Tomonosuke Someya

Congenital fibromuscular dysplasia involving multivessels in an infant with fatal outcome

We report the unusual case of a 2-month-old boy with systemic fibromuscular dysplasia (FMD). He presented with congenital renovascular hypertension due to stenosis of the right renal artery, and later developed renal infarction on the contralateral side resulting in renal failure. The boy subsequently died of intracranial haemorrhage at the age of 14 months. During the course, hemiconvulsion caused by a Moyamoya disease-like vascular lesion was noted. Stenotic lesions of both the abdominal aorta and its branches were also revealed by angiography. Post-mortem examination confirmed that the coronary, splenic and mesenteric arteries were also affected and their histological findings were compatible with FMD. To our knowledge, this is the first congenital case of FMD demonstrating a rapidly progressive course resulting in a fatal outcome. In this case, multivessels in both intracranial and extracranial arteries were involved. Conclusion:our case suggests that the nature of fibromuscular dysplasia is congenital in origin and its aetiology, at least in some cases, is a systemic abnormality of vascular development.

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.

Aberrantly Glycosylated IgA1 as a Factor in the Pathogenesis of IgA Nephropathy

Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN.

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

Successful engraftment and decrease of cytomegalovirus load after cord blood stem cell transplantation in a patient with DiGeorge syndrome

A patient with DiGeorge syndrome showed a decrease of cytomegalovirus load after cord blood stem cell transplantation. A 3-month-old infant was admitted to hospital because of prolonged seizures. He was born at 37 weeks and 2 days gestation with a birth weight of 1864 g. He showed a significant decrease in serum Ca, Na and Cl levels, with inappropriate ADH secretion, and was treated with water restriction and Ca supplementation. Several minor anomalies, such as low-set ears, small-sized jaw, muscle hypotonia, retarded development and growth of body weight 4260 g (-3.0 SD) and body length 54 cm (–3 SD), and absence of thymus, genital hypoplasia, together with hypoparathyroidism (intact PTH <9 pg/ml), and lack of T-cells (5 cells/ll) led to a diagnosis of DiGeorge syndrome on day 100. The boy suffered from persistent fever, diarrhoea, and cough, with interstitial pneumonia, gastroenteritis, hepatitis, and retinopathy. Both cytomegalovirus (CMV) antigen and CMV-DNA were detected in blood and urine samples, suggestive of systemic CMV infection. He was treated with ganciclovir, c-globulin with high titres of CMV-IgG, and foscarnet sodium hydrate. The CMV load decreased from 60,000 genome copies/ 10 ll whole blood to 12,000, but no lower, and the symptoms such as fever, diarrhoea, and cough persisted (Table 1). Cord blood stem cell transplantation (CBSCT) was performed by infusion of 10.3·10 cord blood stem cells without preconditioning and with the use of cyclosporine (5 mg/kg per day) on day 220 (Table 1). Within 20 days after the CBSCT, his general condition, i.e. fever, cough, and general activities improved and a significant increase in T-cells (1690/ll) with dramatic reduction of CMV to 1000 copies was observed without any serious complications. However, respiratory distress and diarrhoea worsened gradually with a relapse of CMV infection up to 11,000 copies after the use of corticosteroids resulting in death on day 253. CMV infection is a fatal complication in T-cell deficient patients. CBSCT is an ideal treatment for introducing T-cell immunity, since premature T-cells do not induce serious graft-versus-host disease (GvHD) in the immune deficient host [1]. The reduction in CMV-DNA copies from 12,000/10 ll whole blood to 1,000 with increased T-cell counts suggests that CBSCT is effective for the treatment of CMV infection in DiGeorge syndrome. Although CBSCT successfully reduced the number of CMV-DNA copies, the respiratory distress and intestinal bleeding progressed. We cannot exclude the possibility that the introduction of lymphocytes accelerated the development of inflammation in the host organ. We do not suspect that these symptoms were caused by GvHD but possibly by systemic CMV disease, since the high CMV load was observed after CBSCT without any typical GvHD symptoms, i.e. skin lesions and liver dysfunction. Corticosteroid Y. Ohtsuka (&) AE T. Shimizu AE K. Nishizawa AE R. Ohtaki T. Someya AE A. Noguchi AE H. Fujita AE Y. Yamashiro Department of Paediatrics, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-8421 Tokyo, Japan E-mail: yohtsuka@med.juntendo.ac.jp Tel.: +81-3-58021075 Fax: +81-3-58000216

Can cranberry juice be a substitute for cefaclor prophylaxis in children with vesicoureteral reflux

Urinary tract infection (UTI) is a common childhood infection. In 30–50% of children with UTI the infections occur recurrently, especially in those with vesicoureteral reflux (VUR), resulting in hospitalizations, and long-term health problems, such as renal scars, hypertension, and end-stage renal disease. To reduce the likelihood of recurrent UTI for children with VUR, antibiotics prophylaxis has been regarded as the therapeutic standard for many years. However, the disadvantage of long-term antibiotic therapy is the potential for development of resistant organisms in the host. Although cranberry juice prophylaxis was found to reduce the frequency of bacteriuria with pyuria in older women, no studies have yet been reported in the literature on children with VUR. The purpose of this study was to examine whether cranberry juice can be substituted for antibiotic prophylaxis in the prevention of UTI in children with VUR.

Is single-daily low-dose cyclosporine therapy really effective in children with idiopathic frequent-relapsing nephrotic syndrome?

