Yoshiyuki Ohtomo

Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial

BACKGROUND Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity. METHODS We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1-18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m(2)) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405. FINDINGS Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223-374) than in the placebo group (101 days, 70-155; hazard ratio: 0·27, 0·14-0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36). INTERPRETATION Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS. FUNDING Japanese Ministry of Health, Labour and Welfare.

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.

Apoptosis of renal tubular cells in Shiga-toxin-mediated hemolytic uremic syndrome.

In order to clarify the mechanism of unusual renal tubular dysfunction seen in a child with Shiga toxin (Stx)-mediated hemolytic uremic syndrome (HUS), we studied the renal biopsy specimens for Stx binding and apoptosis of renal tubular cells. A 7-year-old boy with Stx-2-mediated HUS demonstrated extensive renal tubular damage characterized by nonoliguric acute renal failure, increased urinary tubular enzymes and defective urine-concentrating capacity. His renal biopsy specimens were analyzed for Stx binding and apoptotic cell death. Seven kidney tissue specimens obtained from patients without HUS served as controls. Detection of Stx binding to renal sections and apoptotic cells were performed using mouse monoclonal anti-Stx 2 antibody and the TUNEL method, respectively. Positive staining was observed predominantly in renal tubular cells, while the 7 kidney tissue specimens from control patients did not show positive staining. To the best of our knowledge, this is the first case to show Stx binding and apoptotic cell death in renal tubules on biopsy specimens obtained from a child with Stx-mediated HUS. In conclusion, this case suggests that vascular endothelial cells are not the sole nor the consistent target for Stx-mediated cell injury and that significant renal tubular damage other than glomerular damage might occur in some children with Stx-mediated HUS.

Renal Amyloidosis in Recessive Dystrophic Epidermolysis bullosa

Background: Although it is known that renal amyloidosis may complicate several dermatoses, recessive dystrophic epidermolysis bullosa (RDEB) complicated by nephropathy has been thought to be rare. We, however, had seen a young adult with RDEB who died of renal failure due to systemic amyloidosis. Objective: A retrospective study was performed in order to investigate the incidence and etiology of renal amyloidosis in RDEB. Methods: Routine urinalysis, serum amyloid A protein (SAA) and creatinine levels were repeatedly determined in 11 patients with RDEB (mean age 17.7 years, range 5–28, 7 males, 4 females). Nephropathy was defined as the presence of both proteinuria and hematuria with red blood cell casts. Results: Seven out of 9 generalized RDEB patients had nephropathy including 3 cases with end-stage renal disease (2 died within 2 years from the onset of nephropathy), while 2 patients with localized RDEB did not. Levels of SAA were significantly higher in patients with nephropathy than those in patients without nephropathy (p < 0.05). Conclusion: Nephropathy is a common and serious complication of RDEB. Renal amyloidosis may play an important role in its etiology. We recommend that patients with RDEB should be periodically screened for nephropathy due to amyloidosis by urinalysis and measuring SAA levels.

Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux

Abstract  We studied the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in 78 patients with primary vesicoureteral reflux (VUR), and examined renal function by dimercaptosuccinate (DMSA) renoscintigraphy and diethylenetriaminepenta-acetic acid (DTPA) renogram in each genotype. Patients were classified into three genotypes according to the ACE gene I/D polymorphisms: 32 in II genotype, 36 in ID, and 10 in DD. The incidence of presumably congenital unilateral small kidneys was high in DD patients (70%). Glomerular filtration rate obtained from DTPA renogram was 120.7±35.7 ml/min (expressed as mean±SD) in II genotype, 111.7±33.3 in ID, and 88.0±18.0 in DD. The total quantitative DMSA tracer uptake of both kidneys was also low in patients with the D allele. This study shows that the D allele of ACE gene is closely related to small congenital kidneys with refluxing ureters in patients with primary VUR, and in accordance with previous reports, this allele is also related to the progression of reflux nephropathy.

Low prevalence of hypercalciuria in Japanese children.

Background/Aim: There are several factors, such as race, age, sex, and geographical variations, associated with renal stone formation. Although it is known that the prevalence of urolithiasis in Japanese children is low, the reason remains obscure. We hypothesize that the low prevalence of urolithiasis is associated with the urinary calcium excretion. The aim of our study was to investigate the prevalence of hypercalciuria in Japanese children. Methods: This investigation is a population-based school survey. A group of 529 healthy Japanese children was screened for hypercalciuria by measurement of the urinary Ca/Cr ratio using the morning fasting urine. In addition, the urinary Na/Cr ratio was also calculated for each subject. Results: Hypercalciuria regarded as an urinary Ca/Cr value of more than 0.17 was noted only in 3 out of 529 children (0.6 %), while most cases (494/529, 93.4%) demonstrated hypocalciuria (urinary Ca/Cr <0.05). The mean urinary Ca/Cr value was 0.024 in all subjects combined. Linear regression analysis revealed a positive direct correlation between urinary Ca/Cr and Na/Cr values (rs = 0.14, p < 0.01). The urinary Ca/Cr ratio was not related to age in either sex. Conclusions: The present study demonstrates that the prevalence of hypercalciuria in Japanese children is low as compared with other countries, even though absorptive hypercalciuria and dietary hypercalciuria might be missed in this setting. This low prevalence of hypercalciuria may be associated with the lower prevalence of urolithiasis in Japanese children. As it is suggested that a low dietary intake of calcium and sodium may play some role in the low urinary calcium excretion, a randomized, controlled study comparing the efficacy of different modes of therapy, such as a low-calcium diet and/or a low-salt diet, might provide valuable information for the prevention of urolithiasis.

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

Nephrotic syndrome associated with human parvovirus B19 infection

Abstract.A previously healthy 8-year-old Japanese boy developed nephrotic syndrome during the course of erythema infectiosum due to human parvovirus B19 (PVB19) infection. A renal biopsy showed mesangiocapillary proliferative glomerulonephritis with immune complex deposits associated with PVB19 virus. His renal involvement improved spontaneously.

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.