Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study

This study was undertaken to clarify the effect of corticosteroids on the long-term clinical course of the early stage of progressive IgA nephropathy. The early stage of progressive IgA nephropathy was defined as having moderate proteinuria between 1 and 2 g/day, creatinine clearance values of 70 ml/min or more, and a histological severity score of 7 or more. The number of patients who fulfilled these three conditions during 12 years from 1972 and then were continuously followed up for 10 years or more in our renal unit was 46. Twenty of them received steroid treatment for an average period of 18 months, and the remaining 26 patients had no steroid treatment. The initial data of proteinuria, creatinine clearance values, frequency of hypertensive cases, and histological scores of 7 or more were not different between the two groups: 1.4 +/- 0.4 vs. 1.3 +/- 0.3 g/day, 85 +/- 14 vs. 88 +/- 13 ml/min, 25 vs. 38%, and 10.7 +/- 2.5 vs. 11.0 +/- 3.0, respectively. During the follow-up period of 10 years, the renal survival rate was significantly different between the two groups (100 vs. 84% 5 years after starting therapy and 80 vs. 34% 10 years later; p < 0.001). The final creatinine clearance values were significantly different between the two groups (54 +/- 35 vs. 20 +/- 29 ml/min; p < 0.005). On the other hand, the patient groups with mild histological changes or decreased renal function due to moderate proteinuria showed no significant differences in the final outcome. These results indicate that corticosteroids are beneficial in stabilizing the renal function for a long time during the early stage of progressive IgA nephropathy, although this study was not a randomized one.     

Antiproteinuric effect of angiotensin-converting enzyme inhibition and C5b-9 urinary excretion in membranous glomerulonephritis

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have an antiproteinuric effect in membranous glomerulonephritis (MGN). However, no studies have investigated whether this antiproteinuric effect is influenced by urinary C5b-9 excretion, a marker of immunological activity in this disease. METHODS: Eleven patients with biopsy-proven MGN were treated with captopril for 8 weeks. The evolution of several clinical and biochemical parameters, including 24-h urinary protein excretion was evaluated every 4 weeks. Urinary C5b-9 excretion was measured at the onset and at the end of captopril treatment. RESULTS: Patients with MGN had significantly higher C5b-9 excretions than a group of 14 healthy controls (89 +/- 23 vs 3.7 +/- 1.4 ng/mg UCr; P < 0.001). A significant correlation was found between urinary C5b-9 and the magnitude of proteinuria, both at the onset and at the end of treatment. After 8 weeks of captopril treatment, proteinuria had decreased from 8 +/- 1.8 to 5.2 +/- 1.3 g/day (P < 0.05). Four weeks after captopril discontinuation, proteinuria rose to 7.3 +/- 1.7 g/day (P < 0.05). A marked variability in the antiproteinuric response was observed, ranging from 0 to 85% with respect to baseline values. No correlation between decrease in proteinuria and baseline urinary C5b-9 levels was observed. Several patients with elevated urinary C5b-9 levels had captopril-induced decrease in proteinuria. CONCLUSIONS: ACE inhibition induces an antiproteinuric effect in patients with MGN. The urinary C5b-9 excretion does not predict the magnitude of this response.     

Role of the peripheral renin profile in predicting blood pressure control after bilateral nephrectomy in renal-transplanted patients

