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.

An awareness of the triggers of relapse is critical for the control of steroid-dependent, frequently relapsing nephrotic syndrome (SDFRNS). We have investigated the triggers, usually described as 'episodes', to such relapses within a temporal context. Thirty-five patients with SDFRNS were analyzed retrospectively. A total of 442 relapses occurred in 2499 patient-months. The relapses were classified into two groups: those with episodes (E+) and those without episodes (E-). There were 135 E+ relapses and 296 E- relapses. The common cold was the most common episode (52%) of E+ relapse, followed by school events (18%). These E+ relapses occurred almost evenly throughout the 4 weeks between each follow-up visit. Conversely, 161 (55%) of the 296 E-z relapses occurred within the 3-day period preceding the patient's appointment (relapse-related hospital visit, RRHV). McNemar's test revealed that the concentration of relapses in this period was statistically significant (P < 0.00011). In addition, 15 out of 26 RRHV without additional therapy showed a spontaneous remission. From a chronological perspective, the common cold and school events as well as up-coming hospital visits may trigger relapses in SDFRNS patients.

Cyclosporin A (CsA) is an effective treatment for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can be complicated by renal toxicity and a high incidence of relapses after withdrawal. We report 9 adolescent patients with childhood-onset FR-SDNS who had been treated with long-term CsA that resulted in moderate-to-severe CsA nephropathy (CsAN). They were treated with high-dose (mean: 10.1 mg/kg per day) mizoribine (MZR) in an attempt to allow weaning of CsA and/or steroid therapy, and reduce the frequency of relapses. Seven out of 9 patients were weaned off CsA by 1-year follow-up, although in the remaining 2 patients, MZR did not show any beneficial effects. Overall, this high-dose MZR therapy results in significant steroid sparing and reduction in relapse rates in our patients. Our experience shows that high-dose MZR therapy in patients with FR-SDNS who are also CsA-dependent appears to be effective in reducing CsA exposure as well as in decreasing the frequency of relapses.

We treated a 14-year-old boy with Henoch -Schönlein purpura nephritis (HSPN) who died of an intracranial hemorrhage (ICH). Although ICH is a rare complication of HSPN, the consequence of this complication is sometimes very serious. 1 But there are no reports on the pathology and pathogenesis of ICH occurring in the course of HSPN. We examined the autopsied brain tissue and renal biopsy specimen using in situ hybridization (ISH) and polymerase chain reaction (PCR) of human cytomegalovirus (HCMV). The results indicated that he had had latent HCMV infection on admission to hospital. This suggests that reactivation of latent HCMV infection superimposed on HSPN worsened his vasculitis and resulted in fatal ICH. This is the fi rst report investigating the brain pathology of ICH as a result of severe vasculitis of HSPN. Case reportFive years prior to coming to Surugadai Nihon University Hospital , a 9-year-old boy was admitted to a local hospital for abdominal pain and vomiting. He was diagnosed as having HSPN because purpura had appeared on his legs. He was followed as an outpatient by the hospital and was admitted fi ve times after his fi rst admission due to abdominal colic. The patient had proteinuria and hematuria and was given only dipyridamole during these periods. Two months prior to admission to Surugadai Nihon University Hospital he had pretibial edema, hypertension and abdominal distention with heavy proteinuria. He was referred to Surugadai Nihon University Hospital because of his severe nephritis.On admission he was 6 kg heavier than 1 month previously, and he had hypertension (140/92 mmHg) and anasarca. The laboratory fi ndings on admission were as follows: blood urea nitrogen 25.6 mg/dL, creatinine (Cr) 2.29 mg/dL, total protein (TP) 4.1 g/dL, albumin (Alb) 2.3 g/dL, total cholesterol (T-cho) 272 mg/dL, urine red blood cells >100 per high-power fi eld, and urinary protein 819 mg/dL (3.62 g/day), and creatinine clearance (Ccr) 39.6 mL/min, IgG 338 mg/dL, IgA 233 mg/dL, third component of complement (C3) 97.7 mg/dL, fourth component of complement (C4) 19.2 mg/dL, anti-nucleic antibody, anti ds-DNA antibody, proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) and myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) were negative.Based on these fi ndings a clinical diagnosis of nephronephritic HSPN was made, and treatment with oral prednisolone (2 mg/kg) was started. A renal biopsy showed diffuse mesangial proliferative glomerulonephritis, which was compatible with the International Study of Kidney Disease in Children (ISKDC) grade Vb. Intravenous methylprednisolone pulse therapy in combination with urokinase (3 days/week) was administered for 3 weeks. 2 After this therapy his serum creatinine decreased to 1.5 mg/dL. We then conducted double fi ltration plasmapheresis for 3 days to remove the IgA immune complex (IgA-IC), 3,4 which reduced IgA-IC from 3 mg/dL to 1 mg/dL. But on day 26 he had a fever and complained of a severe headache and delirium. Brain computed tomography (CT) showed a smal...

ABSTRACT: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 ϭ 6); group 2, treated with CsA alone (n ϭ 5); group 3, treated with CsA and MZR (n ϭ 4); and group 4, treated with MZR alone (n ϭ 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 ϩ 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. (Pediatr Res 66: 524-527, 2009)

A 12-year-old girl, who had been diagnosed as having Cockayne syndrome (CS), was admitted for emaciation and dehydration. On admission the patient had mild chronic renal failure (glomerular filtration rate: GFR 50 mL/min) and hyperuricemia. After rehydration, allopurinol was commenced for her hyperuricemia. Then, her renal function rapidly deteriorated (GFR 20 mL/min) with enhancement of proximal tubular dysfunction and hypertension. A renal biopsy showed that the patient had acute tubulointerstitial nephritis (ATIN). Based on this diagnosis, allopurinol was stopped and prednisolone was started (2 mg/kg per day), following which the renal tubular function improved. However, the proteinuria intensified to become nephrotic syndrome. After 1 month the patient developed a gastric ulcer. Famotidine was commenced but GFR deteriorated and renal proximal tubular dysfunction re-occurred. The renal pathology was evaluated by referring to the previous reports of renal pathology in CS. It is suggested that rapid deterioration of the renal function in CS patients might be the result of ATIN. In addition, the present nephrotic syndrome seemed to be accompanied by ATIN, as in other reports.

PGP may play a role in the tapering of corticosteroids after CR in SSNS.

Once-daily CsA therapy appears to be effective in children with steroid-dependent MCNS. However, follow-up renal biopsies should be performed to investigate the presence of CsAN after more than 24 months of treatment with once-daily regimen as well as with the conventional twice-daily regimen.