Increase In Mesangial Matrix Research Articles

Significance of Intraglomerular Expression of .ALPHA.-Smooth Muscle Actin, Desmin, and PDGF Receptor on Glomerulosclerosis in the Rat Remnant Kidney Model.

To elucidate the possible pathomechanism of glomerulosclerosis by partial nephrectomy, male SD rats received 3/4 nephrectomy and were maintained without further treatment for 8 weeks (3/4 nephrectomized group). Another group received a sham operation consisting of laparotomy and manipulation of the renal pedicles but without destruction of renal tissue and were maintained without treatment for 8 weeks (sham-operated group). The following findings were observed in the 3/4 nephrectomized group. The levels of urinary protein elevated after 4 weeks and thereafter reached a plateau. A high blood pressure was present at week 8. Histopathologically, glomerulosclerotic lesions were characterized by capillary obsolescence, proliferation of glomerular cells (including mesangial cells), mesangial matrix increase, and macrophage influx, and associated with expression of α-smooth muscle actin (α-SMA) and desmin in the glomerular tuft (mainly mesangial cells) and platelet-derived growth factor (PDGF) receptor in the glomerular tuft. The present results suggest that the key pathologic changes for glomerulosclerosis are impaired endothelial cells of glomerular capillaries by rapidly increased blood flow into the remaining nephrons and the resultant production of growth factors such as PDGF leading to mesangial cell proliferation. Furthermore, the present expression of α-SMA and desmin in mesangial cells suggests a phenotype switch of mesangial cells responsible for the induction of glomerulosclerosis.

Effects of captopril on morphologic changes in kidney of spontaneously hypertensive rats with adriamycin nephropathy

Antihypertensive therapy has been shown to slow down the progression of chronic renal failure. Angiotensin converting enzyme inhibitors and calcium antagonists have been emphasized as the agents with the most protective effect. Our previous study showed that captopril slowed down renal function deterioration in the early course of adriamycin (ADR) nephropathy in spontaneously hypertensive rats (SHR). The present study was undertaken with the aim to examine morphologic changes associated with that slower renal function deterioration. Adult (24 weeks) female SHR were randomly divided into the following groups: the control group (n = 12) was given tap water to drink; the adriamycin (ADR) group (n = 25) was treated with ADR; the ADR-captopril (ADR-C) group (n = 27) was treated with ADR and thereafter with captopril (60 mg/kg/day). Rats were sacrificed at weeks 6, 12 and 18 and histologic analysis was semiquantitatively performed. In the control group the glomeruli exhibited only minor changes at the end of the study. In the ADR group slight glomerular mesangial hypercellularity appeared in the sixth week and progressed in focal and segmental sclerosis. Some glomeruli showed segmental proliferation and increased fibrular matrix of a tuft adherent to a fibrocellular crescents. In the ADR-C group, glomeruli with a slight increase of mesangial matrix were seen at the end of the sixth week, mesangial hypercellularity developed until the end of the sixth week, mesangial hypercellularity developed until the end of the 12th week and segmental glomerulosclerosis until the end of the study. Semiquantitative analysis revealed that the mean semiquantitative scores for mesangial expansion and glomerular sclerosis were significantly lower in ADR-C group than in ADR group thoughout the study. We concluded that captopril slowed down mesangial expansion and reduced the development of glomerular sclerosis.

A clinicopathological study of adult Japanese IgA nephropathy patients: Early stage cases and cases with exacerbation