BACKGROUND: The unregulated renin release by native kidneys is one of the factors responsible for the high incidence of hypertension after renal transplantation but, even after three decades of transplantation, there is still a lack of a method to identify it as the major cause of hypertension. METHODS: We investigated whether or not peripheral renin activity, before and 90 min after 25 mg of captopril, can play this role. One hundred and five consecutive patients with SCr less than 2 mg/dl were studied 18 +/- 8 months after renal transplantation. Forty-seven of them were considered hypertensive and 58 normotensive. All hypertensive patients were submitted to the captopril test to analyse the peripheral renin activity profile. RESULTS: In the hypertensive group, 17 patients (36%) were considered Renin-pos and 30 (64%) Renin-neg. All Renin-pos (stimulated renin = 19.1 +/- 6.4 ng/ml/h) patients were submitted to bilateral nephrectomy (bNx) and re-evaluated 6 months later. All of them normalized renin activity (4.4 +/- 3.0 ng/ml/h, P = 0.0001) and 10 of 17 (60%) became normotensive and off drugs. The remaining seven (40%) decreased the number of hypotensive drugs from 2.2 +/- 0.5 to 0.5 +/- 0.7/pt/day. There was a correlation between b-Renin and dBP (r = 0.47, P < 0.05) which was lost after bNx. An 'in situ' renal-cell carcinoma was found in two cases. Serum creatinine did not change. CONCLUSIONS: This study shows that the unregulated renin-angiotensin system from the native kidneys plays a major role in the maintenance of hypertension in some patients with normal graft function and that peripheral renin activity can identify those who will benefit from bilateral nephrectomy.     

Renal proximal disfunction based on activity of n-acetyl-beta-d-glucosaminidase in urine of patients with kidney failure

N-acetyl-beta-D-glucosaminidase (NAG) urine activities of 63 patients with stable and unstable chronic renal failure have been investigated. The values of NAG activity obtained from these patients were compared with NAG activity of 33 normal controls. Abnormal NAG values (> 70 nmol/mg of creatinine) were found in 60 (95.2%) patients with chronic renal failure and the median of all values was 327.8 nmol/mg of creatinine. It was 14-fold greater than the median of values for normal controls. There were any significant differences of NAG values between the patients with massive proteinuria (> 1.5 g/24 h), moderate proteinuria and those without 24 hour proteinuria or non-significant proteinuria (respectively 423.5 +/- 286.3 vs 414.4 +/- 334.8 vs 453.0 +/- 451.3 nmol/mg of creatinine). There was no significant difference between the two subgroups of patients with NAG values above and below 280 nmol/mg of creatinine in age, gender, serum urea and uric acid levels. However, the incidence of patients with NAG values higher than 280 nmol/mg of creatinine was statistically significant in unstable course of renal insufficiency and raised serum creatinine levels. It is suggested that the measurement of NAG excretion may be helpful to monitor unstable process in renal failure.     

Feasibility of adjuvant chemotherapy for breast cancer patients

The prevalence and natural history of severe proteinuria in mild to moderate hypertension are not completely defined. We screened 1635 men with a history of hypertension and randomized 1292 with untreated diastolic blood pressure (DBP) 95-109 mmHg to single-drug treatment with either hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem-SR, prazosin, or placebo in a double-blind prospective trial. Twenty-seven of 1635 patients (1.7%) satisfying clinical criteria for primary hypertension were found to have developed proteinuria > 1000 mg/24 hours and were removed from the study. Follow-up data were obtained on 19 of these 27 patients. One patient was found to have focal segmental sclerosis and progressed to end-stage renal disease. Three other patients developed severe (serum creatinine > 3.5 mg/dl) chronic renal failure (one with diabetic nephropathy), one progressed from serum creatinine 1.4 to 2.2 mg/dl, but 14 of the 19 remained with stable serum creatinine < 2.0 mg/dl on follow-up for 6-9 years. Data were available for 1076 of 1155 (93%) treated study patients at end titration, 522/600 (87%) at one year and 322/444 (73%) at two years. There were significant associations for proteinuria with obesity and higher systolic blood pressure. There was a trend toward significant difference in mean 24-hour protein excretion rates at baseline between black (127 mg) and white (139 mg) patients (p = 0.07). There were no statistically significant changes in urinary protein excretion/24 hours between or within the different treatment groups (including placebo). Eighteen patients were removed from the study during the active treatment phase for proteinuria > 1000 mg/24 hours: hydrochlorothiazide 4, placebo 3, diltiazem 3, prazosin 3, atenolol 2, clonidine 2, and captopril 1. We conclude: (1) the prevalence of severe (> 1 g/24 hours) proteinuria in the hypertensive population is significant but does not necessarily imply a poor prognosis; (2) mean 24-hour urinary protein excretion rates did not vary in response to the different classes of antihypertensive drugs; and (3) there was no drug-specific increase in proteinuria detected in this study.     

Relationship between appearance of urinary red blood cell/white blood cell casts and the onset of renal relapse in systemic lupus erythematosus

The purpose of the study was to determine the extent to which urinary sediment findings (changes in red blood cells [RBCs], white blood cells [WBCs], and the appearance of RBC and WBC casts) predict the onset of renal relapse (defined as a specific increase in proteinuria and/or serum creatinine level) in patients with systemic lupus erythematosus (SLE). Seventeen SLE patients with biopsy-proven diffuse proliferative glomerulonephritis at initial presentation were followed prospectively for 1,129 patient-months under a study protocol. Semiquantitative urinalyses were performed at 2-month intervals during periods with little or no SLE activity and, more frequently, during periods with increased SLE activity. Each urinalysis was accompanied by a clinical evaluation and a panel of screening tests relevant to the evaluation of SLE activity. During this study, 877 semiquantitative urinalyses were performed and 43 renal relapses were observed in 14 patients. No relapse occurred in three patients. Of the renal relapses, 30 were defined as proteinuria relapses (mean baseline proteinuria increased from 0.8 +/- 0.1 g/24 hr to 2.7 +/- 0.3 g/24 hr; P < 0.001) and 13 were defined as serum creatinine relapses (mean baseline serum creatinine increased from 2.7 +/- 0.4 mg/dL to 3.8 +/- 0.5 mg/dL; P < 0.001). Red blood cell and/or WBC casts (cellular casts) were observed before or at the onset of 35 of the 43 renal relapses (sensitivity, 81%). The mean and median intervals between the appearance of cellular casts and the onset of renal relapse was 10 +/- 2 weeks and 8 weeks, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of angiotensin-converting enzyme inhibitors on proteinuria in chronic glomerulonephritis

The effect of two angiotensin-converting enzyme (ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (> 1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration rate < 75 ml/min). In a randomized and double-blind cross-over trial the patients received, each time for six weeks, either lisinopril (5 mg/d, sometimes increased to 10 mg/d after 3 weeks) or captopril (twice daily 12.5 mg, sometimes increased to twice 25 mg after 3 weeks). Initially and between the individual treatment phases they were on a placebo phase for 4 weeks. The following were measured: protein excretion, including fractional clearance of albumin and IgG, plasma-renin activity and renal haemodynamics. Protein excretion was not significantly reduced by either drug (placebo: 7.1 +/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril. Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9 ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The renal haemodynamics was only slightly influenced by either drug, but captopril significantly decreased the filtration fraction in the presence of chronic glomerulonephritis and renal failure. - Resulting from their influence on the renin-angiotensin-aldosterone system, ACE inhibitors have, in addition to their known action on renal haemodynamics, an independent effect on the loading barrier of the basal membrane of the kidney.     

Low dose angiotensin converting enzyme inhibition and glomerular permselectivity in renal transplant recipients

In this study, we determined the fractional clearance of neutral polydisperse dextrans (theta D) and monodisperse dextran sulfate (theta DS) to describe glomerular size and charge selectivity in 25 renal transplant recipients with proteinuria. Thirteen were treated with low dose lisinopril for six months (group 1) and 12 patients without ACE inhibitor therapy formed group 2. Mean arterial blood pressure was stable (group 1, 112 +/- 4; group 2, 109 +/- 2 mm Hg at baseline and after 6 months) whereas creatinine clearance, glomerular filtration rate and renal plasma flow decreased nonsignificantly but were comparable at any time. Lisinopril treatment lowered filtration fraction (22 +/- 2 vs. 19 +/- 2%, P = 0.07) whereas no change was seen in group 2 (20 +/- 2%). The fractional protein excretion (mg urinary protein per day/ml creatinine clearance per day) was stable in group 1, but significantly increased in group 2. The same pattern was found for theta D larger than 56 A. theta DS was stable and consistently elevated in both groups at any time. We conclude that low dose ACE inhibitor treatment in proteinuric renal transplant recipients stabilizes glomerular size selectivity independently of its systemic hemodynamic effects.     

Effects of renin inhibition compared to angiotensin converting enzyme inhibition in conscious dogs with pacing-induced heart failure

OBJECTIVE: To compare the effects of angiotensin converting enzyme inhibition (ACEI) (captopril 1 mg/kg i.v.) to direct renin inhibition (CP80794 3 mg/kg i.v.) on left ventricular and systemic hemodynamics and peripheral blood flows in advanced congestive heart failure (CHF). METHODS: Conscious chronically instrumented dogs (n = 14) were treated with captopril, 1 mg/kg, i.v., or CP80794, 3 mg/kg, i.v., before and after development of advanced CHF induced by 4-7 weeks of rapid ventricular pacing. After advanced CHF, comparisons between the inhibitors were made at equihypotensive doses. RESULTS: In advanced CHF, both agents caused comparable reductions in mean arterial pressure (MAP) (-22% from 79 +/- 4 mmHg) and comparable increases (P < 0.01) in cardiac output (CP80794, 1.4 +/- 0.3 to 1.8 +/- 0.1 l/min; captopril, 1.4 +/- 0.1 to 1.9 +/- 0.1 l/min). Neither agent had a significant effect on LV contractility. In contrast, CP80794 caused a greater (P < 0.05) increase in renal blood flow (66 +/- 6% from 64 +/- 5 ml/min) compared to captopril (33 +/- 4% from 66 +/- 7 ml/min). CONCLUSIONS: Renin inhibition with CP80794 and ACEI with captopril caused comparable hemodynamic effects in advanced CHF. However, CP80794 caused significantly greater increases in renal blood flow and suppressed renin activity to a greater degree than captopril.     

Effects of captopril on ventricular arrhythmias in the early and late phase of suspected acute myocardial infarction. Randomized, placebo-controlled substudy of ISIS-4

The antiarrhythmic effect of oral captopril was studied during the early (day 3) and late (day 14) phase of acute myocardial infarction among 304 patients in a randomized placebo-controlled substudy of ISIS-4. Ventricular arrhythmias (ventricular ectopic beats per hour) occurred significantly less frequently among captopril-allocated patients than among those allocated placebo at day 3 (logarithmic scale: 0.48 +/- 0.8 captopril vs 0.84 +/- 1.3 placebo; P < 0.003) and at day 14 (0.51 +/- 1.0 vs 0.77 +/- 1.3; P < 0.05). The number of patients with frequent ventricular arrhythmias (more than 10 ventricular ectopic beats per hour) was also significantly lower among those allocated captopril at day 3 (7.3% vs 14.4%; P < 0.05) and at day 14 (7.3% vs 14.8%; P < 0.05). These results support the hypothesis that the activation of the renin-angiotensin-aldosterone and sympathetic system may underlie heart rhythm disturbances in acute myocardial infarction, and that early use of converting enzyme inhibitor therapy may ameliorate these disturbances.     

Effect of captopril cardioplegia on renin-angiotensin system, prostaglandins, free radicals and electrolytes in the isolated hypothermic ischemic and reperfusion rabbit hearts

The effect of captopril cardioplegia on ischemic and reperfusion myocardium after 3 hours of hypothermic (13 +/- 1 C) arrest and 35 minutes of reperfusion was studied in the isolated working rabbit heart. In comparison with the control group, captopril cardioplegia reduced the content of angiotensin II (381 +/- 56 vs 507 +/- 84 pg/g wt of the control group, P < 0.01) and MDA (50.0 +/- 9.2 vs 85.1 +/- 16.1 pmol/mg pr, P < 0.01) in the reperfusion myocardium; augmented the renin activity of ischemic (1050 +/- 353 vs 669 +/- 301 pg/g wt/h, P < 0.05) and reperfusion myocardium (1261 +/- 421 vs 498 +/- 353 pg/g wt/h, P < 0.01) increased the 6-K-PGF1 alpha/TXB2 ratio in the reperfusion myocardium (by 48.1% of the control group). Meanwhile, captopril cardioplegia could also decrease the content of calcium (0.027 +/- 0.015 vs 0.045 +/- 0.014 microM/mg pr, P < 0.05) and sodium (0.54 +/- 0.26 vs 0.82 +/- 0.15 microM/mg pr, P < 0.05) in the reperfusion myocardium, but had no effect on the potassium content. The results show that the protective effect of captopril on hypothermic myocardium may be related to the free radical scavenging action, inhibition of angiotensin II production, improvement of PGI2/TXA2 ratio and decrease of calcium and sodium overload in the myocardium.     

Long-term treatment of lupus nephritis with cyclosporin A

We evaluated the efficacy and safety of long-term treatment with cyclosporin A (CSA) in type IV lupus nephritis. Seventeen patients with biopsy-proven WHO type IV lupus nephritis were enrolled in a prospective, open study. Twelve of the 17 completed 48 months of treatment with CSA and prednisolone. Three patients required the addition of azathioprine, at 12, 38 and 47 months, respectively, for cutaneous disease flare with refractory rashes. One patient was lost to follow-up at 40 months. The mean +/- SD duration of treatment was 43.2 +/- 10.1 months (range 15.7-48 months). A significant reduction of proteinuria and a significant rise in serum albumin were noted 1 month after initiation of treatment. Improvement was maintained throughout the study except for three patients who relapsed with recurrence of nephrotic syndrome. There were no significant changes in serum creatinine level or creatinine clearances throughout the study. Repeat renal biopsy at 12 months following treatment with CSA showed histological improvement, with WHO type II changes in all 17 patients accompanying significant reduction in activity indices. Patients with baseline haemoglobin (Hgb) levels < 12 g/dl showed significant improvement. Serum C3 and C4 levels were not changed significantly. Corticosteroid-sparing effects were noted. Side-effects included hypertension, gum hypertrophy and mild hirsuitism, but were not serious. Combination therapy using CSA and prednisone is effective and safe for long-term treatment in lupus patients with WHO type IV nephritis.     

Modification of exercise performance by sharp reduction of blood pressure. A study in patients with uncomplicated hypertension

We evaluated exercise performance in 14 patients with uncomplicated essential hypertension 1 h after the administration of a single dose of placebo, nifedipine (20 mg), captopril (50 mg), and propranolol (80 mg). Drugs were administered at the same time of day following a randomized, double-blind protocol. Mean resting blood pressure (+/- SE) was 135 +/- 3 mm Hg with placebo administration, 118 +/- 4 with captopril, 110 +/- 4 with nifedipine, and 115 +/- 5 with propranolol and increased with exercise to 163 +/- 4, 146 +/- 3, 136 +/- 4, 136 +/- 4, respectively. Oxygen consumption at peak exercise and at ventilatory anaerobic threshold (VAT) was 25.2 +/- 1.1 and 18.1 +/- 1.0 ml/min/kg with placebo. Only propranolol (-2.3 ml/min/kg) decreased peak exercise oxygen consumption. Oxygen consumption at VAT was reduced by nifedipine and propranolol but unaffected by captopril. The effects on exercise capacity of blood pressure reduction in hypertensive patients are dependent on the drug utilized and are not related to the amount of blood pressure reduction. The lowered oxygen consumption at VAT observed with nifedipine and propranolol, and not with captopril, might be due to an excessive downward shift of the muscle perfusion pressure--oxygen consumption relationship which might take place during exercise.     

