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Background: Cyclosporine A (CyA) has been shown to be effective in membranous nephropathy (MN). However, the optimal dose and the duration of treatment remain controversial issues. We evaluated the efficacy of low-dose CyA alone or combined with corticosteroids as induction and long-term treatment for nephrotic patients with MN., Methods: In the first part of the study, 51 nephrotic patients with MN were treated either with CyA and prednisolone (n=31) or CyA alone (n=20) for 12 months. Patients who responded with complete remission (CR) or partial remission (PR) were placed on long-term treatment with lower doses of CyA and prednisolone or CyA alone. The mean follow-up of the second part of the study was 26+/-16 months and 18+/-7 months, respectively., Results: After 12 months of treatment, 26 patients in the combination group and 17 patients in the monotherapy group had a CR or PR of proteinuria (P=NS). Renal function was unchanged in the two groups. During long-term treatment relapses were more frequent in the monotherapy group (47 vs 15%, P<0.05). Daily CyA dose was higher in non-relapsers in both groups (combination 1.4+/-0.5 vs 1.0+/-0.3 mg/kg, P<0.001, monotherapy 1.5+/-0.4 vs 1.1+/-0.2 mg/kg, P<0.003). Relapsers in both groups had lower CyA trough levels (72+/-48 ng/ml) compared with non-relapsers (194+/-80 ng/ml) (P<0.03). Renal function and proteinuria remained stable during the follow-up., Conclusion: This study suggests that 12-month therapy with CyA (+/-prednisolone) is effective in inducing remission in most nephrotic patients with MN and well-preserved renal function. Longer treatment with lower doses is a useful approach to maintain remission. Relapses occur more frequently in the monotherapy group and usually are associated with CyA trough levels<100 ng/ml.

Background: Cellular immune responses and C5b-9 seem to play an important role in the pathogenesis and progression of idiopathic membranous nephropathy (IMN). The aim of the study was to investigate the role of C5b-9 and adhesion molecules in the pathogenesis of the disease., Methods: The clinical and pathological data of 35 patients with biopsy-proven IMN were correlated with immunohistochemical findings using monoclonal antibodies against T lymphocytes, monocytes/macrophages (MM), HLA-DR antigens, C5b-9, and adhesion molecules such as alpha3beta1, LFA-1beta, and ICAM-1., Results: In the glomeruli, C5b-9 deposits showed a significant correlation with the intensity of IgG and C3 deposition. The stage of the disease had a significant negative relationship with the glomerular alpha3beta1 expression. In the tubulointerstitium (TIN), the number of HLA-DR(+) cells was highly correlated with the numbers of total T lymphocytes, MM, and LFA-1beta(+) cells, as well as with the percentage of tubules with C5b-9 deposits. The extent of ICAM-1 expression in the TIN was significantly correlated with the numbers of interstitial MM, HLA-DR(+), and LFA-1beta(+) cells, as well as with the extent of tubular C5b-9 deposition. The severity of tubular atrophy and interstitial fibrosis had a relationship with the numbers of total T lymphocytes, MM, HLA-DR(+), and LFA-1beta(+) cells and with the extent of tubular C5b-9 deposition and ICAM-1 expression in the TIN. Serum creatinine (Scr) was highly correlated with the numbers of interstitial total T lymphocytes, MM, HLA-DR(+), and LFA-1beta(+) cells. Moreover, Scr had a significant relationship with the severity of tubular atrophy and interstitial fibrosis, as well as with the extent of tubular C5b-9 deposition and ICAM-1 expression in the TIN. Proteinuria was significantly correlated with the extent of tubular alpha3beta1 expression., Conclusions: In IMN, C5b-9 formation may be secondary to IgG and C3 deposition. Proteinuria may contribute to the TIN damage by altering the expression of alpha3beta1 integrins in tubular cells. De novo ICAM-1 and C5b-9 expression within the TIN as well as the activated interstitial cells may be important factors leading to renal damage and renal function impairment.

The best treatment of idiopathic membranous nephropathy remains an area of clinical controversy. At the moment only patients with nephrotic syndrome and/or declining renal function should be treated. Despite the negative trials, prolonged oral administration of corticosteroids alone may be a safe and an effective first-line treatment in nephrotic patients. If corticosteroids are ineffective, prolonged use of cyclosporine in low-doses can be recommended as an alternative treatment, that diminishes rapidly proteinuria in the majority of patients. Both treatments (intravenous high doses of corticosteroids and cyclosporine) may also be effective in patients with declining renal function. Because of their toxicity, the routine use of alkylating agents for patients with nephrotic syndrome is not justified. They may be retained for patients, in whom other treatment modalities have failed. Chlorambucil may be preferred over cyclophosphamide since it carries less toxicity. A lower dose of chlorambucil, than that usually suggested, for a short period of time seems to be prudent in an effort to avoid serious side-effects.