Summary: Most cases of adult type IgA nephropathy (IgAN) have an insidious onset and asymptomatic course. However, some patients reveal recurrent macroscopic haematuria following episodes of respiratory or urinary tract infections. In order to clarify the correlation between clinical features and histological alterations or prognosis, 42 cases of early stage IgAN and 40 cases with acute exacerbation episodes were investigated and compared with a control group. Early stage cases were defined as having had a renal biopsy within 1 year after the first detection of urinary abnormalities, and had normal urinary findings within the 12 months before the first detection of urinary abnormalities. Acute exacerbation cases were defined as macroscopic haematuria or worsening of urinary abnormalities after acute infectious episodes and undergoing a renal biopsy within 120 days after the onset of these episodes. the early stage cases had better renal function and lower systolic and diastolic blood pressure than that of control group. They also showed milder changes in mesangial cell proliferation, mesangial matrix increase, totally sclerotic glomeruli, and tubulo‐interstitial changes. However, it is important to note that glomerular and interstitial sclerotic changes were observed even in early stage cases. Endothelial detachment was noticed more frequently in the early stage cases. Acute exacerbation cases revealed lesions of endocapillary proliferation, mesangiolysis and endothelial detachment more frequently, although these changes were segmental in each glomerulus. There was no statistical difference in disease prognosis between cases with and without acute exacerbation. These data indicated that there are characteristic histological changes in early stage cases and acute exacerbation cases of IgAN.

Nodular glomerulosclerosis after renal transplantation without diabetes mellitus

tissue contained 15 glomeruli with diffuse thickeningof the glomerular basement membrane as well asNodular glomerulosclerosis is a well-described lesion increase in mesangial matrix in each. In addition,of diabetic nephropathy. Although it was considered mesangial hyaline nodular lesions were present in sevenpathognomonic for this entity, nodular glomerulo- glomeruli (Figure 1). No tubulointerstitial or vascularsclerosis has been also reported in the absence of overt damage was observed. Immunofluorescence stainingglucose intolerance [1–6]. In addition, rare cases of de with Igs,C3,kappa and lambda light chains was nega-nova nodular glomerulosclerosis have been reported in tive. Congo red staining for amyloid was also negative.patients who developed post-transplant diabetes mel- Electron-microscopy (tissue obtained from paraffin)litus [7]. revealed irregular, marked, uniform thickening of theThe purpose of this paper is to describe a renal basement membrane and increased mesangial matrix.transplant patient with typical lesions of diabetic nodu- Immune deposits were absent (Figure 2).lar glomerulosclerosis without past or present glucose One year later, the patient is normotensive. Serumintolerance. creatinine is 5 mg/dl, proteinuria has ranged from 0.4to 4 g/day with normal total protein and serum albu-min. Fasting blood glucose has remained normal.

Enhanced production of glomerular extracellular matrix in a new mouse strain of high serum IgA ddY mice

To investigate the relationship between high serum levels of IgA and glomerular lesions, selective mating was performed in high serum IgA ddY mice, a murine model of spontaneously developing mesangioproliferative glomerulonephritis mimicking human IgA nephropathy. The selection and mating of high IgA ddY mice were accomplished when the mice were three to four months old. In the 12th generation of high IgA ddY (HIGA) mice, significantly higher levels of serum IgA from 10 age weeks to 60 weeks (P < 0.0002 to 0.0001) were observed in comparison with BALB/c mice. Relatively high proteinuria was observed at 40 weeks of age, although hematuria was consistently negative. Microscopic observations of renal tissue disclosed a marked glomerular mesangial matrix increase and a reduction of cell proliferation with age by both semiquantitative and morphometric analyses with moderate tubulointerstitial damage. These mesangial matrices were stained markedly by antisera for collagen type IV and by fibronectin, but not by collagen type I. Localization of TGF-beta protein was also detected in the mesangium of the HIGA mice. The positive mesangial IgA deposition was maintained consistently by this mating procedure and became more marked with age. Size analysis of IgA from ten pooled HIGA mice aged 50 to 60 weeks revealed dominant polymeric IgA in sera and dimeric IgA in glomerular eluates. Clonal analysis of serum IgA disclosed heterogeneous spectrotypes in a wide pH range (4.5 to 6.5), in contrast to very limited spectrotypes in the acidic pH range (4.5 to 5.2) of IgA in the glomerular eluates from these mice. The analyses of retroviral gp70 antigen involvement in the HIGA mice disclosed a significant increase of serum levels of gp70 anti-gp70 immune complexes with age, with no relationship to the severity of glomerular gp70 deposition. Northern blot analysis of renal tissue revealed markedly high mRNA expression of collagen type I, IV, fibronectin and TGF-beta even in 10-week-old HIGA mice in comparison with BALB/c mice. The expression became more significant in 60-week-old animals. The genetic background required to induce the expansion of IgA-producing B-cell clones is suggested to be closely related to the increased gene expression of TGF-beta, which induces enhanced glomerular extracellular matrix (especially fibronectin) accumulation in HIGA mice, being possibly mediated by the mesangial deposition of dimeric and highly acidic IgA. This newly established strain may provide a model for investigating the relationship between progressive glomerular sclerotic lesions and the induction of pathogenic IgA in human IgA nephropathy.

Rat cytomegalovirus infection and chronic kidney allograft rejection

Abstract To investigate the effect of cytomegalovirus (CMV) infection on the development of experimental chronic kidney allograft rejection, orthotropic kidney allografts from DA donors (Ag- RTlal) to WF (Ag- RTlu) recipients were used. The rats received cyclosporine A (CsA) for 12 weeks. A group of recipients was infected with 105 plaque-forming units of rat CMV (RCMV), and another group was left non-infected and used as controls. The grafts were removed 12 weeks after transplantation. RCMV infection significantly enhanced the development of chronic kidney allograft rejection as follows: the intensity of interstitial inflammation (P < 0.025), particularly the degree of pyroninophilic cells in the inflammatory infiltrate (P < 0.025); the glomeruli mesangial matrix increase (P < 0.05) and capillary basement membrane thickening (P < 0.01); the extent of endothelial cell swelling (P < 0.025) and intimae proliferation (P < 0.025) in the graft vasculature; and the extent of tubular epithelial atrophy (P < 0.025). The chronic allograft damage index (CADI) was significantly increased to 4.2 ± 0.9 in RCMV-infected allograft, compared with 0.8 ± 0.4 in non-infected (P < 0.02). At the molecular level, RCMV infection significantly increased vascular endothelial (P < 0.05) and tubular epithelial (P < 0.01) ICAM-1 expression. Viral antigens were detected in tubular epithelial cells and in some inflammatory cells.

Cytomegalovirus infection-enhanced chronic kidney allograft rejection is linked with intercellular adhesion molecule-1 expression

In human kidney allografts, association of acute rejection and glomerulopathy with cytomegalovirus (CMV) infection has been demonstrated. To investigate the effect of CMV infection on the development of experimental chronic kidney allograft rejection, heterotopic kidney allografts from DA (Ag-B4, RT1a1) rat donors to WF (Ag-B2, RT1u) rat recipients were used. The animals received cyclosporine A (CsA) 5 mg/kg/day s.c. either for 1 or 12 weeks. Two groups of recipients were infected with 10(5) plaque-forming units of rat CMV (RCMV) and two other groups were left noninfected and used as controls. The grafts were removed 12 weeks after transplantation for histology and immunohistochemistry. RCMV infection significantly enhanced the development of chronic kidney allograft rejection in rats on continuous CsA the intensity of interstitial inflammation (P < 0.025), particularly the degree of pyroninophilic cells in the inflammatory infiltrate (P < 0.025), the glomerular mesangial matrix increase (P < 0.05) and capillary basement membrane thickening (P < 0.01), the extent of endothelial cell swelling (P < 0.025) and intimal proliferation (P < 0.025) in the graft vasculature, and the extent of tubular epithelial atrophy (P < 0.025). Chronic allograft damage index (CADI) was significantly increased to 4.3 +/- 0.8 in RCMV-infected allografts, compared to 0.8 +/- 0.4 in noninfected (P < 0.02). In addition, RCMV infection significantly increased the number of acute rejection episodes (serum creatinine > 200 mumol/liter, P < 0.05) and almost doubled the end-stage serum creatinine. RCMV infection significantly increased ICAM-1 expression on the vascular endothelium (P < 0.05) and tubular epithelial cells (P < 0.01), and was linked with enhanced interstitial, glomerular, and tubular inflammation. In 80% of allografts on continuous CsA, RCMV antigens could be observed in sporadic inflammatory cells one week after infection and in tubular epithelial cells at 12 weeks. In heavily inflamed allografts where the CsA treatment was discontinued at one week, enhancement of RCMV infection on the histological changes attributable to chronic kidney allograft rejection could not be demonstrated. Our results show that during CsA immunosuppression, RCMV infection enhances chronic kidney allograft rejection associated with increased interstitial inflammation as well as vascular endothelial and tubular epithelial ICAM-1 expression.

