Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy.

BACKGROUND: The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. METHODS: We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearance, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine >135 micromol/l or increase of serum creatinine of >50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. RESULTS: We included 53 patients (33M, 20F). Mean age was 51 years, serum creatinine 99 micromol/l, and proteinuria 7.0 g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time of biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). CONCLUSION: FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.     

Short- and long-term efficacy of oral cyclophosphamide and steroids in patients with membranous nephropathy and renal insufficiency. Study Group

BACKGROUND: Up to half of the patients with idiopathic membranous nephropathy (iMN) will develop renal failure. Preferably, immunosuppressive treatment should be restricted to patients at risk for the development of end-stage renal disease. However, the evidence that immunosuppressive treatment is effective in patients with iMN and renal insufficiency is weak and based on few studies with short follow-up in a limited number of patients. METHODS: We have analyzed the efficacy of immunosuppressive treatment in a large number of patients with membranous nephropathy and renal insufficiency. Since 1991, we have prospectively treated 39 patients (31 M, 8 F) with membranous nephropathy and evidence of deterioration of renal function. Treatment consisted of oral cyclophosphamide, 1.5-2.0 mg/kg body weight for 12 months, and corticosteroids for 6 months. At regular intervals blood pressure, serum creatinine, serum albumin, and proteinuria were measured. Adverse events were recorded. RESULTS: Average follow-up is 32 months (range 6-104), 18 patients have been followed for more than 3 years. Mean age of the patients was 55 +/- 12 years. In the 6 months before start of therapy, serum creatinine increased from 150 +/- 74 to 226 +/- 108 micromol/l. After start of treatment renal function rapidly improved, serum creatinine at 12 months averaging 143 +/- 62 micromol/l. Proteinuria decreased from 10.3 +/- 4.9 g/10 mmol creatinine at baseline to 2.2 +/- 2.4 g/10 mmol creatinine at month 12. These initial favorable effects have persisted. Overall, 12 patients have developed a complete remission of proteinuria (persistent in 11), and an additional 19 have developed a partial remission of proteinuria (persistent in 15). Thus far, only one treated patient has developed end-stage renal disease. Side effects are a major drawback of the treatment, with 7 patients being admitted, mainly for the treatment of infectious complications. CONCLUSIONS: Cyclophosphamide is effective in the treatment of patients with idiopathic membranous nephropathy and deterioration of renal function. The favorable effects are maintained well beyond the one-year treatment period. Therefore, we propose that in patients with iMN immunosuppressive therapy can be restricted to patients at high risk for end-stage renal disease.     

Beta-2-microglobulin is superior to N-acetyl-beta-glucosaminidase in predicting prognosis in idiopathic membranous nephropathy.

BACKGROUND: An accurate prediction of prognosis in patients with idiopathic membranous nephropathy (iMN) would allow restriction of immunosuppressive treatment to patients who are at highest risk for end-stage renal disease (ESRD). Several markers of proximal tubular cell injury have been used as predictors of prognosis. In this study we compared the accuracy of urinary beta-2-microglobulin (U beta 2m) and N-acetyl-beta-glucosaminidase (U beta-NAG) in predicting renal insufficiency and remission rates. METHODS: Fifty-seven patients with iMN (38 M, 19 F; age 48 +/- 16 years), a nephrotic syndrome and a serum creatinine level <135 micromol/l were studied prospectively. At baseline, a standardised measurement was carried out to determine renal function and protein excretion. The end-point renal failure was defined as a serum creatinine exceeding 135 micromol/l or an increase in serum creatinine by >50%. Remission was defined as a proteinuria <2.0 g/day with stable renal function. RESULTS: The mean follow-up was 80 +/- 36 months. The mean serum creatinine concentration was 89 +/- 20 micromol/l, serum albumin 24 +/- 5.3 g/l and proteinuria 8.9 +/- 4.8 g/24 h. Thus far, 28 (49%) patients have reached the predefined end point of renal failure. Multivariate analysis identified U beta 2m as the strongest independent predictor for the development of renal insufficiency. Sensitivity and specificity were 81 and 90% respectively for U beta 2m (threshold value 54 microg/mmol cr), and 74 and 81% respectively for U beta-NAG (threshold value 2.64 U/mmol cr). The overall remission rate was 44%. A remission occurred in 78% of patients with low U beta 2m and in 14% of patients with high U beta 2m, and respectively in 71% of patients with low U beta-NAG and 21% of patients with high U beta-NAG. CONCLUSIONS: Although both U beta 2m and U beta-NAG predicted progression and remission in iMN, U beta 2m was more accurate. High specificity in predicting prognosis should be pursued to avoid unnecessary immunosuppressive therapy. We therefore conclude that U beta 2m is superior to U beta-NAG in predicting prognosis in patients with iMN.     