Tubulointerstitial lesions represent not only a constant component of the pathology of a "classical" glomerular disease such as idiopathic membranous nephropathy but also the most important prognostic indicator and a new "target" for its treatment. Proper "quantification" of the cellular events occurring within the interstitium may enable us to accurately assess the amount of disease activity and identify patients who might benefit from treatment.

Mononuclear inflammatory cells were retrospectively analysed using monoclonal antibodies in the interstitium and glomeruli of 16 renal biopsy specimens from patients with nephrotic syndrome due to idiopathic membranous nephropathy (IMN). The aim of the study was to determine the composition of the infiltrate and to assess the ability to predict the response of proteinuria to corticosteroids. All patients had received prednisolone as a sole treatment. Nine patients had shown a complete or partial remission of proteinuria (group A) and seven did not respond at all (group B). Both groups were matched for age and degree of proteinuria; also both groups had normal renal function at the time of biopsy. Very few intraglomerular leukocytes, mostly monocytes/macrophages (MM) were found. The majority of interstitial T cell population and B cells were a minor component. No significant differences were found between the two groups regarding the types of the intraglomerular cells. However, interstitial T-cells, CD4+ve T helper/inducer cells, CD8+ve T cytotoxic/suppressor cells and MM were significantly higher in group A than in group B. Also HLA-DR expressing interstitial cells were much in excess in group A. In addition patients with complete remission of proteinuria had higher numbers of interstitial cells compared to those with partial response. There was no correlation between the numbers of types of intraglomerular and interstitial cells and the degree of proteinuria at presentation. Also no association was found between intraglomerular or interstitial cell population and subsequent relapse of proteinuria. In conclusion, interstitial but not intraglomerular mononuclear cells seem to determine the initial response of proteinuria to corticosteroids in patients with IMN.

Thirty-six patients with idiopathic membranous nephropathy were retrospectively studied. The mean age was 47 years and the male to female ratio 25 to 11. Twenty-eight patients (77.8%) had nephrotic syndrome at first investigation. Nineteen patients received corticosteroids alone (group A) and 17 received corticosteroids combined with cyclophosphamide (group B). The mean period of follow-up was 58.9 months (range, 12 to 156 months). The two groups did not differ in clinical or laboratory features at the time of biopsy or at the start of treatment. In the entire series a complete remission of proteinuria occurred in 13 of 36 patients (36.1%) and a partial remission occurred in 13 (36.1%); 10 patients (27.8%) had no response. Optimal remission of proteinuria was usually recorded 6 to 12 months after the start of treatment. The two groups showed no statistical differences regarding the rate of complete (seven v six patients; P = not significant) or partial (six v seven patients; P = not significant) remissions. Two patients (one from each group) entered end stage renal failure during follow-up. At last assessment, the number of patients with complete remission (four v three patients; P = not significant), nonnephrotic proteinuria (nine v nine patients; P = not significant), or nephrotic syndrome (five v four patients; P = not significant) was similar in both groups. In addition, final plasma creatinine did not differ significantly between the two groups (1.8 +/- 2.3 mg/dL v 2.6 +/- 2.6 mg/dL; P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Mononuclear inflammatory cells in renal biopsies from 36 patients with membranous nephropathy (MN) were analyzed, using monoclonal antibodies. In the interstitium, monocytes/macrophages and T cells were the predominant cell types (210 +/- 27 and 171 +/- 25/mm2, respectively); in contrast, very few intraglomerular leucocytes, mostly macrophages (1.0 +/- 0.7 cell/glomerular cross-section), were found. Among the interstitial T-cell population, helper/inducer cells (CD4+) predominated (CD4:CD8 ratio, 2.2 +/- 1.5). Natural killer (NK) cells and B lymphocytes were a minor component of the interstitial infiltrates and were almost absent in the glomeruli. Significantly higher numbers of DR-expressing cells were found in the interstitium (322 +/- 20/mm2) than in controls (109 +/- 30), but tubular DR expression was similar to controls (17 +/- 12 mm2). The numbers of total leukocytes and their subsets CD4+, CD8+, monocytes/macrophages, and B cells all correlated with the degree of renal impairment at the time of biopsy, but surprisingly there was no correlation between interstitial cell numbers and the histological severity of tubulointerstitial lesions. Progressive renal impairment over 5 years was associated with many interstitial T cells and monocytes/macrophages in the initial biopsy. Our results suggest that interstitial mononuclear cells may be important determinants in the pathogenesis of MN. Both cellular and humoral immune mechanisms may play a major role in the initiation of the disease, whereas progression toward renal failure seems to be determined mainly by cell-mediated immunity.