Increased content of fibronectin and laminin in glomeruli isolated from chronically rejected human renal allografts.

Increased content of fibronectin and laminin in glomeruli isolated from chronically rejected human renal allografts.

An allograft kidney showing both features of IgA nephropathy and membranous glomerulonephritis: a case report

We report a case of glomerular disease with both mesangial IgA and subepithelial IgG deposits in the allograft kidney. The patient was a 36 year-old man who had received a renal allograft 1 year previously. Fifteen days before admission, he discovered a microscopic hematuria without clinical evidences of allograft rejection. Light microscopy showed diffuse increase of mesangial matrix without mesangial cell proliferation. Capillary walls were diffusely and mildly thickened. Immunofluorescence microscopy demonstrated both granular deposits of IgA in the mesangium and IgG along the capillary walls. On electron microscopy, electron-dense deposits were identified not only in the mesangium but also on the epithelial side of the glomerular basement membrane.

Rat cytomegalovirus infection and chronic kidney allograft rejection.

To investigate the effect of cytomegalovirus (CMV) infection on the development of experimental chronic kidney allograft rejection, orthotopic kidney allografts from DA donors (Ag-B4, RT1a1) to WF (Ag-B2, RT1u) recipients were used. The rats received cyclosporine A (CsA) for 12 weeks. A group of recipients was infected with 10(5) plaque-forming units of rat CMV (RCMV), and another group was left non-infected and used as controls. The grafts were removed 12 weeks after transplantation. RCMV infection significantly enhanced the development of chronic kidney allograft rejection as follows: the intensity of interstitial inflammation (P < 0.025), particularly the degree of pyroninophilic cells in the inflammatory infiltrate (P < 0.025); the glomeruli mesangial matrix increase (P < 0.05) and capillary basement membrane thickening (P < 0.01); the extent of endothelial cell swelling (P < 0.025) and intimal proliferation (P < 0.025) in the graft vasculature; and the extent of tubular epithelial atrophy (P < 0.025). The chronic allograft damage index (CADI) was significantly increased to 4.2 +/- 0.9 in RCMV-infected allografts, compared with 0.8 +/- 0.4 in non-infected (P < 0.02). At the molecular level, RCMV infection significantly increased vascular endothelial (P < 0.05) and tubular epithelial (P < 0.01) ICAM-1 expression. Viral antigens were detected in tubular epithelial cells and in some inflammatory cells.

Selective proteinuria in diabetic nephropathy in the rat is associated with a relative decrease in glomerular basement membrane heparan sulphate