Short-term effects of fish oil treatment on urinary excretion of high- and low-molecular weight proteins in patients with IgA nephropathy

AIMS: Recently, it was shown that fish oil treatment improved renal survival in patients with IgA nephropathy. The precise mechanisms of this protective effect remained unclear. Omega-3 polyunsaturated fatty acids (PUFAs), important active substances of fish oil, are able to attenuate inflammatory responses. Thus, the renoprotective effects of fish oil may be the result of mitigation of glomerular or tubulo-interstitial inflammation. We hypothesized that such a decrease in glomerular or tubulo-interstitial inflammation could result in an improvement of glomerular permselectivity as reflected by the urinary excretion of IgG, or of tubular reabsorption capacity as reflected by the urinary excretion of low-molecular weight proteins (LMWPs), or a decrease of the excretion of the inflammatory mediators MCP-1 and TNF-alpha. METHODS: Twelve patients with a biopsy-proven IgA nephropathy, a persistent proteinuria of > 0.5 g/24 h, and an impairment of renal function (creatinine clearance 44 ml/min/1.73 m2, range 19-72) were treated with fish oil for 6 months. The daily dosage of PUFAs amounted to 3.0 g. Before start of treatment (month 0), at the end of treatment (month 6), and 6 months off treatment (month 12), renal measurements were carried out. Creatinine clearance (ECC) was measured after pretreatment with cimetidine. In timed urine samples albumin, IgG, the LMWPs beta2-microglobulin and alpha1-microglobulin, and both MCP-1 and TNF-alpha were measured. RESULTS: Six months of fish oil treatment had no effect on creatinine clearance (44 ml/min/1.73 m2 vs 42 ml/min/1.73 m2), the urinary excretion of albumin (1,594 +/- 284 vs 1,370 +/- 337 microg/min), IgG (84 +/- 16 vs 82 +/- 20 microg/min), beta2-microglobulin (medians: 1.0 vs 0.8 microg/min), alpha1-microglobulin (38 +/- 9 vs 53 +/- 15 microg/min), MCP-1 (medians: 720 vs 782 microg/min), or TNF-alpha (medians: 31 vs 27 microg/min). Mean arterial pressure gradually decreased from 102 +/- 4 to 96 +/- 4 mmHg at the end of the treatment (n.s.), however, the lowest value was observed after fish oil had been stopped for 6 months (93 +/- 3 mmHg, p < 0.05). Changes in the excretion of the urinary proteins during the 12-month study period were correlated to changes in blood pressure (r = 0.57, p < 0.01), independent of fish oil treatment. The course of the disease over the 12-month study period in our fish oil-treated patients was comparable to that of an untreated control group. CONCLUSIONS: Fish oil treatment in patients with IgA nephropathy, renal insufficiency and proteinuria did not affect the excretion of low- or high-molecular weight proteins, MCP-1 or TNF-alpha. Our data do not provide arguments for beneficial effects of fish oil treatment on glomerular permselectivity of tubulo-interstitial inflammation.     

Efficacy of a second course of immunosuppressive therapy in patients with membranous nephropathy and persistent or relapsing disease activity.

