Hitohiko Murakami

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.

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.

Hypertensive encephalopathy in a boy with biopsy-proven acute post-streptococcal glomerulonephritis

Hypertensive encephalopathy, first described by Oppenheimer and Fishberg in 1928, is a condition characterized by varying degrees of headache, nausea, vomiting, visual disturbances, focal neurologic deficit, and seizures in the setting of severe systemic hypertension that is relatively acute in onset. 1 The report by Wright and Mathews contains 12 pediatric patients with hypertensive encephalopathy, 11 of whom had renal diseases including one with acute post-streptococcal glomerulonephritis (APSGN). 2 In reports of several cases in which hypertensive encephalopathy was the presenting symptom, authors described difficulty in obtaining the diagnosis. 3,4

Charge Selective Function in Childhood Glomerular Diseases

The charge selectivity (CS) function in human renal disease has not been unequivocally demonstrated to date. However, the clearance ratio of IgA to IgG may be theoretically useful in estimating CS in humans, since IgA and IgG have similar sizes and tertiary structures, but distinct isoelectric points (3.5–5.5 [IgA] and 4.5–9.0 [IgG]), and Stokes-Einstein radius: 61 Å (IgA) and 49–60 Å (IgG). Two-dimensional electrophoresis with the following immunoblotting revealed that the considerably anionic portion (isoelectric points [pI] <4.0) of IgA, visible in serum, was absent in the urine in steroid-sensitive nephrotic syndrome (SSNS) but present in the same during IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN). A latex assay revealed the CS index (CSI) was significantly low in patients with podocyte disease (group A), including SSNS, focal and segmental glomerulosclerosis (FSGS) and Finnish-type congenital nephrotic syndrome (FCNS), but high in those with Alport syndrome (AS), IgAN, Henoch-Schönlein purpura nephritis (HSPN), and MPGN (group B). The linear regression analysis of the IgA size selectivity index (IgA SSI; clearance ratio of IgA to transferrin) and SSI (clearance ratio of IgG to transferrin), which represents the clearance ratio of IgA to IgG referring to the transferrin clearance, revealed the influence of the charge more accurately. Indeed, the slope of the regression lines of IgA SSI (y) to SSI (x) were concluded to be y = 0.39x (group A) and y = 1.05x (group B), respectively. These results suggested that the charge selective barrier among podocyte diseases (group A) is preserved to some degree, but lost in cases of nephritis and AS (group B).

Cockayne syndrome with recurrent acute tubulointerstitial nephritis.

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.

Synergistic protective effects of mizoribine and angiotensin II receptor blockade on cyclosporine A nephropathy in rats

Background:Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats.Methods:Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated.Results:Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity.Conclusion:These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.

Nephronophthisis Cannot Be Detected by Urinary Screening Program

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is the most frequent genetic cause for end-stage renal disease (ESRD) in Western countries. In contrast, the actual incidence of NPHP in Japan remains unclear because details of only about 30 Japanese patients have been reported so far. Till date, mutations in 9 NPHP genes (NPHP1-9) have been identified in NPHP subtypes 1 to 9. The first identified NPHP gene NPHP1, which is localized on chromosome 2q13, encodes nephrocystin. Based on the timing for ESRD, the following 3 clinical variants have been described: infantile, juvenile, and adolescent. Of these, juvenile NPHP (NPHP1) is the most common form, which accounts for 5% to 10% of ESRD cases in Caucasian children. To our knowledge, only 2 previous studies have reported on Japanese patients with NPHP in whom genetic diagnosis was made. Here, we report on a girl with NPHP1 who initially visited a local hospital because of general fatigue and was referred to our hospital as she demonstrated anemia associated with chronic renal insufficiency. However, no abnormal findings had been noted during annual school urinary screenings conducted over a long period of time.

