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’sand 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, Universityof Tokyo, Tokyo 113-8655, Japan

ABSTRACTeffective treatment for NDI among these patients.
Conclusion We suggest that adequate diagnosis andtreatment are the most important factors for improving
prognoses. We further suggest that gene analysis shouldbe performed for optimal treatment selection and theearly detection of NDI among siblings.

Background

Nephrogenic diabetes insipidus (NDI) isa rare disease whose complications include polyuria, renal dysfunction, growth disorder and mental retardation.
The details of NDI’s clinical course have been unclear.
To address this uncertainty, we performed a large investigation of the clinical course of NDI in Japan.
Methods Between December 2009 and March 2011,
we provided a primary questionnaire to 26,282 membersof the Japan Endocrine Society, the Japanese Urological
Association, the Japanese Society for Pediatric Endocrinology, the Japanese Society for Pediatric Nephrology,
the Japanese Society of Nephrology, the Japanese Society of Neurology and the Japanese Society of PediatricUrology. In addition, we provided a secondary questionnaire to 121 members who reported experience withcases of NDI. We asked about patient’s age at onset, diagnosis, complications, effect of treatment and patient’s
genotype.
Results
We enrolled 173 patients with NDI in ourstudy. Of these NDI patients, 143 were congenital and 30
were acquired. Of the 173, 73 patients (42%) experienced
urologic complications. Among the 143 with congenital
NDI, 20 patients (14%) had mental retardation. Patientswith NDI mainly received thiazide diuretics, and somepatients responded to treatment with desmopressin acetate (DDAVP). Gene analyses were performed in 87
patients (61%) with congenital NDI, revealing that 65
patients had an arginine vasopressin receptor type 2(AVPR2) gene mutation and that 8 patients (9.2%) had
an aquaporin 2 (AQP2) gene mutation. Patients with
the AVPR2 mutation (D85N) generally showed a mild
phenotype, and we found that DDAVP was generally an

Key words

aquaporin 2; deamino arginine vasopressin; nephrogenic diabetes insipidus; thiazide diuretics;
vasopressin v2 receptor
Nephrogenic diabetes insipidus (NDI) is a rare disease
that is characterized by an inability to concentrate urine
due to insensitivity of the collecting tubule to arginine
vasopressin.1 NDI can be either congenital or acquired.
Common cases of congenital NDI (CNDI) result frommutations in the arginine vasopressin receptor 2 (AVPR2)
gene, which has X-linked recessive inheritance.1, 2 Someother congenital cases result from mutations in the aquaporin 2 (AQP2) gene, which can have autosomal recessive or dominant inheritance.1, 2 Acquired NDI is commonly caused by drugs, such as lithium and demeclocycline.3 However, the clinical status of NDI has remained
unknown.
CNDI is commonly diagnosed as a result of characteristic symptoms, such as polyuria, polydipsia, fever of
unknown etiology, convulsion, vomiting and constipation in early infancy.4 However, it has been reported thatsome cases of CNDI exhibit far milder symptoms suchas night enuresis, and that the diagnosis is only madelater through gene analyses.5 Further, the long-term effects of treatment for NDI, the prognosis of NDI andthe correlation between the phenotype and genotype incases of NDI all remain unknown.
In Japan, Imura et al.6 carried out a nationwide
survey for 5 “hormone receptor diseases” including
NDI from 1977 to 1982. It was reported that there were
78 cases of NDI, which seemed to be comprised of atleast 2 subtypes; early onset type and late onset type.6
Because the responsible genes of CNDI such as AVPR2
and AQP2 genes had not been detected at that time, they

Corresponding author: Masanobu Fujimoto
fujimasa1027@gmail.com
Received 2014 January 15
Accepted 2014 January 31
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor;
ARB, angiotensin receptor blocker; AVPR2, arginine vasopressin receptor type 2; AQP2, aquaporin 2; CNDI, congenital NDI;
DDAVP, desmopressin acetate; MR, mental retardation; NDI,
nephrogenic diabetes insipidus85

M. Fujimoto et al.

awere unable to provide a molecular biological diagnosisof CNDI with a mild phenotype and in female carriers.
Hence, to ascertain the characteristics of NDI in thegeneral population, we conducted the nationwide survey
of NDI in Japan. Here, we report the results of this survey, including clinical findings at onset, complications,the effects of treatment and genotypes in Japan.