BACKGROUND: A single course of immunosuppressive treatment improves renal survival in patients with idiopathic membranous nephropathy (iMN) and renal insufficiency. However, not all patients respond and relapses occur within 5 years in 30% of patients. It is unknown if a second course of immunosuppressive therapy is effective in such patients. METHODS: We have prospectively studied and evaluated the clinical course in 15 patients (14 male, one female; age: 52+/-12 years) with iMN who have received a repeated course of immunosuppressive therapy because of deteriorating renal function associated with relapsing or persistent nephrotic syndrome. RESULTS: The first course of immunosuppression was started 8 months (range: 0-143 months) after renal biopsy and consisted of chlorambucil (n = 8) or cyclophosphamide (n = 7); the second course consisted of cyclophosphamide in all patients. The interval between the first and second course was 40 months (range: 7-112 months). Total follow-up was 110 months (range: 46-289 months). Renal function and proteinuria improved at least temporarily in all patients after the second course. During follow-up, an additional course of therapy was given in four patients. Status at the end of follow-up was complete remission (n = 2), partial remission (n = 8), persistent proteinuria (n = 3), end-stage renal disease (n = 1) and death (n = 1, due to cardiovascular disease while nephrotic). Renal survival was 86% at 5 and 10 years of follow-up. The repeated courses of immunosuppression have resulted in a gain of dialysis-free survival time of > or =93 months (range: 43-192 months). CONCLUSIONS: Our results indicate that patients with iMN who do not respond well or relapse after a first course of immunosuppressive therapy and have renal insufficiency should be offered a second course of immunosuppression. Such a strategy maintains renal function in the majority of patients.     

Cytotoxic therapy for membranous nephropathy and renal insufficiency: improved renal survival but high relapse rate.

BACKGROUND: Patients with idiopathic membranous nephropathy (iMN) and renal insufficiency have a high risk for progression to end-stage renal disease (ESRD). In the short term, treatment with oral cyclophosphamide and steroids attenuates the deterioration of renal function in these patients; however, the long-term efficacy is unknown. METHODS: We have studied prospectively 65 patients with iMN and renal insufficiency (serum creatinine >135 micromol/l) who were treated with oral cyclophosphamide (1.5-2.0 mg/kg/day for 12 months) and steroids (methylprednisolone pulses 3 x 1 g, i.v. at months 1, 3 and 5, and oral prednisone 0.5 mg/kg/48 h for 6 months). RESULTS: Follow-up was 51 (5-132) months. Renal function temporarily improved or stabilized in all patients. A partial remission (PR) occurred in 56 patients followed by a complete remission (CR) in 17. During follow-up, 11 patients had relapsed (28% relapse rate after 5 years), of whom nine were re-treated because of renal function deterioration. At the end of follow-up, 16 patients were in CR, 31 in PR, eight had a persistent nephrotic syndrome, one had mild proteinuria, four had progressed to ESRD and five had died. Overall renal survival was 86% after 5 years and 74% after 7 years, compared with 32% after 5 and 7 years in a historical control group. Treatment-related complications occurred in two-thirds of patients, mainly consisting of bone marrow depression and infections. One patient has developed bladder cancer, another patient prostate cancer. CONCLUSIONS: Renal survival is good if patients with iMN and renal insufficiency are treated with oral cyclophosphamide. However, side effects occur frequently and relapse rate is high during longer follow-up.     

Screening for CLCN5 mutation in renal calcium stone formers patients

Thirty-five patients (23 males and 12 females), age 35 +/- 13 years old, presenting either idiopathic calcium nephrolithiasis, nephrocalcinosis or mild renal failure with idiopathic calcium nephrolithiasis were selected for the analysis of low molecular weight proteinuria and the possible mutations occurrence in the chloride channel gene CLCN5. The urinary ratio of beta2-microglobulin and creatinine (beta2M/Cr) was very high in a transplanted woman with nephrocalcinosis (> 3.23 mg/mmol) and slightly high in five patients (> 0.052 or < 1.0 mg/mmol) with multiple urological manipulations. Other studied patients showed beta2M/Cr ratio at normal range (0.003-0.052 mg/mmol) without gender difference (p > 0.05). Mutation analysis of CLCN5 gene was performed in 26 patients of 35 selected (11 with idiopathic hypercalciuria; 6 men with normal calciuria; 3 with mild renal insufficiency and 6 with nephrocalcinosis) and was normal in all subjects even in those with abnormal molecular weight proteinuria. Conclusion: CLCN5 gene mutation is not a common cause of kidney stone disease or nephrocalcinosis in a group of Brazilian patients studied.     

