Cyclosporin A does not affect platelets in children with idiopathic nephrotic syndrome

The immunosuppressive agents administered to maintain the remission of idiopathic nephrotic syndrome (INS) may have a deleterious effect on several cell types. The aim of this study was to analyze platelet activation and reactivity in children with INS treated with cyclosporin A (CyA). The study groups comprised 16 children with remission of INS induced by CyA and 16 children with glucocorticosteroid-induced remission 8 weeks from the onset of INS relapse. Fifteen healthy children served as controls. Surface expression of CD61, CD62P, and CD42b on resting and thrombin-stimulated platelets was analyzed with flow cytometry. No differences between groups were found in CD61, CD62P, and CD42b surface expression, but markers of the coagulation cascade and fibrinolysis or endothelial injury (F1+2 prothrombin fragments, tissue plasminogen activator inhibitor 1) were elevated in patients treated with CyA compared with children on steroids and healthy controls. No correlations between markers of platelet function and CyA concentration were found. We postulate that CyA administration in nephrotic patients causes an activation of thrombinogenesis but does not influence platelet activation and reactivity in INS.     

Effect of cyclosporin A on glomerular filtration rate in children with minimal change nephrotic syndrome

Cyclosporin A (CyA) is now commonly used in the management of children with steroid-dependent nephrotic syndrome. In order to assess nephrotoxicity related to CyA therapy, we measured glomerular filtration rate (GFR) on 123 occasions in 24 children with minimal change nephrotic syndrome receiving CyA. GFR was estimated from the plasma clearance of⁵¹chromium-EDTA every 3 months during CyA therapy of up to 27 months duration. There was a significant reduction in GFR after 3 months of CyA therapy [118±33 (SD) to 93±24 ml/min per 1.73 m²] but no further fall thereafter, although the reduction in GFR was sustained for the duration of CyA therapy. This reduction in GFR appeared to be reversible upon cessation of CyA, but careful monitoring of renal function is necessary in such patients to prevent the development of longer term nephrotoxic sequelae.     

A controlled study of deflazacort in the treatment of idiopathic nephrotic syndrome

Forty patients with steroid-dependent idiopathic nephrotic syndrome (INS), a mean follow-up of 5.5 years, and a mean number of relapses of ten were blindly assigned to either deflazacort (DFZ) (n = 20) or prednisone (PDN) (n = 20) according to a ratio of equivalence of DFZ/PDN = 0.8. This treatment was given for 1 year. The number of relapses was significantly lower in patients receiving DFZ. After 1 year, 12 remained in remission with DFZ compared with 2 with PDN. Growth velocity was not different in the two groups. Bone mineral content, assessed by quantitative computed tomography of L1 L2 vertebrae, decreased after 1 year by 6% in the DFZ group versus 12% in the PDN group (NS). The mean body weight increase of +3.9±4.1 kg in the PDN group was higher than that of the DFZ group, +1.7±2.8 kg (P = 0.06). Cushingoid symptoms tended to be less after 12 months in the DFZ group. In conclusion, this study shows that DFZ was more effective than PDN in limiting relapses in steroid-dependent INS, and that cushingoid symptoms, weight gain, and decrease in bone mineral content tended to be less marked with this drug than with PDN. Received November 6, 1996; received in revised form and accepted February 25, 1997     

环孢霉素A与环磷酰胺联合激素治疗膜性肾病的疗效比较

目的：比较环孢霉素A（CSA）与环磷酰胺（CTX）联合激素治疗成年人特发性膜性肾病（IMN）的疗效和安全性。方法：76例原发性肾病综合征患者经肾活检确诊为IMN,在诊断上排除了继发性膜性肾病,单用激素治疗无效或复发,随机分两组分别予CSA联用糖皮质激素治疗（CSA组）或CTX联用糖皮质激素治疗（CTX组）,疗程至少12个月。观察各组的24h尿蛋白定量、血浆白蛋白、肾功能、血糖、白细胞总数及其不良反应,以及治疗前后的完全缓解率、部分缓解率。全部患者且在正式进入研究治疗前未用或已停用类固醇激素和细胞毒药物达半年以上。结果：治疗3个月末,CsA组的24h尿蛋白、胆固醇、三酰甘油显著低于CTX组（P均〈0.01）,血清白蛋白显著高于CTX组（P〈0.01）。两组患者的血肌酐比较差异无统计学意义（P〉0.05）,而CTX组的WBC显著低于CsA组（P〈0.01）。CsA组完全缓解率显著高于CTX组（χ2=4.6317,P〈0.05）。治疗12个月末两组的完全缓解率差异无统计学意义（χ2=1.2575,P〉0.05）。CsA组的不良反应发生率（8/40=20.0%）显著低于CTX组（15/36=41.7%）（χ2=4.2146,P〈0.05）。结论：与CTX相比,CsA联用糖皮质激素对IMN治疗12个月的总体疗效相当,但CsA起效更快,近期疗效更好,不良反应更小。CsA≤5mg.kg-1.d-1用于肾功能正常IMN患者是安全有效的。     

