Effects of dehydroepiandrosterone and quinapril on nephropathy in obese Zucker rats.

BACKGROUND: The obese Zucker rat exhibits insulin resistance, develops nephropathy at an early age, and may be a model of diabetic nephropathy. Dehydroepiandrosterone (DHEA) may ameliorate many of the factors that contribute to diabetic nephropathy, while angiotensin-converting enzyme inhibitors are known to be effective. One marker of nephropathy is the expression of alpha-smooth muscle actin. METHODS: We studied the effect of DHEA on the expression of alpha-smooth muscle actin in obese Zucker rats and compared the changes with those in a control group, a group given quinapril, and a group on a low-calorie diet. DHEA (0.6%) added to plain chow, quinapril (0.3 mg/kg) added to drinking water, and a low-calorie diet based on pair-feeding were administered to obese rats from age 4 to 20 weeks. Immunohistochemical expression of alpha-smooth muscle actin, a marker of interstitial and glomerular fibrosis and an early indicator of nephropathy, was measured semiquantitatively in glomeruli, cortical interstitium, and medullary interstitium on a scale of 0 to 4 and was reported as mean +/- SEM. RESULTS: When compared with the obese control group, quinapril exhibited a marked reduction in alpha-smooth muscle actin staining in glomeruli, cortical interstitium, and medullary interstitium (P < 0.0005); DHEA reduced alpha-smooth muscle actin staining in cortical interstitium and medullary interstitium (P < 0. 005), and a low-calorie diet reduced alpha-smooth muscle actin staining in cortical and medullary interstitium (P < 0.005), which was similar to the effects of DHEA. CONCLUSIONS: DHEA was similar to a low-calorie diet in reducing the immunohistochemical staining of alpha-smooth muscle actin in obese Zucker rats. However, quinapril exerted a marked protective effect on the development of fibrosis, as indicated by alpha-smooth muscle actin staining, which was significantly less than that of DHEA at the doses studied.

Renal interstitial sclerosis in aging: effects of enalapril and nifedipine.

The effects of nifedipine and enalapril on age-associated renal interstitial fibrosis were investigated in 60 CF1 female mice. Mice received 20 mg enalapril (ENAL) per L (N = 20), or 40 mg nifedipine (NIF) per L (N = 20) in their drinking water. Control (CONT) mice received tap water ad libitum. The percentages of both interstitial peritubular sclerosis (IPS) in cortex and interstitial medullary sclerosis (IMS) were determined. Kidney tissue was studied using immunological techniques and optical (OM) and electron microscopy (EM) to analyze the expression of renin. alpha-SM-actin and vimentine expression were also evaluated. The results showed that blood pressure levels in ENAL or NIF animals were not different from those of CONT. Renin expression was observed in arcuate vessels (AV) in ENAL animals, whereas no renin staining in AV was found in either NIF or CONT animals. Renin immunoreactivity in the juxtaglomerular apparatus was more intense in ENAL mice, as compared with NIF or CONT animals. Laboratory testing showed the following values: proteinuria (mg/mL): CONT 6.1 +/- 0.6, NIF 11.2 +/- 2.3, and ENAL 1.0 +/- 0.6 (P < 0.05); creatinine: CONT 1.37 +/- 0.24, NIF 0.87 +/- 0.16, and ENAL 0.63 +/- 0.1 (P < 0.01). The percentages of interstitial sclerosis were: %IPS: CONT 18.12 +/- 1.1, NIF 17.40 +/- 0.9, and ENAL 3.42 +/- 1.3 (P < 0.01); %IMS: CONT 23.41 +/- 1.5, NIF 21.80 +/- 1.9, and ENAL 6.12 +/- 1.2 (P < 0.01). Percentages of alpha-SM-actin expression were: CONT 13.10 +/- 1.9, NIF 13.80 +/- 0.2, and ENAL 1.00 +/- 0.1 (P < 0.01). Vimentine staining showed no differences among the groups. It was concluded that enalapril reduces the peritubular and medullar interstitial fibrosis, whereas nifedipine has no effect.

Effects of enalapril on renal parameters in patients with primary glomerulopathies associated with chronic renal failure.

14 patients (8 male, 6 female), aged 35 to 64 years, with glomerulopathies consisting of membranoproliferative glomerulonephritis (GN) [n = 6], membranous GN (n = 3), focal and diffuse glomerulosclerosis (n = 4), and post-streptococcal GN (n = 1) were studied. Diagnosis was established by renal biopsy in 12 of the 14 patients. All 14 patients had impaired renal function (creatinine clearance = 25 to 55 ml/min) and proteinuria (1.0 to 10.4 g/day). Five normotensive patients received enalapril 20 mg/day, whereas 9 patients with hypertension received 20 to 40 mg/day to control blood pressure. Diuretics were administered concomitantly to 8 patients. Patients attended the clinic every 14 days for 30 months and their diets were closely monitored, with sodium intake limited to between 50 and 100 mEq/day and protein to between 1.0 and 1.2 g/kg/day. Blood pressure was significantly controlled in the patients with hypertension. Serum creatinine, blood urea nitrogen, creatinine clearance and 24-hour urinary protein excretion all significantly improved during the 30-month study. No adverse clinical events were noted. Thus, over a period of time, enalapril therapy may improve the prognosis of patients with glomerulonephritis by maintaining glomerular filtration rates and decreasing proteinuria and blood pressure.

Enalapril improved renal function and proteinuria in chronic glomerulopathies.

Ten patients (6 men, 4 women, age range 35-64 years) with glomerulopathies were studied. Diagnoses were membranoproliferative glomerulonephritis (GN; n = 4), membranous GN (n = 3), focal and diffuse glomerulosclerosis (n = 2), and poststreptococcal GN (n = 1). These were confirmed by renal biopsy in 8 of the 10 patients. All patients had reduced function (creatinine clearance 15-55 ml/min); proteinuria ranged from 1.0 to 10.4 g/day. Three normotensive patients received enalapril 10 mg once daily. Seven hypertensives received enalapril 10-40 mg once daily to control blood pressure (BP). Concomitant diuretic therapy (furosemide/bumetanide) was administered to 6 patients. There were visits every 14 days for a mean of 15.9 months (range 9-26 months). Diet was monitored, and BP was significantly controlled in the hypertensive patients but not altered in the normotensives. Serum creatinine, blood urea nitrogen, creatinine clearance, and 24-hour urinary protein improved and did not deteriorate progressively. Serum potassium did not change significantly. No adverse clinical events were noted. Enalapril therapy may improve the prognosis for GN over time by maintaining glomerular filtration rate and decreasing proteinuria.

Effects of alpha-adrenergic blockade on sodium excretion in normal and chronic salt retaining dogs.

The alpha-adrenergic blocking agent phenoxybenzamine (PBA) was administered intravenously (10 mug kg-1 min-1) during a steady state water diuresis under pentothal anesthesia to six normal dogs, six dogs with chronic throacic inferior vena cava constriction and ascites (caval dogs) and seven dogs chronically salt depleted by sodium restriction and furosemide administration. In normal dogs urinary sodium excretion increased significantly from 265+/56 (SEM) to 370+/65 muequiv./min, whereas no increase in sodium excretion was noted in either caval dogs or salt depleted animals after PBA. In all three groups urine volume, fractional free water clearance and distalsodium load did not change significantly. In normal dogs, tubular sodium reabsorption decreased significantly from 73.4+/2.8% to 63.1+/4.0%, whereas no change was noted in caval or salt depleted dogs. Blood pressure and renal hemodynamics were not significantly altered by PBA administration in any group. These data demonstrate a natriuretic effect of alpha-adrenergic blockade in normal dogs with the major effect in the water clearing segment of the nephron. The absence of any effect in chronic caval or salt depleted dogs suggests that increased alpha-adrenergic activity does not play a significant role in the sodium retention of these animals.

