Shuichiro Fujinaga

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Background: Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients. Aims and Methods: In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50–150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed. Results: Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6–144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN. Conclusion: An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.

Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome

BackgroundRituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome.MethodsWe retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan.ResultsSeventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX (P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete (n = 6) and partial remission (n = 6) were achieved. No life-threatening adverse events were experienced.ConclusionsAlthough this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse.

Th1/Th2 balance in childhood idiopathic nephrotic syndrome.

AIMS In view of the conflicting evidence of helper T cell type 1 (Th1) or type 2 (Th2) pattern of cytokine synthesis in childhood idiopathic nephrotic syndrome (INS) this study examined the balance of Th1 and Th2 which are characterized by intracellular cytokine production of interferon-gamma (IFNgamma) and interleukin-4 (IL-4), respectively. SUBJECTS AND METHODS Sixteen children with steroid-sensitive INS (mean age 9.0 years) were included in this study, together with 15 healthy normal children (mean age 7.9 years) for the control group. Intracellular production of both IFNgamma and IL-4 in helper T cell (CD4+ cell) was investigated by a 3-color flow cytometry. RESULTS The cross-sectional data showed no significant differences of percentages of Th0 (IFNgamma+ IL-4+ CD4+ cell), Th1 (IFNgamma+ lL-4- CD4+ cell) and Th2 (IFNgamma- IL-4+ CD4+ cell) in CD4+ cells (p > 0.05). The Th1/Th2 ratio during nephrotic relapse did not differ from those during nephrotic remission and in normal healthy children (p > 0.05). CONCLUSION We conclude that there is no significant skew of Th1/Th2 balance in childhood INS and that the cardinal immunological abnormality does not lie in helper T cells but in other cells, such as suppressor/cytotoxic T cells, natural killer cells or monocytes/macrophage. To clarify the pathogenesis of INS, comprehensive studies for these cells would be worthwhile.

Acute renal failure due to obstructive uric acid stones associated with rotavirus gastroenteritis

Sirs, The prevalence of urolithiasis in Japanese children is very low [1, 2]. Uric acid is rather uncommon as a constituent of childhood urolithiasis: uric acid stones occasionally develop in conditions associated with excessive production of uric acid, such as tumor lysis syndrome or lymphoproliferative/myeloproliferative disorders. Rare inborn errors of uric acid metabolism, i.e., complete or partial deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity, named LeschNyhan syndrome and Kelley-Seegmiller syndrome, respectively [3, 4, 5], may be complicated by uric acid stones. We describe the first case of a previously healthy child with acute renal failure caused by obstructive uric acid stones of the bilateral pelviureteric junctions associated with rotavirus gastroenteritis. A 13-month boy with an 8-day history of vomiting, watery diarrhea, and low-grade fever was initially admitted to a local hospital because of dehydration. On the following day, he was referred to our hospital as he demonstrated prolonged oliguria despite sufficient fluid replacement therapy. He had been previously healthy with no prior medical problems. There was no familial history of renal disease, including urolithiasis. On admission, physical examination revealed mild edema, a blood pressure of 112/96 mmHg, a pulse of 150 beats per minute, a respiratory rate of 96 per minute, and a temperature of 37.8 C. His body weight was 10 kg, which is average for his age. Laboratory investigations were as follows: white blood cell count 19,100/ml, hemoglobin 10.4 g/dl, hematocrit 30.2%, platelets 425,000/ml, blood urea nitrogen 42 mg/ dl, serum creatinine 2.34 mg/dl, uric acid 14.2 mg/dl, sodium 129 mmol/l, potassium 5.3 mmol/l, chloride 97 mmol/l, calcium 8.5 mg/dl, phosphate 5.6 mg/dl, and C-reactive protein 4.04 mg/dl (normal <0.05). Urinalysis by dipstick showed hematuria (occult blood 3+), proteinuria (1+), and leukocyturia (2+). Urine pH and specific gravity were 5.0 and 1.017, respectively. Uric acid excretion per deciliter creatinine clearance for spot morning urine specimens was high (0.70, normal 0.32€0.11 mg/dl) [6]. Rotavirus antigen in the stool was positive. Ultrasound scan of the kidney in the emergency room showed bilateral dilated pelves, although an obstructive lesion could not be identified. Based on these findings, a presumptive diagnosis of acute renal failure resulting from sustained hypovolemia associated with rotavirus gastroenteritis was made. He was treated with continuous venovenous hemodialysis because of hyperkalemia and hypertension refractory to intravenous fluid replacement and diuretics. On the 2nd hospital day, ultrasound scan of the urinary tract was carefully performed again because of prolonged oliguria. Stone-like masses located at bilateral pelviureteric junctions caused severe obstruction resulting in bilateral hydronephrosis. Abdominal computed tomography confirmed this finding. Therefore, percutaneous nephrostomy tubes were inserted bilaterally under ultrasound guidance on the same day. Soon after placement of the nephrostomy tubes, large amount of urine flowed via the tubes and serum levels of creatinine and uric acid returned to normal within several days. Sandy stones excreted through the nephrostomy tubes with urine proved to be S. Fujinaga ()) · Y. Ohtomo · M. Takada Division of Nephrology, Saitama Children’s Medical Center, Japan e-mail: f_shuich@d2.dion.ne.jp Tel.: +81-48-7581811 Fax: +81-48-7581818

Protective effects of Mizoribine on Cyclosporine A nephropathy in rats.

