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Background: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS., Results: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe)., Conclusion: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Inflammation plays a role in the development of diabetic nephropathy (DN) in type 2 diabetes. Although macrophages have been found in experimental models of DN, little is known regarding the presence of macrophages in patients with DN. Therefore, we investigated the presence and phenotype of glomerular and interstitial macrophages in relation to clinical and histopathological parameters in patients with DN., Methods: Renal autopsy samples were obtained from 88 type 2 diabetic patients with histologically proven DN and stained for CD68 and CD163 as general and M2/anti-inflammatory markers of macrophages. Renal damage was scored based on histopathological classification of DN. Control renal autopsy samples were obtained from patients without renal abnormalities and from diabetic patients without DN. Positive cells per glomerulus were counted. Interstitial macrophages were counted semi-quantitatively., Results: Macrophages were present in all groups. In the DN group, the mean number of CD68+ cells per glomerulus and CD163+ cells per glomerulus was 4.2 (range 0-19) and 2.1 (range 0-14.47), respectively. The distribution was similar between all histopathological classes. Glomerular CD163+ macrophages were positively associated with DN class, interstitial fibrosis and tubular atrophy, and glomerulosclerosis. Interstitial CD68+ macrophages were correlated with glomerular filtration rate stage and albuminuria., Conclusions: Our results demonstrate that macrophages are present in the glomeruli and interstitium of type 2 diabetic patients with DN and of controls. Although patients and controls had similar numbers of glomerular macrophages, glomerular anti-inflammatory CD163+ macrophages were associated with pathological lesions in DN. Taken together with the correlation between interstitial macrophages and interstitial fibrosis and tubular atrophy, DN class, and renal function, this finding suggests that macrophages may play a role in DN progression. Therefore, targeting macrophages may be a promising new therapy for inhibiting the progression of DN., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Full-house immunofluorescence in combination with various histopathologic lesions in the renal biopsies of patients without overt systemic lupus erythematosus (SLE) poses a diagnostic challenge. In this setting, the biopsy findings are sometimes termed non-lupus 'full-house nephropathy' (FHN). It is presently unknown whether idiopathic non-lupus FHN is clinicopathologically and prognostically distinct from lupus FHN., Methods: We included non-lupus FHN patients and lupus FHN controls (four or more American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria) who were biopsied between 1968 and 2014 at the Leiden University Medical Centre. Non-lupus FHN patients were studied for progression to SLE and/or the presence of other conditions with FHN. The clinicopathologic characteristics and prognosis of idiopathic non-lupus FHN patients were compared with those of lupus FHN patients., Results: Of 149 included patients, 32 had non-lupus FHN. During the median follow-up of 20 years, no non-lupus FHN patients developed SLE. In all, 20 non-lupus FHN patients had idiopathic non-lupus FHN, and in 12 patients, secondary non-lupus FHN was considered due to membranous nephropathy (anti-PLA2R-positive, n  = 1; cancer-associated, n  = 3), IgA nephropathy ( n  = 4), infection-related glomerulonephritis ( n  = 2) or anti-neutrophil cytoplasmic antibody-associated glomerulonephritis ( n  = 2). Idiopathic non-lupus FHN patients were more often male (P   <   0.001) than lupus FHN patients and their renal biopsies more often showed a mesangial (P   =   0.04) or membranous pattern of injury (P   =   0.02) and less intense C1q staining (P   =   0.002). Clinically, they presented with lower-range erythrocyturia (P   =   0.04), more proteinuria (P   <   0.01) and less complement consumption in the classical pathway (P   <   0.001) than lupus FHN patients. By multivariable Cox regression analysis of patients with a lupus nephritis class III/IV pattern of injury, idiopathic non-lupus FHN compared with lupus FHN was an independent risk factor for end-stage renal disease [hazard ratio 5.31 (95% confidence interval 1.47-19.24)]., Conclusions: Our results show that the clinical recognition of idiopathic non-lupus FHN as a diagnostic category is critical., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

