Glomerular epithelial cell lesions in rat renal isografts

Visceral glomerular epithelial cell lesions--microvillus formation, loss of foot processes, osmiophilic inclusion droplets, balloon-like malformation of cell processes, degeneration, necrosis, and loss of cell processes from capillary basement membranes--are found in rat renal isografts 1 mth after transplantation. The lesions, which are most readily recognized in perfusion-fixed material, are essentially focal, affecting neither all glomeruli, nor all cells in any glomerulus, bear no relation to the degree of interstitial nephritis in the graft, and are associated with albuminuria and with focal capillary sclerosis in some glomeruli. They are not restricted to renal isografts but are found in aging rats, in different experimental models of glomerular disease and in clinical glomerular disorders, again in association with proteinuria and glomerulosclerosis. It is therefore proposed that glomerular epithelial cell damage increases capillary permeability and impairs maintenance of the integrity of the capillary wall, leading to proteinuria and focal glomerulosclerosis.     

Prevention of 11-deoxycorticosterone-salt-induced glomerular hypertrophy and glomerulosclerosis by dietary phosphate binder.

The effects of dietary phosphate binder on deoxycorticosterone (DOC)-salt-hypertensive rats were examined. DOC-treated and non-DOC-treated rats were fed the diet either with or without phosphate binder, dihydroxyaluminum aminoacetate. All rats drank 1% NaCl. DOC-salt-treated rats without binder demonstrated marked glomerular hypertrophy, many globally sclerosed glomeruli, severe proteinuria, focal cardiac fibrosis, and splenomegaly. A significant reduction of glomerular hypertrophy, glomerulosclerosis, severity of proteinuria, splenomegaly, and the myocardial lesion took place when the DOC-salt-treated rats were given phosphate binder. The globally sclerosed glomeruli exhibited remarkable hypertrophy while structurally preserved glomeruli showed little evidence of enlargement. The plasma phosphate level was low in rats with dietary phosphate binder. In conclusion, the dietary phosphate binder ameliorated glomerular hypertrophy, glomerulosclerosis, proteinuria, myocardial fibrosis, and splenomegaly occurring in DOC-salt-treated rats. The data indicated that there was an association between glomerular hypertrophy and glomerulosclerosis in this model. The exact mechanisms of action of the phosphate binder, however, remain far from clear.     

Renal disease in children with the acquired immunodeficiency syndrome

Of 155 children with the acquired immunodeficiency syndrome (AIDS) whom we evaluated during a 6 1/2-year period, 12 were found to have proteinuria. Histologic studies of tissue from these 12 patients revealed a wide spectrum of renal disease: focal glomerulosclerosis in 5, mesangial hyperplasia in 5, segmental necrotizing glomerulonephritis in 1, and minimal change disease in 1. In addition, 6 had tubulointerstitial infiltrates, and 10 had glomerular dense deposits. All 10 renal specimens studied by electron microscopy contained endothelial tubuloreticular inclusions. The mean age (+/- SD) of the five patients with focal glomerulosclerosis when this condition was identified was 27 +/- 19 months. All five had severe renal failure within a year and died of other causes during the following year. The mean age of the five patients with mesangial hyperplasia was 38 +/- 31 months. Although none of them went on to have renal failure, four died within 8 +/- 7 months. Ten of the 12 patients with proteinuria died during the study period. Of the two surviving, one had mesangial hyperplasia and the other had minimal change disease. We conclude that children who acquire human immunodeficiency virus (HIV) infection during the perinatal period may have renal disease, most often focal glomerulosclerosis, as is the case in adults, or mesangial hyperplasia. Although 5 of the 12 children we studied had renal failure during the study period, none died of it. Further studies are needed to determine the correlations between clinical and pathological features and the pathophysiology of AIDS nephropathy in children.     

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.     

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 +/- 138.4 mg/day) was observed in the CUH rats. Immunoperoxidase staining for IgM, C3 and IgG was positive in the glomeruli, 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 micron2 vs. 6,847 microns2). On the other hand, glomerular hypertrophy was observed in non-sclerotic glomeruli of CUH rats (superficial glomeruli; 12,477-16,123 microns2, juxtamedullary glomeruli; 14,635-18,418 microns2). 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.     

