Roberto Boero

The verapamil versus amlodipine in nondiabetic nephropathies treated with trandolapril (VVANNTT) study

BACKGROUND We tested whether the combination of verapamil (V) or amlodipine (A) with trandolapril (T) affected proteinuria differently from T alone in patients with nondiabetic nephropathies. METHODS After T, 2 mg, in open conditions for 1 month, 69 patients were randomly assigned to be administered T, 2 mg, combined with V, 180 mg, plus a placebo or T, 2 mg, plus A, 5 mg, once a day in a double-blind fashion. Patients were followed up for 8 months. RESULTS Proteinuria diminished significantly after T treatment from mean protein excretion of 3,078 +/- 244 (SEM) to 2,537 +/- 204 mg/24 h (P = 0.018). In the randomized phase, there was a slight reduction in proteinuria in both groups without significant differences within and between treatments (T + V, protein from 2,335 +/- 233 to 2,124 +/- 247 mg/24 h; T + A, protein from 2,715 +/- 325 to 2,671 +/- 469 mg/24 h). The selectivity index (SI; calculated as the ratio of immunoglobulin G to albumin clearance) was slightly and not significantly reduced in patients treated with T plus V from a median of 0.20 (interquartile range, 0.13) to 0.16 (interquartile range, 0.15; P = not significant), whereas it significantly increased from 0.20 (interquartile range, 0.14) to 0.30 (interquartile range, 0.14; P = 0.0001) in patients treated with T plus A. Modifications in SI and serum creatinine levels at the end of the study from randomization were significantly directly correlated (r = 0.45; P = 0.001). The number of patients reporting adverse effects was significantly higher in the T plus A than T plus V group (63.8% versus 33.3%; P = 0.016). CONCLUSION In patients with nondiabetic proteinuric nephropathies treated with T, the combination of V or A does not significantly increase its antiproteinuric effect.

Acute Effects of Hemodialysis on Erythrocyte Sodium Fluxes in Uremic Patients

The acute effects of both acetate and bicarbonate hemodialysis on erythrocyte transmembrane sodium fluxes were investigated in 15 patients with chronic uremia. We observed a significance (p less than 0.01) stimulation of the Na+,K+ pump in both procedures, with a significant correlation to the amount of fluid removed during hemodialysis (r = 0.56, p less than 0.03). Outward Na+ cotransport fluxes significantly rose (p less than 0.05) after acetate hemodialysis and decreased (p less than 0.05) after bicarbonate hemodialysis. Minor and not significant pre- and posthemodialysis bidirectional changes were observed as regards the intraerythrocyte Na+ and K+ concentration, passive Na+ and K+ permeability, and Na+,Li+ countertransport. Hemodialysis may acutely affect the erythrocyte sodium pump and cotransport fluxes, possibly through the modulation of hormonal factors triggered by the extracellular volume changes.

ACUTE PYELONEPHRITIS: ANALYSIS OF 52 CASES

Acute pyelonephritis (APN) is a frequent disease, but diagnostic approach, evolution into abscesses, and indication to hospitalization are still open problems. We have made a retrospective analysis of APN cases observed in our hospital. We identified 58 patients (pt) and selected 52 of these who presented fever and loin pain at the onset (31 were hospitalized in Nephrology and 21 in other units). Urine culture was positive in 11/48 cases (22.9%), blood cultures in 3/26 cases (11.5%) (Escherichia coli). Renal sonography was normal in 20/48 cases (41.6%) and suggestive for APN in 23/48 cases (47.9%). CT with contrast medium was normal in 9/28 cases (32.1%) and positive in 19/28 cases (67.8%), with evidence of unique or multiple hypodense areas; abscesses were found in 8 patients (28.5%). No statistically significant differences were found between patients with positive or negative CT as regards fever, leukocytosis, ESR, CRP, CRP at 20 days, urinary leukocytes, urine culture, duration of symptoms before hospitalization. Moreover no differences were found between patients with and without abscesses. CT was performed more frequently among patients hospitalized in Nephrology than among patients hospitalized in other services (24/31—77.4%—vs. 4/21—19%—, p = 0.05). NMR was abnormal in 6/9 cases. A radiographic documentation of APN was obtained in 61.53% of patients with clinical diagnosis of APN. Of these, only 18.7% had positive urine culture. In conclusion, our data suggest that demonstration of urine infection is not necessary for APN diagnosis, when clinical and/or radiologic diagnosis of APN has been made. Evolution into abscesses is frequent and not easily susceptible on clinical ground; for this reason we think it is advisable to perform CT or NMR systematically. Differences in clinical behavior between different units suggest the need for diagnostic guidelines.

Excess dietary sodium and inadequate potassium intake by hypertensive patients in Italy: Results of the Minisal-SIIA study program

Introduction: The aim of the study was to assess the age-specific, sex-specific, and region-specific average sodium and potassium intake and its association with anthropometric characteristics in a sample of the Italian adult hypertensive population. Methods: A total of 1232 hypertensive patients were recruited consecutively by 47 centers recognized by the Italian Society of Hypertension. The enrolled participants were on stable antihypertensive treatment. Anthropometric indices, blood pressure, 24-h urinary sodium, and potassium excretion were measured and used as proxy for the average daily sodium and potassium intake. Results: The average sodium intake was 172 mmol (or 10.1 g of salt/day) among men and 138 (or 8.1) among women, with no difference among geographical areas. Over 90% of men and 81% of women had a consumption higher than the recommended standard dietary intake of 5 g/day. The average potassium intake was 63 and 56 mmol, respectively in men and women, again without geographical differences, nearly 92% of men and 95% of women having an intake lower than the recommended intake (100 mmol/day or 3.9 g/day). There was a significant trend to a gradual decrease in sodium intake with age in both sexes (P <0.001). There was also a direct association between BMI and sodium intake in both sexes, this association being independent of age (P < 0.001). Conclusion: In this national sample of the Italian hypertensive population, dietary sodium intake was largely higher and potassium intake much lower than the recommended intakes, and this was true for all geographical areas. Overweight and obese hypertensive patients had particularly high sodium intakes.

Outcome of dialysis patients submitted to coronary revascularization

Cardiovascular disease accounts for almost half of the total mortality in patients with end stage renal disease (ESRD). It has recently been debated whether coronary revascularization has the same rate of risks and successes in this cohort of patients compared to patients without renal disease. Since 1991, 17 dialysis patients were submited to coronary revascularization in our center. Seven patients were following peritoneal, 10 hemodialytic treatment. Four patients were submitted to percutaneous transluminal coronary angioplasty (PTCA) and 13 to surgical revascularization (CABG). In 2 patients the coronary lesion was unique, in the others stenosis of multiple vessels were found. Six patients were diabetic. The mean age at the onset of the coronary artery disease (CAD) was 57.17 ± 11.6 years. The mean time elapsed from the onset of the CAD and the performance of the PTCA or CABG was 30.1 ± 35.4 months. The mean time from beginning of dialysis treatment to revascularization was 48.2 ± 39.6 months. Mean hemoglobin values were 9.7 ± 1 g/dL, mean phosphorus values were 5.2 ± 8.7 mg/dL, mean cholesterol values were 211 ± 49.5 mg/dL. The procedure was technically successful in all patients. Mean survival was 25.09 ± 28.12 months. Twelve patients died, 5 of whom within one month. Survival at one month was 70.5%, at 6 months 58.8%, at one year 52.9%, at 2 years 47%. There was neither significant difference patients submitted to PTCA and those submitted to CABG, nor between diabetic and non-diabetic patients. In conclusion, coronary revascularization in our experience is a high risk procedure in dialysis patients. The reasons for this could be the severe general conditions of these patients affected with diffuse vasculopathy and the long time elapsed since the onset of the ischemic cardiopathy. Thus, our results could suggest the opportunity of performing earlier screening of coronary situation and revascularization treatment in CAD dialysis patients.