In the early 1990s, an international working group of experienced renal pathologists, the Renal Histology group, set up a scoring system for biopsies with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. This scoring system subdivided glomerular, interstitial and vascular lesions and served as a tool for the evaluation of all renal biopsies from studies of the European Vasculitis Study Group (EUVAS). Histopathological studies gave new insights into the prediction of renal outcome in patients with ANCA-associated glomerulonephritis. Percentage of normal glomeruli and a selected number of interstitial parameters were reliable predictors of long-term follow-up glomerular filtration rate in all studies. Out of these results, a histopathological classification distinguishing focal, crescentic, mixed and sclerotic classes of ANCA-associated glomerulonephritis was developed. Until today, 13 studies have validated this classification system. Future studies will try to determine if and how renal histology could be helpful in guiding treatment of ANCA-associated glomerulonephritis., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: The clinical utility of performing repeat biopsies during lupus nephritis flares is questionable and data pointing towards frequent class switches are based on the old WHO classification. This retrospective study investigates the hypothesis that clinically relevant switches from proliferative to non-proliferative lesions and vice versa as determined by the new ISN/RPS classification are a rare event and that repeat biopsies are unnecessary in many cases., Methods: Thirty-five patients with lupus nephritis and one or more repeat renal biopsies were included. Eighty-four biopsies were blindly reassessed according to the ISN/RPS classification., Results: Twenty-five patients had one repeat biopsy, 6 patients had two and 4 patients had three repeat biopsies. Forty-nine comparisons between reference and repeat biopsies could be made. In 25 cases (54.3%), there was no shift in ISN/RPS class on repeat biopsies. In 41 instances, paired biopsies showed proliferative lesions both on reference and repeat biopsies, whereas five of six cases with non-proliferative lesions on a reference biopsy switched to proliferative lesions on a repeat biopsy. Clinically significant class switches during lupus nephritis flares were more frequent in patients with non-proliferative lesions in their reference biopsy (P < 0.001)., Conclusion: The results show that patients with proliferative lesions in the original biopsy rarely switch to a pure non-proliferative nephritis during a flare. Therefore, a repeat biopsy during a lupus nephritis flare is frequently not necessary if proliferative lesions were found in the reference biopsy. However, in the case of a non-proliferative lesion in the reference biopsy, class switches are frequently found and repeat biopsies are advisable.

Background: We reported previously that in renal disease in relation to antineutrophil cytoplasm auto-antibodies (ANCA)-associated vasculitis, renal outcome correlates better with the percentage of normal glomeruli than with separate active lesions. This may imply that glomeruli, once affected by necrotizing and crescentic lesions, are irreversibly damaged. We quantified and evaluated the course of renal lesions in the present study., Methods: We retrospectively analysed 31 patients with renal disease in relation to ANCA-associated vasculitis, all treated with immunosuppressive drugs. In all patients, a renal biopsy was performed at diagnosis. A follow-up biopsy was performed in all patients on the indication of a suspected renal relapse, after a mean interval of 31 months., Results: The mean percentage of normal glomeruli in the renal biopsy did not change over time (29% in the initial and 30% in the follow-up biopsy). The mean percentage of glomeruli with crescents, however, significantly decreased from 57 to 30% (P<0.001). The percentage of glomerulosclerosis significantly increased from 12 to 39% (P<0.001). The data were independent of diagnosis, gender, age, time interval between the biopsies, and treatment., Conclusions: This is the first study to quantify glomerular changes between two time points in patients with renal vasculitis. Our results suggest that, on average, no new glomeruli are recruited into the active disease process. The sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies is larger than the percentage of sclerotic glomeruli in the follow-up biopsies. Thus, therapy seems not only to prevent normal glomeruli from being recruited into the active disease process for a certain time, but seems also to allow part of the active lesions to revert into a normal phenotype, although another part of the active lesions will be transformed to a chronic phenotype.

