Acute kidney injury in idiopathic nephrotic syndrome of childhood is a major risk factor for the development of chronic kidney disease

Background: Acute kidney injury (AKI) is an important complication of idiopathic nephrotic syndrome (INS) and is associated with adverse outcomes, especially the development of chronic kidney disease (CKD). We aimed to determine the clinical profile of children with INS who developed AKI and its short-term outcome.

Material and methods: This prospective study was conducted from March 2014 to October 2015. A total of 119 children of INS (age: 2–18 years) fulfilling the pediatric RIFLE criteria for the diagnosis of AKI were enrolled and followed up for 3 months to determine the outcome. Factors predisposing to CKD were studied.

Results: The mean age at presentation was 8.8?±?3.59 years and males were 74 (62.2%). At presentation, 61 (51.3%) children were in Risk category, 43 (36.1%) in Injury category, and 15 (12.6%) in Failure category. Most of them (41.2%) had steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) on histopathology (33.6%).

Infections were the major predisposing factor for AKI in 67 (56.3%) cases. Drug toxicity was the next common, found in 52 (43.7%) children. A total of 65 (54.6%) children recovered from AKI, while 54 (45.4%) did not. CKD developed in 49 (41.2%) non-recovered cases and 5 (4.2%) children succumbed to acute illness. SRNS, cyclosporine use, FSGS on histology, and drug toxicity were significant factors associated with the development of CKD.

Conclusion: AKI associated with INS is a reversible condition in most cases but it can progress to CKD, especially among those who have SRNS, FSGS, and drug toxicity.     

Effect of cyclosporine therapy on idiopathic membranous nephropathy presented with refractory nephrotic syndrome

Background. Recent studies suggested the possible benefits of cyclosporine (CsA) therapy in patients with membranous nephropathy, although most of these studies were short-term. An uncontrolled retrospective study was undertaken to evaluate the long-term effect of CsA therapy on idiopathic membranous nephropathy presented with refractory nephrotic syndrome. Methods. The subjects were eight patients with idiopathic membranous nephropathy presenting with refractory nephrotic syndrome. All patients had received a course of corticosteroid therapy before CsA therapy, and had not responded to the corticosteroid, including one or two administrations of intravenous methylprednisolone pulse therapy. The CsA doses were adjusted to maintain trough blood level at 100 ng/ml during the first 3 months and then reduced to maintain the level at 50 ng/ml in patients who had responded to partial remission. Results. CsA therapy induced a marked decrease in proteinuria from the first month, and a significant decrease from month 3 and thereafter. The mean serum total protein and albumin levels rose, and total cholesterol fell significantly with CsA therapy. The serum creatinine level was unchanged during CsA therapy. Three patients showed complete remission and two were in partial remission, while three were nephrotic at 12 months of CsA therapy. From 18 to 24 months of CsA therapy, three patients were in complete remission, four were in partial remission, and one patient was nephrotic. There were no side effects of CsA, except for gum hyperplasia and hypertrichosis in one patient. Conclusion. These results suggest that long-term CsA therapy at a low or moderate dose is potentially effective and safe in most nephrotic patients with idiopathic membranous nephropathy refractory to corticosteroid therapy. Received: February 22, 1999 / Accepted: July 30, 1999     

Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety

Background: To observe effectiveness and renal safety of long-term low-dose cyclosporine in idiopathic membranous nephropathy (IMN).

Methods: Sixty-eight patients were enrolled in this prospective cohort study. Renal endpoint was defined as a decrease in eGFR?≥50% from baseline and a development of eGFR ≤60?ml/min/1.73m².