Sodium-Lithium Countertransport Activity in Red Blood Cells of Patients With IgA Nephropathy

In this paper we report some results of our studies on patients with immunoglobulin (Ig)A nephropathy regarding (1) the familiar aggregation of erythrocyte sodium-lithium (Na,Li) countertransport; (2) the association of Na,Li countertransport with the presence of arterial hypertension and lipid abnormalities; (3) the correlation between Na,Li countertransport activity and renal functional reserve; and (4) the preliminary results of a longitudinal study. In 13 families of patients with IgA nephropathy, selected because both parents were available, we found a significant correlation between midparent and offspring Na,Li countertransport activity (Spearmans rank correlation = 0.65; P = 0.023), but no husband-wife relationship. In 49 patients, the activity of Na,Li countertransport was significantly higher in erythrocytes from 20 hypertensive patients than from either 29 normotensive patients or from 36 healthy age- and sex-matched normal subjects. Hyperlipidemic patients had an erythrocyte Na,Li countertransport activity significantly higher than normolipidemic patients and controls. In 17 patients a significant inverse correlation was found between the peak variation of creatinine clearance over baseline value after an oral protein load and the erythrocyte Na,Li countertransport activity (Spearman r = 0.54; P = 0.03). In a longitudinal study of 36 patients followed from 12 to 36 months, those showing a progression toward renal failure had an erythrocyte Na,Li countertransport activity higher than median value. The results of our studies show that in patients with IgA nephropathy a high erythrocyte Na,Li countertransport rate, genetically determined, is associated with the presence of arterial hypertension and lipid abnormalities, and perhaps with a less favorable disease outcome.

Is it possible to diagnose primary anti-phospholipid syndrome (PAPS) on the basis of renal thrombotic microangiopathy (PAPS nephropathy) in the absence of other thrombotic process?

The kidneys are a major target of PAPS. The histologic lesions of PAPS nephropathy are vascular; among them thrombotic microangiopathy (TMA) is the most characteristic. It is still not clear in the literature whether the nephropathy can be the unique manifestation of PAPS in the absence of other thrombotic processes; that is: do the renal microthrombotic lesions allow to make the diagnosis of PAPS in presence of anti-phospholipid antibodies (APA)? With this purpose we present three clinical cases. The first patient had severe hypertension C4 hypocomplementemia, thrombocytopenia, and mitralic valve insufficiency. LAC and anti-cardiolipin antibodies at high titre were positive. The histologic picture was characterized by basement membrane reduplication and arteriolar mucoid degeneration, which are features of early phase of TMA. The second patient had severe hypertension. The detection of anti-cardiolipin antibodies was performed several times and resulted positive three times, four months after the diagnosis as well. The renal histologic features were consistent with late lesions of TMA. The third patient had severe hypertension, rapidly progressive renal failure, tricuspidal valve insufficiency and two positive anti-phospholipid antibodies determinations three weeks apart (in two occasions anti-cardiolipin and in one occasion LAC as well were found). The renal lesions were characteristic for TMA. In conclusion we think that patients with TMA and anti- phospholipid antibodies can be considered affected by PAPS, as the thrombotic process is represented by thrombosis in preglomerular arterioles, which leads to TMA.