Acute renal failure at the onset of idiopathic nephrotic syndrome in two children

Two children with idiopathic nephrotic syndrome (INS) developed acute renal failure (ARF) at the onset of the disease. Although the initial renal biopsy showed minimal change (MC) lesions with prominent interstitial edema, repeat renal biopsy revealed focal segmental glomerulosclerosis (FSGS). ARF has been reported to be a relatively rare complication in childhood INS. However, the initial manifestation of ARF may increase the risk for subsequent progression to FSGS in a proportion of children with INS with MC lesions. Received: April 3, 2000 / Accepted: October 31, 2000     

Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome

We aimed to test if fosinopril reduces urinary protein excretion and alleviates renal tubular damage in normotensive children with steroid-resistant idiopathic nephrotic syndrome (SRINS). We also aimed to evaluate whether there are changes in steady-state blood pressure and serum concentrations of serum angiotensin-converting enzyme (ACE) and plasma renin activity or angiotensin II (AT-II) in children under this treatment. Forty-five normotensive patients with SRINS were randomly divided into two groups. Group I was treated with fosinopril and prednisone for 12 weeks, while group II was treated with prednisone alone for the same duration. The values of 24-h urinary protein excretion were 1.25±0.64 vs 2.52±0.56 g/24 h (P<0.05), 1.16±0.45 vs 2.42±0.24 g/24 h (P<0.05), and 1.10±0.41 vs 2.05±0.46 g/24 h (P<0.05) in group I and group II patients, respectively, at 4, 8, and 12 weeks. Patients in group I showed lower serum concentrations of urinary retinol-binding protein and β₂-microglobulin (P<0.01) at the end of the study, but the patients’ blood pressure and components of the renin-angiotensin system (RAS) had no change during treatment. The result suggested that fosinopril significantly reduced proteinuria and alleviated renal tubular damage, but did not influence blood pressure and components of systemic RAS in normotensive children with SRINS.     

Risk factors for steroid dependency in children with idiopathic nephrotic syndrome

Minimal change disease, the most common cause of idiopathic nephrotic syndrome (INS) in children, has a high relapse rate, with approximately half of patients developing steroid dependency. This study was aimed at determining the predictive risk factors for the development of steroid dependency in children diagnosed with INS. A retrospective study of 123 children with steroid-responsive INS, followed for at least 6 months between December 1974 and December 1999, was conducted. The following parameters were studied as predictors of steroid dependency: age at onset, gender, race, microscopic hematuria at onset, atopy, concomitant upper respiratory tract infections (URTI) during relapses, and days to remission with initial steroid therapy. Of the 91 children who fulfilled the inclusion criteria, 61.5% became steroid dependent. Both univariate and logistic regression analyses revealed that initial remission time of 9 or more days (P=0.02, OR=3.0, 95% CI=1.2–7.9) and concomitant URTI during relapses (P=0.01, OR=3.4, 95% CI=1.3–8.8) were significant predictors of steroid dependency. By identifying those children with predictive factors of steroid dependency, the clinician will be better able to plan the long-term management of these patients and reduce the morbidity seen with the frequent relapses and steroid treatment, in a disease that is otherwise associated with a favorable prognosis. Received: 4 October 2000 / Revised: 27 August 2001 / Accepted: 28 August 2001     

环孢素A联合激素治疗难治性肾病综合征31例临床疗效观察

目的 探讨环孢素A（cyclosporine-A,CsA）联合激素治疗难治性肾病综合征的临床疗效及安全性.方法 对31例难治性肾病综合征患者使用糖皮质激素联合CsA治疗：CsA起始剂量平均（1.57±0.25）mg·kg^-1 ·d^-1,泼尼松起始剂量平均（0.69±0.20）mg· kg^-1·d^-1,分别测定CsA治疗前及治疗后1、3、6个月患者的24 h尿蛋白定量、肝功能[丙氨酸氨基转移酶（glutamate-pyruvate transaminase,AST）、天冬胺酸氨基转移酶（glutamic oxalacetic transaminase,ALT）、血浆白蛋白（serum albumin,Alb）]、肾功能[血肌酐（serum creatinine,SCr）、血尿酸（uric acid,UA）]、血常规[白细胞（white blood corpuscle,WBC）、血红蛋白（hemoglobin,Hb）、血小板（blood platelet,PLT）]及环孢素血药浓度等指标的变化,并记录不良反应.结果 加用CsA治疗后患者各项指标均较治疗前明显好转,治疗3个月时24 h尿蛋白定量由治疗前的（5.56±2.13）g降至（1.37±1.41） g（P＜0.05）,血浆白蛋白由（24.80±4.69） g/L升至（37.5±5.03） g/L（P＜0.05）,完全缓解9例,部分缓解12例,缓解率67.7％;治疗6个月时24 h尿蛋白定量由治疗前的（5.56±2.13）g降至（0.83±1.21）g（P＜0.05）,血浆白蛋白由（24.80±4.69） g/L升至（41.08±5.64） g/L（P＜0.05）,完全缓解16例,部分缓解11例,无效4例,缓解率87.1％,治疗前后结果差异有统计学意义（P＜0.05）.结论 CsA联合激素治疗可显著减少肾病综合征患者的尿蛋白,且不良反应少,可用于难治性肾病综合征的治疗.     

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.     

Long-term cyclosporin A treatment of minimal-change nephrotic syndrome of childhood

We evaluated the efficacy of long-term cyclosporin A (CyA) treatment in the maintenance of remission in 40 children with steroid-dependent minimal-change nephrotic syndrome (MCNS). CyA was given in an initial dose of 5 mg/kg per day, adjusted to maintain a trough whole blood level of 50–150 ng/ml. All the 40 children received CyA for 1 year. In 18 patients, CyA was continued for a further period of at least a year without interruption; 9 patients had a second course of CyA therapy after an interval of at least 1 month. Of the 40 children 29 (72%) had one or more relapses during treatment with CyA, with 16 (40%) relapsing during the 1st year. During the second period of CyA, 10 (56%) of the 18 children treated continuously relapsed, whereas all the 9 children who had an interrupted course of therapy relapsed. CyA was discontinued at one time in 27 patients, all of whom subsequently relapsed, with a median time to relapse of 26 days. Long-term prednisolone in addition to CyA was required to maintain remission in 16 (40%) of the whole group. The results suggest that the long-term use of CyA is able to maintain remission of MCNS, although 40% of the patients also required low-dose alternate-day steroids; patients appeared to fare worse if the CyA course was interrupted; no patient experienced a long-term remission after CyA was stopped.     

A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome

Idiopathic minimal lesion nephrotic syndrome (IMLNS) was proposed to be a disorder of T-cell dysfunction by Shalhoub in 1974. The mechanisms by which T-cells increase glomerular permeability have remained elusive (and unproven). There is evidence that IMLNS may be due to a circulating factor released from activated T-cells. In recent years, efforts have been made to identify this pathogenetic cytokine as well as to understand the mechanism(s) for the increased release of this factor. This review attempts to critically analyze the available published data. Using different methodologies, investigators have focused on the production of cytokines in patients with IMLNS during relapse and remission. This has resulted in a plethora of data without definitive conclusions. The pathogenetic cytokine has not been identified, and it is questionable whether there is a Th2 dominance in IMLNS. The review of the available data illustrates the difficulties encountered when one is studying the cytokine secretory pattern in patients with IMLNS. Differences in patient population, type of cells studies, sample preservation, and methodology used to measure cytokines are some of the factors that could account for the disparity of observed results.     

Up-regulation of interleukin-2 mRNA in children with idiopathic nephrotic syndrome

The current hypothesis for the pathogenesis of childhood idiopathic nephrotic syndrome (INS) favors the involvement of a T cell-mediated immune response. Various cytokines derived from T cells may play a critical role in INS. Previous studies have measured serum or urine cytokine levels and suggest an imbalance of the T cell-mediated immune response. To elucidate the true profile of T cell-derived cytokines, we determined interleukin (IL)-2, interferon (IFN)-, IL-4, IL-10, and tumor necrosis factor (TNF)- mRNA expression in children with INS. We collected mRNA from peripheral blood mononuclear cells together with plasma and urine from nine children in the acute and remission phases of INS. Expression of IL-2, IFN-, IL-4, IL-10, and TNF- mRNA was determined by a quantitative real-time PCR assay. Plasma and urine cytokine concentrations were measured using a specific enzyme-linked immunosorbent assay. These data were compared between the acute and remission phase in the same patients. The IL-2 mRNA levels were significantly higher in the acute phase than in the remission phase, whilst no significant difference was found in the other cytokines investigated. There was no significant difference in the plasma and urine cytokine concentrations between the acute and remission phase. Our results indicate increased expression of IL-2 mRNA in the acute phase of INS, suggesting that IL-2, at least in part, might be involved in the pathophysiology of childhood INS.     

Immunosuppressive therapy in the nephrotic syndrome in children

The high incidence of remission and prevention of relapse of minimal change nephrotic syndrome (MCNS) in children, produced by corticosteroids is reviewed. With the introduction of corticosteroids over 30 years ago and the increased expertise in their use, the mortality rate has been reduced to less than 5%. There is no justification for a clinical trial to test the effect of corticosteroids in inducing remission, but the need remains to evaluate methods of administration in order to achieve therapeutic benefit with minimum toxicity. children with frequently relapsing, steroid-dependent MCNS will usually enter remission following treatment with an alkylating agent such as cyclophosphamide. In about 50% no further relapse in experienced. The results of recent experience using cyclosporin A immunosuppression suggest a beneficial effect associated with steroid responsiveness. Approximately 30% of children with focal segmental glomerulosclerosis enter remission following treatment with corticosteroids. Some 30% require dialysis and transplantation within 5 years of diagnosis and immunosuppressive therapy to prevent deterioration of renal function is probably justified.     

Two-year cyclosporin treatment in children with steroid-dependent nephrotic syndrome

 We describe a prospective study of 2-year moderate-dose cyclosporin (CS) treatment in 13 children with steroid-dependent minimal change nephrotic syndrome (MCNS). CS treatment was commenced at 100–150 mg/m² per day after remission was attained with prednisolone therapy, was adjusted to a target trough level of 100 ng/ml, and was administered for 2 years. The number of relapses during CS treatment significantly decreased compared with before CS treatment, all patients were able to discontinue prednisolone therapy, and steroid toxicity was reduced; 54% of patients remained in remission during CS treatment. Renal biopsies performed before CS treatment all showed MCNS without tubulointerstitial lesions. Creatinine clearance and urinary β₂-microglobulin levels during CS treatment were normal in all patients, but renal biopsies performed after CS treatment revealed chronic CS nephrotoxicity in 7 patients. Clinical data, including CS dose and CS trough blood levels, were not significantly different between patients with and without nephrotoxicity. In conclusion, 2-year moderate-dose CS treatment in children with steroid-dependent MCNS is effective in preventing relapse and decreasing steroid toxicity. This treatment can, however, result in a high incidence of chronic nephrotoxicity. Renal function is not a reliable indicator of chronic CS nephrotoxicity. Renal biopsy is therefore necessary to monitor chronic CS nephrotoxicity. Received: 4 March 1998 / Revised: 28 April 1998 / Accepted: 25 June 1998     

Long-term linear growth of children with severe steroid-responsive nephrotic syndrome

The present study was designed to evaluate the risk of permanent linear growth impairment in a selected group of 42 children with steroid-dependent nephrotic syndrome (SDNS) and 14 children with frequently relapsing nephrotic syndrome (FRNS). Longitudinal height measurements were available in all patients from the onset of the disease for a mean follow-up of 11.7±3.5 years. During the prepubertal period, patients lost 0.49±0.6 height SD score (HtSDS) (P<0.001). Twenty-three patients have reached their final height with an average loss of 0.92±0.8 HtSDS from the onset of their disease (P<0.001) and 0.68±0.7 from their target HtSDS (P<0.001). The pubertal growth spurt was mildly delayed in male but not female patients. Steroid therapy, calculated as the mean duration of prednisone (PDN) treatment or as the average cumulative PDN dose, was the only predictor of poor growth evolution. Partial catch-up growth occurred after PDN withdrawal. Children with early onset NS and adolescent patients, who were still receiving PDN after the age of 9 years in girls and 11 years in boys, were at higher risk for HtSDS loss. In conclusion, children with severe steroid-responsive NS are at risk of permanent growth retardation secondary to prolonged courses of steroid treatment.     