In the present study we investigated whether glomerular hyperfiltration and albuminuria in streptozotocin-induced diabetic nephropathy in male Wistar-Münich rats are associated with changes in the heparan sulphate content of the glomerular basement membrane. Rats with a diabetes mellitus duration of 8 months, treated with low doses of insulin, showed a significant increase in glomerular filtration rate (p < 0.01) and effective renal plasma flow (p < 0.05), without alterations in filtration fraction or mean arterial blood pressure. Diabetic rats developed progressive albuminuria (at 7 months, diabetic rats (D): 42 +/- 13 vs control rats (C): 0.5 +/- 0.2 mg/24 h, p < 0.002) and a decrease of the selectivity index (clearance IgG/clearance albumin) of the proteinuria (at 7 months, D: 0.20 +/- 0.04 vs C: 0.39 +/- 0.17, p < 0.05), suggesting loss of glomerular basement membrane charge. Light- and electron microscopy demonstrated a moderate increase of mesangial matrix and thickening of the glomerular basement membrane in the diabetic rats. Immunohistochemically an increase of laminin, collagen III and IV staining was observed in the mesangium and in the glomerular basement membrane, without alterations in glomerular basement membrane staining of heparan sulphate proteoglycan core protein or heparan sulphate. Glomerular basement membrane heparan sulphate content, quantitated in individual glomerular extracts by a new inhibition ELISA using a specific anti-glomerular basement membrane heparan sulphate monoclonal antibody (JM403), was not altered (median (range) D: 314 (152-941) vs C: 262 (244-467) ng heparan sulphate/mg glomerulus). However, the amount of glomerular 4-hydroxyproline, as a measure for collagen content, was significantly increased (D: 1665 (712-2014) vs C: 672 (515-1208) ng/mg glomerulus, p < 0.01). Consequently, a significant decrease of the heparan sulphate/4-hydroxyproline ratio (D: 0.21 (0.14-1.16) vs C: 0.39 (0.30-0.47), p < 0.05) was found. In summary, we demonstrate that in streptozotocin-diabetic rats glomerular hyperfiltration and a progressive, selective proteinuria are associated with a relative decrease of glomerular basement membrane heparan sulphate. Functionally, a diminished heparan sulphate-associated charge density within the glomerular basement membrane might explain the selective proteinuria in the diabetic rats.

Vitronectin in children with renal disease--1. Immunofluorescence study of vitronectin and C5b-9 in childhood IgA nephropathy

Renal biopsy specimens from 54 children (33 boys, 21 girls) with IgA nephropathy were investigated by immunofluorescence microscopy to determine the localization of vitronectin and C5b-9. vitronectin and C5b-9 deposits were found within the glomeruli of all cases and the intensity of vitronectin and C5b-9 deposits was as follows: vitronectin: (3+) 17 cases, (2+) 21 cases, (1+) 16 cases and C5b-9: (3+) 28 cases, (2+) 18 cases, (1+) 8 cases. In 19 cases and C5b-9 deposits were shown to be more predominant than vitronectin (Group C) and the same or less intense in 35 cases (Group V). In 33 cases, vitronectin deposits were demonstrated in the mesangial area only (M type), while in 21 cases deposits were presented both the mesangial area and the capillary wall (MC type). Linear staining of vitronectin was noted in Bowman's basement membrane and in the tubular basement membrane. Granular staining of vitronectin was observed in Bowman's basement membrane (29 cases) and tubular basement membrane (46 cases). M type C5b-9 deposits were demonstrated in 34 cases and MC type in 20 cases. C5b-9 deposits were observed in Bowman's basement membrane (19 cases) and in tubular basement membrane (37 cases). Intensely stained vitronectin was found in the sclerotic glomeruli and segmental sclerotic portion of the tissues. In serial biopsy, the intensity of both vitronectin and C5b-9 deposits became less intense. It was found that many patients of Group C had heavy proteinuria (P < 0.05) and that nephrotic patients were more frequent in Group C than in Group V (p < 0.05). In the light microscopic examination, most cases with intense C5b-9 deposits had mesangial proliferation (p < 0.10) and an increase in mesangial matrix (p < 0.10). Mesangial sclerosis index was correlated with the intensity of vitronectin deposits (p < 0.05). These findings suggest that vitronectin and the terminal complement system may play a critical role as a mediator of immunological tissue injury, especially mesangial sclerotic lesion in childhood IgA nephropathy.

Renal allograft histology and correlation with function in children on triple therapy

Histopathological findings of 13 LRD and 17 CAD renal allografts of paediatric recipients were prospectively semiquantitatively scored and correlated with clinical and functional parameters 18 and 36 months after transplantation. The most common findings at 18 months were diffuse interstitial fibrosis (incidence 57%), glomerular mesangial matrix increase (91%), arteriolar intimal proliferation (70%), and tubular atrophy (83%). Most changes were mild and most biopsies were scored normal or borderline (Banff classification). At 18 and at 36 months 30% of grafts showed mild chronic rejection (CR). Only two grafts showed grade II CR at 18 months and one graft grade III CR at 36 months. Progressive CR was not seen. Donor source or recipient age had no effect on graft histology. Vascular-interstitial cyclosporin (CsA) nephrotoxicity was not found. On the contrary, cumulative CsA dose (mg/kg/day) showed an inverse correlation with arteriolar intimal proliferation (P < 0.001). 51Cr-EDTA and lithium clearances showed inverse correlations with diffuse interstitial fibrosis and lymphocytosis. PAH clearance did not correlate with interstitial or vascular changes. The results indicate good prognosis in children on triple immunosuppression (with CsA administered in three doses/day to pre school children) regardless of donor source.

Renal function and histopathologic changes in children after liver transplantation

Up to 60% reduction of renal function has been reported after orthotopic liver transplantation (OLT) in patients receiving cyclosporine. We prospectively investigated renal function and histopathology in 16 children on triple immunosuppression therapy during 3 years after OLT. Cyclosporine was administered in 3 doses/day to preschool children. The median age at OLT was 5.4 years. Determinations of chromium 51-labeled ethylenediaminetetraacetic acid, p = aminohippuric acid, lithium, and sodium clearances, measurements of serum and urinary electrolytes, and urinary concentration tests were performed. Renal biopsy specimens were taken 18 and 36 months after transplantation. The mean glomerular filtration rate was 121.5 ml/min per 1.73 m 2 before transplantation, 86.3 at discharge, and 119.4 36 months after OLT. Hyperuricemia, hyperkalemia, and reduced urinary concentrating capacity were common. Hyperkalemia occurred in 13% to 19% of the patients, only during the first 6 months. Hyperuricemia and reduced concentrating capacity occurred with incidences of 17% to 44% and 40% to 63%, respectively. Histopathologic changes were mild, and severe nephrotoxic effects of cyclosporine was not seen. However, tubular atrophy, mesangial matrix increase, and mesangial cell proliferation were common. We conclude that triple immunosuppression with cyclosporine administration, in three doses per day, to small children and careful renal follow-up ensure good renal function after OLT. (J P EDIATR 1994;125:863-9)

Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats.

High levels of tissue advanced glycation end products (AGEs) that result from the spontaneous modification of proteins by glucose occur in diabetes and aging. To address the potential pathogenic role of AGEs in the glomerulosclerosis of diabetes or nephrosclerosis of aging, doses of AGE-modified rat albumin (25 mg per kg per day, i.v.) sufficient to elevate circulating AGE levels to the range of diabetic serum were administered daily to healthy rats alone or in combination with the AGE inhibitor aminoguanidine. After 5 months, the AGE content of renal tissues in AGE-treated rats rose to 50% above controls (P < 0.025), whereas serum contained 2.8-fold greater AGE levels (P < 0.025). Light and electron microscopy of kidneys from AGE-treated rats revealed a more than 50% increase in glomerular volume compared to controls (P < 0.001), significant periodic acid/Schiff reagent-positive deposits, basement membrane widening, and mesangial extracellular matrix increase and indicated significant glomerulosclerosis compared to untreated (P < 0.002) or albumin-treated controls (P < 0.002). These changes were associated with significant loss of protein (P < 0.005) and albumin (P < 0.002) in the urine of AGE-treated rats compared to controls. Cotreatment with aminoguanidine markedly limited both the structural and functional defects. These in vivo data demonstrate that AGEs influence glomerular structure and function in a manner leading to glomerulosclerosis. The effects are AGE-specific, as they are ameliorated by a pharmacological AGE inhibitor, aminoguanidine.

Effects of aging and dietary protein intake on uninephrectomized geriatric dogs

Summary Thirty-one clinically normal Cocker Spaniels, Miniature Schnauzers, and Doberman Pinschers (28 female, 3 male) 7 to 8 years old were uninephrectomized (month −2) to increase the risk of renal damage associated with reduction of renal mass. Two diets, differing principally in protein concentration, were used to test the hypothesis that high dietary protein intake causes renal damage in aging dogs. For 2 months after uninephrectomy, all dogs were fed diet A (18% protein). After glomerular filtration rate (gfr) was measured (month 0), 16 dogs were assigned to group A and were fed diet A for an additional 48 months. The other 15 dogs were assigned to group B, and were fed diet B (34% protein) for the subsequent 48 months. At 6-month intervals, GFR and urine protein-to-creatinine ratio (UP/C) were determined. At 48 months, terminal studies were done, survivors were euthanatized, and tissues were examined. Of 16 dogs in group A, 10 survived, compared with 13 of 15 in group B. Among survivors, a significant difference in GFR was not found between groups A and B, and decrease in GFR was not evident with time in either group. At 48 months, oral administration of casein caused minor acute effects on GFR and renal plasma flow in dogs of groups A and B. The UP/C values increased significantly (P = 0.001) from baseline values, but the increase was not progressive. The UP/C values were not affected by diet. Some dogs in both groups developed UP/C &gt; 1.0. Morphologic studies performed on kidneys removed at -2 months (nephrectomy) and at 48 months (necropsy) revealed increased kidney weight in both groups at month 48, compared with month −2 (P = 0.003); at month 48, kidney weight change was significantly (P = 0.004) greater in group-B than in group-A dogs. Increased glomerular area at month 48, compared with month −2, was significantly (P = 0.000) related to time, but not to diet. Significant (P = 0.000) increase in glomerular mesangial matrix, interstitial fibrosis (P = 0.001), cell infiltration (P = 0.000), and lesions of the renal pelvis (P = 0.04) was observed between month −2 and month 48. Time, representing combined effects of uninephrectomy and aging, was the major factor responsible for the morphologic changes. Diet effects were significance (P = 0.008) for cell infiltration, but did not reach significance for mesangial matrix accumulation, fibrosis, or pelvic lesions. Kidney mineral analysis revealed no renal mineralization in either group between −2 and 48 months. Results indicated that GFR did not decrease with time during the geriatric peroid studied, but severity of renal lesions was increased. Effects of time and uninephrectomy, although not separable, were more important than those of dietary protein intake on progression of renal lesions.

A quantitative analysis of the glomeruli in focal segmental glomerulosclerosis.

Quantitative analysis of the glomerular area, mesangial matrix and mesangial cells was performed using renal biopsy specimens from 22 children with focal segmental glomerulosclerosis (FSGS) and 20 with minimal change nephrotic syndrome (MCNS). Non-sclerotic glomeruli were examined. All children in both groups showed nephrotic syndrome at the time of biopsy. Children with benign haematuria were examined as controls. Glomerular area increased with age in the FSGS, MCNS and control groups. The glomerular area was significantly greater in FSGS (1.5 +/- 0.4 x 10(4) microns 2) than in MCNS (1.2 +/- 0.2 x 10(4) microns 2) or in controls (1.2 +/- 0.3 x 10(4) microns 2) (P < 0.05). Mesangial matrix was increased with age in the three groups. The mesangial matrix was significantly increased in FSGS (28.3 +/- 4.0%; mesangial matrix area/glomerular area) compared with MCNS (24.9 +/- 4.1%) and controls (23.0 +/- 3.0%) (P < 0.01). These findings suggest that both glomerular hypertrophy and mesangial matrix increase in non-sclerotic glomeruli in FSGS may lead to glomerular sclerosis.

Clinical significance of allograft glomerulopathy

During the period from January 1973 to December 1990, 774 renal transplantations in 698 children were performed in our renal unit. A total of 540 grafts were examined both by light and immunofluorescence microscopy at least once. Recurrent glomerulonephritis was diagnosed in 62 grafts, de novo glomerulonephritis in 68 and allograft glomerulopathy in 38 (7%). The term allograft glomerulopathy (AGP) refers to the very specific pattern of glomerular involvement unique to renal allografts and characterized by: (1) widespread reduplication of the glomerular basement membrane due to a widening of the subendothelial space associated with (2) moderate increase in mesangial matrix and (3) interposition of mesangial matrix and cells. AGP is a glomerular manifestation of chronic rejection and is almost always associated with obliterative vascular changes. In our experience it is present in 25% of long-standing grafts (more than 10 years), but may develop early in the post-transplantation period (5 cases within the first year). In 13 of 33 patients in whom early biopsies were available, a different pattern characterized by a hypercellularity and the presence of monocytes-macrophages in the mesangial areas was observed. We suggest that this hypercellular pattern might be the early stage of the disease and could be called "acute allograft glomerulopathy" as opposed to the pattern characterized by reduplication of the glomerular basement membrane which deserves the name of "chronic allograft glomerulopathy." The exact relationship between these two patterns remains to be determined. Clinicopathologic correlations showed that chronic AGP is often associated with marked proteinuria. However, in our series proteinuria was absent or minimal in 25% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

The impact of acute episodes of rejection on the generation of chronic rejection in rat renal allografts.

We have investigated the impact of the frequency of acute rejection episodes on the generation of chronic rejection in long-surviving rat renal allografts. A total of 33 renal transplantations was performed from DA to WF rats, receiving different cyclosporine-based immunosuppressive regimens. As a consequence, different numbers of acute rejection episodes were recorded in the recipients, all of which were successfully treated with cyclosporine. Upon sacrifice at 12 weeks posttransplantation, the frequency of acute rejection episodes was correlated with the major histological parameters of chronic rejection and with graft function. The intensity of the major histological parameters of chronic rejection, exemplified by vascular intimal proliferation and glomerular mesangial matrix increase, and the decline in graft function between the no-rejection vs. rejection groups, were directly proportional to the number of acute rejection episodes. Vascular intimal proliferation increased from 0.5 +/- 0.4 (arbitrary units) in the no-rejection group to 1.7 +/- 0.9 (P = 0.0093) after one rejection episode, to 2.2 +/- 0.3 (P = 0.0001) after two, and to 2.2 +/- 0.5 (P = 0.0014) after three or four rejection episodes. Glomerular mesangial matrix increased from 1.2 +/- 0.3 (arbitrary units) in the no-rejection group to 1.9 +/- 0.6 (P = 0.017) after one, to 2.2 +/- 0.5 (P = 0.0005) after two, and to 2.1 +/- 0.4 (P = 0.003) after three or four rejection episodes. Serum creatinine increased from 93 +/- 24 mumol/L in the no-rejection group to 196 +/- 92 mumol/L (P = 0.016) after one, to 238 +/- 38 mumol/L (P = 0.0001) after two, and to 308 +/- 85 mumol/L (P = 0.0016) after three or four rejection episodes. Prolongation of the preoperative ischemia time from 30-60 min correlated with an increase in the number of acute rejection episodes as well as an increase in chronic changes. To conclude, in the rat renal allograft model, acute allograft rejection carries a highly significant correlation with the development of chronic rejection.

Prenatal diagnosis of congenital nephrosis of the Finnish type (CNF) in the second trimester

Congenital nephrosis of the Finnish type is an hereditary, autosomal recessive disease which leads to death in early infancy. This is a case report concerning an affected fetus with legal interruption in the 24th week of gestation on the basis of certain sonographic changes in the fetal kidneys and changes in the protein profile in amniotic fluid, which were consistent with nephrotic damage of the kidneys. Light and electron microscopy showed evidence of CNF, i.e. increase of mesangial matrix and cells in glomeruli, dilated tubular segments, and effaced and plumb foot-processes of the glomerular epithelial cells. Antenatal diagnosis of CNF therefore seems feasible in the second trimester of gestation by means of AFP determinations in maternal serum and amniotic fluid as well as by using sonographic criteria and determination of proteins in amniotic fluid.