Sharon Anderson

Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat.

Micropuncture and morphologic studies were performed in six groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 4 received no specific therapy. Groups 2 and 5 were treated with the angiotensin I-converting enzyme inhibitor, enalapril, 50 mg/liter, in the drinking water. Groups 3 and 6 were treated with reserpine (5 mg/liter), hydralazine (80 mg/liter), and hydrochlorothiazide (25 mg/liter). All rats were fed standard chow. Groups 1-3 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure gradient (delta P) and glomerular plasma flow rate (QA). In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained delta P at near-normal levels without significant reduction in SNGFR and QA. In contrast, triple drug therapy normalized systemic hypertension, but failed to lower delta P in group 3 rats. Groups 4-6 were followed for 12 wk after renal ablation. Untreated group 4 rats demonstrated continuous systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and frequent areas of segmental sclerosis. In group 5 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 12-wk period and dramatically limited the development of proteinuria and glomerular lesions. Despite equivalent systemic blood pressure control in group 6 rats, failure of triple drug therapy to control glomerular hypertension was associated with progressive proteinuria and glomerular lesions comparable to those seen in untreated group 4 rats. Thus, unless glomerular capillary hypertension is corrected, control of systemic blood pressure is insufficient to prevent progressive renal injury in rats with reduced renal mass.

Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.

Micropuncture and morphologic studies were performed in four groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 3 received no specific therapy. Groups 2 and 4 were treated with the angiotensin I converting enzyme inhibitor, enalapril, 50 mg/liter of which was put in their drinking water. All rats were fed standard chow. Groups 1 and 2 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure difference and glomerular plasma flow rate. In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained the mean glomerular transcapillary hydraulic pressure gradient at near-normal levels without significantly compromising SNGFR and the glomerular capillary plasma flow rate, as compared with untreated group 1 rats. Groups 3 and 4 were studied 8 wk after renal ablation. Untreated group 3 rats demonstrated persistent systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and segmental sclerosis. In group 4 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 8-wk period and significantly limited the development of proteinuria and glomerular lesions. These studies suggest that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further support the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced.

Protein-calorie malnutrition associated with alcoholic hepatitis. Veterans administration cooperative study group on alcoholic hepatitis

Three hundred sixty-three alcoholic patients with alcoholic hepatitis were studied in six Veterans Administration medical centers. By history, alcohol consumption was 227.9 g per day, with a mean duration of 23.8 years. Cirrhosis accompanied the alcoholic hepatitis in 58.7 percent of the patients who underwent biopsy or autopsy. Complete nutritional assessment was performed in 284 patients, and observed nutritional changes were classified into those associated with marasmus or those characterizing kwashiorkor. A smaller comparison group of 21 alcoholic patients matched for age and alcohol consumption but without clinically evident liver disease was also studied in an identical manner. None of the patients with liver disease was completely free from malnutrition, whereas 62 percent of the alcoholic patients without liver disease showed abnormalities. In patients with alcoholic hepatitis, some findings associated with marasmus were seen in 86 percent, and some features of kwashiorkor were observed in 100 percent. When present together, the complete picture of kwashiorkor and marasmus correlated closely with the clinical severity of the liver disease (p less than 0.005). The nearly constant association of either complete or partial kwashiorkor or marasmus suggests that the separation of these two entities is artificial in alcoholic patients with liver disease. Although, experimentally, malnutrition may not be essential for the development of alcoholic hepatitis, clinically, it appears to precede the development of the liver injury, which suggests an interaction. Recognition is important so that appropriate nutritional therapy can be provided.

Effects of aging on the renal glomerulus

The biologic price of aging includes progressive deterioration of renal function and structure. After the age of 30, glomerular filtration and renal blood flow rates decline in a linear fashion, so that values in octagenarians are only half to two thirds those measured in young adults. Renal mass similarly declines, and the incidence of sclerotic glomeruli increases with advancing age. Accordingly, the aging kidney is at high risk of eventual failure when functioning nephron number is further reduced by acquired renal disease. Recent evidence suggests that limitation of dietary protein intake delays the development of age- and disease-related glomerular sclerosis in experimental animals, and that dietary protein restriction may postpone end-stage renal disease in patients with progressive renal insufficiency.

Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.

Infusion of atrial natriuretic peptide (ANP) increases the glomerular filtration rate (GFR), and ANP is released from cardiac myocytes in response to extracellular fluid volume expansion. Since diabetes mellitus is associated with glomerular hyperfiltration and volume expansion, we investigated the relationship between ANP and GFR in diabetic rats given insulin to achieve stable moderate hyperglycemia or normoglycemia. At 2 wk after induction of diabetes, moderately hyperglycemic diabetic rats exhibited elevations of plasma ANP levels averaging 281 +/- 28 pg/ml vs. 158 +/- 15 pg/ml in normoglycemic diabetic rats. In hyperglycemic rats, the GFR was also elevated on average to 2.24 +/- 0.28 ml/min as compared with 1.71 +/- 0.13 ml/min in normoglycemic diabetic rats. To test further the relationship between ANP and GFR in diabetes, moderately hyperglycemic diabetic rats were infused either with a specific ANP antiserum or with nonimmune serum. The infusion of specific ANP antiserum uniformly reduced the GFR on average from 2.38 +/- 0.1 ml/min to 1.60 +/- 0.1 ml/min, whereas the infusion of nonimmune serum was without effect. It is concluded that elevated endogenous ANP levels contribute to the hyperfiltration observed in early diabetes in the rat.

Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.

Functional and morphologic measurements were performed in Munich-Wistar rats after a single central venous injection of puromycin aminonucleoside (PA) or saline vehicle (sham). During phase I, PA rats exhibited overt nephrotic syndrome and impaired glomerular filtration, primarily due to a reduction in the glomerular capillary ultrafiltration coefficient. The morphologic counterpart of the latter consisted of effacement of glomerular epithelial cell foot processes and decrease in the number of filtration slit diaphragms. Administration of the angiotensin I converting enzyme inhibitor (CEI) enalapril to PA rats did not ameliorate glomerular dysfunction. During phase II, PA rats exhibited spontaneous resolution of proteinuria, impaired function, and morphologic abnormalities. However, PA rats now demonstrated marked glomerular capillary hypertension and continued, albeit lesser, reductions in the ultrafiltration coefficient. Concurrent CEI administration modestly lowered systemic arterial pressure, and normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. Additional rats were studied during phase III, 70 wk after injection. In PA rats, prior glomerular hypertension was associated with development of recurrent proteinuria and extensive glomerular sclerosis, whereas concurrent CEI administration limited these parameters to values comparable to those in sham rats. Glomerular hypertension thus may explain the development of glomerular sclerosis and renal failure long after an episode of acute glomerular injury.

Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation.

Functional and/or structural measurements were performed in eight groups of Munich-Wistar rats after five-sixths nephrectomy. Groups 1 and 5 received no therapy. Groups 2 and 6 received daily doses of methylprednisolone (MP). Groups 3 and 7 received MP plus the angiotensin I converting enzyme inhibitor (CEI), benzazepril. Groups 4 and 8 received CEI alone. Groups 1 through 4 underwent micropuncture study 2 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate due to glomerular capillary hyperperfusion and hypertension. Administration of MP in group 2 resulted in comparable systemic hypertension, with further elevation of the single nephron glomerular filtration rate due to even higher values for glomerular perfusion and hydraulic pressure. Concurrent treatment with CEI in groups 3 and 4 controlled systemic and glomerular hypertension despite equivalent renal ablation and, in group 3, comparable doses of MP. Groups 5 through 8 were followed for 12 wk. Untreated group 1 rats demonstrated continued systemic hypertension, progressive proteinuria, and eventual glomerular sclerosis. Addition of MP in group 6 dramatically accelerated the development of proteinuria and glomerular sclerosis, while CEI (groups 7 and 8) afforded striking protection against disease progression. Thus, potent vasodilator glucocorticoids may amplify hemodynamically mediated glomerular injury, whereas control of systemic and glomerular hypertension prevents this undesirable consequence of chronic steroid therapy.