Glomerular overproduction of oxygen radicals in Mpv17 gene-inactivated mice causes podocyte foot process flattening and proteinuria: A model of steroid-resistant nephrosis sensitive to radical scavenger therapy

Focal segmental glomerulosclerosis is a steroid-resistant glomerular disease characterized by foot process flattening and heavy proteinuria. A similar disease was found to occur spontaneously in mice in which the Mpv17 gene was inactivated by retroviral insertion (Mpv17-/- mice). Here evidence is provided that glomerular damage in this murine model is due to overproduction of oxygen radicals and accumulation of lipid peroxidation adducts that were found in isolated glomeruli of Mpv17-/- mice. The development of glomerular disease in Mpv17-/- mice was inhibited by scavengers of oxygen radicals (dithiomethylurea) and lipid peroxidation (probucol), but not by steroid treatment. Although the glomerular polyanion was greatly reduced in proteinuric Mpv17-/- mice, it was preserved by antioxidative therapy. These results indicate that the glomerular disease in Mpv17-/- mice qualifies as a model of steroid-resistant focal segmental glomerulosclerosis and that experimental therapies with scavengers of oxygen radicals and lipid peroxidation efficiently ameliorate glomerular damage.     

Morphometric analysis of the glomerular capillary area--a comparison of minimal change nephrotic syndrome, focal glomerular sclerosis, and pre-eclampsia.

A morphometric analysis was performed to compare the capillary area in non-sclerotic glomeruli in focal glomerular sclerosis (FGS), pre-eclampsia with focal sclerotic change of the glomeruli, and minimal change nephrotic syndrome (MCNS). The mean and standard deviation of the capillary area was greater in FGS than in pre-eclampsia and MCNS. Tubulo-interstitial lesions, such as tubular atrophy, interstitial fibrosis, and lymphocytic infiltration, were more severe in FGS than in pre-eclampsia. The presence of tubulo-interstitial changes including tubular atrophy and interstitial fibrosis with lymphocytic infiltration is thought to be an important prognostic factor in pre-eclampsia as well as in FGS. Unequal dilatation of the glomerular capillaries in non-sclerotic glomeruli may be harmful to the glomeruli and may lead to the development of glomerular sclerosis.     

Ultrastructure of transplant glomerulopathy

Thirty-one specimens of tissue were obtained from 15 renal allografts 3–96 months after transplantation and studied by light, electron and in some cases also by immunofluorescence microscopy. All patients had a degree of renal insufficiency and almost all had proteinuria and moderate hypertension; nephrotic syndrome was present in one and hematuria in two. On histological examination one patient showed cellular proliferation suggestive of glomerulonephritis (recurrent or de novo ) and another patient had numerous crescents. The most frequent glomerular lesion was widening of the lamina rara interna with subendothelial accumulation of finely granular material, formation of new subendothelial basement membrane and deposition of microfibrils and fine filaments. The mesangial changes were mainly those of mesangiolysis and mesangial sclerosis with deposition of mesangial matrix and microfibrils, but little cellular proliferation. Fragmented red blood cells were seen in nearly half of the patients. In another seven patients the lesion resembled focal segmental glomerulosclerosis. This combination of changes termed transplant glomerulopathy leads to diffuse glomerular sclerosis. Arterial intimal thickening and occasionally also thrombosis produced ischaemic changes in the kidney and in the glomeruli and contributed significantly to the process of transplant rejection.     

Age-dependent glomerulosclerosis and proteinuria occurring in rats of the Milan normotensive strain and not in rats of the Milan hypertensive strain

The development of an age-dependent glomerulosclerosis and proteinuria was investigated in two strains of rats in a model of moderate hypertension comparing rats of the Milan Hypertensive Strain (MHS) with rats of the Milan Normotensive Strain (MNS). Serum creatinine, urinary protein excretion, renal morphology (light- and electronmicroscopy) and morphometry of the media thickness of the intrarenal arteries and of the thickness of the glomerular basement membrane were studied in 2- to 16-month-old MHS and MNS rats. Serum creatinine did not differ between MNS and MHS rats in any age group. MNS rats developed a significant proteinuria which coincided with a glomerulosclerosis in about 22% of the glomeruli at 13 to 16 months. In contrast, urinary protein excretion in MHS rats remained stable during the entire observation period; glomerulosclerosis occurred only in 3% of the glomeruli at 13 to 16 months. As a consequence of hypertension media thickness of intrarenal arteries of MHS rats significantly exceeded that of MNS rats, in the interlobular arteries already at 2 months and in the arcuate arteries at 13 to 16 months. In contrast, thickness of the glomerular basement membrane of MHS rats never exceeded that of MNS rats. From these data we conclude, that glomeruli of MHS rats may be protected against the development of an age-dependent glomerulosclerosis and proteinuria. Further support for this conclusion may also be derived from recent experiments showing that the tubuloglomerular feedback sensitivity is significantly higher in MHS than in MNS rats (41).     

The effects of high-fat diet on the renal structure and morphometric parametric of kidneys in rats

To characterize the kidney in a high-fat-induced obesity model, we examined the renal structure of adult Sprague-Dawley rats fed a control diet or a high-fat diet for 3 months. Ten adult female Sprague-Dawley rats were fed a diet consisting highly of fat (30%) for a period of 3 months. Ten control rats were maintained with standard rat chow. All animals were weighed every 10 days for 3 months. At the end of the experiment, the naso-anal length of the anaesthetized rats was measured to calculate body mass index, and subsequently whole kidneys of intracardially formalin-perfused animals were removed. Quantitative features of the kidney were analysed with the Cavalieri and physical dissector methods applied to serial paraffin sections. Kidney samples were also examined histologically. The body mass indices of the control and treatment groups were 4.528 +/- 0.242 and 5.876 +/- 0.318 kg m(-2), respectively. The difference between the body mass indices of the two groups was statistically significant (P < 0.01, Mann-Whitney U-test), suggesting that the animals fed with a high-fat diet may be overweight. Stereological examination of the kidneys revealed differences in kidney weight, total kidney volume, volume of cortex, medulla, glomeruli, proximal and distal tubules, and numerical density of glomeruli and glomerular height in the treatment group compared with the control group. Light microscopic investigation showed a dilatation in blood vessels and Bowman's space, mononuclear cell infiltration, degeneration in nephrons, including glomerulosclerosis and tubular defects, and an increase in the connective tissue in the kidneys in the treatment group. We concluded that a fatty diet is responsible for the rats' obesity and may lead to renal deformities as a result of histopathological changes such as dilatation, tubular defects, inflammation and connective tissue enlargement of the kidney.     

Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis

Vascular endothelial growth factor (VEGF) regulates angiogenesis through endothelial cell proliferation and plays an important role in capillary repair in damaged glomeruli. We tested the hypothesis that VEGF might be beneficial in rats with severe glomerular injury in glomerulonephritis (GN) based on its angiogenic and vascular remodeling properties. Acute GN with severe glomerular destruction was induced in rats by injection of anti-Thy-1.1 antibody (day 0) and Habu-snake venom (day 1). Rats were intraperitoneally injected with recombinant human VEGF(165) (10 microg/100 g body wt/day) or vehicle from day 2 to day 9, and monitored changes in glomerular capillaries, development of glomerular inflammation, and progression to glomerular sclerosis after acute glomerular destruction in both groups. Rats that received anti-Thy-1.1 antibody and Habu-snake venom showed severe mesangiolysis and marked destruction of capillary network on day 2. VEGF was expressed on glomerular epithelial cells, proliferating mesangial cells, and some infiltrating leukocytes, and VEGF(165) protein levels increased in damaged glomeruli during day 5 to day 7. Normal, damaged, and regenerating glomerular endothelial cells expressed VEGF receptor flk-1. However, endothelial cell proliferation and capillary repair was rare in vehicle-treated rats with severe glomerular damage, which progressed to global sclerosis and chronic renal failure by week 8. In contrast, in the VEGF-treated group, VEGF(165) significantly enhanced endothelial cell proliferation and capillary repair in glomeruli by day 9 (proliferating endothelial cells: VEGF(165), 4.3 +/- 1.1; control, 2.2 +/- 0.9 cells on day 7, P < 0.001; and glomerular capillaries: VEGF(165), 24.6 +/- 4.8; control, 16.9 +/- 3.4 capillaries on day 7, P < 0.01). Thereafter, damaged glomeruli gradually recovered after development of capillary network by week 8, and significant improvement of renal function was evident in the VEGF-treated group during week 8 (creatinine: VEGF(165), 0.3 +/- 0.1; control, 2.6 +/- 0.9 mg/dl, P < 0.001; proteinuria: VEGF(165), 54 +/- 15; control, 318 +/- 60 mg/day, P < 0.001). We conclude that the beneficial effect of VEGF(165) in severe glomerular injury in GN emphasizes the importance of capillary repair in the resolution of GN, and may allow the design of new therapeutic strategies against severe GN.     

Relationship among altered glomerular barrier permselectivity, angiotensin II, and mesangial uptake of macromolecules

Clinical and experimental studies suggest that accumulation of phlogogenic macromolecules in the glomerular mesangium may lead to mesangial expansion and eventual glomerulosclerosis. In focal glomerulosclerosis and nephrotic syndrome entrapment of macromolecules is observed in areas of glomerulosclerosis. To determine whether mesangial uptake of radiolabeled, heat-aggregated IgG (AG125I), a biologically active macromolecular protein, is influenced by increased glomerular filtration barrier permeability, we evaluated the glomerular uptake of AG125I in three models of proteinuria: aminonucleoside of puromycin nephropathy (PAN), adriamycin nephropathy, and Heyman's nephropathy. Rats were studied approximately 1 week after onset of proteinuria. AG125I was measured in preparations of isolated glomeruli and compared to simultaneous blood, liver, and spleen levels. Only rats with PAN had a marked increase in glomerular AG125I compared to control rats, 7.8 versus 2.6 micrograms/mg of glomeruli, respectively. We then evaluated whether a continuous infusion of a competitive inhibitor of angiotensin II, saralasin (300 micrograms/kg of body weight/minute), influenced mesangial uptake of AG125I in PAN rats. Strikingly, glomerular AG125I in rats with PAN was reduced to levels comparable to that observed in control rats infused with only saralasin, 2.8 versus 3.0 micrograms/mg of glomeruli, respectively. This effect on glomerular AG125I content was independent of any significant effect of saralasin on blood, hepatic, or splenic levels of AG125I. Moreover, these changes in glomerular AG125I in saralasin-infused rats with PAN did not appear to directly correlate with changes in whole kidney function. These studies also demonstrated that proteinuria per se did not influence mesangial uptake of macromolecules. Thus, these data indicated that angiotensin II had an important effect on intraglomerular factors that modulate mesangial localization of phlogogenic macromolecules.     

Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia-induced glomerular injury in mice

Hyperhomocysteinemia (hHcys) enhances ceramide production, leading to the activation of NADPH oxidase and consequent glomerular oxidative stress and sclerosis. The present study was performed to determine whether acid sphingomyelinase (Asm), a ceramide-producing enzyme, is implicated in the development of hHcys-induced glomerular oxidative stress and injury. Uninephrectomized Asm-knockout (Asm(-/-)) and wild-type (Asm(+/+)) mice, with or without Asm short hairpin RNA (shRNA) transfection, were fed a folate-free (FF) diet for 8 weeks, which significantly elevated the plasma Hcys level compared with mice fed normal chow. By using in vivo molecular imaging, we found that transfected shRNAs were expressed in the renal cortex starting on day 3 and continued for 24 days. The FF diet significantly increased renal ceramide production, Asm mRNA and activity, urinary total protein and albumin excretion, glomerular damage index, and NADPH-dependent superoxide production in the renal cortex from Asm(+/+) mice compared with that from Asm(-/-) or Asm shRNA-transfected wild-type mice. Immunofluorescence analysis showed that the FF diet decreased the expression of podocin but increased desmin and ceramide levels in glomeruli from Asm(+/+) mice but not in those from Asm(-/-) and Asm shRNA-transfected wild-type mice. In conclusion, our observations reveal that Asm plays a pivotal role in mediating podocyte injury and glomerular sclerosis associated with NADPH oxidase-associated local oxidative stress during hHcys.     

Selective inhibition of platelet thromboxane generation with low-dose aspirin does not protect rats with reduced renal mass from the development of progressive disease.

Rats with extensive renal mass reduction develop hypertension, proteinuria and progressive glomerulosclerosis. Previous studies have demonstrated that these changes are associated with an increased urinary excretion of thromboxane compared with normal rats and that the administration of a thromboxane synthetase inhibitor prevents glomerulosclerosis and progressive renal function deterioration. On this basis it has been speculated that the thromboxane synthetase inhibitor, by inhibiting platelet thromboxane, reduces platelet aggregation and prevents the generation of substances that can influence glomerular functional properties. Because the thromboxane synthetase inhibitor also inhibits thromboxane synthesis by resident glomerular cells and lowers blood pressure in these animals, the question of whether platelet thromboxane is indeed the factor implicated in the development of renal disease after renal ablation remains unanswered. To address this issue the authors administered at different time intervals from the surgical procedure a low-dose of oral aspirin (ASA) to rats with remnant kidney. This approach resulted in selective inhibition of platelet cyclooxygenase leading to an almost complete prevention of platelet thromboxane generation. Low-dose ASA spared renal cyclooxygenase as documented by a lack of significant inhibition of glomerular and urinary 6-keto-PGF1 alpha and did not lower blood pressure. Renal function studies showed that low-dose ASA, despite inhibiting platelet aggregation, had no effect on proteinuria and progressive renal insufficiency irrespectively if administered late (ie, 80 days after surgery) and given daily for all the observation period (ie, 20 days) or earlier in the course of the disease (ie, 40 and 10 days after surgery). Histologic data showed that the degree of glomerulosclerosis and tubulo-interstitial damage was not significantly different in rats with reduction of renal mass alone compared with rats with remnant kidney given low-dose ASA. In conclusion, the present findings indicate that inhibition of platelet aggregation and thromboxane formation does not prevent the progressive glomerulosclerosis that develops in rats with surgical reduction of renal mass. It is suggested that the beneficial results obtained previously in the same model by the use of a thromboxane synthesis inhibitor must be attributed either to an effect on resident glomerular cell thromboxane synthesis or to lowering systemic blood pressure.     

Renal expression of intercellular adhesion molecule-1 in immunoglobulin A nephropathy: tubulointerstitial injury and prognosis

In immunoglobulin A nephropathy (IgAN), the abnormal expression of intercellular adhesion molecule-1 (ICAM-1) on proximal tubule epithelium is associated with the glomerular and interstitial infiltration of leucocytes, but its clinical significance remains uncertain. We analysed the relationship between the ICAM-1 (CD54) expression in tubular epithelial cells and interstitial leucocytes, macrophages (CD14) and T lymphocytes (CD3) with the histologic features, proteinuria and serum creatinine at the time of renal biopsy and after 2.42 years in 45 patients with IgAN and after 1.8+/-1.5 years in 29 patients with non-glomerulonephritis (non-GN). In IgAN, ICAM-1+ tubule epithelium was 0.1+/-0.18 (x+/-SD), and this was associated with extracapillary proliferation (up to 20% of Bowman's space), glomerular sclerosis involving less than 50% of glomerular area, interstitial cellular infiltration, tubular atrophy and proteinuria level. ICAM-1+ interstitial leucocytes were correlated with glomerular sclerosis involving less than 50% of glomerular area, glomerular sclerosis involving more than 50% of glomerular area, tubular atrophy, interstitial fibrosis and serum creatinine level. In patients with an increase of 50% in serum creatinine, ICAM-1+, CD14+ and CD3+, interstitial leucocytes were significantly outnumbered than in patients with stable serum creatinine. In non-GN, ICAM-1+ tubule epithelium was 0.02+/-0.04 (U=344, P<0.05, vs IgAN), and this was inversely correlated with the percentage of the normal glomeruli and associated with glomerular sclerosis covering more than 50% of glomerular area, tubular atrophy and serum creatinine level. The association between tubular ICAM-1 and proteinuria and the association between interstitial ICAM-1+, CD14+ and CD3+, leucocytes and renal failure at presentation and the deterioration in IgAN in contrast with non-GN suggest that tubular and interstitial expression of ICAM-1 may be a marker of tubulointerstitial disturbance in IgAN.     

IgA nephropathy. A comparative study of the clinicopathologic features in children and adults

A comparative study of the clinicopathologic features of IgA nephropathy in 24 children and 46 adults was undertaken. In children, microscopic hematuria was present in all cases and was associated with gross hematuria in 83% and proteinuria in 58%. In adults, microscopic hematuria was present in 91%, gross hematuria in 25%, and proteinuria in 80%. During followup, renal failure was recorded among 5.5% of children and 10% of adults. Biopsy specimens were obtained from all patients and were examined by light, electron, and immunofluorescence microscopic technics. Morphologic changes in the glomeruli were classified according to the degree of mesangial hypercellularity, sclerosis, and crescent formation into four groups. The most common glomerular pattern in children was diffuse, mesangial hypercellularity, while mesangial proliferation associated with focal segmental glomerulosclerosis predominated among adults. These observations suggest that glomerular morphology correlates with age at diagnosis and influences the clinical outcome of the disease.     

The glomerular changes in children with reflux nephropathy

While heavy proteinuria and focal segmental glomerulosclerosis (FSGS) are well-recognized features of progressive reflux nephropathy in adults, little is known of their early evolution. We have studied the glomerular changes in renal biopsy specimens obtained from 24 patients aged 5.2-18.8 years, in whom urinary protein excretion was measured as early morning urine protein creatinine ratios, using the Coomassie blue dye-binding method. Segmental sclerotic lesions were found in eight biopsies and traced through serial sections to a hilar origin in every instance. There was a strong positive correlation between the extent of glomerular involvement and the amount of proteinuria (P less than 0.0001). Parahilar hyaline deposits were observed in 16 biopsies, including five of the eight showing FSGS. All unsclerosed glomeruli were enlarged, and the hilar arterioles showed both enlargement and thickening, their walls frequently containing subendothelial hyaline deposits. Since in most patients renal function was comparatively well preserved, despite extensive loss of renal substances, we believe that these glomerular and vascular changes represent the stages in the evolution of hyperfiltration. Microproteinuria is the earliest clinical manifestation of FSGS, and should be sought routinely in all patients with reflux nephropathy.     

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.     

Time course and localization of endothelin-1 gene expression in a model of renal disease progression.

Experimental and human proteinuric glomerulopathies are associated with tubulo-interstitial injury that correlates with the decline of renal function even better than glomerular lesions do. Mechanism(s) leading to tubulo-interstitial damage are unknown. It has been proposed that excessive reabsorption of filtered proteins activates renal cells to produce vasoactive and inflammatory molecules including endothelin-1. The aim of the present study was twofold: we first evaluated the cellular origin of excessive renal endothelin-1 production in the renal mass reduction model and then related endothelin-1 distribution to the development of kidney lesions. Four groups of renal mass reduction (n = 15) and four groups of control rats (n = 5) were studied at 7, 14, 21, and 28 days after surgery. Urinary proteins in renal mass reduction rats were comparable with controls at day 7 but became significantly higher thereafter. Renal mass reduction rats first developed tubulo-interstitial changes, which were already evident at day 14 in the majority of them. At 28 days, renal mass reduction rats also developed glomerulosclerosis. A parallel increase of renal endothelin-1 gene expression and synthesis of the corresponding peptide in renal mass reduction rats versus controls was observed from day 14. Nonradioactive in situ hybridization confirmed a pattern of endothelin-1 mRNA consistent with the distribution of lesions. At day 14, endothelin-1 staining was stronger in renal mass reduction than in control kidneys and mainly localized to the cytoplasm of tubular cells, whereas glomeruli were negative. At day 28, endothelin-1 expression further increased in renal mass reduction rats as compared with controls, and the staining was apparent also in glomeruli. Thus, in renal mass reduction, a progressive up-regulation of endothelin-1 occurs during the development of renal injury, that first involves the tubules and, only in a subsequent phase, the glomeruli.     

Acquired glomerular lesions in patients with Down syndrome

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.