Significance of mesangial IgA deposition in minimal change nephrotic syndrome: a study of 60 cases

We studied 60 cases of minimal change nephrotic syndrome (MCNS) with mesangial IgA deposits occurring over a 6 year period. There were 43 adults and 17 children. Hematuria occurred in 69.0% of the adults and 88.2% of the children. Two adults and six children had gross hematuria during the course of the disease. Mesangial IgA deposits were noted in 100% of the cases, and concomitant IgG or IgM deposits were found in 78.6% of adults and 73.7% of children. The fluorescent intensity of mesangial IgA deposits was trace (+/-) to 1+ in 86.1% and 70.6% of the adults and children respectively. Most of the patients showed electron microscopic findings consistent with minimal change nephrotic syndrome. We speculate that most of our cases are variants of minimal change nephrotic syndrome but are neither IgA nephropathy nor an overlapping syndrome, and that environmental or genetic factors may be related to the deposition of IgA in these MCNS patients.     

Mesangial alterations in steroid-responsive minimal change nephrotic syndrome

Summary Renal biopsies from 25 children with steroid-sensitive minimal change nephrotic syndrome were evaluated retrospectively to determine whether there is any relation between the morphological changes and the frequency of relapses. Biopsy material was examined by light-, immunofluorescence-, and electron microscopy, and by morphometric methods. The patients were divided in a group of 15 children with frequent relapses (FR) and another group of 10 children with an absence of, or only infrequent, relapses (NR/IR). Semiquantitative evaluation of biopsy specimens disclosed no significant differences between groups, but morphometric measurements performed on toluidine stained semithin sections showed a significant increase of mesangial nuclei in FR compared with NR/IR (P<0.01). Furthermore, the mean area of mesangial nuclei was decreased and the relative frequency of smaller nuclear profiles was higher in patients with FR compared to NR/IR (p<0.01). These findings suggest mesangial cell activation in FR which may be related to a longer course of the disease prior to renal biopsy (mean 4.0 years in FR vs. 1.4 years in NR/IR). In our opinion, morphometric assessment of discrete mesangial alterations is a promising method for exploring clinicopathological correlations in minimal change nephrotic syndrome.Presented in part at the 5th International Symposium of Pediatric Nephrology, Philadelphia, USA, October 6–10, 1980     

Immune status of children suffering from minimal change nephrotic syndrome.

Twenty five children suffering from minimal change nephrotic syndrome were studied for immunological alterations at different stages of this disease i.e., onset, relapse and remission. Changes were found mainly at onset and during relapse in the form of altered helper and suppressor cell ratio, depressed delayed cutaneous hypersensitivity reaction, decreased S-IgG bearing lymphocytes with low serum IgG concentration, and increased S-IgM bearing lymphocytes with high serum IgM concentration. Majority of these parameters returned to normal values during remission. Serum IgE was found high at all stages of this. These alterations suggest defects in cell mediated immunity resulting in secretion of some substance which modifies the glomerular anionic charges.     

Mesangial myofibroblastic transformation in steroid-dependent minimal change nephrotic syndrome

Patients with minimal change nephrotic syndrome (MCNS) occasionally show frequent relapses with proteinuria after cessation of steroid treatment, even though no significant pathological abnormalities are found in the glomeruli, compared with those in nonrelapsed and good-prognosis cases of MCNS. To resolve this contradiction, we immunohistochemically and ultrastructurally examined a biopsied renal tissue of a patient who showed glomerular features of MCNS and frequent clinical relapses. Immunohistochemistry demonstrated the overexpression of alpha-smooth muscle actin (ASMA) and vimentin in glomerular mesangial cells despite no mesangial cell proliferation, compared with nine nonrelapsed cases of MCNS. These facts may be an important clue to the investigation of the pathogenesis of steroid-dependent MCNS with frequent relapses. Furthermore, the immunohistochemical examination of ASMA and vimentin may be useful to detect mesangial myofibroblastic transformation that is not demonstrated in conventional light microscopy and immunofluorescence study.     

A case of rheumatoid arthritis associated with minimal change nephrotic syndrome]

A 55-year-old Japanese woman has been treated with various kinds of anti-rheumatic drugs under a diagnosis of rheumatoid arthritis(RA) for 18 years of disease duration. She persistently had right elbow joint pain and swelling and X-ray showed bone erosion on humerus. Thus, the synovectomy was performed with typical histopathology of RA on April 1999. On the end of February 2000, she had suddenly fatigue and anasarca with profound proteinuria of nephrotic syndrome. The renal biopsy showed minimal change glomerulopathy and no cellular infiltration in interstitial tissue by light microscopy and partial fusion of foot process by electron microscopy. Renal function was sustained normally. All of anti-rheumatic drugs including D-penicillamine(D-Pc) except NSAID were stopped and she was treated with bed rest, diet therapy, diuretics and albumin infusion without steroid therapy. Edema and proteinuria gradually disappeared. Membranous and amyloid nephropathy in RA patients associated with nephrotic syndrome are found in high incidence in literature. In low incidence, MCNS is associated with NSAID or D-Pc induced nephropathy in RA. In our case, nephrotic syndrome disappeared in 6 weeks without discontinuation of NSAID and application of steroid therapy. Thus, MCNS might be co-incidentally associated with RA.     

Impaired immunoglobulin G production in minimal change nephrotic syndrome in adults.

Serum IgG, T and B cell subsets, cytoplasmic IgG positive cells (cB gamma) and IgG in the medium (cIgG) of a 5 day culture of peripheral lymphocytes in both stimulated and non-stimulated (spontaneous) conditions with pokeweed mitogen (PWM) were studied in 30 adult patients with minimal change nephrotic syndrome (MCNS). In the nephrotic phase (11 patients), surface IgG positive B cells (sB gamma) and spontaneous cB gamma increased (P less than 0.05), whereas PWM-stimulated cIgG did not increase, and serum IgG decreased significantly (P less than 0.05). The cB gamma/sB gamma ratio calculated as an index of IgG synthesis in B cells increased spontaneously (P less than 0.05), but did not increase under PWM-stimulation. The cIgG/cB gamma ratio as an index of IgG secretion from each matured B cell, reduced in both spontaneous and stimulated conditions (P less than 0.05, P less than 0.01, respectively). In the phase of unstable remission maintained by steroid therapy (10 patients), these parameters tended to normalize and the OKT4/OKT8 ratio decreased (P less than 0.05), while the ratio remained unchanged in the nephrotic phase. However, after discontinuation of steroid (nine patients), spontaneous cB gamma and the spontaneous cB gamma/sB gamma ratio were again increased, and the cIgG/cB gamma ratio decreased (P less than 0.05) as observed in the nephrotic phase. These results suggest that B cells in patients with MCNS both in the nephrotic state and stable remission after discontinuation of steroid are activated spontaneously, but the secretory process of IgG from the matured cells is impaired, and that steroid improves these abnormalities.     

Cyclosporin a treatment in children with minimal change nephrotic syndrome and focal segmental glomerulosclerosis

Summary In a pilot study 23 children with nephrotic syndrome were treated with cyclosporin A (Cs) for 6–45 months. 8 children suffered from steroid dependent minimal change nephrotic syndrome (MCNS) and had experienced at least one course with cytotoxic drugs, but had relapsed thereafter. 2 children had diabetes mellitus type I with nephrotic syndrome and 13 children had steroid resistant focal segmental glomerulosclerosis (FSGS). Cs was started with 100 mg/m2/day in two doses and increased stepwise to obtain a Cs whole blood trough level of 200–400 ng/ml. In steroid dependent MCNS treatment with Cs reduced relapse rate significantly, and prednisone therapy could be stopped completely. After discontinuation of Cs, relapses reoccurred as frequently as before. Renal function remained unimpaired despite repeated Cs treatment courses up to 38 months. In cases of nephrotic syndrome with diabetes type I Cs treatment led to complete remission without changing the insulin requirement. However, after discontinuation of Cs relapses reoccurred. In steroid resistant FSGS 6 children benefited from Cs treatment: 4 went into complete remission, 2 into partial remission. The 2 children with complete remission relapsed but remained Cs responsive. The remaining 7 children with FSGS did not respond to Cs but continued the course of their disease, with two patients rapidly progressing to terminal renal failure. Side-effects of Cs treatment were mild. It is concluded that Cs is an effective agent in steroid dependent MCNS and can be used as an alternative drug in specific cases like steroid toxicity or diabetes mellitus. In steroid resistant FSGS a trial with Cs seems to be warranted since some cases do respond favorably. To avoid nephrotoxicity treatment with Cs should always be monitored closely by determination of blood levels and renal function.Abbreviations MCNS minimal change nephrotic syndrome - FSGS focal segmental glomerulosclerosis - Cs Cyclosporin A     

Electron microscopic findings suggestive of focal and segmental glomerulosclerosis in patients with steroid-resistant nephrotic syndrome

Distinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0–3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico–medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.     

Involvement of allergic mechanism in minimal change nephrotic syndrome (MCNS)]

In this study we evaluated the involvement of allergic mechanisms in patients with adult onset MCNS (17 cases) by measuring serum IgE levels and RAST scores to house dust 1 (H.D.1), house dust 2 (H.D.2), Dermatophagoides farinae (D.f.), Dermatophagoides ptenonyssinus (D.p.). Out of the 17 cases, three cases showed high levels of IgE (more than 1000 IU/ml) and the mean level of serum IgE was 877 IU/ml before treatment. All cases were treated with steroid and/or cyclophosphamide. After the treatment, all cases returned to remission. The level of IgE decreased to the normal range in four out of seven cases which had shown high levels of IgE before treatment. RAST was carried out on seven of the 17 cases. RAST scores for D.f. and D.f. were found to be positive in three cases, but these became negative in two cases after treatment. In five cases relapsed, the all cases showed to have the increased level of serum IgE and two of four cases which were examined RAST score showed to have the increased RAST score for D.f. and D.p. Thus, the data indicated that allergic mechanism, especially against D.f. and D.p. antigen, seemed to play one of the factors in the pathogenesis of MCNS.     

Pathogenic role of polyclonal and polymeric IgA in a murine model of mesangial proliferative glomerulonephritis with IgA deposition.

Molecular size and charge distribution of IgA of sera and glomerular eluates were investigated in ddY mice, spontaneously developing mesangial proliferative glomerulonephritis (GN) with IgA deposition after 40 weeks of age. Serum IgA levels were increased in aged ddY mice more than 40 weeks old with a significant increase (P less than 0.01) at the age of 60 weeks, comparing with those of BALB/c mice. The isoelectric focusing (IEF) spectrotype of pooled serum IgA in 60-week-old mice ranged from 4.2 to 5.5, being similar to those in younger ddY (16 weeks old) and control BALB/c mice (12 weeks old) without enhanced expression of specific IgA peaks. However, IgA in the glomerular eluate from the 60-week-old mice showed limited anionic spectrotypes from pH 4.2 to 4.8. HPLC of IgA in pooled sera and glomerular eluates of 16-, 40- and 60-week-old ddY mice, revealed markedly increased ratios of the dimeric IgA (dIgA) and polymeric IgA (pIgA) in the total IgA with age. In the contrast to serum profiles, monomeric IgA (mIgA) was always detected as the smallest peak of the IgA fractions in glomerular eluates. Furthermore, aged mice with severe GN showed a higher percentage of dIgA and pIgA in total IgA (80%) in the sera than that of the mice with mild GN (64%). HPLC analysis under acid condition of glomerular IgA from 40-week-old ddY mice showed a similar pattern of dIgA and pIgA peaks in neutral buffer without the appearance of mIgA. These findings suggest that there is a selective mechanism for glomerular accumulation of more acid IgA among the polyclonally expanded IgA in old ddY mice, and that the polymeric form of IgA plays a pathogenic role in the development of mesangial proliferative GN in these mice.     

Acute renal failure associated with a minimal change nephrotic syndrome in a systemic lupus erythematosus patient

In systemic lupus erythematosus (SLE), acute renal failure (ARF) is usually associated with severe lupus nephritis and ARF associated with other glomerular diseases is extremely rare. We recently encountered a patient with ARF that was associated with a minimal change nephrotic syndrome (MCNS) in SLE. A 41-year-old woman presented with a nephrotic syndrome and ARF. She fulfilled four of the American College of Rheumatology criteria for the classification of SLE. However, a renal biopsy revealed that there were no glomerular abnormalities and no deposition of immune complex. The generalized edema disappeared and the high creatinine levels decreased after prednisolone therapy.     

Glomerular macrophages and the mesangial proliferative response in the experimental nephrotic syndrome.

Mesangial cell proliferation, which is a harbinger of glomerulosclerosis, occurs in both immune and nonimmune glomerulopathies. The proximity of infiltrating glomerular macrophages to the contractile mesangial cells during acute puromycin aminonucleoside (PA) nephrosis suggests the possibility of a paracrine effect on mesangial cell growth. To test this, three maneuvers to either raise or lower the glomerular macrophage number during acute PA nephrosis (2 weeks after PA) were employed: 1) an essential fatty acid-deficient (EFAD) diet; 2) a cholesterol-supplemented diet (CSD); and 3) a single dose (600 rad) whole-body X-irradiation (XI) given to CSD-fed PA rats. Both the glomerular macrophage number and proliferation within the mesangium were evaluated immunohistochemically with ED-1, a mouse monoclonal anti-rat macrophage label, and 19A2, a mouse monoclonal anti-proliferating cell nuclear antigen (PCNA)/cyclin antibody, respectively. Immunohistochemical detection of 5'-bromo-2'-deoxyuridine (BrdU) incorporation confirmed that proliferation was occurring within the mesangial zones. The EFAD diet significantly reduced both the glomerular macrophage and PCNA/cyclin-positive cell number at 2 weeks after PA with a positive correlation (r = 0.89, P < 0.05). The CSD maneuver significantly increased both the glomerular macrophage and PCNA/cyclin cell number with a strong degree of correlation (r = 0.95, P < 0.01). X-irradiation administered to CSD-fed PA rats significantly lowered both the glomerular macrophage and PCNA/cyclin-positive cell number at 2 weeks. In all groups, the glomerular tufts did not express muscle actin using HHF 35, a specific immunolabel, suggesting that the proliferation in this model is not related to direct mesangial cell injury. This study shows that maneuvers that modulate the glomerular macrophage number are also associated with corresponding changes in the number of proliferating cells within the mesangium, suggesting a paracrine growth stimulation by the infiltrating macrophage during acute PA nephrosis. The infiltrating glomerular macrophage may be an effector mechanism for the propagation of initial glomerular injury to glomerulosclerosis by augmenting mesangial cell proliferation early in the course of this nonimmune progressive glomerulopathy.