Several clinical studies have confirmed that histomorphometric changes in the tubulointerstitial compartment contain the best correlating parameters to predict the development of progressive renal insufficiency. The process of interstitial fibrosis is accompanied by an influx of inflammatory cells, up-regulation of fibrogenic cytokines such as transforming growth factor-beta and basic fibroblast growth factor, transient down-modulation of their antagonists, generation and proliferation of myofibroblasts, and, finally, by accumulation of interstitial collagens and proteoglycans. A careful morphometric analysis of interstitial fibrosis requires sensitive parameters through which the severity can be quantified and by which the progression into renal insufficiency can be predicted. We have addressed these issues by morphometric analysis of both human biopsies and by refining existing experimental models in the rat. Morphometric analysis was performed using a Zeiss microscope equipped with a full colour 3CCD camera and KS-400 image analysis software from Zeiss-Kontron. For studies with human material, biopsies were examined from patients with various renal diseases including patients with chronic allotransplant dysfunction. The development of interstitial fibrosis was correlated with clinical parameters. In experimental models, we analysed the interstitial composition and eventual glomerular alterations in rats with bovine serum albumin (BSA)-induced protein overload nephropathy and with human IgG-induced chronic serum sickness nephritis. Finally, we adapted and refined the model of ureter obstruction-induced interstitial fibrosis in the rat. For this purpose, custom-made titanium clips (S&T, Neuhaus, Switzerland) were implanted around the ureter in the abdomen of rats to obstruct the ureter without causing necrosis. The clips were removed at various time points after obstruction of the ureter (1-14 days). The subsequent remodelling of the interstitium was studied thereafter, in order to establish whether uraemia-induced interstitial fibrosis remains reversible at all times. In rat models, we have found that both protein overload-induced and serum sickness-induced interstitial fibrosis are accompanied by the development of focal and segmental glomerulosclerosis. Only in the ureter obstruction model did selective interstitial fibrosis develop, and remained reversible at all times studied. For the reliable assessment of interstitial fibrosis we have found that the best correlating parameters of interstitial fibrosis with renal function were: (i) the ratio of protein accumulation of TGF-beta-1 and its antagonist decorin; (ii) interstitial expression of smooth muscle alpha-actin; and (iii) accumulation of interstitial collagens (as determined by immunoperoxidase and by Sirius red staining).

In order to relate histopathological findings of the kidney in systemic vasculitis to renal outcome, scoring of various morphological parameters is necessary. Therefore, we conducted a standardization study for evaluating renal biopsies from patients with systemic vasculitis. Four experienced renal pathologists from four European centres joined in the study. A scoring protocol was devised that required the observers to score an extensive number of histopathological lesions either quantitatively (as a percentage of the total number of glomeruli) or dichotomously (on a present/absent scale). Twenty renal biopsies were scored individually by all the observers, from which the inter-observer variability was analysed. Ten randomly chosen biopsies were scored again, in order to obtain the intra-observer variability. For inter-observer agreement, the evaluation of the quantitative variables was satisfactory for both rounds (0.55 < or = Kendall's W < or = 0.95 and 0.59 < or = W < or = 0.96, respectively, with all P < 0.05). However, the inter-observer agreement for the dichotomous data was poor (kappa < or = 0.30 in more than half of the parameters in both rounds). Also the data on intra-observer agreement showed more favourable results for the analysis of the quantitative data (Pearson's r > 0.45 in more than 85% of the variables in both rounds) than for the dichotomous scoring system (kappa < or = 0.30 in more than half of the variables). It is concluded that even between experienced renal pathologists discrepancies occur in scoring kidney biopsies. Inter- and intra-observer agreement is greater if a quantitative method for reviewing the biopsies is applied that requires the observers to score the tissue specimens systematically.