Risk factors for contrast nephropathy in diabetic patients undergoing cardioangiography

Risk factors for contrast nephropathy were prospectively studied in 17 patients with non-insulin dependent diabetes mellitus undergoing cardioangiography. Contrast nephropathy, defined as a serum creatinine increase of greater than 25% at 3 day after angiography, occurred in 29.4% of diabetic patients. Patients who developed contrast nephropathy had significantly higher serum creatinine (Cr), fractional excretion of sodium (FENa), urinary albumin excretion rate (AER), and lower 24hr Ccr than patients who did not (Cr: 1.5 +/- 0.3 mg/dl vs. 0.8 +/- 0.1 mg/dl, FENa: 1.9 +/- 0.5% vs. 0.6 +/- 0.1%, AER: 522 +/- 335 micrograms/min vs. 27 +/- 13 micrograms/min, 24hr Ccr: 39.1 +/- 11.6 ml/min vs. 86.2 +/- 9.3 ml/min, P < 0.05). Contrast nephropathy developed in all of two patients with overt proteinuria (AER more than 200 micrograms/min), but none of eight patients with normoalbuminuria (AER below 15 micrograms/min). Three of seven patients with microalbuminuria developed contrast nephropathy, and two of them had advanced nephropathy. FENa obtained next day was significantly elevated over baseline in patients with contrast nephropathy (1.9 +/- 0.5% vs. 9.7 +/- 4.5%, P < 0.05), but unchanged in patients without contrast nephropathy. The rise in C beta 2-microglobulin/Ccr and enzymuria was noted in both group. Percentage decrease of Ccr on the next day was positively correlated with FENa before angiography (r = 0.645, p < 0.01). Of 24hr Ccr, AER, and FENa before angiography, FENa was revealed as a statistically significant discriminant factor for contrast nephropathy by stepwise discriminant analysis (p = 0.0008). These results suggest that contrast nephropathy develops predominantly in the stage not of incipient but of overt diabetic nephropathy indicated by a decline of glomerular filtration, overt proteinuria, and tubular dysfunction. Of them, tubular dysfunction may be the most important risk factor for contrast nephropathy.     

Inhibition of plasma endothelin-1 concentration by captopril in patients with essential hypertension

The aim of this study was to determine whether captopril has any effect on plasma endothelin-1 (ET-1) concentration in patients with essential hypertension. Nine normotensives and eleven hypertensives were included in this study. Blood pressure and pulse rate were monitored before and at 60 min after captopril ingestion (25 mg). Simultaneously, blood samples for plasma ET-1 and plasma renin activity (PRA) determination were obtained. In the normotensives, captopril treatment resulted in a significant rise in PRA, but without statistical changes in blood pressure and plasma ET-1. By contrast, in the hypertensives, although PRA elevated similarly after captopril, both blood pressure and plasma ET-1 decreased significantly compared with their respective preloading level. These data suggest that the blood pressure-lowering effect of captopril in essential hypertension may be at least in part, mediated by its inhibition of ET-1 production from the vascular endothelium.     

The effect of minoxidil on blood pressure and plasma renin activity in patients with essential and renal hypertension

The effect of the new vasodilator, minoxidil, on blood pressure and plasma renin activity was studied in 21 hypertensive patients: 12 patients with essential and 9 with renal hypertension. The average maximum dosage of minoxidil was 27.9 +/- 6.0 mg/day (M +/- SD). Average duration of treatment was 84.5 days. During the observation period the average systolic blood pressure fell from 195 +/- 18 to 159 +/- 7 mm Hg (M +/- SD), and the mean diastolic blood pressure fell from 120 +/- 8.3 to 92.5 +/- 8 mm Hg (p less than 0.01). These patients had been treated earlier with other antihypertensive agents, such as reserpine, saluretics, hydralazine, alpha-methyldopa, and clonidine, without any significant reduction in blood pressure. Before treatment, plasma renin activity after resting was 59 +/- 6.4 ng/ml/16 h (M +/- SE) and after saluretics and orthostasis 89 +/- 12.7 ng/ml/16 h. After treatment, the decline in renin value after resting was statistically significant: 42.7 +/- 3.3 ng/ml/16 h (p less than 0.05), and the stimulated renin had fallen to 70 +/- 3.4 ng/ml/16 h (p greater than 0.1). A comparison of the renin stimulation values of patients with renal hypertension also revealed a significant reduction (p less than 0.01). Side effects which appeared at a daily dose of 15 to 30 mg consisted mainly of tachycardia and fluid retention and could be controlled by the administration of propranolol and chlorthalidone. In 5 women and in 1 man was observed a cosmetically disturbing, reversible hypertrichosis. Orthostatic hypotension was observed in one patient. Minoxidil is an effective antihypertensive agent. However, because of its side effects, it generally must be administered with beta-receptor blocking agents and saluretics. It is possible that its blood pressure lowering effect is due, at least in part, to a suppression of the plasma renin activity.     

The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin

Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function.     

A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group

BACKGROUND: The n-3 fatty acids in fish oil affect eicosanoid and cytokine production and therefore have the potential to alter renal hemodynamics and inflammation. The effects of fish oil could prevent immunologic renal injury in patients with IgA nephropathy. METHODS: In a multicenter, placebo-controlled, randomized trial we tested the efficacy of fish oil in patients with IgA nephropathy who had persistent proteinuria. The daily dose of fish oil was 12 g; the placebo was a similar dose of olive oil. Serum creatinine concentrations, elevated in 68 percent of the patients at base line, and creatinine clearance were measured for two years. The primary end point was an increase of 50 percent or more in the serum creatinine concentration at the end of the study. RESULTS: Fifty-five patients were assigned to receive fish oil, and 51 to receive placebo. According to Kaplan-Meier estimation, 3 patients (6 percent) in the fish-oil group and 14 (33 percent) in the placebo group had increases of 50 percent or more in their serum creatinine concentrations during treatment (P = 0.002). The annual median changes in the serum creatinine concentrations were 0.03 mg per deciliter (2.7 mumol per liter) in the fish-oil group and 0.14 mg per deciliter (12.4 mumol per liter) in the placebo group. Proteinuria was slightly reduced and hypertension was controlled to a comparable degree in both groups. The cumulative percentage of patients who died or had end-stage renal disease was 40 percent in the placebo group after four years and 10 percent in the fish-oil group (P = 0.006). No patient discontinued fish-oil treatment because of adverse effects. CONCLUSIONS: In patients with IgA nephropathy, treatment with fish oil for two years retards the rate at which renal function is lost.     

Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.     

Overt proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease

The amount of proteinuria is a prognostic indicator in a variety of glomerular disorders. To examine the importance of urinary protein excretion in autosomal dominant polycystic kidney disease, this study determined the clinical characteristics of autosomal dominant polycystic kidney disease patients with established proteinuria and the frequency of microalbuminuria in hypertensive autosomal dominant polycystic kidney disease patients without proteinuria. In 270 autosomal dominant polycystic kidney disease patients, mean 24-h urinary protein excretion was 259 +/- 22 mg/day. Forty-eight of 270 autosomal dominant poly-cystic kidney disease patients had over proteinuria (> 300 mg/day). The patients with established proteinuria had higher mean arterial pressures, larger renal volumes, and lower creatinine clearances than did their nonproteinuric counterparts (all P < 0.0001), a greater pack year smoking history (P < 0.05), and the projection of a more aggressive course of renal disease (P < 0.05). All autosomal dominant polycystic kidney disease patients with established proteinuria were hypertensive, as compared with 67% without established proteinuria (P < 0.001). Forty-nine patients with hypertension and left ventricular hypertrophy without established proteinuria were examined for microalbuminuria; 41% demonstrated microalbuminuria. Those with microalbuminuria had higher mean arterial pressure, larger renal volumes and increased filtration fraction. Therefore, established proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease patients are associated with increased mean arterial pressure and more severe renal cystic involvement.