Verapamil in Arterial Hypertension with Renal Disease

Dr. Roberto Boero, Divisione di Nefrologia e Dialisi, Nuova Astanteria Martini,, Piazza Donatore di Sangue 3, I-10154 Torino (Italy) Dear Sir, Calcium antagonist drugs have been proved effective in the treatment of essential hypertension [1]. However, information regarding the hypotensive effect of these drugs in hypertensive patients with chronic renal disease is scanty; recently two papers appeared concerning the use of nifedi-pine in these patients [2,3]. We report our experience on the renal and antihypertensive effects of the calcium entry blocker verapamil in a slow-release preparation (Isoptin Retard®; Knoll AG) in a group of patients with hypertension secondary to renal parenchymal disease. We investigated 9 patients (6 males, 3 females). The mean age was 44 years (range 24–55 years). The diagnosis of renal disease was chronic interstitial nephritis in 6 cases, polycystic kidney disease in 2, and chronic glomerulonephritis in 1. Six had a creatinine clearance below 80 ml/min (serum creati-nine ranging from 1.5 to 3.4 mg/dl). After 2 weeks of placebo washout, the patients received verapamil retard for 4 weeks, starting with 120 mg twice daily. If the diastolic blood pressure was > 95 mm Hg after the first 2 weeks, verapamil retard was increased to 240 mg twice daily. After the placebo period and the first 2 weeks of treatment, effective renal plasma flow was evaluated, as well as the I-hippuran clearance [4]. The main results are shown in table I; in 4 cases the dosage of verapamil was increased to 480 mg/day. The heart rate did not change significantly during the study. The glomerular filtration rate, as assessed by the endogenous creatinine clearance, was not significantly modified, even in patients with impaired renal function. The drug was well tolerated: no adverse effect emerged on atrioventricular conduction and cardiac function; only 2 patients complained of mild constipation. Our results demonstrate that verapamil exerts a good antihypertensive effect, even in mild to moderate hypertension secondary to renal parenchymal disease. Moreover, in spite of blood pressure reduction, no adverse effect on renal hemodynamics was observed: in fact the renal plasma flow was maintained or slightly increased in Table I. Antihypertensive and renal effects of verapamil retard (mean ± SE) Placebo Verapamil retard 2 weeks 4 weeks

Pathogenesis of arterial hypertension in chronic uraemia: the role of reduced Na,K-ATPase activity.

In 38 uraemic dialysed patients (17 normotensive, 21 hypertensive) we measured (1) erythrocyte sodium concentration [Na] and ouabain-sensitive sodium efflux, and (2) arterial pressure, cardiac index and total peripheral resistance. Erythrocyte Na—K pump activity was lower in hypertensive than in normotensive patients (P < 0.02). Hypertensive patients had significantly higher peripheral resistance than normotensive patients (P < 0.05), while the cardiac index was similar in both groups. Inverse correlations were found between the rate constant for ouabain-sensitive sodium efflux in erythrocytes and both systolic and diastolic pressure (r = −0.43 and r = −0.45, respectively; P < 0.01) and total peripheral resistance (r = −0.76; P < 0.0001). Our data suggest that reduced sodium transport by the Na-K pump plays a role in the pathogenesis of arterial hypertension in patients with chronic uraemia.

Erythrocyte Na,Li Countertransport and Arterial Pressure in Diabetic Adolescents

ABSTRACT. The aim of this study was to analyze Na,Li countertransport in erythrocytes from adolescents with insulin dependent diabetes mellitus (IDDM) and to see if those with elevated values present distinct clinical features, in particular as regards arterial pressure and urinary albumin excretion (UAE). Twenty‐nine adolescents with IDDM (17 males, 12 females, mean age 15 ± 0.6 years, mean diabetes duration 11.4 ± 0.7 years) and fifteen healthy age‐matched control subjects (8 males, 7 females, age 14.5 ± 1 years) were investigated. Diabetic adolescents had a RBC Na,Li countertransport activity higher than age matched normal controls; geometric mean 283 (95% limits 259‐340) vs. 193 (169‐252) μmol/l RBC/h; p<0.01. Seven out of 29 subjects had values higher than the 95th percentile of normal subjects (Counter+). Both systolic and diastolic arterial pressures were significantly higher in Counter+ than in Counter‐ patients. No significant differences were found as regards age, body mass index, diabetes duration, HbAlc, fructosamine, serum potassium, triglycerides, creatinine clearance and UAE. The logarithm of systolic pressure was independently positively correlated with In Na,Li countertransport (r=0.38; p<0.05), In [Nai] (r=0.38; p<0.05), and In body mass index (r=0.5; p<0.01) in diabetic patients. The main finding of this study is that diabetic adolescents with a high erythrocyte Na,Li countertransport rate have an arterial pressure significantly higher than patients with normal Na,Li countertransport fluxes.