Pietro Zucchelli

Effect of the Angiotensin-Converting–Enzyme Inhibitor Benazepril on the Progression of Chronic Renal Insufficiency

Background Drugs that inhibit angiotensin-converting enzyme slow the progression of renal insufficiency in patients with diabetic nephropathy. Whether these drugs have a similar action in patients with other renal diseases is not known. We conducted a study to determine the effect of the angiotensin-converting–enzyme inhibitor benazepril on the progression of renal insufficiency in patients with various underlying renal diseases. Methods In a three-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (in 192 patients), interstitial nephritis (in 105), nephrosclerosis (in 97), polycystic kidney disease (in 64), diabetic nephropathy (in 21), and miscellaneous or unknown disorders (in 104). The severity of renal insufficiency was classified according to the base-line creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, 46 to 60 ml per minu...

Methylprednisolone plus Chlorambucil as Compared with Methylprednisolone Alone for the Treatment of Idiopathic Membranous Nephropathy

BACKGROUND AND METHODS Treatment with methylprednisolone and chlorambucil may protect renal function and increase the chance of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. To determine whether similar results might be obtained with methylprednisolone alone, we compared the effects of methylprednisolone and chlorambucil with those of methylprednisolone alone in 92 patients with the nephrotic syndrome caused by idiopathic membranous nephropathy. The patients were randomly assigned to receive either alternating one-month courses of methylprednisolone and then chlorambucil for a total of six months (group 1) or methylprednisolone alone for six months at the same cumulative dosage (group 2). RESULTS Four of the 45 patients in group 1 (9 percent) and 1 of the 47 in group 2 (2 percent) stopped treatment because of side effects. At one, two, and three years, the percentage of patients who did not have the nephrotic syndrome was significantly higher in group 1 than in group 2. It was 58, 54, and 66 percent, respectively, in group 1, as compared with 26, 32, and 40 percent in group 2 (P = 0.002, 0.029, and 0.011). By year 4, the difference was no longer statistically significant: 62 percent of the patients in group 1 and 42 percent of those in group 2 did not have the nephrotic syndrome (P = 0.102). The patients in group 1 were in remission longer than those in group 2 (P = 0.008). CONCLUSIONS In patients with the nephrotic syndrome caused by idiopathic membranous nephropathy, treatment with methylprednisolone and chlorambucil for six months induces an earlier remission of the nephrotic syndrome than methylprednisolone alone, but the difference may diminish with time.

Blood Volume Regulation During Hemodialysis

Hemodialysis (HD)-induced hypotension may be precipitated by severe hypovolemia. To avoid the appearance of destabilizing hypovolemias, we have developed a biofeedback control system for intradialytic blood volume (BV)-changes modeling. The system, incorporated in a dialysis machine, is based on a multivariable closed-loop control with a dependent output variable, the BV changes, and two independent control variables, the ultrafiltration rate (Qf) and dialysate conductivity (DC). The relative BV changes occurring during HD are measured by an optical device. The Qf and DC are continuously adjusted by the control model during the treatment to minimize any discrepancies between the ideal targets for the BV, the patients body weight reductions, and the experimentally obtained results. The system manages three kinds of errors: in BV changes, the total weight loss, and the sodium balance. The latter is controlled by a dedicated kinetic model that continuously calculates the equivalent DC and, by the end of the session, tends to make the sodium balance the same as the one obtained in conventional HD with constant DC. This systems capacity to improve intradialytic hemodynamic tolerance has been assessed in a crossover study of eight highly symptomatic patients. Conventional HD (CHD; period A) was compared with blood volume-controlled dialysis sessions (BV-CHD; period B) following a protocol with an A1-B-A2 sequence, with each period lasting 1 month. A lower decrease in BV (-10.6%) was obtained during BV-CHD (period B) compared with CHD (-12.3% in period A1 and -12.5% in period A2). The predialysis to postdialysis systolic arterial pressure changes were lower in period B (-12.4%) than in period A (-20% in A1 and -17.5% in A2; P < 0.05) despite similar total Qf and mean treatment times. A significant reduction in the number of severe hypotensive episodes (three in period B v 26 in period A1 and 16 in period A2; P < 0.05) and the overall incidence of complaints, especially of muscular cramps, was found in BV-CHD. These results were reflected in a reduced need for therapeutically administered isotonic saline in each session (60 mL in B v160 mL in A1 and 95 mL in A2; P < 0.05). In conclusion, the proposed biofeedback system for intradialytic BV control may be useful to avoid severe hypovolemic states, to stabilize BV by modeling its trend, and to avoid reaching individual critical BV thresholds in hypotension-prone patients.

Angiotensin-converting enzyme inhibitors and kidney protection : The AIPRI trial

A protective effect of angiotensin-converting enzyme (ACE) inhibitors has been shown in patients with diabetic nephropathy but has not been clearly established in nondiabetic renal disease. A multicenter European study was designed to determine whether the ACE inhibitor benazepril was safe and effective in protecting residual renal function in patients with various renal diseases and mild to moderate renal failure. The trial involved 583 patients from 49 centers in Italy, France, and Germany. The patients were randomized to receive benazepril or placebo plus other antihypertensive agents, the target being a diastolic blood pressure of less than 90 mm Hg. Thirty-one patients in the benazepril group and 57 patients in the placebo group reached the end point [the time elapsed from entry to (a) doubling of serum creatinine (SCr) concentrations and (b) start of renal replacement therapy; p < 0.001 at 3 years]. The associated reduction in the relative risk of reaching the end point was 53% in benazepril-treated patients, with actuarial renal survival probability significantly better at 3 years. The best survival of renal function was observed in patients with chronic glomerular diseases and proteinuria greater than 1.0 g/24 h. Benazepril is effective in slowing the rate of progression and improving the survival of renal function in patients with renal diseases of various origins. This protective effect is associated with a clinically relevant decrease in both blood pressure and proteinuria.

Automatic control of blood volume trends during hemodialysis.

Dialysis induced hypovolemia plays an important role in triggering intradialytic hypotension. The authors developed an automatic system (BVAC) with feedback changes in the ultrafiltration rate (UFR) and dialysate conductivity (DC) to match blood volume (BV) intradialytic profiles with the desired trajectories. The system consists of three subunits: (1) an optical probe to continuously detect the BV changes derived from hemoglobin changes, and (2) a dialysis machine interfaced with (3), a personal computer in which a time-dependent model is implemented. The model is based on a dynamic regulator that can set the actual BV changes against the corresponding desired values. Any discrepancy is offset by changes in UFR and DC. To verify the efficacy of the BVAC system in reducing intradialytic cardiovascular instability, five hypotension-prone patients were studied during a three period protocol (A1-B-A2) that lasted six sessions per period per patient. During periods A1 and A2, the dialysis procedure was conventional hemodialysis (HD) with linear UFR and constant DC. During period B, both UFR and DC were automatically regulated by the BVAC system. Mean BV reduction and its variability were lower during period B than during periods A1 and A2 (-10.2%, -11.3%, and -11.5, respectively). Episodes of hypotension were significantly (P < 0.05) fewer during period B (n = 1) than during periods A1 (n = 8) and A2 (n = 5). The therapeutic interventions defined as infused milliliters of isotonic and hypertonic solution were fewer during period B compared with periods A1 and A2. Total UF and end-dialysis plasma sodium concentrations did not differ in the three study periods. BVAC was effective in improving cardiovascular tolerance to treatment.

Influence of ultrafiltration on plasma renin activity and adrenergic system.

The influence of efficient ultrafiltration without dialysis fluid was compared to the standard dialysis technique in two groups of 4 patients with chronic renal failure on maintenance haemodialysis. Supine plasma renin activity (PRA), plasma concentration of noradrenaline (NA), and adrenaline (A) and the Valsalva manoeuvre were determined before and after the period of ultrafiltration at the beginning and at the end of the experiment. The behaviour of these parameters was related to changes of blood pressure and body weight. The rapid weight loss was well tolerated during ultrafiltration only, with a significant increase of plasma catecholamines concentration; in contrast, patients treated with ultrafiltration and dialysis showed no significant increase of NA and A levels and they frequently became hypotensive. No relationship was observed between changes in PRA and those in body weight and blood pressure. Our data suggest that rapid removal of catecholamines during standard dialysis hinders the compensatory increase of the adrenergic activity and is responsible for hypotension.

The Diagnostic Dilemma of Hypertensive Nephrosclerosis: The Nephrologist's View

The appearance of progressive renal disease in elderly patients with essential hypertension, sometimes irrespective of blood pressure control, is frequently related to the association of hypertension and atheromatous renal disease. This disease may lead to renal failure through a renal artery stenosis and/or chronic microembolization into the kidney. Nonsevere uncomplicated essential hypertension is constantly associated with renal vascular changes that are qualitatively indistinguishable from those related to aging. Notwithstanding the fairly constant presence of so-called benign hypertensive nephrosclerosis in patients with established hypertension, only a subset of these patients show progressive renal damage. Three mechanisms of progression may be at play: (1) a combination of ischemic and hypertensive glomerular mechanisms in some susceptible humans; (2) nonhemodynamic factors such as local immune mechanisms; or (3) the involvement of metabolic abnormalities which favor glomerulosclerosis.

Lymphocyte Subpopulations in Minimal-Change Nephropathy

It has been suggested that minimal-change nephropathy (MCN) may be related to a disorder of cell-mediated immunity. Lymphocyte cell-surface markers (E and EAC rosettes) and functional markers (mitogen

Fibromuscular Dysplasia of the Renal Arteries Associated With Antiphospholipid Autoantibodies: Two Case Reports

A relationship appears to exist between antiphospholipid autoantibodies (APLA) and vascular occlusion, although the exact mechanism is still a matter of debate. We present and comment on two cases of renal artery occlusion in patients with concomitant presence of arterial fibromuscular dysplasia and high APLA titers.

Glomerulonephritis with Organized Deposits: A New Clinicopathological Entity? Light-, Electron-Microscopic and Immunofluorescence Study of 12 Cases

Twelve cases of glomerulonephritis in patients without systemic diseases, displaying organized glomerular deposits, were reported. Microfibrils (11-30 nm diameter) were found in 9 patients and microtubules (20-35 nm diameter) in the other 3. Histochemical stainings for amyloid were always negative. By light microscopy, mesangial proliferative, membranous and membranoproliferative patterns were seen in 5, 3 and 4 patients, respectively. By immunofluorescence, granular deposits, mainly of IgG and C3, were found in all cases, either in the mesangium or in the mesangium and in the capillary walls. A second biopsy was performed in 2 patients. The number of hyaline glomeruli was increased, but the general pattern of glomerular changes remained unchanged. The commonest clinical findings were hypertension, microhematuria and proteinuria, often of nephrotic range. At variance to what is reported in the literature, 2 pediatric cases were found as well, and the overall prognosis (mean follow-up 54.3 months) was mostly favorable. The diagnostic relevance of these findings is pointed out, but further investigations are needed, before suggesting a new clinicopathological entity.