Mcl-1, an anti-apoptotic Bcl-2 family member, essentially overlaps with insulin-producing cells in neonatal nesidioblastosis

Dear Sirs, We report here that anti-apoptotic protein Mcl-1 is closely related to the abnormal development of insulin-producing cells in neonatal nesidioblastosis. Nesidioblastosis, first reported by Dr. Laidlaw in 1938, was identified as the proliferation of endocrine cells differentiating from the pancreatic ductal epithelium to form islets, but the term “nesidioblastosis” has recently been used for histopathological abnormalities with hyperinsulinemic and hypoglycemic events [4]. Mcl-1, one of the anti-apoptotic Bcl-2 family members, is dispersed in fetal and adult pancreatic islets [1, 2, 6], and Mcl-1-positive cells have a distribution closely correspondent to that of glucagon-producing cells [2]. We have recently shown that Mcl-1 transgenic mice develop islet cell hyperplasia or insulinoma [3], indicating that constitutional persistent expression of Mcl-1 causes abnormal proliferation or new development of insulin-inducing cells in various islet cell disorders. This suggests that Mcl-1 is involved in pathogenesis of nesidioblastosis. We have observed a neonate patient with intractable hyperinsulinemic and hypoglycemia whose histopathological findings showed typical features of diffuse nesidioblastosis. To clarify the anti-apoptotic role of Mcl-1 in nesidioblastosis, we carried out an immunohistochemical investigation using antibodies against Mcl-1 [5, 6] (1:50, rabbit polyclonal), insulin (1:400; rabbit polyclonal; DAKO Cytomation, Kyoto, Japan), glucagon (1:50; guinea pig polyclonal; DAKO Cytomation), and Ki-67 (1:50; mouse monoclonal, MIB-1; DAKO Cytomation). Staining was developed with a 3, 3′-diaminobenzidine (DAB) or True Blue (KPL, Gaithersburg, MD). Slides were counterstained with hematoxylin or nuclear fast red. As opposed to reported in the normal fetal and adult pancreas, the distribution of Mcl-1-positive cells almost matched that of insulin-positive cells (Fig. 1a, Mcl-1; b, insulin) and rarely overlapped with that of glucagon-positive cells in nesidioblastosis (Fig. 1c). Mcl-1 was also expressed at low levels in the pancreatic ducts and intercalated ducts, which highlighted ductulo-insular proliferative lesions (Fig. 1d). We next addressed the question of whether or not these Mcl-1-positive cells possess proliferative properties. We performed double immunostaining for Mcl-1 and Ki-67. Most of the proliferating Mcl-1-positive cells in the pancreatic islets were devoid of Ki-67 labeling (Fig. 1e). Lack of Ki-67 staining was also observed in the Mcl-1positive cells in the ductulo-insular proliferation (Fig. 1f). Thus, our results suggested that Mcl-1 expression contributes to development of new insulin-producing cells rather than cell proliferation. We have shown overexpression of Mcl-1 in the ectopic and proliferative insulin-producing cells of human nesidioblastosis, which is consistent with the Mcl-1 transgenic mice model [3]. As endocrine cells derived from progenitor Virchows Arch (2008) 452:469–470 DOI 10.1007/s00428-007-0567-4

Rapidly progressive acute post-streptococcal glomerulonephritis in a child with IgA nephropathy.

Shuichiro Fujinaga, Yoshiyuki Ohtomo, Hiroshi Mochizuki, Hitohiko Murakami, Toshiaki Shimizu, Yuichiro Yamashiro and Kazunari Kaneko Divisions of Nephrology and Pathology, Saitama Children’s Medical Center, Magome, Saitama City, Saitama, Department of Paediatrics, Juntendo Nerima Hospital, Takanodai, Department of Pediatrics, Juntendo University School of Medicine, Hongo, Tokyo and Department of Pediatrics, Kansai Medical University, Moriguchi City, Osaka, Japan

Recurrence of Henoch–Schoenlein purpura nephritis after long-term remission in a 15-year-old girl

Sirs, Although the prevalence of renal involvement during the course of Henoch–Schonlein purpura (HSP) is approximately 33% (ranging from 20% to 55%), HSP nephritis is mostly a one-shot disease, usually resolving in 3–6 months. We describe a late recurrence after 6 years in a girl with HSP nephritis who had initially achieved complete remission by aggressive treatment with methylprednisolone pulse followed by daily oral administration of prednisolone. The biopsy did not show fibrous crescents; however, more than 5 years later, heavy proteinuria developed, again associated with the second attack of purpura. A 9-year-old girl was referred to our hospital in February 1999 because of heavy proteinuria and macroscopic hematuria associated with purpuric rash on the extremities. Her family history and past illness were unremarkable. Renal histology from March 1999 showed grade III by the International Study of Kidney Disease in Childhood (ISKDC) classification, and focal mesangial proliferation with cellular crescents in three of 33 glomeruli by light microscopy (Fig. 1a). Immunofluorescence revealed predominant IgA deposition with C3 in the mesangial area. She was treated intravenously with three courses of