Background: Acute rejection is characterized histologically by infiltration of the interstitium by mononuclear cells. Monocyte chemoattractant protein 1 (MCP-1) has recently been identified as a monocyte chemotactic factor. This study examined the possible role of MCP-1 in renal transplantation., Methods: The concentration of MCP-1 in urine and serum of 19 renal transplant patients was investigated using an inhibition radioimmunoassay. The patients were divided into a non-rejection (NRj) and a rejection (Rj) group. Normal healthy volunteers were included as controls. Immunoperoxidase staining for MCP-1 and CD14, as a marker for macrophages, was performed in renal biopsies of transplant patients with rejection and six biopsies from histologically normal kidneys, as controls. The size of urinary MCP-1 was determined by gel filtration chromatography and in a number of fractions assessed for monocyte chemotactic activity using a modified Boyden chamber assay., Results: Urinary excretion of MCP-1 in the Rj group ranged between 250 ng/mmol Cr and 3148 ng/mmol Cr with a median of 612 ng/mmol Cr. This is significantly higher than the results in the NRj group, ranging between 47 ng/mmol Cr and 288 ng/mmol Cr with a median of 229 ng/mmol Cr. In the normal control group, urinary MCP-1 levels ranged between 38 ng/mmol Cr and 74 ng/mmol Cr with a median of 50 ng/mmol Cr. The fractional excretion of MCP-1, calculated on the basis of MCP-1 and creatinine clearances, was found also to be significantly higher in the Rj group as compared to the NRj group. However, there was no significant difference in the serum levels of MCP-1 between the Rj, NRj, and normal control group. The intensity of MCP-1 staining in tubular epithelial cells and the degree of CD14+ cells in the interstitium was significantly higher in renal allograft biopsies than in the normal kidneys. In addition, MCP-1 isolated from urine of renal transplant patients with rejection was filtered with apparent molecular weight of 13 kDa and 11 kDa. Both sizes are chemotactically active for monocytes., Conclusions: These data suggest that urinary excretion of MCP-1 can be used as a marker for the episodes of acute rejection. The increase of urinary excretion of MCP-1 most likely is the result of local production by tubular epithelia cells. MCP-1 produced locally may, at least in part, be responsible for the influx of macrophages into the interstitium during rejection.

Renal biopsies were performed 1 week following renal transplantation at a time without clinical evidence of rejection in 43 patients (13 females, mean age 48 years range 18-60 and 30 males, mean age 43 years range 17-59 years). Thirty-six biopsies were available for histological or immunohistochemical analysis. Immunohistochemical analyses were performed with monoclonal antibodies against leukocytes (CD45), monocytes (WT14), complement factor 3 (C3), T-cells (Leu4), T-cell receptor alpha beta and gamma delta, tumour necrosis factor alpha (TNF alpha), IL-2 receptor (IL2-R, TAC), intercellular adhesion molecule-1 (ICAM1) and HLA-DR. The slides were scored semiquantitatively with the observers having no knowledge of clinical or patient data. TNF alpha and IL-2R were also measured by quantative PCR. None of the studied parameters correlated to delayed graft function or graft loss. Histological analysis showed that both focal interstitial infiltrate (18/35) and tubular basement membrane disruption (11/35) were followed by a higher incidence of subsequent rejection (P = 0.03 and 0.02 respectively). Also positivity for WT14 around tubuli (P = 0.02) was associated with subsequent occurrence of rejection. The intensity of staining of ICAM-1 on PTC as well as TAC on proximal tubular cells was associated with the number of subsequent rejection episodes. The association between the IL-2 receptor and subsequent rejection was also found applying PCR to the tissue specimens. We conclude that the presence of focal interstitial infiltrates and tubulitis in 1-week biopsies from well-functioning grafts carries an increased risk of subsequent rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute interstitial rejection is an important clinical problem after cadaver kidney transplantation. Recently we have reported that six of 17 graft-infiltrating cell (GIC) lines isolated from kidneys undergoing such rejection episodes recognize graft-derived proximal tubular cells but not lymphoid cells from the same donor. In this study we characterized the specificity of one such GIC line in more detail. From this T-cell line, 18 cytotoxic T-cell (CTL) clones were isolated. Four of these were also cytotoxic against donor lymphoid cells. Nine tissue-specific clones were selected for further analysis. They all contained CD8+ and TCR alpha/beta+ cells and cytotoxicity by these cells was class I restricted. Only proximal tubular epithelial cells (PTEC) expressing HLA-A31 (an antigen present in the donor but absent in the recipient) were recognized by all clones. There were, however, three clones that did not lyse all HLA-A31+ PTEC lines, demonstrating recognition of an HLA-A31 tissue-associated polymorphism. Thus during rejection episodes after renal transplantation GIC may recognize various tissue-derived peptides bound to a mismatched HLA molecule on the cell surface of renal parenchymal cells. These GIC are likely to contribute to the observed destruction of tubuli during episodes of acute rejection after kidney transplantation.

Glomerulonephritis in BALB/c mice following infection with Trypanosoma brucei is characterized by albuminuria and glomerular deposition of immunoglobulins. Electron-dense deposits are present in the mesangium, as well as subendothelially and subepithelially along the glomerular capillary wall. In this study the nature of intracytoplasmic, electron-dense, round structures observed in glomerular endothelial cells was investigated by immunoelectron-microscopy and enzyme histochemistry. The presence of these structures was related in time with the development of proteinuria. Mice from the C57BL10 strain, which upon infection develop glomerular immune complexes without proteinuria, were examined as well. The results demonstrated that the first endothelial changes, occurring 3-4 weeks after infection, were swelling of endothelial cells containing intracytoplasmic, electron-dense, round structures. These changes were seen prior to the onset of proteinuria, and were not present in glomeruli of mice that did not develop proteinuria. The endothelial granules were shown to contain immunoglobulins and typical lysosomal enzymes, providing evidence for phagocytosis by the glomerular endothelial cells. Liver endothelial cells did not show comparable changes. Thus, local phagocytosis by glomerular endothelial cells is shown to be a specific event in the development of glomerular disease.

Extraction of RNA has been described for rat and rabbit glomeruli but not for mouse glomeruli. Due to their small size, mouse glomeruli cannot be isolated by relatively simple sieving techniques. Based on recently reported methods for the isolation of mouse glomeruli, we developed an RNA isolation technique by performing comparative methodological studies. Two standard RNA extraction methods were compared. In addition in separate experiments the influence was studied of protease inhibitors and freezing and thawing of whole kidney prior to glomeruli isolation, on the yield and degradation of RNA. Therefore kidneys were perfused with 10 ml 0.01 M PBS containing 1.25% Fe3O4 through the aorta. Kidneys were decapsulated and passed through a 75-microns metal screen. After pelletting and washing, tubes were placed against a magnet and pelleted glomeruli were washed three times. In a second experiment protease inhibitors were added to the PBS. As a third method, kidneys were frozen before the isolation of glomeruli. From isolated glomeruli RNA was extracted using either caesium chloride or lithium chloride method. The yields of RNA (OD 260) were highest using the lithium chloride method. Hybridization of Northern blots of extracted RNA with cDNA probes showed the best results when RNA was extracted using the lithium chloride method, while the caesium chloride method led to considerable degradation of RNA. Freezing of kidney tissue prior to RNA extraction led to the virtual absence of any signal. We then applied this method successfully in an in-vivo model of experimental lupus nephritis. This is the first description of an optimal protocol for the extraction of RNA from mouse glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic serum sickness was induced in four groups of Wistar rats by immunization with BSA, cationized BSA (cBSA), human IgG (HuIgG), or human IgM (HuIgM), followed by repeated intraperitoneal (i.p.) injection of the antigen used, to study the effect of the characteristics of an antigen on renal immunopathology. Renal tissue sampled 2, 4, 7, and 9 weeks after the start of the i.p. injections was examined by light-, immunofluorescence-, and electron-microscopy. Proteinuria was measured in urine collected over 24 h. All animals given BSA, cBSA, or HuIgG developed progressive renal disease characterized by initial deposition of antigen and rat Ig in the mesangium of rats given BSA or HuIgG, and minimal amounts in those given cBSA, followed by the appearance in the first instance of subendothelial deposits in the animals receiving BSA or HuIgG, and later subepithelial deposits in those given BSA, cBSA, or HuIgG. The appearance of immunoglobulin deposits along the glomerular capillary wall was associated with the onset of massive proteinuria reaching average levels of 450 mg/24 h for rats given BSA or cBSA, and 500 mg/24 h for those given HuIgG. Animals injected with HuIgM showed only mesangial deposits of human IgM and rat Ig without the development of proteinuria. Under light-microscopy, rats given BSA, cBSA, or HuIgM showed minimal abnormalities, whereas those receiving HuIgG showed transient but severe influx of granulocytes in glomeruli with the development of diffuse proliferative glomerulonephritis in association with a long-lasting phase characterized by subendothelially localized immune aggregates.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the pathogenesis of glomerulonephritis in mice that had been infected with Trypanosoma brucei. Polyclonal B cell activation was evaluated, with special attention to the presence of autoantibodies, which are known to be involved in other models for glomerulonephritis. The BALB/c mice studied developed severe albuminuria. Light-microscopy of the kidneys showed increase of mesangial matrix and thickening of the glomerular capillary walls. Immunofluorescence studies showed immunoglobulins in a mixed linear-granular pattern along the glomerular capillary wall and in the mesangium. Trypanosomal antigens were not found in these aggregates. Electron-microscopy revealed mesangial, subendothelial, and subepithelial electron-dense deposits. During the course of this infection, significant levels of antibodies directed against known nephritogenic renal autoantigens, i.e. GBM, laminin, RTE, and gp330, were measured in serum and glomerular eluates. These findings led us to conclude that mice infected with T. brucei and treated with diminazene aceturate develop an autoimmune-mediated glomerulonephritis, characterized by mesangial, subendothelial, and subepithelial immune aggregates. This murine model seems to offer a useful tool for the study of immunological aspects of polyclonal B cell activation in infection-related glomerular disease.

A rat model of chronic serum sickness was used to study the pathogenesis of progressive glomerulosclerosis complicating experimental immune-complex glomerulonephritis. Chronic serum sickness was induced by immunising rats with bovine serum albumin followed by intraperitoneal administration of the antigen. Early lesions consisted of mesangial deposits of rat immunoglobulins, followed later by transient subendothelial and persistent subepithelial immune aggregates. On the basis of the peak level of proteinuria around day 80, three groups of rats were distinguished: I physiological proteinuria; II 50-500 mg/24 h; and III greater than 500 mg/24 h. The animals were killed at day 220 and the presence of mesangial proliferation, epithelial proliferation, and synechiae, as well as focal glomerulosclerosis was scored. It appeared that all and only proteinuric animals developed progressive glomerulosclerosis, although all three groups of animals passed through a phase with mesangial and subendothelial immune deposits. A strong correlation was found between the degree of proteinuria and the proportion of glomeruli affected. We conclude that the combination of mesangial and subendothelial deposits on the one hand and subepithelial deposits associated with increased protein loss on the other constitute a conditio sine qua non for the development of progressive glomerulosclerosis in this model. The use of specific antibodies to investigate the composition of the sclerotic lesions showed the presence of laminin and type IV collagen, but not of types I and III collagen in sclerotic areas of glomeruli. This indicates that the development of progressive glomerulosclerosis in this model is due to an increased production of glomerular basement membrane components by presumably solely glomerular cells after the occurrence of immunological glomerular injury.