Results: A cyclosporine dose of 2.0?±?0.5?mg/kg/d and a prednisone of 0.3?±?0.2?mg/kg/d were prescribed. The duration of cyclosporine treatment was 27 (3–80) months. The overall remission rate was 91% with a relapse rate of 42%. Fourteen patients had cyclosporine-related acute renal injury (CsA-ARI) within the first three months, and 16 patients had cyclosporine related chronic renal injury (CsA-CRI) within the first year. At the end of follow-up (50?±?18?months), 16 patients (24%) reached renal endpoint. Presence of intimal fibrosis of small artery and higher time-averaged proteinuria were identified as independent risk factors for renal endpoint. RAS inhibition treatment decreased the risk of poor renal outcome. Patients in CsA-ARI group had the highest proteinuria at the third month, the highest time-average proteinuria and the highest proportion of cases reaching renal endpoint. Patients with CsA-CRI were of the oldest age and with the lowest baseline eGFR.

Conclusions: Low-dose cyclosporine is effective in treating IMN. CsA-ARI and no response in proteinuria during the first three months of cyclosporine treatment had the lowest benefit/risk ratio, and these patients should be switched to non-calcineurin-inhibitor based regimen. Patients of older age, with lower baseline eGFR, or having intimal sclerosis of small artery, are more likely to develop progressive renal dysfunction.     

Non-diabetic urine glucose in idiopathic membranous nephropathy

This study aims to analyze the characteristics of idiopathic membranous nephropathy (iMN) with nondiabetic urine glucose during the follow-up. We retrospectively analyzed the data of 1313 patients who were diagnosed iMN. The prevalence of nondiabetic urine glucose during follow-up was 10.89%. There were significant differences between the patients with nondiabetic urine glucose and those without urine glucose in gender, hypertension ratio, proteinuria, N-acetyl-β-glucosaminidase, retinol binding protein, serum albumin, serum creatinine (Scr), cholesterol, triglyceride and positive anti-phospholipase A2 receptor antibody ratio, glomerular sclerosis ratio, acute and chronic tubular injury lesion at baseline. To exclude the influence of the baseline proteinuria and Scr, case control sampling of urine glucose negative patients was applied according to gender, baseline proteinuria and Scr. The proteinuria nonremission (NR) ratio was 45.83 versus 12.50% of the urine glucose positive group and case control group. Partial remission (PR) ratio of the two groups was 36.46 versus 23.96% and complete remission (CR) ratio was 19.79% versus 63.54%, respectively. Patients with urine glucose had higher risk of 50% estimated glomerular filtration rate (eGFR) reduction. Cox regression showed that urine glucose and baseline Scr were risk factors of 50% reduction of eGFR. Urine glucose remission ratio of the patients with proteinuria NR, PR, and CR was 13.33, 56.25, and 94.73% (p < 0.005). Patients who got urine glucose remission also had better renal survival. In conclusion, non-diabetic urine glucose was closely related to proteinuria. It could be applied as a tubular injury marker to predict renal function.     

Efficacy of mizoribine followed by low-dose prednisone in patients with idiopathic membranous nephropathy and nephrotic-range proteinuria

Abstract

Background: Idiopathic membranous nephropathy (IMN) patients with persistent high-grade proteinuria are at the highest risk for developing end-stage renal failure. We previously reported the effects of treatment with mizoribine followed by low-dose prednisone treatment in 4 IMN patients. The purpose of the present study was to further assess the effects of this combined treatment in a larger study group. Method: Thirteen patients with IMN and nephrotic-range proteinuria received combined treatment. Mizoribine was initiated at a dose of 150?mg/day, and 2–3 months later, 20?mg/day prednisone was added to the mizoribine regimen. The dosage of prednisone and/or mizoribine was tapered according to the urinary protein-to-creatinine ratio (P/C). We evaluated patient responses for up to 12 months after the initiation of combination therapy. Results: Before treatment, patient urinary P/C ranged from 3.7 to 15.9?g/g. Although these values did not decrease during mizoribine monotherapy, all patients showed dramatic P/C decreases over the course of combination therapy. At 3, 6, and 12 months after combination therapy, 15%, 31%, and 62% of patients attained complete remission, respectively, and all patients were in partial or complete remission 6 months after combination therapy. No notable side effects were observed. Conclusion: The addition of prednisone after mizoribine monotherapy can be beneficial for all IMN patients with nephrotic-range proteinuria syndrome. The risks associated with immunotherapy can be decreased by initially prescribing mizoribine alone, which might act as a base for establishing therapy, followed by low-dose prednisone treatment.     

Plasma total homocysteine concentration in nephrotic patients with idiopathic membranous nephropathy.

BACKGROUND: The atherothrombotic risk pattern of the nephrotic syndrome resembles that of hyperhomocysteinemia. However, the effect of nephrotic range proteinuria on homocysteine metabolism has never been studied. METHODS: The study included 11 male nephrotic patients with idiopathic membranous nephropathy who underwent a treatment trial with adrenocorticotrophic hormone and 11 male non-nephrotic, renal function-matched control subjects. The nephrotic patients were studied before and after the treatment, which induced a marked reduction in urinary protein excretion and a moderate improvement in renal function in all cases. RESULTS: Plasma total homocysteine (tHcy) concentration did not change significantly during treatment, whereas the nephrotic patients had significantly lower tHcy than the non-nephrotic patients (14.2 +/- 3.4 micromol/l vs 19.0 +/- 5.4 micromol/l). tHcy correlated significantly with serum concentrations of creatinine (r = 0.53, P < 0.05) and albumin (r = 0.43, P < 0.05), glomerular filtration rates (GFRs) (iohexol clearances) (r = -0.42, P < 0.05) and urinary albumin excretion (r = -0.47, P < 0.05). CONCLUSION: The expected tHcy-lowering effect of improved renal function may have masked a tHcy-elevating effect due to reduced proteinuria leading to no net change in tHcy during treatment. The notion of an increase in tHcy associated with remission of the nephrotic syndrome is in accordance with the significantly lower tHcy in the nephrotic renal patients compared with the non-nephrotic renal function-matched patients, and the relationships between tHcy and serum albumin concentrations as well as urinary albumin excretion. Thus, the results of this small study suggest that nephrotic range proteinuria directs homocysteine metabolism towards a decrease in tHcy. However, the findings need to be confirmed in larger patient populations and in different varieties of the nephrotic syndrome.     

Comparison of immunosuppressive therapeutic regimens in patients with nephrotic syndrome due to idiopathic membranous nephropathy

In this prospective randomized trial, we compared the effects of cyclosporine- and cyclophosphamide-based treatment regimens in patients with idiopathic membranous nephropathy. Twenty-eight patients were randomized to receive treatment with one of the three therapeutic regimens: cyclosporine with methylprednisolone, cyclophosphamide with methylprednisolone or lisinopril (control). Renal function and nephrotic syndrome parameters were determined at baseline and during a 9-month treatment period. At the end of the study period, renal function improved significantly in the cyclophosphamide and deteriorated significantly in the cyclosporine group. Serum albumin levels increased significantly in the cyclosporine and cyclophosphamide group. Total cholesterol levels and proteinuria were significantly reduced in all groups. In the comparison between the groups, serum albumin levels were significantly lower in the control group and there were no differences in the rest of the studied parameters at the end of the study. Six patients from the cyclosporine group (1/10 complete and 5/10 partial), all cyclophosphamide-treated (4/8 complete and 4/8 partial) and all 10 lisinopril-treated patients (10/10 partial) were on remission at the end of the study. In conclusion, cyclosporine-based regimens are not inferior to cyclophosphamide-based regimens. Cyclophosphamide is associated with more complete remissions after 9 months of treatment. Lisinopril is associated with a significant proteinuria reduction and without inducing any complete remissions.     

Acute renal failure in children with idiopathic nephrotic syndrome

Acute renal failure (ARF) is an uncommon but alarming complication of idiopathic nephrotic syndrome. The renal failure could be secondary to causes evident from the history and evaluation, such as severe intravascular volume depletion, acute tubular necrosis, allergic interstitial nephritis, bilateral renal vein thrombosis, acute pyelonephritis, or rapid progression of the original glomerular disease. It may be termed idiopathic if the underlying cause is undetermined. We present three children with idiopathic nephrotic syndrome who were admitted with acute renal failure. One case was due to drug-induced allergic interstitial nephritis. The other two were idiopathic in nature. Improvement in renal function occurred in the three patients over a variable period of 10 days to 4 weeks. After careful exclusion of well-known causes of acute renal failure, idiopathic acute renal failure (IARF) should be considered as a diagnostic possibility in these patients. The exact pathophysiology of IARF is not understood. Possible proposed explanations include interstitial edema, tubular obstruction, altered glomerular permeability, and unrecognized hypovolemia.     

Tiopronin-induced membranous nephropathy: a case report

Background: Tiopronin, a glycine derivative extensively used to treat cystinuria and hepatic cell injury, can give rise to rare complications such as proteinuria and nephrotic syndrome. However, the pathological characteristics of this secondary nephropathy are poorly understood. Here, we report a case of tiopronin-induced nephrotic syndrome. Case presentation: A 65-year-old Chinese man with a history of myasthenia gravis admitted tiopronin for hepatoprotection therapy. After 3 months later, he presented with rapid weight gain, massive peripheral edema, and proteinuria in the nephrotic range. Laboratory findings included serum albumin (20?g/L), total protein (38?g/L), and total cholesterol (11.78?mmol/L). A 24-hour urine protein collection contained 8620?mg. Percutaneous renal biopsy revealed a uniformly thickened glomerular and rigid basement membrane with immunoglobulin G (IgG) and complement C3 deposited along the glomerular capillary wall. Withdrawal of tiopronin-induced proteinuria complete remission and clinical resolution of nephrotic syndrome. Conclusions: Potential risk of kidney injury exists with long-term tiopronin treatment. Membranous nephropathy was a common renal pathologic feature. Proteinuria in the nephrotic range may spontaneously remit after tiopronin withdrawal. Periodic urine analysis and patient follow-up are recommended with tiopronin therapy.     

The efficacy and safety of tacrolimus monotherapy in adult-onset nephrotic syndrome caused by idiopathic membranous nephropathy

Introduction: The purpose of the study is to evaluate the efficiency and safety of tacrolimus (TAC) monotherapy in the treatment of nephrotic idiopathic membranous nephropathy (IMN) compared with the protocol of cyclophosphamide (CTX) combined with corticosteroids.

Methods: In total, 58 patients with nephrotic syndrome and biopsy-proven IMN were included in this study. 30 patients received TAC monotherapy with an initial dose of 0.05–0.1?mg/kg/day. 28 patients received transvenous CTX at a dose of 0.5–0.75?g/m² once in every month initially for 6?months and once in every 2 or 3?months for the later period, and the regimen was combined with corticosteroids (prednisone 1?mg/kg/d). All patients were observed for the treatment effects, recurrence and side effects.

Results: Twelve months after the initial treatment, a total of 24 (80%) patients in the TAC group and 23 (82.1%) patients in the CTX group achieved remission (either partial or complete remission). The survival curve of the probability of remission and complete remission were similar between the two groups (p?>?.05). Proteinuria (based on 24?h urinary protein excretion) was significantly decreased, and serum albumin was significantly increased after immunosuppressive treatment in both the groups. Estimated glomerular filtration rate (eGFR) was comparable between before and after treatment. The main adverse effects in TAC treatment were glucose intolerance, diabetes and abnormal aminotransferase.

Conclusions: TAC monotherapy is an alternative therapeutic regimen for patients with nephrotic IMN. Its short-term efficiency and patient tolerance are both acceptable.     