Converting enzyme inhibitor therapy limits progressive glomerular injury in rats with renal insufficiency

Sustained increases in glomerular capillary pressure and flow accompany systemic hypertension in rats that have undergone extensive ablation of the renal mass. These intrarenal hemodynamic changes are, in turn, associated with the progressive development of proteinuria and glomerular sclerosis, leading ultimately to failure of remnant nephron units. The efficacy of antihypertensive therapy with enalapril was evaluated in this animal model of chronic renal insufficiency. A dose of enalapril sufficient to prevent systemic hypertension normalized the glomerular capillary pressure without reducing the glomerular filtration rate in the remnant kidney. Maintenance of normal capillary pressure markedly reduced the development of proteinuria and sclerotic lesions in remnant glomeruli. These results suggest that antihypertensive therapy directed at reducing the glomerular capillary pressure could retard the progressive loss of renal function in patients whose functional renal mass has been reduced by disease.

Renal hemodynamic effects of calcium antagonists in rats with reduced renal mass.

The intrarenal hemodynamic effects of antihypertensive agents vary considerably, and these microcirculatory effects may contribute to long-term structural sequelae in the setting of chronic renal disease. To investigate the consequences of blood pressure reduction with calcium antagonists, 5/6 nephrectomized Munich-Wistar rats underwent baseline determinations of mean arterial pressure, whole kidney function, and single nephron giomerular filtration rate, after which intravenous infusions of verapamil or diltiazem were given in doses that acutely normalized blood pressure; control rats received saline vehicle. During the baseline period, all rats exhibited comparably elevated values for mean arterial pressure and single nephron giomerular filtration rate. During the experimental infusion, control rats exhibited continued single nephron hyperfiltration (84±8 nl/min) as a result of elevations in both giomerular capillary plasma flow rate (330 ±36 nl/min) and giomerular capillary hydraulic pressure (68 ±3 mm Hg), whereas the giomerular capillary ultrafiltration coefficient was low [0.050 ±0.009 nl/(secmm Hg)]. Both verapamil (148±6 to 103±3 mm Hg, p<0.05) and diltiazem (154±6 to 102 ±2 mm Hg, p<0.05) normalized arterial pressure, which did not change in control rats (150±7 to 142±8 mm Hg). Single nephron hyperfiltration and hyperperfusion were comparable among groups during the experimental period; compared with baseline values, diltiazem (97 ±8 to 71±7 nl/min, p<0.05) but not verapamil (90±7 to 83±6 nl/min, p=NS) modestly lowered the single nephron giomerular filtration rate. Compared with vehicle rats, giomerular capillary pressure was reduced in rats receiving verapamil (52±2 mm Hg) and diltiazem (50±2 mm Hg), whereas both agents increased the ultrafiltration coefficient [0.102±0.012 and 0.123±0.018 nl/(secmm Hg), respectively]. Thus, calcium antagonists acutely control giomerular hypertension and improve the ultrafiltration coefficient in remnant kidney rats.

Dietary Protein Intake and Progressive Glomerular Sclerosis: The Role of Capillary Hypertension and Hyperperfusion in the Progression of Renal Disease

Unrestricted intake of protein-rich foods is accompanied by sustained increases in glomerular capillary pressures and flows. Intrarenal hypertension and hyperperfusion associated with protein intake may eventually cause glomerular sclerosis and account for decreased renal function seen with aging. Further elevation of glomerular capillary pressures and flows contributes to progressive glomerular destruction and eventual loss of renal function when nephron number has been reduced by renal disease. Progressive loss of renal function may be retarded by restriction of protein intake. Protein restriction appears to preserve renal function by limiting intrarenal capillary hypertension and hyperperfusion.