HLA-DRB1 alleles in Kuwaiti children with idiopathic nephrotic syndrome

We have studied the effect of HLA-DRB1 alleles on the clinical presentation of 61 Kuwaiti Arab children with idiopathic nephrotic syndrome. DR7(*0701) was the most prevalent DR allele, found in 41/61 patients (67%) compared with 10/59 healthy controls (17%) (p<0.001). DR3(*0301–0308) allele was the second most common, found in 25% of patients compared with 26% of controls (not significant). There was no significant difference between DRB1*0701(DR7)-positive and DRB1*0701-negative patients in terms of steroid sensitivity, steroid dependency, or steroid resistance. Nevertheless, the former group had a significantly lower mean age of onset (35 months vs 53 months) and a shorter remission period following treatment with cyclophosphamide or chlorambucil (8 months vs 29 months). Our data highlight the role of the DRB1*0701 allele in predisposing Kuwaiti Arab children with idiopathic nephrotic syndrome to a more prolonged course of the disease. Received: 2 July 1999 / Revised: 20 April 2000 / Accepted: 23 April 2000     

Tacrolimus-induced HUS: an unusual cause of acute renal failure in nephrotic syndrome

Acute renal failure (ARF) is an uncommon complication in children with nephrotic syndrome. We report here the case of a 10-year-old male child with primary steroid-resistant nephrotic syndrome who was non-responsive to steroids and cyclophosphamide. A kidney biopsy revealed that he had focal segmental glomerulosclerosis. His treatment was initiated with tacrolimus (dose of 0.15 mg/kg/day) in two divided doses along with prednisolone 60 mg/m²/daily. After 1 month of treatment, he was diagnosed as having acute renal failure secondary to HUS. This was postulated to be due to the tacrolimus therapy, which was withdrawn. Two weeks after stopping the adminsitration of tacrolimus, his urine output improved, and the hemoglobin and serum creatinine normalized. Thus, tacrolimus-induced HUS is a rare cause of ARF in nephrotic syndrome. With the increasing use of tacrolimus in steroid-resistant nephrotic syndrome, the treating physicians need to be aware of this rare, but potentially life-threatening side effect.     

Increased cystatin C concentration in urine of nephrotic children

The aim of this study was to evaluate changes in urine and plasma concentrations of cystatin C in children with a relapse of the idiopathic nephrotic syndrome (INS). The study group comprised 12 children with INS with proteinuria and 12 children in an 8-week remission, both treated with steroids. Twelve healthy children served as controls. Cystatin C was detectable in the urine of children with proteinuria. The study suggests that massive proteinuria may influence renal cystatin C handling.     

Long-term prognosis of idiopathic nephrotic syndrome in children

Abstract

Background: To investigate the demographic, clinical and laboratory data of the children with idiopathic nephrotic syndrome (INS), and to determine prognostic factors that affect the clinical outcome of the patients. Methods: Medical charts of 372 patients diagnosed to have INS and followed up at least 5 years between January 1990 and December 2008 were evaluated, respectively. After initial demographic, clinical and laboratory findings of the patients were documented, therapeutic protocols, prognosis and prognostic factors were investigated. Results: 299 of the patients (80.4%) were steroid responsive and 73 (19.6%) were not. Focal segmental glomerulosclerosis (FSGS) was observed in 57%, minimal change disease (MCD) in 20.6% and diffuse mesengial proliferation in 21.9% renal biopsy materials. Steroid sensitivity was higher in patients with MCD and under the age of five years. Resistance to steroids was higher in children with FSGS. Complete remission was achieved in 96% of patients who were sensitive to steroids and in 46.6% who were resistant. 15% of patients who were steroid resistant developed chronic kidney disease (CKD). Conclusion: Intercurrent infections and response to steroid therapy are the most important factors affecting the prognosis of the disease.