ACE inhibition induces regression of proteinuria and halts progression of renal damage in a genetic model of progressive nephropathy.

Experimental data consistently indicate that renal disease progression is fully prevented in proteinuric glomerulopathies by long-enough angiotensin-converting enzyme (ACE) inhibition therapy. Whether regression of established proteinuria to normal can be achieved is, however, ill defined. The current study was designed with the aim to clarify whether ACE inhibition may induce regression of established proteinuria and renal structural damage in MWF rats, a genetic model of progressive proteinuria and renal injury. Animals treated with the ACE inhibitor lisinopril from 20 weeks of age (time when proteinuria is already important) and age-matched untreated rats were followed for 10 weeks. ACE inhibition normalized systolic blood pressure and progressively reduced proteinuria (from 172 +/- 79 to 81 +/- 23 mg/24 hours). In these animals, a highly significant correlation was obtained between baseline proteinuria and antiproteinuric response. At variance in untreated rats, proteinuria showed a marked increase in the 10-week follow-up period (from 165 +/- 57 to 325 +/- 86 mg/24 hours). Lisinopril prevented the progression of renal damage, as documented by a significantly lower incidence of glomeruli affected by sclerotic lesions (P < 0.01) than in untreated animals after the 10-week study period. Kidney tissue damage was comparable in lisinopril-treated rats and in untreated animals at 20 weeks of age, indicating that structural changes were arrested by the treatment. Thus, in proteinuric MWF rats, late-onset ACE inhibition normalized blood pressure, effectively and progressively restored high protein excretion rate toward normal values, and arrested progression of tissue damage.

Beneficial effects of calcium channel blockade on acute glomerular hemodynamic changes induced by cyclosporine.

Experimental and human studies have documented that cyclosporine (CsA) acutely reduces glomerular filtration rate (GFR). It has been reported that this effect can be partially prevented by calcium (Ca) channel blockade; however, the mechanisms by which this combination exerts its beneficial effects are unknown. We evaluated glomerular ultrafiltration determinants during acute CsA administration in the rat. First, we determined that maximal whole-kidney functional changes occur between 120 and 150 minutes after CsA administration and confirmed that pretreatment of MWF rats with the Ca channel blocker lacidipine effectively prevents a reduction in GFR. Micropuncture measurements in CsA-treated animals showed that a reduction in GFR (0.49 +/- 0.24 v 0.88 +/- 0.26 mL/min; P < 0.05; CsA-treated v untreated rats) is associated with a significant increase in glomerular capillary pressure (Pgc; 63.1 +/- 2.1 v 52.8 +/- 2.8 mm Hg; P < 0.01) and efferent arteriolar resistance, whereas single-nephron (SN) GFR and ultrafiltration coefficient (Kf) are both importantly reduced (34.0 +/- 11.7 v 68.9 +/- 23.8 nL/min; P < 0.05 and 1.04 +/- 0.33 v 4.40 +/- 2.36 nL/min/mm Hg; P < 0.01, respectively). Lacidipine partially prevented SNGFR (43.1 +/- 14.3 nL/min) and Kf decline (2.08 +/- 1.10 nl/min/mm Hg) despite the presence of elevated Pgc. This study further documents that Ca channel blockade has favorable effects on CsA-induced acute renal dysfunction. The mechanism of protection includes the prevention of glomerular hemodynamic changes induced by CsA, mainly GFR decline and reduction in glomerular Kf.

[Percutaneous transluminal valvuloplasty of mitral stenosis. Apropos of 17 cases]. / Valvuloplastie transluminale percutanée des sténoses mitrales. A propos de 17 cas.

Percutaneous mitral commissurotomy using balloon catheters was attempted in 17 patients (16 of whom were women) with rheumatic mitral valve stenosis. The patients' age ranged from 15 to 34 years (men 21 years). Functionally, 15 of the patients were in stage III of the New York Heart Association classification, and 2 were in stage II. Sinus rhythm was present in all cases. Slight mitral regurgitation was noted in 2 cases, associated with mild aortic disease in one of them; 3 other patients presented with slight aortic regurgitation. In all 17 cases the mitral stenosis was tight, uncalcified, with flexible valves and little or no alteration of the subvalvular system. One single balloon catheter was used in 11 patients and 2 balloon catheters were introduced simultaneously in the remaining 6 patients. The new therapeutic method was successful in all patients. Following valvuloplasty, the mean transmitral gradient was reduced from 25 +/- 3 to 11 +/- 2 mmHg (P less than 0.001), the mean capillary pressure fell from 26.8 +/- 7.1 to 13.5 +/- 3.7 mmHg (P less than 0.001) and the cardiac index increased from 3.3 +/- 1 to 4.2 +/- 1.2 l/min/m2 (P less than 0.001). The mitral valve area, measured by two-dimensional echocardiography, increased from 1.0 +/- 02 to 2.1 +/- 0.3 cm2 (P less than 0.001). The mitral valve regurgitation observed in 2 patients before valvuloplasty was aggravated, although still moderate, in one of them and remained stable in the other.

Progressive glomerular injury in the MWF rat is predicted by inborn nephron deficit.

It has been suggested that a reduced number of nephrons may predispose to systemic hypertension and glomerular injury. Compensatory hemodynamic changes, due to a low number of glomeruli, might be responsible for glomerular functional and structural changes. It is difficult to evaluate this hypothesis in humans because of limitations in estimating the number of nephrons in the living kidney. The aim of the present study was to estimate nephron number, single glomerular hemodynamics, and glomerular volume in male and female MWF rats, a strain that spontaneously develops systemic hypertension, proteinuria, and glomerulosclerosis. Male and female Wistar rats were used as controls. At 12 to 14 wk of age, male MWF rats developed proteinuria, whereas female MWF and Wistar rats showed normal urinary protein excretion rate. Glomerular number was significantly reduced in male and female MWF rats (13,690+/-1,489 and 12,855+/-1,781 gl/ kidney, respectively) compared with Wistar rats (26,955+/-2,171 and 27,166+/-1,754 gl/kidney, respectively). The mean number of nephrons per unit of body weight was also lower in MWF males (88+/-10) compared with MWF females (139+/-20) and compared with male and female Wistar animals (142+/-14 and 221+/-22 gl/g body wt). Whole-kidney hemodynamic parameters and the number of nephrons were used to calculate single-nephron filtration rate and plasma flow. Both measures were markedly elevated in male MWF rats relative to values obtained in the other three groups. Similarly, glomerular volume was significantly greater in MWF males than in other animals. These results suggest that an inborn deficit of nephrons may be responsible for spontaneous development of later-in-life hypertension and renal dysfunction. The data also indicate the need to investigate the role of this potential pathogenetic factor for human hypertension and kidney disease in humans.

Prevention of renal injury in diabetic MWF rats by angiotensin II antagonism.

We studied the effect of the combination of streptozotocin-induced diabetes and spontaneous renal injury in male MWF rats. Renal hemodynamics was studied by micropuncture 1 month after streptozotocin administration, and kidney morphological evaluation was performed after 4 months of diabetes. We also studied the effect of angiotensin II antagonism on development of renal lesions. Untreated animals developed mild hypertension, proteinuria, and glomerulosclerosis. Induction of diabetes, and maintenance of a moderate hyperglycemic state, was associated with slight but significant elevation in systemic and glomerular capillary blood pressure. Development of proteinuria was not accelerated or exacerbated by diabetes. Glomerular and tubular structural changes were also not worsened by diabetes. Antihypertensive treatment with an ACE inhibitor (benazepril) or with an AII receptor antagonist (valsartan) almost completely prevented systemic and glomerular capillary hypertension, proteinuria and renal structural changes. No significant differences in glomerular volume were observed among the four groups. That induction of experimental diabetes, although associated with glomerular capillary hypertension, did not aggravate the rate of progression of renal dysfunction would suggest that glomerular injury is not directly influenced by glomerular hemodynamic conditions in these animals. Prevention of renal functional and structural abnormalities by antagonism of AII activity in diabetic MWF rats suggests a pathogenetic role for angiotensin in inducing the renal disease in these animals.