A case of minimal change nephrotic syndrome with immunoglobulin A nephropathy transitioned to focal segmental glomerulosclerosis.
ABSTRACT A 50-year-old woman with a 1-month history of lower extremity edema and a 5 kg weight increase was admitted to our hospital with suspected nephrotic syndrome in October 1999. Urine protein level was 3.5 g per day, 10-15 erythrocytes in urine per high-power field, and serum albumin level 2.5 g/dl. Furthermore, an accumulation of pleural effusion was confirmed by chest X-ray. The results of a renal biopsy indicated slight mesangial proliferation in the glomeruli by light microscopy, and an immunofluorescence study confirmed the deposition of immunoglobulin (Ig) A and C3 in the mesangial area. Diffuse attenuation of foot processes and dense deposits in the mesangial area were observed by electron microscopy. Treatment with 40 mg/day of prednisolone was effective, and proteinuria was negative 1 month later. Because of this course, we diagnosed minimal change nephrotic syndrome complicated by mild-proliferative IgA nephropathy. In November 2000, there was a relapse of nephrotic syndrome, which was believed to be induced by an influenza vaccination, but response to increased steroid treatment was favorable, and proteinuria disappeared on day 13 of steroid increase. A second relapse in May 2001, showed steroid resistance with renal insufficiency, and an increase in the selectivity index to 0.195. Light microscopy revealed focal sclerotic lesions of the glomeruli, and an immunofluorescence study revealed attenuation of mesangial IgA and C3 deposition. These findings led to the diagnosis that minimal change nephrotic syndrome had transitioned to focal segmental glomerulosclerosis, whereby mesangial IgA deposition was reduced by immunosuppressive treatment. Subsequently, her renal function gradually worsened to the point of end-stage renal failure by 27 months after the second relapse of nephrotic syndrome.
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ABSTRACT: An experimental model of focal sclerosis (FS) following chronic administration of aminonucleoside (AMNS) is described in rats with pathologic features similar to those observed in human steroid-resistant idiopathic nephrotic syndrome. Six groups of rats were given intraperitoneal injections of either 0.9% normal saline or aminonucleoside (13 mg. per 100 gm. of body weight); four groups underwent a right nephrectomy on day 22; a second series of injections of saline or aminonucleoside were then administered to all six groups: group I (five animals), saline-saline; group II (10 animals), AMNS-AMNS; group III (10 animals), AMNS-nephrectomy-AMNS; group IV (five animals), AMNS-nephrectomy-saline; group V (five animals), saline-nephrectomy-AMNS; group VI (five animals), saline-nephrectomy-saline. A relationship between the percentage of glomeruli with focal sclerosis and the total amount of protein excreted during the course of the experiment was observed (r=0.80). An apparent threshold level of protein excretion essential for the development of FS was also noted in that all rats excreting greater than 2.2 integral units developed FS whereas those excreting less than this amount did not. The highest incidence of FS was seen in rats that had received AMNS after unilateral nephrectomy: 62% of glomeruli with FS in group III and 26% in group V; whereas no FS was seen in groups I and VI or in rats evaluated 7 to 23 days after a single injection of AMNS. These studies indicate a quantitative relationship between the breakdown in the permeability barrier to protein and the ultimate development of FS. The prior demonstration of epithelial cell alteration in acute AMNS disease and the morphologic changes presented in this and the subsequent paper (Velosa JA, Glasser RJ, Nevins TE, Michael AF: Lab Invest 36:527, 1977) support the concept that irreversible epithelial cell injury may be the primary event in the development of FS.Laboratory Investigation 06/1977; 36(5):519-26. · 3.96 Impact Factor
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ABSTRACT: The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of "bare" GBM. which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architectural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis.Kidney International 10/1998; 54(3):687-97. · 7.92 Impact Factor
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ABSTRACT: The selectivity of proteinuria, introduced in clinical nephrology in 1960 and useful in predicting steroid responsiveness in nephrotic syndrome, found little place in clinical practice in subsequent decades, since its assessment did not appear to help predict histologic diagnosis or determine prognosis. The amount of proteinuria and the degree of tubulointerstitial damage appeared to be better predictors of functional outcome. A correlation between them has been found, referred to some toxicity of proteinuria on tubular cells, but so far no single feature or component of proteinuria has been identified as being responsible for this toxicity. We evaluated 89 patients with nephrotic syndrome [9 with minimal change disease (MCD), 29 with primary focal segmental glomerulosclerosis (FSGS), and 51 with idiopathic membranous glomerulonephritis (MGN)] to determine if the selectivity of proteinuria was associated with tubulointerstitial damage. A semiquantitative grading of histologic lesions and qualitative evaluation of the "tubular" component of proteinuria expressed as a pattern of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and as fractional excretion of the low molecular weight (LMW) protein alpha1-microglobulin (FE alpha1m) were used. A second aim of the study was to assess the predictive value on functional outcome [remission or progression to chronic renal failure (CRF)] and response to therapy of the selectivity of proteinuria, considered alone and in combination with FE alpha1m. Proteinuria was classified as highly selective [selectivity index (SI) < or = 0.10, N = 15], moderately selective (SI > or = 0.11 < or = 0.20, N = 34), or nonselective (SI > or = 0.21, N = 40). A significant relationship was found between the SI and the histologic degree of tubulointerstitial damage (score 0 to 1 vs. score > or =2, P = 0.000), severity of the tubular component of proteinuria (mixed SDS-PAGE pattern with LMW proteins not lower than 23 kD vs. mixed pattern with LMW proteins up to 20 to 10 kD, P = 0.000), and FE alpha1m (values below vs. above a defined cut-off, P = 0.000). The functional outcome was evaluated in 60 patients with baseline normal renal function (serum creatinine 0.97 +/- 0.19 mg/dL). The patients with high, moderate, or nonselective proteinuria had 100, 50, and 29% of complete or partial remission (P = 0.0001) and 0, 25, and 35% of progression to CRF, respectively (P = 0.050). In 45 patients with moderately selective (N = 28) and nonselective (N = 17) proteinuria, according to some arbitrary cutoffs for FE alpha1m (MGN, < or = vs. > 0. 240% of creatinine clearance; FSGS and MCD, < or = vs. > 0.350%), the remission rate was 62 versus 6% in patients with FE alpha1m below or above the cutoffs (P = 0.0001), and progression to CRF was 7 and 69%, respectively (P = 0.0001). The response to therapy (complete or partial remission at the last observation), evaluated retrospectively in 40 patients, was 100, 67, and 33% in high, moderate, and nonselective proteinuria (P = 0.0002); in 30 patients with moderate and nonselective proteinuria, according to an FE alpha1m value that was < or = or > the cutoffs, the response rate was 75 versus 10% (P = 0.001). There is a significant relationship between selectivity of proteinuria and tubulointerstitial damage. Moreover, the selectivity of proteinuria has a predictive value on functional outcome. When proteinuria is highly selective, the tubulointerstitial damage is rather infrequent, and 100% of patients develop clinical remission. When proteinuria is moderately selective or nonselective, increasing numbers of patients develop tubulointerstitial damage; in these patients, the functional outcome and response to therapy is partly dependent on tubulointerstitial involvement, and the best predictor of functional outcome is the combination of SI and FE alpha1m.Kidney International 10/2000; 58(4):1732-41. · 7.92 Impact Factor