Number of patients
0

30

60

90

120

Age at diagnosis

0–1

MATERIALS AND METHODS
The questionnaire and data analysis

Between December 2009 and March 2011, we provided
a primary questionnaire to 26,282 members of the Japan
Endocrine Society, the Japanese Urological Association,
the Japanese Society for Pediatric Endocrinology, theJapanese Society for Pediatric Nephrology, the JapaneseSociety of Nephrology, the Japanese Society of Neurology and the Japanese Society of Pediatric Urology. On
the primary questionnaire, we asked about experiencesin clinical practice and the number of patients who had
NDI. In addition, we provided a secondary questionnaire
to 121 members (96 hospitals) who reported experience
with cases of NDI. We asked about patient’s age at onset,
diagnosis, complications, effect of treatment, patient’s
genotype and administration of angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin receptor
blockers (ARBs) during the fetal period. Gene analyses
were performed in individual facilities. We used the results of gene analyses. Attending physicians determined
the type of NDI and the presence of secondary urologic
complications, based on disease’s clinical manifestationand patient’s laboratory data. When the same case wasreported by multiple members, we excluded each of theredundant reports based on the age and sex of the patient or the name of the healthcare facility. In the survey,
we asked for information regarding patients of all ages,
complications, genders and races. We carefully analyzed the results of the secondary questionnaire. At least
2 researchers checked each report, and several teammeetings were conducted to ensure the accuracy of oursurvey results. To assess the coverage rate of our survey,
we compared the number of NDI patients aged less than
20 years in our survey with the number of patients who
were registered as having CNDI in the Medical Aid
Program for Chronic Pediatric Diseases of Specified
Categories in Japan, from fiscal 2009 to fiscal 2011. The
study was approved by the Ethics Committee of Tottori
University (approval number 1384).

1–4
5–9
10–19

20–29
(yr)

Male

b

FemaleNumber of patients
0

2

4

6

8

10

Age at diagnosis

0–9
10–29

30–49
50–69
70 <
(yr)

Fig. 1. Histogram of the age at diagnosis with CNDI (a) and acquired NDI (b). The number of male patients is depicted with aclosed bar. The number of female patients is depicted with an open
bar. CNDI, congenital NDI; NDI, nephrogenic diabetes insipidus.

RESULTSWe received 5,139 responses to our primary questionnaire from 26,282 members. Together, the primary
questionnaires reported 210 NDI patients. We provided
a secondary questionnaire to 121 members (96 hospitals)
who had reported experience with cases of NDI. Respondents to the secondary questionnaire reported 183
patients with NDI. Ten patients were excluded because
of insufficient information; we analyzed 173 patients.
Of these, 143 patients had CNDI (124 males and 19 females) and 30 patients had acquired NDI (14 males and
16 females). There was no duplicated case. Our study
included 96 CNDI patients who were under 20 years asof 2009. In the database of the Medical Aid Programfor Chronic Pediatric Diseases of Specified Categories
in Japan, a yearly mean of 131 CNDI patients were re-Statistical analysis

For our statistical analyses, we relied on the MannWhitney U-test and Fisher’s exact test. Values of P lessthan 0.05 were defined as significant.
86Nephrogenic diabetes insipidus in Japanported from fiscal 2009 to fiscal 2011. Accordingly, thecoverage achievement rate of our survey was estimatedto be 73%, which is high.

Genetic analysis

Analyses of the AVPR2 and/or AQP2 genes were performed for 87 (61%) of all CNDI patients. For 10 of the87, we were unable to obtain the name of the gene inwhich a mutation was detected. Most of them (65 of 87;75%) had AVPR2 gene mutations, surprisingly including 10 female patients. On the other hand, AQP2 geneabnormalities were identified in 8 patients (4 males and4 females; 9.2%). In 4 patients (2 males and 2 females;4.6%), AVPR2 or AQP2 mutation was not detected bymutation analysis. Our survey results included 35 distinct AVPR2 mutations and 4 distinct AQP2 mutations
that caused CNDI (Tables 2 and 3). Of the 39 mutations,
14 (12 in AVPR2 and 2 in AQP2) have not been reported
previously. These novel AVPR2 and AQP2 mutations
are marked in Tables 2 and 3. Missense mutations in
the AVPR2 gene were the most common mutations. The
p.D85N mutation was detected in 7 patients (11%) of the65, and p.R106C was detected in 5 (7.7%). In previous
reports, p.D85N, p.V88M, p.R104C, p.R106C, p.Y128S,
p.N317K, p.P322S, p.S333del AVPR2 gene mutations
were reported as being associated with a mild phenotype;7, 8 these were detected in 22 patients (34%) of the
65 in our study. Of the 22, 19 patients (81%) were diagnosed at the age younger than 3 years, and 11 patients(50%), at the age younger than 6 months. Ten patientswere diagnosed after 3 years of age; p.D85N, p.R104C,
and p.Y128S were among the mutations detected inthese patients, as was W99X (1 case), a previously unreported mutation. Four of the 10 patients did not receive
gene analyses.

Congenital NDI

In this study, 143 patients had CNDI (124 males and 19
females), out of a total of 173 patients with any form of
NDI. Details of age at diagnosis are presented in Fig. 1.
The median age of CNDI diagnosis was 2.0 months (n =125), and the mean [s] age was 1.2 [4.6] years (n = 125).
Ninety-eight patients (69%) with CNDI were diagnosed
within the 1st year of life, and 19 patients (13%) werediagnosed between 1 year and 4 years of age. Eightpatients with CNDI were diagnosed between 5 and 29
years of age, half of whom had siblings or children who
were diagnosed with NDI beforehand. We were unable
to obtain the information on the age of CNDI diagnosis
in 18 patients. Three patients were diagnosed as with
CNDI in their 20s, 1 of whom had the mutation p.D85N
in the AVPR2 gene, which resulted in a mild phenotype,as was described subsequently.7
The symptoms and signs at the onset of CNDI
are presented in Table 1. Polyuria was the most common symptom at onset (79 of the 143 patients; 55%).
Polydipsia was the second common symptom (69 of
the 143; 48%). It is well known that many patients with
CNDI have fever at onset;5 53 patients (37%) had feverat onset and 30 patients with CNDI (21%) presented no
symptoms at onset except for fever. Although it has beenreported that vomiting and anorexia occur at the onsetof 70% of CNDI patients,5 vomiting and anorexia were
found in only 18 patients (13%) in our study. On theother hand, infant patients (diagnosed before 6 monthsof age, n = 90) were more likely to present with fever at
onset (49 of the 90; 54%) than the total survey sample.
Approximately 40% of the patients who were less than
6 months had either poor weight gain, or polydipsia andpolyuria. Eight patients (5.6%) with CNDI were diagnosed among those who already had mental retardation(MR).
The incidence of MR is critically related to prognosis such as quality of life. Twenty patients with CNDI
(14%) were complicated with MR. In 3 of the 20, MR
was severe. Because of the limited sample size, we could
not find any significant differences in age (P = 0.908,
Mann-Whitney U-test) or the serum sodium levels in
CNDI patients with and without MR at the time of diagnosis. However, patients with MR were diagnosed at anage range from 0.5 to 2.5 years, and generally appeared
to be older than patients with other complications at thetime of diagnosis (the mean age of CNDI diagnosis was
2.0 months overall).

Table 1. Symptoms and signs at the onset of congenital NDI (n = 143)
Symptoms and signsnPolyuria
Polydipsia
ThirstNocturnal enuresis
Fever
Poor weight gain
Failure to thrive
Mental retardation
Vomiting
Anorexia
Convulsion
Disturbance of consciousness
Constipation
Others*

79
69
19
15
53
41
14
8
12
6
3
1
1
9

NDI, nephrogenic diabetes insipidus.
* Urinary tract infection, dysphoria, weight loss, bradycardia.