BACKGROUND A recent study on renal transplant patients has shown that a single dose of cyclosporine (CsA) has added the advantage of decreasing dosages and adverse effects, while maintaining graft function. However, the efficacy of this regimen in children with idiopathic frequent-relapsing nephrotic syndrome (NS) remains controversial. METHODS 20 children with steroid-dependent NS or CsA-dependent NS (18 with minimal change disease, MCD and 2 with focal segmental glomerulosclerosis, FSGS) were enrolled in this prospective study. CsA was commenced at 1.5 â 2 mg/kg, given as a single daily dose before breakfast, and the dose was adjusted to reach 2 hours post-dose CsA levels (C2) of 600 - 800 ng/ml. RESULTS In 9 out of 18 patients with MCD, treatment with single-daily CsA for a median of 13 months (range 7 - 21) resulted in a reduction of mean minimum prednisolone (PSL) dose from 1.1 A+/- 0.55 to 0.04 A+/- 0.09 mg/kg on alternate days (p < 0.01), and the median relapse rate from 1.3 (1.1 - 2.5) to 0 (0 - 0.2) episodes/6 months (p < 0.01). Of them, PSL could be weaned off in 7 patients (4 of 6 with steroid-dependent NS, only 3 of 14 with CsA-dependent NS) without relapse of NS while on this therapy. However, 11 out of 20 were considered to have treatment failure: 1 with steroid-dependent NS and 10 with CsA-dependent NS. In 2 patients having FSGS, this method showed no beneficial effects. In 18 patients with MCD, relapse free ratio on single-daily CsA therapy was significantly higher in patients whose average C2 levels were greater than 700 ng/ml (p < 0.05). CONCLUSIONS Our experience demonstrates that single-daily low-dose CsA therapy maintaining C2 levels greater than 700 ng/ml may be effective in children with steroid-dependent NS or MCD, with no relapse. In contrast, the usefulness of this regimen in children with CsA-dependent NS appears to be limited.

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity

Background:  Cyclosporine A (CsA) is an effective agent for frequently relapsing steroid‐dependent nephrotic syndrome (FR‐SDNS), but its use can also be complicated by renal toxicity. Because no biochemical markers from urine or blood samples have yet been established for detecting CsA‐induced renal injury to date, repeated renal biopsies are therefore required for all patients with long‐term CsA treatment. The purpose of the present study was therefore to detect early change of CsA nephropathy (CsAN) using blood samples.

Low-dose pulse methylprednisolone followed by short-term combination therapy and tonsillectomy for childhood IgA nephropathy

Sirs, We read with great interest the article by Yata et al. concerning the long-term outcome in Japanese children with immunoglobulin (Ig)A nephropathy [1]. These authors found a marked improvement in renal survival since the 2-year combination therapeutic regimen of prednisolone and immunosuppressive agent was first introduced for Japanese children with severe IgA nephropathy [2]; simultaneously, adverse effects, such as growth retardation and aseptic necrosis of the femur, associated with the longterm administration of steroids, were also observed with this combination therapy [2]. Alternatively, Pozzi et al. reported the impressive benefits of treatment with pulse methylprednisolone and short-term prednisolone (6 months) with respect to reducing proteinuria and preventing endstage renal failure in adult patients—without considerable toxicity [3]. Hotta et al. showed that tonsillectomy combined with low-dose pulse methylprednisolone followed by short-term oral prednisolone (12 months), which is regarded as the standard treatment of adulthood IgA nephropathy in Japan, was effective in resolving urinary abnormalities in Japanese adult patients, especially during the earlier course of the disease [4, 5]. We report here the findings of a cohort patients with IgA nephropathy who were treated with low-dose pulse methylprednisolone followed by short-term combination therapy with (n=5) or without tonsillectomy (n=5). Ten consecutive patients (six boys, four girls) with newly biopsy-proven IgA nephropathy and urinary protein excretion of more than 0.5 g/m daily who had been referred to Saitama Children’s Medical Center between 2003 and 2006 were enrolled into the study. Their age at the start of therapy ranged between 6.3 and 14.7 years (mean 10.5 years). The mean urinary protein excretion was 1.2 g/m per day (range 0.5–2.1 g/m per day). The mean percentage of glomeruli showing crescents and segmental sclerosis on renal biopsy in the patients was 32 and 6%, respectively. The treatment regimen consisted of low-dose pulse methylprednisolone (intravenously 15–20 mg/kg/day; maximum 600 mg/day) for three consecutive days weekly for 3 weeks, followed by short-term combination therapy (approximately 12 months) of alternate-day prednisolone (initially 1 mg/kg; maximum 30 mg), mizoribine (5 mg/kg per day)/azathioprine (2 mg/kg per day), and dipyridamole (5 mg/kg per day). The oral prednisolone dosages were tapered off at a dose of 2.5–5 mg every 4–8 weeks on the basis of the reduction in urinary protein excretion. Beginning in 2006, tonsillectomy was additionally performed within 3 months after the initiation of pulse methylprednisolone therapy in five patients. The primary endpoint was the disappearance of protein excretion defined as a morning urinary protein-to-creatinine ratio (mg/ mg) <0.1. The interval between the initial presentation Pediatr Nephrol (2010) 25:563–564 DOI 10.1007/s00467-009-1239-1

Evaluation of kidney dysfunction and angiotensinogen as an early novel biomarker of intrauterine growth restricted offspring rats

Background:Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring.Methods:Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed.Results:The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin–angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring.Conclusion:Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes.