Focal Segmental Glomerular Hyalinosis and/or Sclerosis in Rats with Congenital Unilateral Hydronephrosis

Focal segmental glomerular hyalinosis and/or sclerosis (FSHS) was observed in five Wistar-Imamichi rats with congenital unilateral hydronephrosis (CUH rats). Marked proteinuria (164.9+138.4mg/day) was observed in the CUH rats. Immunoperoxidase staining for IgM, C3 and IgG was positive in the glomerull, showing in a focal, segmental pattern that corresponded to the areas of FSHS seen by light microscopy. These glomerular findings were extremely similar to those of human focal glomerular sclerosis (FGS). FSHS was found to be common to both the hydronephrotic kidney and the contralateral kidney without hydronephrosis. Morphometry revealed that the glomerular area of the juxtamedullary glomeruli was greater than that of superficial glomeruli in control rats (11,037 μm² vs. 6,847 μm²). On the other hand, glomerular hypertrophy was observed in non-sclerotic glomeruli of CUH rats (superficial glomeruli; 12,477–16,123 μm², juxtamedullary glomeruli; 14,635–18,418 μm²). Also, a decreased in the number of glomeruli within the range 1.8-4.1 per unit area (1 mm²) was seen in CUH rats compared with control rats (mean 4.4). These results suggest that the increased rate of development of FSHS is based on hyperfiltration in the remaining functional nephrons. Acta Pathol Jpn 41: 653–660, 1991.     

Glomerulosclerosis and hyalinosis in rabbits.

Histological appearances of remnant kidney in female New Zealand white rabbits undergoing left nephrectomy at 6 mths were studied. All 20 rabbits had evidence of previous Encephalitozoon cuniculi (E. cuniculi) infection. Half of the 10 uninephrectomized and 10 control animals completed 3 pregnancies before sacrifice (15 mths). Twelve of 30 kidneys at sacrifice showed focal and segmental hyalinosis and sclerosis (FSHS), a lesion not previously reported in rabbits. Four of 5 kidneys in both uninephrectomized pregnant and uninephrectomized virgin animals showed FSHS compared with 2 of 10 in both control pregnant and non-pregnant rabbits (p = 0.0026). More glomeruli were sclerosed in control pregnant (median 3.5%) than non pregnant animals (median 0.4%) (p < 0.005). Median right kidney weights per kilogram body weight were greater in previously nephrectomized animals (3.9 gm/kg) than controls (2.6 gm/kg), (p < 0.001). Absolute glomerular area was increased in hypertrophied kidneys, however, after correction for kidney weight, glomerular area was smaller in previously uninephrectomized animals than controls (p < 0.0001).     

Age-related nephropathy and proteinuria in rats with intact kidneys exposed to diets with different protein content

Tubulointerstitial damage and glomerular sclerosis are findings commonly observed in the experimental models of adriamycin and puromycin aminonucleoside nephrosis. It has been suggested that in such models proteinuria might be an important mediator of tubulo-interstitial damage which in turn may determine the progression of the disease favoring the development of glomerulosclerosis. The objective of the present investigation was to establish the temporal relationship between proteinuria, tubulo-interstitial damage and glomerulosclerosis in aging rats with intact kidneys exposed to diets with different protein content. There were six groups of rats studied. Animals of groups 1, 5, and 6 (N = 10) were fed diets containing 20, 35, and 6% protein, respectively, for 20 months and sacrificed at the end of the experimental period. Rats in groups 3 and 4 (N = 6) exhibited marked and mild proteinuria, respectively, after 14 months of maintenance on standard diet, and followed for two additional months after the onset of proteinuria with the aim of evaluating the pattern of renal damage after a relatively short period of proteinuria. Rats in group 2 (N = 10) were fed standard diet and sacrificed before (5 months) and at the onset of proteinuria (10 months). Protein excretion and plasma creatinine were measured for each animal every month. Pathologic examination was performed by light and electron microscopy. At the onset of proteinuria neither renal structural nor functional abnormalities were detected. After 20 months, rats fed standard diet developed tubulo-interstitial damage (score: 1.29 +/- 1.05) and focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 16.70 +/- 16.40). A significant correlation was found between the degree of tubulo-interstitial damage and the percentage of glomeruli with focal glomerular sclerosis (r = 0.99, p less than 0.01). Development of tubulo-interstitial damage and focal glomerular sclerosis were correlated with heavy and sustained proteinuria. The high protein diet significantly worsened proteinuria (at month 20: 247.08 +/- 101.73 mg/day), tubulo-interstitial changes (score: 1.99 +/- 0.70), focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 21.50 +/- 9.44) and was associated with deteriorating renal function (at month 20, plasma creatinine: 1.20 +/- 0.50 mg/dl).(ABSTRACT TRUNCATED AT 400 WORDS)     

Ultrastructure of the non-sclerotic glomeruli in childhood nephrotic syndrome

An electron-microscopic (EM) study of the non-sclerotic glomeruli was made in 96 children with the nephrotic syndrome in whom light microscopy had shown minimal change, focal global glomerulosclerosis or segmental glomerulosclerosis. EM showed a variety of alterations. Foot process fusion, duplication and crenation of the lamina densa, and granular and lucent expansion of lamina rara interna were noted in almost all patients in all three groups. Localised ulceration of the podocytes was noted in some patients in each group. There was no difference in the mean thickness of the glomerular basal lamina but there was an increase with age in minimal change. Curious extracellular curved striated bodies, clusters of electron-dense, round microparticles and microfilaments were found in all three. but most frequently in segmental glomerular sclerosis. Electrondense deposits were seen in all but one of the patients with segmental glomerular sclerosis and usually involved the capillary wall. They were seen in one third of those with minimal change and focal glomerular sclerosis but rarely in the capillary wall. There were no specific features which distinguished segmental glomerular sclerosis although the various types of deposits were more extensive and more frequent than in minimal change and focal glomerular sclerosis. These observations are consistent with common pathogenetic factors operating at different intensities in segmental glomerular sclerosis, focal glomerular sclerosis and minimal change.     

Extratubular efflux and nephropathy

The extratubular efflux of periodic acid-Schiff (PAS) positive material is used as a histological indicator of intrarenal reflux, and correlation of the PAS positive material and interstitial as well as glomerular changes were analyzed in 114 surgical specimens consisting of renal calculi, hydronephrosis, vesicoureteral reflux, and others. (1) The incidence of extratubular efflux was apparently higher in the kidneys of hydronephrosis. (2) PAS positive material was seen not only in the interstitium but also flowed into the venous and lymphatic spaces. (3) Potent interstitial mononuclear cell infiltration and larger amounts of PAS positive material were seen in the kidneys showing a moderate grade of hydronephrosis rather than renal calculi. (4) Global glomerular sclerosis was the most frequent glomerular lesion, and segmental sclerosis and crescentic epithelial reaction in a small number of glomeruli were also noted. These results imply that intrarenal reflux could play an important role in the development of various renal tissue injuries.     

Comparison of size of juxtamedullary and outer cortical glomeruli in normal adult kidney

Summary Abnormally large glomeruli are susceptible to hyperfiltration-associated sclerosis. We used an established morphometric method to test the general belief that juxtamedullary glomeruli are larger than those in the outer cortex, in a population with no clinical or pathological evidence of renal disease. Overall, juxtamedullary glomeruli were significantly larger, but this varied according to the amount of global glomerulosclerosis present. Global sclerosis increased with age, particularly in the outer cortex, and the ratio of juxtamedullary to outer cortical glomerular size showed a positive correlation with overall, and outer cortical, global sclerosis. Thus in the truly normal adult kidney, juxtamedullary glomeruli are not significantly larger than outer cortical glomeruli. However, global sclerosis increases with age and is most marked in the outer cortex, and this leads to compensatory enlargement of predominantly the juxtamedullary glomeruli. These findings suggest that in single kidneys, or in conditions characterised by ischaemic glomerulosclerosis such as hypertension, morphological changes related to hyperfiltration may appear first, and therefore become most severe, in juxtamedullary glomeruli.     

Glomerular hyalinosis and its relation to hyperfiltration

Reduction in renal mass in rats results in hyperfiltration of the remnant nephrons, accompanied by injury to the glomeruli and their eventual sclerosis. This study was undertaken in a rat model with 5/6 reduction of renal mass to follow the evolution of glomerular damage, over an 11-week period, with particular emphasis on the widely prevalent, although seldom discussed, lesion of hyalinosis. Light, electron, and immunofluorescence microscopic studies were performed and blood pressure, excretion of urinary albumin, and serum creatinine levels determined. Systolic blood pressure, urinary albumin excretion, and serum creatinine levels were all increased by the third week following operation. Blood pressure and serum creatinine continued to increase throughout the period of study. Glomerular damage was focal and segmental, and glomeruli were equally affected in both the juxtamedullary and outer zones of the cortex. Endothelial injury was noted to be the first indicator of glomerular damage, followed closely by alterations in the epithelial cells. The early hyalinosis lesion was characterized by an accumulation of homogeneous electron-dense material beneath damaged endothelial cells with later encroachment on the capillary lumen resulting in the easily recognizable eosinophilic, periodic acid-Schiff-positive lesion by light microscopy. These alterations were accompanied by complex changes within the mesangium, including both mesangiosclerosis and mesangiolysis. Glomerular hyalinosis, glomerular sclerosis, vascular damage, blood pressure, and albuminuria were ranked in order of severity and the rankings subjected to multiple regression analysis. Significant correlations were present between glomerular sclerosis and hyalinosis, arterial damage and blood pressure, and hyalinosis and urinary albumin excretion. The hyalinosis lesion accompanying the progressive glomerular sclerosis in this model resembles that seen in a number of human conditions. In addition, the correlations of hyalinosis with glomerular sclerosis and albuminuria reflect its association with glomerular injury; it is likely that it will prove to be a reliable marker of hyperfiltration injury.     

Glomerular sclerosis in Wistar rats: analysis of its variable occurrence after unilateral nephrectomy.

Individual differences in susceptibility to the development of focal and segmental glomerular hyalinosis and sclerosis (FSGHS) were studied in rats after unilateral nephrectomy. A total of 20 male Wistar rats underwent unilateral nephrectomy at 3 months of age. Glomerular number in the removed kidney ranged from 17,000 to 32,700 with a mean value of 25,997 (n = 19). At death 30 weeks later, the incidence of glomeruli with FSGHS in the remaining kidney varied from 0 to 20% with a mean of 4.4%. However, the percentage of glomeruli with FSGHS and the degree of proteinuria did not correlate either with glomerular number per kidney (left and right kidneys were shown to be equivalent for glomerular number) or with glomerular volume on killing. The occurrence of FSGHS correlated significantly with mean protein excretion (P less than 0.01) and serum cholesterol levels (P less than 0.01). In conclusion, in the rat a relatively low number of nephrons in the kidneys does not increase susceptibility to the development of FSGHS.     

Glomerular sclerosis in Wistar rats: analysis of its variable occurrence after unilateral nephrectomy

Individual differences in susceptibility to the development of focal and segmental glomerular hyalinosis and sclerosis (FSGHS) were studied in rats after unilateral nephrectomy. A total of 20 male Wistar rats underwent unilateral nephrectomy at 3 months of age. Glomerular number in the removed kidney ranged from 17,000 to 32,700 with a mean value of 25,997 (n = 19). At death 30 weeks later, the incidence of glomeruli with FSGHS in the remaining kidney varied from 0 to 20% with a mean of 4.4%. However, the percentage of glomeruli with FSGHS and the degree of proteinuria did not correlate either with glomerular number per kidney (left and right kidneys were shown to be equivalent for glomerular number) or with glomerular volume on killing. The occurrence of FSGHS correlated significantly with mean protein excretion (P less than 0.01) and serum cholesterol levels (P less than 0.01). In conclusion, in the rat a relatively low number of nephrons in the kidneys does not increase susceptibility to the development of FSGHS.     

Adaptive changes of juxtamedullary glomerular filtration in the remnant kidney

The participation of surviving juxtamedullary nephrons in the adaptive changes of glomerular filtration that occur in response to loss of functioning nephron mass was examined by direct micropuncture of the rat renal papilla. The solitary remnant kidney (RK) in rats with an 85% reduction of renal mass demonstrated strikingly elevated values for single nephron glomerular filtration rate (SNGFR) in both superficial (46.1±3.2 nl/min) and juxtamedullary (73.5±6.1 nl/min) nephrons in comparison to respective values observed in normal hydrophenic rats (superficial SNGFR=15.0±1.9nl/min,P<0.001, and juxtamedullary SNGFR=30.2±3.2 nl/min,P<0.001). In RK rats, the proximal portions of both superficial and juxtamedullary nephrons exhibited a marked increase in absolute fluid reabsorption as well as a markedly enhanced delivery of fluid to more distal portions of the nephron. These observations indicate that similar, not preferential, functional adaptations in glomerular filtration occur concommitantly in both superficial and juxtamedullary nephrons consequent to reduction of renal mass.     

Ferritin deposition in the glomerular deposits of focal glomerular sclerosis in the rat

The glomerular lesions of focal sclerosis clinically associated with a steroid-resistant nephrotic syndrome, are of unknown origin. IgM and C3 deposits and electron dense material found in areas of sclerosis are not convincing evidence of an immune pathogenesis. These deposits have been studied in a rat model of focal sclerosis induced by uninephrectomy and repeated aminonucleoside administration. Sclerotic lesions closely resembling human disease developed in the remaining kidney. There was a severe progressive proteinuria. Seventy-eight days after initial aminonucleoside injection 65 per cent of glomeruli were sclerotic with IgM, IgG, C3 and fibrinogen deposits, and electron dense deposits by electron microscopy. To study macromolecule deposition in this model of focal sclerosis, ferritin uptake 4 and 24 h after intravenous ferritin given at 77 days was compared in focal sclerosis rats with control rats without sclerosis (uninephrectomy plus saline-only injections). In focal sclerosis rats sclerotic areas contained massive accumulations of ferritin. In unaffected segments of sclerotic glomeruli, and normal glomeruli of focal sclerosis rats, ferritin concentration was no different from controls. Abnormal ferritin trapping in areas of sclerosis suggests that the presence of IgM and C3 may be due to a similar mechanism, and is not indicative of an immune pathogenesis for focal sclerosis.     

Decrease in laminin content and protein excretion rate after five sixths nephrectomy and low-dose irradiation in the rat.

The effect of low-dose irradiation on laminin distribution and urine protein excretion in the remnant rat kidney has been studied. The rat remnant kidney formed after 5/6 nephrectomy is an experimental model of chronic renal failure. In the remnant kidney, focal segmental glomerulosclerosis is developed characterized by focal or segmental sclerosis in glomeruli, alterations in the tubules and thickening of the glomerular basement membrane. Low dose irradiation has been presumed to suppress sclerotic processes. In this study 24 male Wistar rats were subdivided into the nephrectomized group, nephrectomized and irradiated groups (1 or 3 Grey), and healthy control group. Animals were sacrificed at 2, 4 and 8 weeks after beginning the experiment. Laminin immunohistochemical staining was found along the tubular and glomerular basement membranes in all experimental groups, but with varying intensity. Laminin content in the basement membranes was decreased in early stages (week 2), especially after irradiation followed by increase during the later stages with relatively high levels at the end of the experiment (week 8). Irradiation at a dose of 3 Grey decreased protein excretion compared to the nephrectomized rats at all stages, while 1 Grey dose was ineffective. Based on decreased proteinuria we conclude that moderate low-dose irradiation has beneficial effects on the rat remnant kidney and that laminin in basement membranes is probably not the most crucial component in regulating membrane permeability.     

Induction of glomerulosclerosis by dietary lipids. A functional and morphologic study in the rat

Clinical and experimental data indicate that glomerular function and morphology may be influenced by plasma lipids. In familial lecithin-cholesterol-acyltransferase (LCAT) deficiency and in Fabry's disease, lipids accumulate in glomeruli and are assumed to induce sclerosis. The present study was undertaken to examine if dietary lipids could exert effects on the glomeruli of normal, unilaterally nephrectomized rats, and of rats with two-kidney, one clip (2-K,1C) hypertension. In rats with two kidneys on a diet rich in fat and cholesterol, cholesterol concentrations in very low density lipoproteins increased. In these rats the number of glomeruli with sclerotic foci was significantly higher than in rats on a low fat, cholesterol free diet. After 6 months on the diet the percentage of glomeruli with sclerosis (SC) was 13.2 +/- 4.1 (N = 9) in rats with a cholesterol diet and 1.8 +/- 0.6 (N = 11) in control rats (p less than 0.05). The fat and cholesterol diet exacerbated glomerular lesions in the remnant kidney model of uninephrectomized rats. The sclerosis in rats with only one kidney was 38.2 +/- 9.5 (N = 6) on a cholesterol diet compared with 8.7 +/- 3.0 (N = 6) in control rats after 6 months (p less than 0.05). After 3 to 4 months on a fat rich diet cholesterylester was increased in isolated glomeruli. The composition of the dietary lipids influenced the development of glomerular lesions. A linseed oil diet that is rich in unsaturated fatty acids, especially linolenic acid, did not cause major plasma lipid abnormalities and was accompanied by a low sclerosis (1.2 +/- 0.3; N = 9) for rats with two kidneys. In rats with chronic 2-K, 1C hypertension the percentage of glomeruli with partially sclerosed tufts in the unclipped kidney was significantly higher on a fat and cholesterol diet (F) than on a control diet (N) (SC: diet F 31.0 +/- 4.0, N = 13; diet N 12.2 +/- 2.6, N = 12; P less than 0.05). In the clipped kidney, protected against the arterial hypertension, only an increased number of glomeruli with mesangial expansion was noted in rats with the cholesterol diet. Glomerular hemodynamic factors seem to play an important pathogenetic role in the induction of glomerular sclerosis by a lipid rich diet. The fact that dietary lipids can aggravate glomerular lesions in states of arterial hypertension and nephron loss may have implications for the progression of renal disease in humans.     

Micropuncture studies on the filtration rate of single superficial and juxtamedullary glomeruli in the rat kidney

Summary Single nephron filtration rates of superficial and juxtamedullary nephrons were determined in high and low sodium rats. Single nephron GFR was calculated from TF/P inulin and tubular flow rate in superficial nephrons and single juxtamedullary GFR from corresponding data in long loops of Henle. In low sodium rats superficial nephron GFR was 23.5±6.4 (SD)×10^–6 ml/min×g KW, juxtamedullary nephron GFR was 58.2±13.6 and total kidney GFR (C _In) was 0.94±0.16 ml/min×g KW. Using these single nephron values, total kidney GFR and a total number of 30,000 glomeruli per kidney, the number of superficial and juxtamedullary glomeruli was calculated to be 23,267 and 6,733, respectively. During high sodium diet superficial nephron GFR increased to 38.1±11.3 and single juxtamedullary GFR decreased to 16.5±6.6, total kidney GFR increasing to 1.01±0.24. Calculation again revealed the same distribution of the two nephron types. End-proximal TF/P inulin in superficial nephrons was 2.36±0.36 in low sodium and 2.31±0.28 in high sodium rats. Loops of Henle TF/P inulin and intratubular flow rate were inversely related: the highest TF/P inulin values and lowest intratubular flow rates were found in the descending limb. These data quantify the distribution of superficial and juxtamedullary nephrons on a functional basis and suggest a mechanism by which the kidney adjusts sodium excretion by altering the contribution of each nephron type to total kidney GFR.Supported by the Deutsche Forschungsgemeinschaft and the U.S. Department of the Army, through its European Research Office.     

Functional and morphologic maturation of superficial and juxtamedullary nephrons in the rat.

The development of single nephron glomerular filtration rate (SNGFER) was studied in both superficial and juxtamedullary nephrons in rats in relation to concomitant morphologic maturation. These experiments were carried out in rats between 23 and 91 days of age (between 36 nad 275 g body weight) with the [14C]ferrocyanide infusion technique. 2. SNGFR of the superficial and juxtamedullary nephrons increased with body weight, glomerular volume and proximal tubular length. 3. The ratio SNGFR of the superficial (S) nephrons/SNGFR of the juxtamedullary (JM) nephrons rose from 0-60 in the 40-60 g rats to 0-84 in the adult rats, demonstrating the centrifugal functional maturation of the nephrons. 4. The S/JM ratio for both glomerular volume and tubular length was constant and averaged 0-72+/--0-12 and 0-81+/-0-05, respectively, indicating that while the increase in SNGFR was greater for S than for JM nephrons, this was not accompanied by concomitant disproportionate increases of glomerular volume and/or proximal tubular length between these nephron categories during development in the rat.     

Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model.

Expansion of the mesangial extracellular matrix (ECM) with subsequent glomerular sclerosis is a prominent finding in most progressive renal diseases. To investigate the chronology of accumulation of ECM components as it relates to previously described cellular events, biopsies were obtained from rats at various times following 5/6-nephrectomy as well as from sham-operated controls. The biopsies were stained with PAS as well as immunostained for PCNA (a cell proliferation marker), monocytes/macrophages, types I and IV collagen, laminin, s-laminin, fibronectin, heparan sulfate proteoglycan and entactin/nidogen. Immunostaining of biopsies obtained from 5/6 nephrectomized rats demonstrated an early glomerular cell proliferation, peaking at week 2. Expansion of the glomerular tuft area with rare glomeruli demonstrating focal sclerosis were also seen at week 2. Glomerular macrophage influx correlated with later ECM expansion and glomerulosclerosis. A progressive accumulation of all ECM proteins investigated was noted in the pathological mesangial matrix at week 2 and later time points. Northern analysis of total glomerular RNA at weeks 2 and 6 after 5/6 nephrectomy showed de novo expression type I collagen mRNA as well as small increases of glomerular mRNA levels for type IV collagen (1.2- and 1.4-fold over control RNA) and laminin (1.3- and 1.5-fold) but not s-laminin (1.1- and 0.9-fold). We conclude that cellular events including glomerular cell proliferation and macrophage influx are associated with increased gene and protein expression by ECM proteins in the remnant kidney model and may contribute to the development of sclerosis.     

Regional and single glomerular blood flow in the rat kidney prepared for micropuncture. A methodological study.

Regional renal and single glomerular blood flow was investigated in rats using 141-Ce and 85-Sr labelled microspheres. The kidneys were prepared for micropuncture and also the artery was catheterized with a steel cannula in order to make injections of 133-Xenon and vasoactive substances selectively into one kidney. The microspheres were first separated by sedimentation into a narrow fraction and then injected as a plasma suspension into the carotid arter; the two batches were infused at half an hour intervals. Single glomeruli were sampled from kidney sections with the aid of silicon rubber casts allowing the identification of the glomeruli both with respect to their localisation and their postglomerular appearance. The results showed a relatively high blood flow in the superficial and juxtamedullary glomeruli of above 100 nl/min per 100 g rat whereas in the other glomeruli the blood flow was about 70 nl/min per 100 g rat. No differences could be observed between the right untouched kidney and the left prepared for micropuncture. Futhermore no discrepancies between the results from the two injections could be found. The data on the total renal blood flow obtained by the 133-Xenon wash-out method agreed well with the microsphere method.     

Progressive renal lesions induced by administration of monoclonal antibody 1-22-3 to unilaterally nephrectomized rats.

A new animal model of progressive glomerulosclerosis was developed by administering a single i.v., injection of MoAb 1-22-3 to unilaterally nephrectomized rats. Renal morphological analysis revealed that glomerular lesions characterized by mesangial cell proliferation and mesangial matrix expansion were induced in about 95% of the glomeruli. Approximately 20% of the glomeruli of the unilaterally nephrectomized rats showed sclerosis or segmental sclerosis by week 6 after MoAb injection and crescent formation was observed in some glomeruli (ca 4%). Cellular infiltration was also noted in some parts of the interstitium. Increased expression of transforming growth factor-beta (TGF-beta) was observed in the unilaterally nephrectomized rats treated with MoAb 1-22-3, but we could not demonstrate pathological involvement of platelet-derived growth factor (PDGF), even though early-stage mesangial cell proliferation was observed. The mechanism of mesangial cell proliferation in this model remains to be elucidated. The relatively short period of time needed to induce the sclerotic changes in considered to be a great advantage of this model for clarifying the mechanisms involved in the chronic progression of mesangial proliferative glomerulonephritis.     

Focal glomerular sclerosis in the fawn-hooded rat.

We have examined the nature of focal glomerular sclerosis (FGS) in fawn-hooded (FH) rats. The fawn-hooded rat develops pathologic features similar to those observed in steroid-resistant focal glomerular sclerosis, ie, by light microscopy some of the glomeruli appear normal but others show areas of solidification confined to one or two lobules of the tuft. The pathogenesis of this disease is not well known and there is a great need for an animal model. In the FH animal, a marked difference in the development of the lesion was noted between male and female rats. Fifty percent of 4-month-old males had proteinuria in excess of 10 mg/day (none of the females had significant proteinuria), while all 12-month-old males had proteinuria in excess of 45 mg/day (female 12-month-old FH rats had mean proteinuria of 7 mg/day). At 6 months of age continuing through 12 months of age, male FH rats had mesangial deposits of IgG, IgM, and, occasionally, C3, demonstrable by immunofluorescence, whether or not FGS was present. Subepithelial electron-dense deposits were never seen by electron microscopy either at 6 of 12 months. Six-month-old animals frequently did not exhibit FGS. Instead, the glomerular epithelial cells, exhibited fusion of foot processes, vacuolization, and, in some areas, focal loss of the epithelial covering on the glomerular basement membrane (GBM). Six-month-old males with proteinuria exhibited focal loss of negative charge from all layers of the filtration barrier. The GBM from sclerotic glomeruli of 12-month-old rats was commonly denuded of epithelium. None of the animals in this study was uremic. FH rats demonstrated FGS associated with progressive glomerular epithelial cell injury.     

CHRONIC MASUGI NEPHRITIS IN THE RAT

Chronic focal glomerulonephritis was induced in the rat by using goat nephrotoxic IgG. In the later stage (6 to 15 months) a number of glomeruli were found to be attached to Bowman's capsule with variable segmental sclerosis and/or hyalinosis. The morphogenesis of the changes was studied by electron microscopy. It was found that partial cytoplasmic necrosis of podocytes was an initiating event of the capsular adhesion. When this occurred in the peripheral tufts, the denuded portion of the glomerular basement membrane (GBM) became attached to the parietal epithelium, resulting in progressive thickening of the mesangium and GBM, deposition of hyaline or proteinaceous material, and desquamation of the endothelial sheet, the features being compatible with segmental glomerular sclerosis and/or hyalinosis. It seemed that these changes, in turn, accelerated podocyte desquamation and extension of the capsular adhesion, producing a progressive cycle that terminated in global glomerular hyalinosis. Such a sequence of events most often occurred in rats with massive proteinuria, suggesting that persistent, severe proteinuria caused the podocyte lesion which led to the development of segmental glomerular sclerosis and/or hyalinosis.