Prospective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome

BACKGROUND: Retrospective and anecdotal data suggest that mycophenolate mofetil (MMF) might be effective when given as rescue therapy for membranous nephropathy (MN). Prospective controlled data on MMF and prednisolone as primary therapy are lacking. METHODS: A prospective, randomized, controlled, open-label study was performed to investigate the efficacy and tolerability of MMF and prednisolone as primary treatment in MN with nephrotic syndrome. MMF and prednisolone given for 6 months was compared against a modified Ponticelli regimen in 20 patients, with follow up of 15 months. RESULTS: MMF with prednisolone and the comparative immunosuppressive regimen showed similar efficacy in proteinuria reduction, despite a lower cumulative prednisolone dose in the MMF group (3.80 +/- 0.28 vs 9.93 +/- 0.25 g, P < 0.001). Remission (composite of 'complete' and 'partial') rates were 63.6% and 66.7% in the MMF group and control group, respectively (P = 1.000). Serum creatinine and creatinine clearance remained stable during follow up. Cumulative relapse rate was 23.1% at 2 years. Chlorambucil resulted in more leucopenia compared with MMF. CONCLUSION: Data from this pilot study indicate that more than 60% of patients with MN and nephrotic syndrome respond to combined MMF and prednisolone treatment, and suggest potential benefits of MMF as being steroid-sparing and having less adverse effects compared with other commonly used cytotoxic agents.     

Serum free fatty acid elevation is related to acute kidney injury in primary nephrotic syndrome

The aim of this research was to examine the clinical characteristics of acute kidney injury (AKI) in primary nephrotic syndrome (NS) and discuss the relationship between serum lipids and AKI. A total of 1028 patients diagnosed with primary NS with renal biopsy results were enrolled in this study. The patients were divided into AKI (n = 81) and non-AKI (n = 947) groups, and their characteristics were compared using a propensity score analysis for the best matching. Serum free fatty acid (FFA) was an independent predictor for AKI in the postmatch samples (p = 0.011). No significant difference in FFA levels was observed among AKI stages or different pathological types in the AKI and non-AKI groups. The AUC (area under the ROC curve) was 0.63 for FFA levels to distinguish AKI. In primary NS, elevated FFA levels tend to be related to a high risk of AKI. FFAs have diagnostic value and may serve as biomarkers for AKI in NS.     

Benefit and cost from the long-term use of cyclosporine-A in idiopathic membranous nephropathy

Aim: Idiopathic membranous nephropathy (IMN), the most common cause of nephrotic syndrome in adults, is usually treated by cyclosporin A (CsA). Estimation of the effectiveness of long‐term use of CsA in the remission and relapse rate of nephrotic syndrome along with histological changes in repeat renal biopsies was the aim of the study. Methods: Thirty‐two nephrotic patients with well‐preserved renal function treated by prednisolone and CsA were studied. A repeat biopsy was performed in 18 patients with remission of nephrotic syndrome, after 24 months of treatment, to estimate the activity of the disease and features of CsA toxicity. Results: Complete remission of nephrotic syndrome was observed in 18 (56%) and partial remission in 10 patients (31%) after 12 months of treatment (total 87%). Relapses were observed in 39% and 60% of patients with complete and partial remission, respectively, and multiple relapses in 25% of patients, who showed gradual unresponsiveness to CsA and decline of renal function. Progression of stage of the disease and more severe glomerulosclerosis and tubulointerstitial injury were recognized in 55% and 61% of patients respectively. Features of CsA nephrotoxicity were not observed. The severity of histological changes was related to the time elapsed from the first biopsy (r = 0.452, P < 0.05). Conclusion: Low doses of CsA with prednisolone induce remission of nephrotic syndrome in most idiopathic membranous nephropathy patients. Although typical features of CsA nephrotoxicity are not observed, significant deterioration of histological lesions occurs with time, even in patients with remission. Long‐term use of CsA should be examined with caution.     

Efficacy of cyclosporin in difficult-to-treat idiopathic membranous nephropathy

SUMMARY: Poor tolerance and the potential long-term toxicity have limited the widespread use of corticosteroids and cytotoxic drugs in the treatment of idiopathic membranous nephropathy (IMN). Cyclosporin A (CyA) has been proven to be a less toxic alternative, but its efficacy needs further confirmation. Cyclosporin A (2–3mg/kg per day) in combination with low-dose methylprednisolone (4mg/day) was given to 28 nephrotic patients with IMN who had failed to respond, or tolerate, or to complete treatments with steroids and/or cytotoxic drugs. the mean duration of treatment was 11 ± 7 months. Seven patients (25%) showed a complete remission of proteinuria, 17 (60%) a partial one, and four (15%) did not respond at all. the average time to achieve optimal remission was 4.2 ± 1.4 weeks following the initiation of therapy. In those who responded completely or partially, plasma creatinine (Per) did not change significantly from pre CyA levels during follow up (1.0 ± 0.3 vs 1.2 ± 0.3mg/dL, P =NS). the remaining four patients who had renal insufficiency already before CyA (mean Per: 2.1 ± 0.8mg/dL), showed a rapid deterioration of renal function after the initiation of CyA (mean Per: 3.1 ± 1.5 mg/dL, P <0.01), and as a consequence, the drug was discontinued. A mul-tivariate analysis on the clinical and histological features demonstrated that the degree of renal function impairment ( P <0.02), the percentage of obsolete glomeruli ( P <0.01), and the severity of interstitial fibrosis ( P <0.005) independently predicted the response to therapy. Low dose CyA is an effective and safe alternative treatment for patients with IMN and normal renal function. However, the drug should be given with caution to patients with established renal insufficiency.     

Preeclamptic nephropathy associated with membranous nephropathy

We report a patient who had nephropathy of toxemia of pregnancy associated with membranous glomerulonephritis, which deteriorated 3 months after delivery. Electron microscopy revealed electron-dense deposits on the subepithelial surface of the glomerular basement membrane and finely granular/fibrillar materials in the subendothelial space. As a result of treatment with prednisolone and anticoagulants, marked alleviation of both proteinuria and edema was achieved. We therefore consider that the change from subclinical to clinical membranous nephropathy could be attributed to pregnancy. Received: February 22, 2001 / Accepted: July 12, 2001     

False positivity for PLA2R1 antibody measured by ELISA in a nephrotic patient with no membranous nephropathy

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Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome.

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.     

Thrombotic complications in childhood-onset idiopathic membranous nephropathy

While the most common clinical feature of nephrotic syndrome is generalized edema, patients are at risk of developing other problems, such as bacterial infections, electrolyte abnormalities, and venous thromboses. Adults with membranous nephropathy appear to be at the greatest risk for developing thromboses, especially renal vein thrombosis. However, the same is not true for children with membranous nephropathy. A review of pediatric membranous nephropathy stated that renal vein thrombosis is unrecorded in childhood-onset membranous nephropathy. We present our experience in managing two children with idiopathic membranous nephropathy who developed venous thromboses. To our knowledge, this is the first report of pediatric patients with membranous nephropathy to develop a thromboembolic complication without evidence of predisposing factors or coagulation abnormalities. This report emphasizes the need for appropriate evaluation of patients with membranous nephropathy who develop signs and symptoms suggestive of arterial or venous occlusion in order to avoid missing this potentially life-threatening medical complication.     

Nephrotic syndrome as a result of membranous nephropathy caused by renal cell carcinoma

A 77‐year‐old woman was admitted for a renal biopsy to evaluate a case of nephrotic syndrome. In the course of the examination, a right renal tumor was incidentally found. We performed a right radical nephrectomy in advance of the renal biopsy. Histologically, the tumor was diagnosed as a renal cell carcinoma (clear cell carcinoma) and the non‐neoplastic renal cell tissue showed membranous nephropathy (MN). After surgery, the nephrotic syndrome remitted without any further medical treatment and the MN was considered to be a malignancy associated syndrome. There have been few case reports in the literature regarding this association and we wish to describe another case.