Long-term outcome of patients with membranous nephropathy after complete remission of proteinuria

To assess the prognostic significance of complete remission in patients with idiopathic membranous nephropathy, 33 patients were followed for a median of 96 months after remission of proteinuria. All patients had had a histological diagnosis of membranous nephropathy and a nephrotic syndrome. Only patients with a complete remission lasting for at least six months and with a follow-up of at least four years after remission were considered. No relapse of proteinuria developed in 17 patients (51%), 7 patients had relapse of non-nephrotic proteinuria (21%) and 9 (27%) relapse of nephrotic proteinuria. However proteinuria disappeared again in some patients so that at follow-up 73% of patients are in complete remission, 21% have non-nephrotic proteinuria and only 6% have nephrotic syndrome. All patients maintained a normal plasma creatinine over the years. It is concluded that complete remission of proteinuria is a strong predictor of long-term favourable outcome in patients with idiopathic membranous nephropathy.     

Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis.

BACKGROUND: The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy. METHODS: In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine. RESULTS: Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, 18 U/g urinary Cr; FSGS and MCD, 24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs. CONCLUSION: Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.     

Beta2-Microglobulin and Alpha1-Microglobulin as Markers of Balkan Endemic Nephropathy,a Worldwide Disease

Background:?Urine beta2-microglobulin (beta2-MG) was mainly used as a tubular marker of Balkan endemic nephropathy (BEN) but recently alpha1-microglobulin (alpha1-MG) was proposed for the diagnosis of BEN. In this study, the potential of urine beta2-MG, alpha1-MG, albumin, and total protein in the differentiation of BEN from healthy persons and patients with glomerulonephritis (GN) and nephrosclerosis (NS) was examined.?Methods:?This study involved 47 patients with BEN, 36 with GN, 11 with NS, 30 healthy subjects from BEN families, and 46 healthy subjects from non-BEN families.?Results:?In BEN patients area under the curve (AUC) for urine beta2-MG (0.828) and alpha1-MG (0.782) was higher than for urine albumin (0.740), but in GN patients AUC for urine protein (0.854) and albumin (0.872) was significantly higher than for the two low molecular weight proteins. AUC for all four urinary markers in NS patients was significantly lower than in BEN patients, ranging between 500 and 595. Median urine beta2-MG excretion in BEN patients was 17.5 times higher than in GN patients and 18.3 times higher than in controls; median alpha1-MG excretion was higher only 3.0 and 2.25 times, respectively. In the differentiation of BEN from healthy controls, beta2-MG had higher sensitivity and specificity at the cutoff levels (p < 0.001) than alpha1-MG (p < 0.05). In the differentiation of BEN from GN, beta2-MG was the best marker.?Conclusion:?All four urinary markers can be used for the differential diagnosis of BEN, beta2-MG being the best. Like in aristolochic acid nephropathy, beta2-MG seems to be an early marker of tubular damage in BEN.     

Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases

Tubular proteinuria defined by a study of Dent's ( CLCN5 mutation) and other tubular diseases. BACKGROUND: The term "tubular proteinuria" is often used interchangeably with "low molecular weight proteinuria" (LMWP), although the former implies a definite etiology. A specific quantitative definition of tubular proteinuria is needed, and we address this by studying five different renal disorders. METHODS: Tubular proteinuria was assessed by measuring urinary retinol-binding protein (RBP), beta2-microglobulin (beta2M), alpha1-microglobulin (alpha1M), and albumin in 138 patients: 26 affected males and 24 female carriers of the X-linked syndrome "Dent's disease," 6 patients with other Fanconi syndromes, 17 with distal renal tubular acidosis (dRTA), 39 with glomerulonephritis (GN), and 26 with Chinese herbs nephropathy (CHN). RESULTS: RBP was better than beta2M or alpha1M in identifying the tubular proteinuria of Dent's disease. Median urinary RBP levels in mg/mmol creatinine were: affected male Dent's, 18.2, N = 26; carrier female Dent's, 0. 30, N = 24; dRTA, 0.027, N = 17; GN, 0.077, N = 39; and normal adults, 0.0079, N = 61. Elevated urinary RBP (>0.017) and albumin < (10 x RBP) + 2 identified all patients with the LMWP of Dent's disease and clearly distinguished their LMWP from that of dRTA and GN. This is a quantitative definition of tubular proteinuria. Consistent with this definition, 80% of those patients with CHN who had an elevated RBP had tubular proteinuria. Urinary RBP and albumin in carriers of Dent's disease were strikingly correlated over a 100-fold range (R = 0.933). CONCLUSION: The combination of elevated urinary RBP (>0.017) and albumin < (10 x RBP) + 2 (mg protein/mmol creatinine) is a quantitative definition of tubular proteinuria. Furthermore, our findings suggest that a shared defect in tubular RBP and albumin reuptake causes this form of proteinuria.     