Evidence for enhanced distal tubule sodium reabsorption in chronic salt-depleted dogs.

In order to assess the renal tubular site(s) at which sodium reabsorption is enhanced in chronic sodium-depletion, seven normal dogs, six salt-depleted dogs, and three normal dogs receiving aldosterone were studied during a steady-state water diuresis under Pentothal anesthesia and during progressive hypotonic saline diuresis. For both maintenance of the water diuresis and progressive hypotonic saline diuresis 0.45% NaCl was used. During the steady state water diuresis delivery of sodium to the diluting segment of the nephron as approximated by solute-free water clearance + sodium clearance/glomerular filtration rate (CH2O + CNa/GFR) was significantly lower in salt-depleted dogs compared to normal dogs with or without aldosterone. During progressive hypotonic saline infusion fractional free water excretion (CH2O/GFR) was similar in all three groups as CH2O + CNa/GFR increased up to 12-14 ml/min-100 ml GFR. Thereafter, CH2O/GFR continued to rise in virtually a straight line in salt-depleted dogs but leveled off in normal dogs with or without aldosterone. These data demonstrate that enhanced sodium reabsorption in the diluting segment of the nephron is an important determinant of the renal sodium retention in chronic extracellular volume contraction in dogs in addition to confirming the presence of increased proximal tubule sodium reabsorption in these animals.

The effect of the plasma bicarbonate level on proximal tubule sodium reabsorption in NH4Cl-loaded dogs.

In an attempt to examine the effects of mild and severe chronic metabolic acidosis on proximal tubule sodium reabsorption, 6 dogs were given 10 mEq. per kilogram per day and 5 dogs were given 20mEq. per kilogram per day of ammonium chloride for 3 days and compared to 12 normal dogs during a steady-state water diuresis and following the administration of ethacrynic acid (EA) intravenously (2 mg. per kilogram) utilizing standard clearance methodology, In the severely acidotic group (pH decrease is greater tthan 0.2) plasma pH was 7.08 +/- 0.06 and plasma bicarbonate was 6.3 +/- 1.0 Eq. per liter compared to a pH of 7.33 +/-0.02 and bicarbonate of 13.4 +/- 0.7 in mild acidosis (pH decrease is less than 0.2). During a steady-state water diuresis urine flow was 14.2 +/- 0.9 in severely acidotic compared to 10.5 +/-0.7 ml. per minute per 100 ml. glomerular filtration rate (GFR) in normal dogs (p is less than 0.01). Following EA sodium clearance increased 38.4 +/- 3.5 in severely acidotic dogs and 27.6 +/- 2.0 ml. per minute per 100 ml. GFR in normal dogs (p is less than 0.02). In mild acidosis, steady-state fractional urine flow and the increase in fractional sodium clearance following EA were not significantly different than normal dogs. We conclude that chronic metabolic acidosis leads to an increase in distal solute load and enhanced natriuretic effect of EA secondary to a decrease in proximal tubule sodium reabsorption which may be dependent upon the degree of reduction in the plasma bicarbonate level.

Acute renal failure secondary to ureteral fungus ball obstruction in a patient with reversible deficient cell-mediated immunity.

A patient with a single functioning kidney and anuria due to ureteropelvic obstruction by a Candida fungus ball is described. During treatment with amphotericin B administered via a nephrostomy tube the drug was not detected in the serum, indicating that absorption from urothelium was not significant. Immunological studies demonstrated a lack of cell-mediated immunity which was probably brought about by a long course of prednisone and later restored when this drug was discontinued. This immunosuppression was evident even with a relatively small dosage of prednisone (5 mg daily). The literature concerning renal candidiasis and predisposing factors is reviewed.