010 with documented AF episode(s) were recruited and followed-up for 2 years. OAT and antiplatelet intake, age, dialytic age, comorbidities and percentage time in the target international normalized ratio (INR) range (target therapeutic range; TTR) were considered as predictors of hazard of death, thromboembolic and bleeding events. RESULTS At recruitment, 134 patients out of 290 were taking OAT. During the follow-up, 115 patients died (4 strokes, 3 haemorrhagic and 1 thromboembolic). Antiplatelet therapy, but not OAT, was associated with increased mortality (HR 1.71, CI 1.10-2.64, P = 0.02). The estimated survival of patients always taking OAT tended to be higher than that of patients who stopped taking (68.6 versus 49.6%, P = 0.07). OAT was not correlated to a significant decreased risk of thromboembolic events (HR 0.12, CI 0.00-3.59, P = 0.20), while it was associated with an increased risk of bleeding (HR 3.96, CI 1.15-13.68, P = 0.03). Higher TTR was associated with a reduced bleeding risk (HR 0.09, CI 0.01-0.76, P = 0.03), while previous haemorrhagic events were associated with higher haemorrhagic risk (HR 2.17, CI 1.09-4.35, P = 0.03). CONCLUSIONS In our population of HD patients with AF, the mortality is very high. OAT is not associated with increased mortality, while antiplatelet drugs are. OAT seems, on the contrary, associated with a better survival; however, it does not decrease the incidence of ischaemic stroke, whereas it increases the incidence of bleeding. Bleeding risk is lower in subjects in whom the INR is kept within the therapeutic range.

Hereditary Nephropathy with Nerve Deafness (Alport’s Syndrome)

Alport’s syndrome is a glomerulopathy of unknown pathogenesis that should be considered in any patient with unexplained hematuria. Four new kindreds of carefully studied family backgrounds were invest

Ultrastructural Changes of the Glomeruli of the Rat Induced by Indomethacin

Since indomethacin diminishes the intensity of proteinuria in glomerulonephritis, experiments were undertaken to identify the morphological elements that might explain the reduction in the permeability of the glomerular capillary wall. In normal rats, the treatment with indomethacin produced first of all in the podocytes morphological signs of a possible activated function and in later stages a reaction of mesangial cells. The possible role of these two types of cells in the production of the basal membrane of the glomerular capillary, and the significance that their ‘activated function’ may have on the permeability of the capillary wall are discussed.

The nephrologist's anticoagulation treatment patterns/regimens in chronic hemodialysis patients with atrial fibrillation

BackgroundThe prevalence of atrial fibrillation (AF) is high in hemodialysis (HD) patients. It was suggested that oral anticoagulant therapy (OAT), the choice treatment for reducing the thromboembolic risk in AF patients, increases the incidence of both ischemic and hemorrhagic strokes in the HD population. Moreover, the therapy-related bleeding risk is particularly high in these patients. For these reasons there is no agreement on the use of OAT in HD patients with AF. The aim of this study was to evaluate the criteria adopted by nephrologists in prescribing OAT in HD patients with AF.MethodsAll the patients presenting AF (paroxysmal, persistent or permanent) at 31/10/2010 (n = 290) were recruited from 1529 HD patients from ten Italian HD centres. To detect factors related to OAT administration the main clinical features, CHADS2 and HASBLED scores were evaluated in logistic regression models.ResultsThe presence of permanent AF (OR = 4.28, p < 0.0001) was the only clinical factor directly associated to OAT administration, while previous bleedings (OR = 0.35, p = 0.004) were inversely related. The CHADS2 score was not associated with OAT prescription (OR = 0.85, p = 0.08), while an inverse relation was found with the hemorrhagic risk score (OR = 0.74, p = 0.03).ConclusionA high AF prevalence was observed in our HD population, but less than 50 % of these patients received OAT. Patients with permanent AF were more frequently treated with warfarin, while OAT administration was uncommon in those with previous bleedings. The thromboembolic risk score was not associated with warfarin prescription, while there was an inverse relation with the hemorrhagic risk score.

Treatment of secondary hyperparathyroidism: the clinical utility of etelcalcetide

Secondary hyperparathyroidism (SHPT), a very frequent, severe, and worsening complication of chronic kidney disease, is characterized by high serum parathyroid hormone (PTH), parathyroid gland hyperplasia, and disturbances in mineral metabolism. Clinically, SHPT shows renal osteodystrophy, vascular calcification, cardiovascular damage, and fatal outcome. Calcium-sensing receptor (CaSR) is the main physiological regulator of PTH secretion; its activation by calcium rapidly inhibits PTH. Another important player in regulating mineral metabolism is vitamin D receptor (VDR), which is under the influence of vitamin D and influences the intestinal absorption of calcium and phosphate, PTH gene expression, and bone calcium mobilization. Serum phosphate levels influence fibroblast growth factor 23 (FGF-23) production, a phosphatonin that modulates serum phosphate reabsorption, PTH synthesis, and vitamin D production. Current therapeutic approaches consist of 1) phosphate intake control by diet or phosphate binders, 2) vitamin D by VDR activation, and 3) calcimimetic agents that activate CaSR. Recently, a new long-acting peptide (etelcalcetide) belonging to the calcimimetics class was approved for intravenous use in hemodialysis patients with SHPT. Etelcalcetide binds directly to CaSR, by a sulfide bond, inhibiting the production and secretion of PTH by parathyroid glands. After intravenous administration in rats, etelcalcetide is quickly distributed to the tissues and eliminated by kidneys, while in uremic animals the nonrenal excretion is only 1.2%. In hemodialysis patients, the treatment itself is the main route of elimination. Etelcalcetide in hemodialysis patients with SHPT was more effective than placebo and cinacalcet, with a PTH reduction of >30% in 76% of patients with etelcalcetide versus 10% with placebo. Particular attention was paid to the safety of the drug; the most common adverse event was asymptomatic blood calcium reduction, similar to cinacalcet, while gastrointestinal symptoms were less frequent. This promising new drug available for better control of SHPT will, together with drugs already in use, optimize the treatment to normalize the biochemical parameters.

Mortality, sudden death and indication for cardioverter defibrillator implantation in a dialysis population

BACKGROUND The incidence of sudden death among dialysis patients is high, but end stage renal disease was an exclusion criterion in the trials that demonstrated the benefit of implantable cardioverter defibrillator (ICD) for sudden death prevention. METHODS Dialysis patients alive on January 2010 or starting dialysis between January 2010 and January 2013 were enrolled and retrospectively evaluated. Patients were divided into three groups: No-Indication, Indication-With ICD and Indication-Without ICD. Cox and Fine and Gray regression models were used to estimate the total and cause-specific (sudden or non-sudden) mortality hazard ratio (HR, HR(cpRisk)), respectively. Survival was defined as the time from start of dialysis to the time of death. RESULTS 154/2072 patients (7.4%) had indication for ICD implantation and 52 (33.8%) of them received the device; 688 (33.2%) deaths were recorded. Mortality was different among groups [Indication-With ICD vs No-Indication: HR 1.59 (95% CI 1.06-2.38) and Indication-Without ICD vs No-Indication: HR 2.67 (95% CI 2.09-3.39, p < 0.001)]. 84/688 (12.2%) were sudden deaths. The cumulative incidence of sudden death was higher in patients with ICD indication [Indication-With ICD vs No-Indication HR(cpRisk) 3.21 (95% CI 1.38-7.40) and Indication-Without ICD vs No-Indication: HR(cpRisk) 4.19 (95% CI 2.38-7.39), p < 0.001], but also No-Indication patients showed a high rate of sudden death [8.5% (95% CI.6.5-10.9) at 8 years of follow-up]. CONCLUSIONS Dialysis patients with ICD indication had a worse survival than No-Indication subjects and the prognosis was particularly poor for the Indication-Without ICD group. Sudden death incidence was much higher than in the general population, even among No-Indication subjects.

Lactic Acidosis Coma in Continuous Ambulatory Peritoneal Dialysis

Dr. A. Tommasi, Servizio di Nefrologia e Dialisi, Ospedale di Vimercate, Via Cereda 2, 20059 Vimercate (Italy) Dear Sir, We have recently observed a case of lactic acidosis coma in a patient on continuous ambulatory peritoneal dialysis (CAPD). The patient, a 69-year-old female, weighing 78.5 kg and 162 cm tall, had been on CAPD treatment for 2 months because of analgesic nephropathy, proved by anamnestic investigation and by kidney biopsy. She developed severe lactic acidosis with abrupt onset and without warning, during an episode of peritonitis and circulatory failure. The maintenance therapy consisted of digoxine, nifedipine and aluminum hydroxide. Laboratory data were: arterial blood pH 7.19, Pa02 64.1 mm Hg, PaC02 32.6 mm Hg, plasma bicarbonate 11.5 mEq/1, plasma lactate concentration 120 mg/l00 ml (normal values 5–22 mg/l00 ml), sodium 136 mEq/1, potassium 6.49 mEq/1, chloride 95 mEq/1, BUN 77 mg/l00 ml, creatinine 8.35 mg/l00 ml, glucose 91 mg/l00 ml, hema-tocrit 24.7%, hemoglobin 7.6 g/l00 ml. We treated lactic acidosis with sodium bicarbonate infusion (600 mEq in 48 h) and acetate hemodialysis (4 h twice a day for the 1st day and once a day for the following 2 days). The patient recovered after 2 days of treatment. Laboratory data were: arterial blood pH 7.41, Pa02 59.7 mm Hg, PaC02 37.9 mm Hg, plasma bicarbonate 24.7 mEq/l, plasma lactate 17 mg/l00 ml; and after 4 days of treatment: arterial blood pH 7.43, Pa02 68.8 mm Hg, PaC02 46 mm Hg, plasma bicarbonate 30 mEq/l, plasma lactate 13 mg/l00 ml. An increased plasma lactate concentration has been reported to occur during intermittent peritoneal dialysis (IPD) [1], but lactic acidosis has never been reported during CAPD. It is possible that more concomitant mechanisms have determined the severe lactic acidosis in our patient: (a) hepatic failure because of hepatitis following long-term exposure to paracetamol [2,3]; that may justify the lack of a metabolic way of lactate to piruvate; (b) circulatory failure, which may induce a shift from aerobic metabolism to anaerobic glycolysis and thereby produce lactic acidosis [4]; (c) fasting in the presence of obesity, which may induce accumulation of lactic acid in significant amounts [4].

Indomethacin and lysine acetylsalicylate in rats with autologous nephrotoxic serum nephritis. Biochemical and morphological studies.

The effects of indomethacin and lysine acetylsalicylate (L-ASA) were compared in rats in which autologous nephrotoxic serum nephritis had been induced. The aim of this study was to offer support to the hypothesis that indomethacin might reduce proteinuria through increased synthesis of glomerular basement membrane by the podocytes. Both drugs were injected intraperitoneally at the dosage of 4 mg/kg body weight daily during a 6-day period into 40 rats rendered nephritic by rabbit nephrotoxic serum injection. Rats treated with indomethacin showed a marked decrease of proteinuria (tested by the 3% sulfosalicylic aicd method) and a clear ultrastructural picture of hyperplasia and hypertrophy of podocytes. Rats given L-ASA showed only a slight correction of proteinuria and less specific ultrastructural modification. These observations suggest that indomethacin decreases proteinuria in nephritic rats not only through its anti-inflammatory activity, but possible also by a peculiar mechanism, namely an increase in podocytic basement membrane synthesis.

Aminonucleoside Nephrosis in Rats

The concomitant administration of Indomethacin reduced the biochemical signs of the nephrotic syndrome induced in rats by aminonucleoside; in the rats treated with both drugs a morphological picture suggesting activated function of podocytes was found at the electron microscopic examination of the renal glomerular structures, together with the lesions characteristic of the aminonucleoside nephrosis. The possibility is discussed that Indomethacin could modify the permeability of the glomerular capillary wall by stimulating thepodocytes to synthesize basement membrane material.

The Cardiovascular Burden in End-Stage Renal Disease

It is well documented that chronic kidney disease patients have an extremely high risk of developing cardiovascular (CV) disease (CVD) compared to the general population. Declining renal function itself represents a continuum of CV risk, and in those individuals who survive to reach end-stage renal disease, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Several pathophysiological pathways have been suggested to account for this, including endothelial dysfunction, dyslipidemia, inflammation, left ventricular hypertrophy, troponins, phosphate, vitamin D, fibroblast growth factor-23, and NT-proBNP. All these conditions and biomarkers may have clear associations with current and subsequent CVD.