Predictive factors of response to steroids and cyclophosphamide therapy in idiopathic membranous nephropathy

Objectives To investigate demographic and clinical factors which could be predictive of clinical remission or relapse in patients with idiopathic membranous nephropathy treated with oral steroids and iv cyclophosphamide therapy. Methods This was a retrospective cohort study where a total of 83 patients with biopsy-proven IMN who had received oral prednisone and iv cyclophosphamide for at least 6 months were enrolled. Demographic and clinical factors of these patients were analyzed at baseline and three months after the initiation of therapy to evaluate their respective effects upon clinical remission and relapse. Results Median follow-up duration was 20 (12-30) months. At the end of follow-up, 80.7% (67/83) of the patients attained remission and 47.0% (39/83) attained complete remission (CR). The amount of proteinuria at baseline and the reduction rate of proteinuria three months after treatment predicted clinical remission and CR. 54 patients in the remission group were followed up to the endpoint and 14 of them relapsed with nephroticsyndrome. The presence of a PR versus CR significantly predicted relapse (HR: 40.198, 95%CI: 5.023-333.355, P=0.001). Infection was the most common adverse event. Two patients developed malignancies after onset of cyclophosphamide treatment. Conclusions A high rate of good response and a relatively low rate of adverse events were observed in this study. Baseline proteinuria and reduction rate of proteinuria 3 months after onset of cyclophosphamide regimen were independent predictive factors of response. Compared with CR, PR was predictive of a high probability of relapse.     

Association of diabetes with failure to achieve complete remission of idiopathic membranous nephropathy

International Urology and Nephrology - The association of type 2 diabetes with proteinuria remission and renal function decline in patients with idiopathic membranous nephropathy (IMN) remains...     

Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis.

BACKGROUND: Treatment of rheumatoid arthritis with anti-tumour necrosis factor alpha (TNFalpha) agents may lead to autoantibody formation and flares of vasculitis, but renal complications are rare. METHODS: We report the clinical and pathologic findings in five patients with longstanding rheumatoid arthritis (duration of rheumatoid arthritis, 10-30 years; mean, 23 years) who developed new onset of glomerular disease after commencing therapy with anti-TNFalpha agents (duration of therapy, 3-30 months; median, 6 months). RESULTS: At presentation, three patients were receiving etanercept, one adalimumab and one infliximab. Two subjects presented with acute renal insufficiency, haematuria, nephrotic-range proteinuria, positive lupus serologies, and hypocomplementemia, and renal biopsies showed proliferative lupus nephritis. Two individuals presented with new onset renal insufficiency, haematuria and proteinuria, and renal biopsies showed pauci-immune necrotizing and crescentic glomerulonephritis. One of these subjects, who had anti-myeloperoxidase autoantibodies, also developed pulmonary vasculitis. The fifth patient presented with nephrotic syndrome and renal biopsy findings of membranous glomerulonephritis, associated with immune complex renal vasculitis. A pathogenic role for anti-TNFalpha therapy is suggested by the close temporal relationship with development of glomerular disease, and by the improvement in clinical and laboratory abnormalities after drug withdrawal and initiation of immunosuppressive therapy in most cases. CONCLUSIONS: Rheumatoid arthritis patients receiving anti-TNFalpha agents may develop glomerulonephritis via the induction of rheumatoid arthritis-related nephropathy or de novo autoimmune disorders.     

Urinary protein and renal prognosis in idiopathic membranous nephropathy: a multicenter retrospective cohort study in Japan

Background: Several studies have revealed a relationship between proteinuria and renal prognosis in idiopathic membranous nephropathy (IMN). The benefit of achieving subnephrotic proteinuria (<3.5?g/day), however, has not been well described.

Methods: This multicenter, retrospective cohort study included 171 patients with IMN from 10 nephrology centers in Japan. The relationship between urinary protein over time and a decrease of 30% in estimated glomerular filtration rate (eGFR) was assessed using time-dependent multivariate Cox regression models adjusted for clinically relevant factors.

Results: During the observation period (median, 37?months; interquartile range, 16–71?months), 37 (21.6%) patients developed a 30% decline in eGFR, and 2 (1.2%) progressed to end-stage renal disease. Time-dependent multivariate Cox regression models revealed that lower proteinuria over time were significantly associated with a lower risk for a decrease of 30% in eGFR (primary outcome), adjusted for clinically relevant factors. Complete remission (adjusted hazard ratio [HR], 0.005 [95%CI, 0.0–0.09], p?p?=?.002), and 1.0 to 3.5?g/day (ICR II) (adjusted HR, 0.12 [95%CI, 0.02–0.64], p?=?.013) were significantly associated with avoiding a 30% decrease in eGFR, compared to that at no remission.

Conclusions: Attaining lower proteinuria predicts good renal survival in Japanese patients with IMN. This study quantifies the impact of proteinuria reduction in IMN and the clinical relevance of achieving subnephrotic proteinuria in IMN as a valuable prognostic indicator for both the clinician and patient.     

Clinical course and outcome of idiopathic membranous nephropathy in Japanese children

We retrospectively studied 12 Japanese children (8 boys, 4 girls) with idiopathic membranous nephropathy (IMN), aged 2.9–15.8 (mean 7.7) years at onset. All patients were identified through either screening or a routine urinalysis; proteinuria was present in all, haematuria, which was macroscopic in 4, in 11. Three had nephrotic syndrome (NS) at or soon after onset. Stages on electron microscopy, performed in 10 patients, were I in 3, II in 5 and III in 2. Steroids alone or with cyclophosphamide were administered to 5 patients, including the 3 patients showing NS. Complete remission of proteinuria occurred in 8 patients 0.3–1.6 (mean 0.6) years after onset, and proteinuria did not recur. After a follow-up of 1.6–11.6 (mean 5.9) years, these 8 patients were in complete remission and the remaining 4 had only mild proteinuria; none had hypertension or impaired renal function. Thus, we infer that IMN in Japanese children may have a better course and outcome than IMN in non-Japanese children. Based on a comparative study of Japanese (previously reported cases added to ours) and non-Japanese (mostly Caucasian) children with IMN, this was confirmed: it is possible that steroid therapy in Japanese patients is more effective in inducing remission of NS and preserving renal function.     

Treatment of nephrotic idiopathic membranous nephropathy with monthly i.v. pulse cyclophosphamide and oral steroids: a single centre's retrospective study

Aim: While the best treatment of nephrosis‐inducing idiopathic membranous nephropathy (IMN) is controversial, some trials have suggested positive outcomes following treatment with oral cyclophosphamide used in combination with steroids. However, data on i.v. cyclophosphamide plus steroids in treatment of nephrotic IMN are few. Methods: The charts of every patient diagnosed with membranous nephropathy in the Renal Division of Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, from January 2003 to December 2009 (n = 189) were retrospectively analyzed. Patients with nephrotic IMN (n = 32) were treated with monthly i.v. cyclophosphamide (500–750 mg/m²) and oral prednisone for at least 6 months. Efficacy as well as safety and tolerability of this regimen were evaluated. Result: Thirty‐two patients with nephrotic IMN (56% male, age 51.5 ± 12.6 years, estimated glomerular filtration rate 73.7 ± 20.0 mL/min per 1.73 m²) were included in our study. During the median follow‐up duration of 30.0 (12.5–42.8) months, 40.6% of patients achieved complete remission, while 40.6% achieved partial remission. Relapse occurred in five patients in a median of 16 (11.5–26) months after cessation of immunosuppressive treatment. No patients developed renal insufficiency during the follow up, while 16 side‐effects were noted in 10 patients. Complete remission rates at 3, 6 and 15 months were 0%, 12.5% and 40.6% and remission rates were 21.9%, 68.8% and 81.2%, respectively. Complement 3 deposition was significantly associated with the probability of non‐remission. Conclusion: Monthly i.v. pulse cyclophosphamide plus oral steroids may be an alternative treatment option in Chinese patients with nephrotic IMN.     

