Motoshi Hattori

Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder

Masafumi Fukagawa, Keitaro Yokoyama, Fumihiko Koiwa, Masatomo Taniguchi, Tetsuo Shoji, Junichiro James Kazama, Hirotaka Komaba, Ryoichi Ando, Takatoshi Kakuta, Hideki Fujii, Msasaaki Nakayama, Yugo Shibagaki, Seiji Fukumoto, Naohiko Fujii, Motoshi Hattori, Akira Ashida, Kunitoshi Iseki, Takashi Shigematsu, Yusuke Tsukamoto, Yoshiharu Tsubakihara, Tadashi Tomo, Hideki Hirakata, and Tadao Akizawa for CKD-MBD Guideline Working Group, Japanese Society for Dialysis Therapy

Origin and Phenotypic Features of Hyperplastic Epithelial Cells in Collapsing Glomerulopathy

The characteristic pathological feature of collapsing glomerulopathy (CG) is marked cell hyperplasia and hypertrophy within the glomeruli. The present study investigated the phenotypic alteration of hyperplastic epithelial cells in CG to determine their origin. Renal biopsy specimens from two patients with CG were analyzed by immunohistochemical staining, using markers for podocytes (PHM-5), parietal epithelial cells (PECs; cytokeratin), and cell proliferation (Ki-67). In collapsed glomeruli, hyperplastic and hypertrophic epithelial cells were frequently connected to PECs and collapsed glomerular basement membranes (GBMs). These epithelial cells were more often Ki-67 positive and expressed cytokeratin, whereas PHM-5 was almost invariably negative. Serial section analysis showed that a small number of hyperplastic epithelial cells expressed both PHM-5 and cytokeratin, suggesting phenotypic conversion between podocytes and PECs. Moreover, cytokeratin-positive cells were associated with the sclerotic glomerular segments. Thus, we suggest that the majority of hyperplastic and hypertrophic epithelial cells in CG are of PEC origin. These epithelial features may participate in the development of characteristic tuft collapse and glomerulosclerosis in CG.

Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Approximately 10% of cases are classified as atypical due to the absence of Shiga toxin-producing bacteria as a trigger. Uncontrolled activation of the complement system plays a role in the pathogenesis of atypical HUS (aHUS). Although many genetic studies on aHUS have been published in recent years, only limited data has been gathered in Asian countries. We analyzed the genetic variants of 6 candidate genes and the gene deletion in complement factor H (CFH) and CFH-related genes, examined the prevalence of CFH autoantibodies and evaluated the genotype-phenotype relationship in 10 Japanese patients with aHUS. We identified 7 causative or potentially causative mutations in CFH (p.R1215Q), C3 (p.R425C, p.S562L, and p.I1157T), membrane cofactor protein (p.Y189D and p.A359V) and thrombomodulin (p.T500M) in 8 out of 10 patients. All 7 of the mutations were heterozygous and four of them were novel. Two patients carried CFH p.R1215Q and 3 other patients carried C3 p.I1157T. One patient had 2 causative mutations in different genes. One patient was a compound heterozygote of the 2 MCP mutations. The patients carrying mutations in CFH or C3 had a high frequency of relapse and a worse prognosis. One patient had CFH autoantibodies. The present study identified the cause of aHUS in 9 out of 10 Japanese patients. Since the phenotype-genotype correlation of aHUS has clinical significance in predicting renal recovery and transplant outcome, a comprehensively accurate assessment of molecular variation would be necessary for the proper management of aHUS patients in Japan.

Japan Renal Biopsy Registry and Japan Kidney Disease Registry: Committee report for 2009 and 2010

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1xa0%) by the J-RBR and 680 (16.9xa0%) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7xa0%) and 575 other cases (12.3xa0%) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9xa0%) and 171 renal grafts (5.1xa0%) and 3,869 native kidneys (94.2xa0%) and 237 renal grafts (5.8xa0%) were registered in 2009 and 2010, respectively. Patients younger than 20xa0years of age comprised 12.1xa0% of the registered cases, and those 65xa0years and over comprised 24.5xa0% of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4xa0% and 50.0xa0% in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4xa0% and 27.0xa0%); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6xa0% and 30.4xa0%), followed by primary glomerular diseases (except IgA nephropathy) (27.2xa0% and 28.1xa0%). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3xa0%) and minor glomerular abnormalities (50.0xa0%) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.

Pre-dialysis chronic kidney disease in children: results of a nationwide survey in Japan

BACKGROUNDnChronic kidney disease (CKD) in children is a progressive and intractable condition that may severely impair the childs growth, development and quality of life. Epidemiological information on pediatric CKD, particularly in Asians, is scant.nnnMETHODSnWe conducted a nationwide, population-based survey of Japanese children aged 3 months to 15 years with pre-dialysis CKD to examine the prevalence of pediatric CKD in Japan. CKD was classified according to newly established criteria derived from reference serum creatinine levels in Japanese children. Surveys were sent to 1190 institutions across Japan to report on cases of pediatric CKD managed as of 1 April 2010.nnnRESULTSnA total of 925 institutions (77.7%) responded. Information on 447 children was collected. When subdivided according to our diagnostic criteria, 70.5% of children had stage 3 CKD, 23.9% stage 4 and 5.6% stage 5. The estimated prevalence of Japanese children with CKD was 2.98 cases/100,000 children. Of 407 CKD cases with non-glomerular disease, 278 (68.3%) had congenital anomalies of the kidney and urinary tract (CAKUT). The newly established criteria showed good validity compared with existing criteria, including the abbreviated Schwartz equation.nnnCONCLUSIONSnFindings from the first nationwide survey of pre-dialysis CKD in Asian children indicate that the prevalence of stage 3-5 CKD in children in Japan aged 3 months to 15 years is 2.98 cases/100,000 children. Most children with CKD presented with non-glomerular disease, most frequently CAKUT. Improved management of CAKUT, including renoprotective treatment and urological intervention, is required.

LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy

BACKGROUNDnNail-patella syndrome (NPS) is a rare autosomal-dominant disorder caused by LMX1B mutation. In patients with the renal lesions typical of NPS without skeletal or nail findings, it is described as nail-patella-like renal disease (NPLRD). However, the pathogenesis of NPLRD is largely unknown.nnnMETHODSnA 6-year-old girl with microscopic haematuria and mild proteinuria was diagnosed with NPLRD because of an aberrantly thickened glomerular basement membrane (GBM) and deposition of Type III collagen in the GBM observed by electron microscopy. Immunohistological analyses of podocyte protein expression were performed on biopsy tissues. Sequence analysis of LMX1B was performed, and the functional consequences of the detected mutation were analysed by luciferase reporter assay.nnnRESULTSnWhen analysing molecules that are important for podocyte development, maintenance and maturation, CD2AP expression was found to be altered in the podocytes. A novel LMX1B missense mutation (R246Q) was identified. Functional analyses revealed partial but significant impairment of R246Q transcriptional activity. However, no dominant-negative effect of R246Q was detected, which suggests that NPLRD is caused by LMX1B haploinsufficiency.nnnCONCLUSIONSnThis is the first report on LMX1B mutation identified in a patient with NPLRD. Residual transcriptional activity would account for normality of the nails and patella in this case. Genetic and pathological analyses of additional cases would clarify the role of LMX1B in glomerulopathy without systemic symptoms, which, together with nephropathy in NPS, can be designated as LMX1B nephropathy.

Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society.

Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of approximately 25%, and with approximately 50% of cases resulting in end‐stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely.

Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the joint committee of the Japanese society of nephrology and the Japan pediatric society

AbstractnAtypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of ~25xa0%, and with ~50xa0% of cases resulting in end-stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely.

Podocyte expression of nonmuscle myosin heavy chain-IIA decreases in idiopathic nephrotic syndrome, especially in focal segmental glomerulosclerosis

BACKGROUNDnPrevious studies have identified significant associations between the development of idiopathic focal segmental glomerulosclerosis (FSGS) and MYH9 encoding nonmuscle myosin heavy chain-IIA (NMMHC-IIA). However, these studies focused only on the linkage of MYH9 polymorphisms and development of FSGS. There have been no reports on pathological changes of NMMHC-IIA in human glomerular diseases. Here we report on the precise localization of NMMHC-IIA in podocytes and changes in NMMHC-IIA expression in pathological states in rats and humans.nnnMETHODSnImmunocytochemical (immunofluorescence and immunoelectron microscopy) studies were performed to determine the precise localization of NMMHC-IIA. Expression levels of NMMHC-IIA were investigated in puromycin aminonucleoside (PAN)-treated rats; and expression levels of NMMHC-IIA and other podocyte-related proteins were investigated in glomeruli of patients with idiopathic FSGS and other heavy proteinuric glomerular diseases.nnnRESULTSnNMMHC-IIA was located primarily at the cell body and primary processes of podocytes; this localization is distinct from other podocyte-related molecules causing hereditary FSGS. In PAN-treated rat kidneys, expression levels of NMMHC-IIA in podocytes decreased. Immunohistochemical analysis revealed that expression levels of NMMHC-IIA markedly decreased in idiopathic nephrotic syndrome, especially FSGS, whereas it did not change in other chronic glomerulonephritis showing apparent proteinuria. Changes in NMMHC-IIA expression were observed in glomeruli where expression of nephrin and synaptopodin was maintained.nnnCONCLUSIONSnConsidering previous genome-wide association studies and development of FSGS in patients with MYH9 mutations, the characteristic localization of NMMHC-IIA and the specific decrease in NMMHC-IIA expression in idiopathic nephrotic syndrome, especially FSGS, suggest the important role of NMMHC-IIA in the development of FSGS.

Darbepoetin alfa for the treatment of anemia in children undergoing peritoneal dialysis: a multicenter prospective study in Japan

BackgroundDarbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD).MethodsPediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28xa0weeks. The conversion to the initial dose of DA was calculated as 1xa0μg DA for 200xa0IU rHuEPO, and DA was administered intravenously once every 2xa0weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0xa0g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4xa0weeks.ResultsIn the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9xa0±xa01.0 to 11.1xa0±xa01.0xa0g/dL at 8xa0weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88xa0% of these patients, and 60xa0% maintained this target value on completion of the study. The dosing frequency was extended to once every 4xa0weeks in 60xa0% of patients. Twenty-four adverse events were noted in 11 of 25 patients (44xa0%); however, there was no causality between DA and adverse events.ConclusionsThe results of this study suggest that intravenous administration of DA once every 2 or 4xa0weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD.