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Clinical Overview of Nephrogenic Diabetes Insipidus Based on a Nationwide Survey in Japan

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Clinical Overview of Nephrogenic Diabetes Insipidus Based on a Nationwide Survey in Japan Yonago Acta medica 2014;57:85–91 Original Article Clinical Overview of Nephrogenic Diabetes Insipidus Based on a Nationwide Survey in Japan Masanobu Fujimoto,* Shin-ichi Okada,* Yuki Kawashima,* Rei Nishimura,* Naoki Miyahara,* Yasuo Kawaba,* Keiichi Hanaki,† Eiji Nanba,‡ Yoshiaki Kondo,§ Takashi Igarashi and Susumu Kanzaki* *Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago 683-8504, Japan, †Department of Women’s and Children’s Family Nursing, Tottori University Faculty of Medicine, Yonago 683-8504, Japan, ‡Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago 683-8504, Japan, §Health Care Services Management, Nihon University School of Medicine, Tokyo 173-0032, Japan and Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan ABSTRACT effective treatment for NDI among these patients. Background Nephrogenic diabetes insipidus (NDI) is Conclusion We suggest that adequate diagnosis and a rare disease whose complications include polyuria, re- treatment are the most important factors for improving nal dysfunction, growth disorder and mental retardation. prognoses. We further suggest that gene analysis should The details of NDI’s clinical course have been unclear. be performed for optimal treatment selection and the To address this uncertainty, we performed a large inves- early detection of NDI among siblings. tigation of the clinical course of NDI in Japan. Methods Between December 2009 and March 2011, Key words aquaporin 2; deamino arginine vasopres- we provided a primary questionnaire to 26,282 members sin; nephrogenic diabetes insipidus; thiazide diuretics; of the Japan Endocrine Society, the Japanese Urological vasopressin v2 receptor Association, the Japanese Society for Pediatric Endocri- nology, the Japanese Society for Pediatric Nephrology, Nephrogenic diabetes insipidus (NDI) is a rare disease the Japanese Society of Nephrology, the Japanese Soci- that is characterized by an inability to concentrate urine ety of Neurology and the Japanese Society of Pediatric due to insensitivity of the collecting tubule to arginine Urology. In addition, we provided a secondary question- vasopressin.1 NDI can be either congenital or acquired. naire to 121 members who reported experience with Common cases of congenital NDI (CNDI) result from cases of NDI. We asked about patient’s age at onset, di- mutations in the arginine vasopressin receptor 2 (AVPR2) agnosis, complications, effect of treatment and patient’s gene, which has X-linked recessive inheritance.1, 2 Some genotype. other congenital cases result from mutations in the aqua- Results We enrolled 173 patients with NDI in our porin 2 (AQP2) gene, which can have autosomal reces- study. Of these NDI patients, 143 were congenital and 30 sive or dominant inheritance.1, 2 Acquired NDI is com- were acquired. Of the 173, 73 patients (42%) experienced monly caused by drugs, such as lithium and demeclocy- urologic complications. Among the 143 with congenital cline.3 However, the clinical status of NDI has remained NDI, 20 patients (14%) had mental retardation. Patients unknown. with NDI mainly received thiazide diuretics, and some CNDI is commonly diagnosed as a result of charac- patients responded to treatment with desmopressin ac- teristic symptoms, such as polyuria, polydipsia, fever of etate (DDAVP). Gene analyses were performed in 87 unknown etiology, convulsion, vomiting and constipa- patients (61%) with congenital NDI, revealing that 65 tion in early infancy.4 However, it has been reported that patients had an arginine vasopressin receptor type 2 some cases of CNDI exhibit far milder symptoms such (AVPR2) gene mutation and that 8 patients (9.2%) had as night enuresis, and that the diagnosis is only made an aquaporin 2 (AQP2) gene mutation. Patients with later through gene analyses.5 Further, the long-term ef- the AVPR2 mutation (D85N) generally showed a mild fects of treatment for NDI, the prognosis of NDI and phenotype, and we found that DDAVP was generally an the correlation between the phenotype and genotype in Corresponding author: Masanobu Fujimoto cases of NDI all remain unknown. 6 [email protected] In Japan, Imura et al. carried out a nationwide Received 2014 January 15 survey for 5 “hormone receptor diseases” including Accepted 2014 January 31 NDI from 1977 to 1982. It was reported that there were Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; 78 cases of NDI, which seemed to be comprised of at ARB, angiotensin receptor blocker; AVPR2, arginine vasopres- 6 sin receptor type 2; AQP2, aquaporin 2; CNDI, congenital NDI; least 2 subtypes; early onset type and late onset type. DDAVP, desmopressin acetate; MR, mental retardation; NDI, Because the responsible genes of CNDI such as AVPR2 nephrogenic diabetes insipidus and AQP2 genes had not been detected at that time, they 85 M. Fujimoto et al. were unable to provide a molecular biological diagnosis a Number of patients of CNDI with a mild phenotype and in female carriers. 0 30 60 90 120 Hence, to ascertain the characteristics of NDI in the general population, we conducted the nationwide survey 0–1 of NDI in Japan. Here, we report the results of this sur- vey, including clinical findings at onset, complications, 1–4 the effects of treatment and genotypes in Japan. 5–9 MATERIALS AND METHODS The questionnaire and data analysis Between December 2009 and March 2011, we provided 10–19 a primary questionnaire to 26,282 members of the Japan Age at diagnosis Endocrine Society, the Japanese Urological Association, 20–29 the Japanese Society for Pediatric Endocrinology, the (yr) Japanese Society for Pediatric Nephrology, the Japanese Society of Nephrology, the Japanese Society of Neurol- Male Female ogy and the Japanese Society of Pediatric Urology. On b the primary questionnaire, we asked about experiences Number of patients 0 2 4 6 8 10 in clinical practice and the number of patients who had NDI. In addition, we provided a secondary questionnaire 0–9 to 121 members (96 hospitals) who reported experience with cases of NDI. We asked about patient’s age at onset, 10–29 diagnosis, complications, effect of treatment, patient’s genotype and administration of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor 30–49 blockers (ARBs) during the fetal period. Gene analyses were performed in individual facilities. We used the re- 50–69 sults of gene analyses. Attending physicians determined Age at diagnosis the type of NDI and the presence of secondary urologic 70 < complications, based on disease’s clinical manifestation (yr) and patient’s laboratory data. When the same case was Fig. 1. Histogram of the age at diagnosis with CNDI (a) and ac- reported by multiple members, we excluded each of the quired NDI (b). The number of male patients is depicted with a redundant reports based on the age and sex of the pa- closed bar. The number of female patients is depicted with an open tient or the name of the healthcare facility. In the survey, bar. CNDI, congenital NDI; NDI, nephrogenic diabetes insipidus. we asked for information regarding patients of all ages, complications, genders and races. We carefully ana- lyzed the results of the secondary questionnaire. At least RESULTS 2 researchers checked each report, and several team We received 5,139 responses to our primary question- meetings were conducted to ensure the accuracy of our naire from 26,282 members. Together, the primary survey results. To assess the coverage rate of our survey, questionnaires reported 210 NDI patients. We provided we compared the number of NDI patients aged less than a secondary questionnaire to 121 members (96 hospitals) 20 years in our survey with the number of patients who who had reported experience with cases of NDI. Re- were registered as having CNDI in the Medical Aid spondents to the secondary questionnaire reported 183 Program for Chronic Pediatric Diseases of Specified patients with NDI. Ten patients were excluded because Categories in Japan, from fiscal 2009 to fiscal 2011. The of insufficient information; we analyzed 173 patients. study was approved by the Ethics Committee of Tottori Of these, 143 patients had CNDI (124 males and 19 fe- University (approval number 1384). males) and 30 patients had acquired NDI (14 males and 16 females). There was no duplicated case. Our study Statistical analysis included 96 CNDI patients who were under 20 years as For our statistical analyses, we relied on the Mann- of 2009. In the database of the Medical Aid Program Whitney U-test and Fisher’s exact test. Values of P less for Chronic Pediatric Diseases of Specified Categories than 0.05 were defined as significant. in Japan, a yearly mean of 131 CNDI patients were re- 86 Nephrogenic diabetes insipidus in Japan ported from fiscal 2009 to fiscal 2011. Accordingly, the coverage achievement rate of our survey was estimated Genetic analysis to be 73%, which is high. Analyses of the AVPR2 and/or AQP2 genes were per- formed for 87 (61%) of all CNDI patients. For 10 of the Congenital NDI 87, we were unable to obtain the name of the gene in In this study, 143 patients had CNDI (124 males and 19 which a mutation was detected. Most of them (65 of 87; females), out of a total of 173 patients with any form of 75%) had AVPR2 gene mutations, surprisingly includ- NDI. Details of age at diagnosis are presented in Fig. 1. ing 10 female patients. On the other hand, AQP2 gene The median age of CNDI diagnosis was 2.0 months (n = abnormalities were identified in 8 patients (4 males and 125), and the mean [s] age was 1.2 [4.6] years (n = 125). 4 females; 9.2%). In 4 patients (2 males and 2 females; Ninety-eight patients (69%) with CNDI were diagnosed 4.6%), AVPR2 or AQP2 mutation was not detected by within the 1st year of life, and 19 patients (13%) were mutation analysis.
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