Serum low-molecular-weight proteins in haemodialysis patients: effect of residual renal function

Serum low-molecular-weight proteins, beta-2-microglobulin and alpha-1-microglobulin, were measured in 34 patients undergoing maintenance haemodialysis. There was a strong positive correlation between beta 2M and alpha 1M and predialysis serum creatinine and strong negative correlations between these proteins and 24-h urine volume and creatinine clearance. Good correlation was also demonstrated with total duration of haemodialysis, which also correlated with residual renal function. It is suggested that the elevated beta 2M and alpha 1M in haemodialysis patients merely reflect the severity of renal failure and are not directly influenced by the duration of dialysis or type of dialysis membrane.     

Glomerular involvement in myelodysplastic syndromes

Several reports have documented various forms of glomerular diseases in adults with myelodysplastic syndromes (MDS), but similar reports in children are lacking. We describe two children with MDS-associated steroid-responsive nephrotic syndrome (NS). Patient 1, who had MDS with myelofibrosis, presented with hepatosplenomegaly, pancytopenia, chronic hepatitis, moderate proteinuria, hypocomplementemia and elevated ANA titer. During initial prednisone treatment proteinuria markedly diminished and partial but transient hematological improvement occurred. Relapse subsequently occurred that manifested by overt NS and pancytopenia. High doses of prednisolone led to remission of the renal disease, but hematological remission did not occur. Persisting pancytopenia and repeated infections terminated in sepsis, 2 years after the onset of the MDS. Patient 2, who had refractory anemia with clonal monosomy 19, presented with bowel disease, hepatosplenomegaly, anemia and non-organ-specific autoantibodies. Prednisone led to both clinical and hematological remission. The hematologic disease relapsed 12 months later, when nephrotic-range proteinuria, hematuria and mild azotemia were also found. Corticosteroid treatment led to long-lasting renal and hematologic remission, maintained by a small dosage of prednisone. In both patients, renal biopsy findings were consistent with those seen in idiopathic NS. A Medline search disclosed 16 cases of glomerulopathy in the course of MDS in adult patients. Clinical features included NS, usually accompanied by renal insufficiency with acute, chronic, or rapidly progressive glomerulonephritis. On biopsy, membranous nephropathy, crescentic or mesangial proliferative glomerulonephritis, and AL amyloidosis were found. We conclude: (1) that glomerular disease may be present and should be searched for in patients with MDS and (2) that MDS can be added to the list of rare conditions associated with corticosteroid-responsive NS in children. Received: 12 October 2000 / Revised: 30 May 2001 / Accepted: 29 June 2001     

Membranous nephropathy: recurrence after kidney transplantation

BACKGROUND.: It is supposed that about 5% of dialysis patients had membranousnephropathy as a cause for their renal failure. Despite of thisprevalence, only 33 cases of recurrent membranous nephropathyafter kidney transplantation have been reported in the Englishliterature. METHODS.: Among 509 recipients of renal allografts, membranous glomerulonephritiswas the cause of renal failure in five patients, who receivedsix transplants. RESULTS.: Recurrence of the disease was observed in three allografts (50%)in three patients, all of them were on treatment with cyclosporinand low-dose prednisone. Proteinuria appeared at 2, 5 and 19months after grafting. One patient experienced a spontaneousremission after 12 months and he is free from proteinuria andwith good renal function after 5 years. The remaining two patientspresented progressive renal function deterioration and returnedto haemodialysis 24 and 17 months after the appearance of proteinuria.In these patients increasing the immunosuppression did not produceany beneficial effect. One of those patients underwent a secondtransplant; recurrence of the membranous nephropathy has notbeen observed after 3 years of follow-up. CONCLUSIONS.: In this study three new cases of recurrence of membranous nephropathyare reported. One patient experienced a spontaneous remissionof proteinuria. Recurrence of membranous nephropathy in renalallograft was very high in our series. Its appearance was associatedwith poor prognosis of the graft in most patients, althoughspontaneous remission of proteinuria is possible.