The therapeutic benefits of Cyclosporine A (CsA) are often limited by the chronic nephrotoxicity of its long-term use. Chronic nephrotoxicity is manifested by renal function impairment and progressive histopathological kidney lesions characterized by tubular vacuolization, tubular necrosis, interstitial fibrosis, and afferent arteriolopathy. This study tested the hypothesis that the concurrent administration of Mizoribine (MZR) may improve chronic CsA nephrotoxicity. Sprague-Dawley male rats were divided into the following four groups: group 1, control (n = 6); group 2, treated with CsA alone (n = 5); group 3, treated with CsA and MZR (n = 4); and group 4, treated with MZR alone (n = 6). The anti-inflammatory and antifibrotic effects of MZR were studied by evaluating the concentrations of the inflammatory mediator, osteopontin, renal function, and histopathology. The interstitial fibrosis was stained blue with Elastica-Massontrichrome and the sections were quantified. The CsA-treated rats showed decreased renal function and increased histologic parameters in comparison with the control rats and also showed significantly increased interstitial fibrosis area and macrophage in comparison with the control rats. The CsA + MZR treatment significantly improved the interstitial fibrosis area and macrophage in comparison with the CsA-treated rats. On the basis of these findings, we suggest MZR effectively attenuates renal macrophage accumulation and the progression of interstitial fibrosis.

Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: general therapy

Nephrotic syndrome is a disorder characterized by severe proteinuria, hypoproteinemia, and generalized edema resulting from damage to the glomerular basement membrane. In Western countries, nephrotic syndrome affects 2 of 100,000 children per year [1]. In Japan, approximately 1,300 new cases per year of pediatric nephrotic syndrome are reported to the Medical Aid for Specific Chronic Disease of Children and the disease develops in 5 of 100,000 children per year. Approximately 90 % of the cases of pediatric nephrotic syndrome are idiopathic, or of unknown cause. The first-line treatment for an initial episode of pediatric idiopathic nephrotic syndrome is oral steroid therapy, which leads to remission in approximately 80 % of cases (steroidsensitive nephrotic syndrome) [2]. However, 80 % of children with steroid-sensitive nephrotic syndrome experience one or more relapses, [3] and 50 % of these children have frequent relapses [4]. Those with frequently relapsing nephrotic syndrome are prone to suffer steroid-induced side effects such as obesity, growth impairment, hypertension, diabetes mellitus, osteoporosis, and adrenal insufficiency. Many cases of steroid-resistant nephrotic syndrome, where steroids are ineffective, progress to renal failure. Pediatric idiopathic nephrotic syndrome is a very important disease in the field of pediatric nephrology. The Scientific Committee in the Japanese Society for Pediatric Nephrology previously published the ‘‘Clinical Practice Guideline for Pediatric Idiopathic Nephrotic Syndrome’’ (2013). This is the English translation from the ‘‘Medical Therapy’’ portion of the guideline.Nephrotic syndrome is a disorder characterized by severe proteinuria, hypoproteinemia, and generalized edema resulting from damage to the glomerular basement membrane. In Western countries, nephrotic syndrome affects 2 of 100,000 children per year [1]. In Japan, approximately 1,300 new cases per year of pediatric nephrotic syndrome are reported to the Medical Aid for Specific Chronic Disease of Children and the disease develops in 5 of 100,000 children per year. Approximately 90 % of the cases of pediatric nephrotic syndrome are idiopathic, or of unknown cause. The first-line treatment for an initial episode of pediatric idiopathic nephrotic syndrome is oral steroid therapy, which leads to remission in approximately 80 % of cases (steroidsensitive nephrotic syndrome) [2]. However, 80 % of children with steroid-sensitive nephrotic syndrome experience one or more relapses, [3] and 50 % of these children have frequent relapses [4]. Those with frequently relapsing nephrotic syndrome are prone to suffer steroid-induced side effects such as obesity, growth impairment, hypertension, diabetes mellitus, osteoporosis, and adrenal insufficiency. Many cases of steroid-resistant nephrotic syndrome, where steroids are ineffective, progress to renal failure. Pediatric idiopathic nephrotic syndrome is a very important disease in the field of pediatric nephrology. The Scientific Committee in the Japanese Society for Pediatric Nephrology previously published the ‘‘Clinical Practice Guideline for Pediatric Idiopathic Nephrotic Syndrome’’ (2013). This is the English translation from the ‘‘Medical Therapy’’ portion of the guideline.

Effects of human milk and spermine on hydrogen peroxide-induced oxidative damage in IEC-6 cells

Objective: Oxidative stress is intimately involved in the pathologic processes of serious diseases in the perinatal period. Human milk (HM) contains various bioactive substances, some of which are known as antioxidants, including polyamines such as spermine (SPM). We examined the antioxidative properties of HM and SPM in an intestinal epithelial cell line. Method: Confluent Intestinal Epithelial Cells-6 (IEC-6) cells were preincubated with 100-fold dilutions of defatted HM, bovine milk, or three artificial milks for 24 hours, followed by hydrogen peroxide (H2O2) challenge (0.5 mM, 30 min) for oxidative stress. Cells were preincubated with either HM or increasing concentrations (within the range of HM) of SPM for 24 hours followed by an H2O2 challenge (0.25 mM, 30 min). Results: HM-treated cells showed the highest survival rate (50%) compared with no pretreatment (27%), bovine milk-treated (6%), or artificial formula-treated (13-16%) cells. Significantly higher survival rates were observed in the cells treated with HM (44.0%) and in those treated with 0.5, 1, or 5 μM of SPM (12.6, 13.1, or 22.2%, respectively) in comparison with the nontreated cells (7.0%). Conclusion: Our results demonstrated that HM and SPM alleviated H2O2-induced oxidative damage in IEC-6 cells, whereas bovine milk and artificial formula did not show any antioxidative capacity. These results suggest that HM acts as an antioxidant in the gastrointestinal tract of infants and that SPM plays an important role in the antioxidative properties of HM.

Cyclosporine A for heavy proteinuria in a child with Henoch−Schönlein purpura nephritis

Henoch–Schönlein purpura (HSP) is a systemic vasculitis characterized by the tissue deposition of IgA containing immune complexes. 1 Nephropathy is a major complication of HSP (HSPN) and usually develops within a few days to 4 weeks after the onset of general symptoms. 2 The findings include gross and microscopic hematuria, cellular cast, proteinuria, and in some cases, progressive renal failure. Although there is no established treatment for severe HSPN, some published reports suggest that pulse intravenous methylprednisolone therapy (PMT) or multiple drug combined therapy including immunosuppressive agents might be beneficial. 3,4 There are also published reports on the use of intravenous immune globulin or plasmapheresis to treat severe HSPN. 5,6

Combined pharmacotherapy for nocturnal enuresis

Abstract  Nocturnal enuresis is a common childhood disorder. Tricyclic antidepressants and anticholinergic agents have been the well accepted pharmacological treatment for this disorder and are efficacious in 40–70% and 10–50% of cases, respectively. The present study was performed to evaluate the effect of a combined treatment of tricyclic antidepressant and an anticholinergic agent.Twenty-two children aged 6–12 years with primary monosymptomatic nocturnal enuresis who did not prefer to use a conditioning alarm were given a combined treatment of these drugs. After a control period of 1 month, each patient was treated for 6 months and then observed for 3 months. A 30-mg dose of amitriptyline or imipramine was given with either 2–4 mg oxybutinin or 10–20 mg propiverine. Efficacy was determined relative to the number of wet nights per week compared with the control period, with more than a 50% decrease in wet nights per week taken to indicate efficacy.The mean wet nights per week decreased from 6.1 to 1.7 (P<0.01), and efficacy was established in 20 patients (90.9%). Relapses occurred in 60.0% of patients during the follow-up period. No significant side effects were observed.The efficacy of the combined therapy in monosymptomatic nocturnal enuresis appears to be greater than that reported for either drug alone, and therefore can be a choice of treatment in order to motivate children with nocturnal enuresis.

Uncertainty in management of childhood-onset idiopathic nephrotic syndrome: is the long-term prognosis really favorable?

Despite the recent establishment of clinical practice guidelines, many areas in the management of childhood idiopathic nephrotic syndrome (INS) remain uncertain. In this edition of Pediatric Nephrology Samuel et al. report significant differences between Canadian pediatric nephrologists’ practice and guideline recommendations, including initial duration of glucocorticoid treatment, choice of glucocorticoid-sparing agents in cases of frequently relapsing or steroid-dependent INS, and biopsy timing. Although evidence is emerging that the incidence of subsequent relapse can be reduced with longer initial glucocorticoid therapy, even with this new regimen relapse occurs in more than half of the children with steroid-sensitive INS. Cyclosporine (CsA) as a glucocorticoid-sparing agent for children with frequently relapsing or steroid-dependent INS is believed to provide protection from steroid toxicity and significantly improve the quality of life. However, recent follow-up studies of the post-CsA era have revealed a high incidence of INS relapse in adulthood in patients treated with CsA in childhood, and CsA use itself is a significant predictor of recurrent relapses. Therefore, pediatric nephrologists must recognize the potential of adverse effects that may appear later in life because of prolonged immunosuppressive therapy in childhood.