We quantitated the glomerular size and the degree of sclerosis simultaneously in individual glomeruli with the use of three-dimensional histological analysis on serial sections obtained from remnant kidneys with highly heterogeneous glomerular lesions after subtotal nephrectomy (sNPX). Four to six weeks after sNPX (Group I, N = 7), 90% of glomeruli had mild sclerosis (sclerosis index, SI; less than 1.5 on a 0 to 4 scale) with a strong positive correlation between the maximum planar area of glomerulus (PAmax) versus SI. Twelve weeks after sNPX (Group II, N = 6) more than 50% of glomeruli had advanced sclerosis (average SI:1.88), and a significant positive correlation was again found between PAmax and SI in glomeruli with mild to modest sclerosis (SI less than 1.5), whereas these two variables were correlated inversely in glomeruli with advanced sclerosis. Administration of enalapril (50 mg/liter drinking water) or hydralazine (200 mg/liter) + hydrochlorothiazide (50 mg/liter) for 12 weeks (Group III, N = 12) markedly attenuated the sclerosis to comparable degrees (average SI: 0.15 vs. 0.22). The former antihypertensive therapy decreased glomerular capillary hydraulic pressure (PGC) to normal range, whereas the latter triple drug therapy was largely without effect on PGC. Of note, the positive correlation between SI and PAmax remained unaffected by these anti-hypertensive drugs. SI of the glomeruli from both treated groups was expressed as a first-order function of PAmax. The correlation coefficient is identical to that found in non-treated Group II remnant glomeruli, so that the degree of sclerosis is mathematically uniquely correlated with the glomerular size, regardless of drug treatment. Thus, within a given remnant kidney, the magnitude of glomerular hypertrophy has a direct correlation with the degree of sclerosis, while the altered glomerular hemodynamic pattern has little modulatory role in determining the magnitude of this hypertrophy. Enalapril and triple drug therapy, at equi-depressor doses in regard to systemic blood pressure, had identical potency in sparing glomerular structure. The primary determinant for this antisclerotic potency appears to be related to the drugs' potency to inhibit glomerular growth rather than an effect on the abnormal hemodynamics which develop in the glomerulus.

We studied the effect on the progression of glomerular sclerosis of two different experimental maneuvers, peritoneal dialysis and oral adsorbent, which remove circulating substances in different fashions. Munich-Wistar rats with established glomerular sclerosis, verified by renal biopsy analysis at seven weeks after subtotal nephrectomy, were treated for four weeks with either peritoneal dialysis (PD) or oral charcoal adsorbent (AST-120). Treatment was initiated at eight weeks. Rats were paired in treatment and control groups according to the similarity in the degree of sclerosis determined at biopsy with a minimum of 50 glomeruli analyzed. Systolic blood pressure and BUN and creatinine clearance, measured at seven to eight weeks, were not different among groups. In Group 2 rats, PD was performed with 1.5% dextrose for eight one-hour cycles, six days per week, while Group 1 control rats had zero indwelling time of the dialysate. Group 4 rats received AST-120, an oral adsorbent charcoal, mixed 5% by weight with standard rat chow and given ad libitum from 8 to 12 weeks after subtotal nephrectomy, while control Group 3 rats received only rat chow. Whole kidney GFR at 12 weeks was significantly higher in Group 2 PD versus Group 1 control (0.50 +/- 0.08 vs. 0.30 +/- 0.05 ml/min, P less than 0.05). There was no statistical difference for BUN and whole kidney creatinine or inulin clearance in Group 4 AST-120 treated versus Group 3 control rats. Light microscopic studies in autopsy specimens revealed that both PD and AST-120 attenuated progression of glomerular sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

We tested the effect of angiotensin I converting enzyme inhibitor (ACEI) on established glomerular sclerosis. Starting eight weeks after subtotal nephrectomy (sNPX), rats were given enalapril for four weeks in a dose of 50 (Group II, N = 5) or 200 mg/liter drinking water (Group III, N = 5). A third group of sNPX rats not given ACEI served as control (Group I, N = 10). Glomerular sclerosis index (S1, 0 to 4 scale) was assessed three-dimensionally on serial thin sections for individual glomeruli at biopsy (Bx, 8 weeks), and divided into four different ranks of severity and compared to autopsy (Ax, 12 weeks). In Group I control rats, 48% of the glomeruli at Bx had SI between 0 and 1 (rank 1, average: 0.49 +/- 0.06), 36% between 1 and 2 (rank 2, average: 1.53 +/- 0.06), 9% between 2 and 3 (rank 3, average: 2.45 +/- 0.12) and 7% between 3 and 4 (rank 4, average: 3.54 +/- 0.10). Glomeruli of the same rats at Ax were ranked according to severity of sclerosis, and then divided into percentile groups, corresponding to the percent of distribution at Bx. The 48% least sclerotic glomeruli at Ax had average SI of 0.69 +/- 0.08, the next 36% 2.58 +/- 0.11, and next 9% 3.97 +/- 0.02 and the most sclerotic 7% 4.00 +/- 0.00. Thus, sclerosis advanced during the last four weeks after biopsy in all glomeruli, with more accelerated progression occurring toward later stages of sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

ABSTRACT. The alterations in single glomerular hemodynamics, glomerular size, and development of glomerular sclerosis after subtotal nephrectomy were assessed in -32-d-old young and >3-mo-old adult Munich-Wistar rats. In 6 wk, young rats developed more pronounced glomerular sclerosis and more marked elevation in blood urea nitrogen. The deep (versus superficial) cortical region of young rats was characterized by having a greater number of glomeruli with advanced sclerosis. Single nephron glomerular filtration rate of superficial glomeruli of the young increased to a much greater extent than whole kidney glomerular filtration rate, whereas there were comparable post-subtotal nephrectomy increases in whole kidney glomerular filtration rate in these two age groups, indicating that the deep glomeruli were exposed to a lesser hemodynamic load than were the superficial. Since the remnant nephrons of young and adult rats achieved equally high glomerular pressures and comparably large glomerular size shortly after subtotal nephrectomy, the unique susceptibility of young glomeruli to sclerosis is attributed to the intrinsic property of these glomeruli, rather than the abnormal hemodynamics or stimuli promoting hypertrophy and mesangial matrix accumulation imposed upon the glomeruli. (Pediatr Res 28: 270-276,1990) Abbreviations BUN, blood urea nitrogen BW, body weight GFR, glomerular filtration rate PAmean, mean planar area of glomeruli Pee, glomerular capillary pressure SBP, systolic blood pressure SNGFR, single nephron glomerular filtration rate sNPX, subtotal nephrectomy In view of the marked functional and structural internephron heterogeneity seen in chronically diseased kidneys in both humans and animals ( 1 -4), various initial immune or nonimmune insults appear to cause loss of a selected population of functioning nephrons. Extensive nephron population loss leads to functional