87M. Fujimoto et al.
Table 2. Summary of AVPR2 mutations reported in thisstudy

Table 4. Urologic complications in patients with NDI(n = 173)

Gene

Symptoms and signsnHydronephrosis
Hydroureter
Renal failure
Vesicoureteral reflux
Slightly dilatation of renal pelvic
Dilatation of bladderRenal atrophy/dwarf kidney
Neurogenic bladderAcidosis

47
24
11
11
7
3
3
2
1

Type

Mutation

Frequency

AVPR2 Complete–
2
deletion
Splicing
Intron 2†
1
Missense A37P§
1
		
L44F
1
		
D85N
7
		 V88M
1
		 R104C
2
		 R106C
5
		 G107E
1
		
G107R§
1
		 R113W
1
		 Y128S
2
		 W164R
1
		 P178L§
1
		 R181C
2
		
R202C
3
		
P286S
1
		 N317K
1
		 P322S
2
		 S329G
1		
L336P§
1
Nonsense W99X§
2
		
W156X§
1
		 L161X
1
		 W200X
1
		 R337X
1
Deletionc.528delG§
1
		 V278del§1
		 S333del1
		 c.727-728delAG1		
5’UTR-AVPR2 DEL 32,787
2		
Others3
Insertion c.299 300insA§1
		
c.498 499insTC (L168RfsX45)§ 1
		c.855 856insCGCA§
1
Frameshift L35fs.§
1
Unknown‡ −8

NDI, nephrogenic diabetes insipidus.

Acquired NDI

The age of onset of acquired NDI ranged widely among
patients. The peak age of onset was at approximately
50 to 69 years. In 15 patients (50%), acquired NDI wascaused by administration of lithium carbonate. Between
10 and 49 years of age, the ratio of female patients withacquired NDI was higher. This sex difference may be
due to the fact that both depression and bipolar disorder,
which are treated with lithium carbonate, are more common in females. Two patients acquired NDI by ACEI or
ARB treatments for their mothers during the fetal period. In 13 patients, the underlying cause was unknown.
Seven patients with acquired NDI (23%) had MR as acomplication. MR was severe in 3 of them.
Urologic complications of NDI

In 73 patients (42%) of the 173, NDI was accompanied
by urologic complications. The frequencies of various
urologic complications are presented in Table 4. Elevenpatients (6.4%) had renal failure. We found no significant
difference in the rate of whole urologic complication
between CNDI and acquired NDI (P = 0.536, Fisher’s
exact test). However, CNDI was more frequently accompanied by hydronephrosis and/or hydroureter (P = 0.0454,
Fisher’s exact test). Two cases lacked information on
urologic complications. No patients required clean intermittent catheterizations.

AVPR2, arginine vasopressin receptor type 2.
† Splice acceptor AG CG.
‡ There was a mutation but detail was unknown.
§ Novel mutation.

Table 3. Summary of AQP2 mutations reported in this
study
Gene

Type

AQP2
Missense				Deletion
Unknown‡

Mutation

Frequency

A130V§
N184H§
R254Q
c.763 722del
−

1
1
2
2
2

Treatment

Details of treatment efficacy are presented in Fig. 2.
Most patients with NDI were treated with thiazide diuretics (hydrochlorothiazide or trichlormethiazide) withor without potassium supplementation, low-sodium diet,non-steroidal anti-inflammatory agents (NSAIDs) andaldosterone antagonists (amiloride or spironolactone).
Thiazide diuretics were effective in 110 (92%) of
120 patients with CNDI. All 15 patients treated withaldosterone antagonists were also treated with thiazide

AQP2, aquaporin 2.
‡ There was mutation but detail was unknown.
§ Novel mutation.

88

Nephrogenic diabetes insipidus in JapanaJapan. Our survey is believed to include almost 3/4 of
CNDI patients in the Medical Aid Program for Chronic
Pediatric Diseases of Specified Categories in Japan during fiscal 2009.
NDI is characterized by resistance of the kidney to
AVP due to genetic or acquired causes.9 CNDI is rare,
and is known to be caused by mutations in AVPR2 (Xq28)
or AQP2 (12q13.12).1, 2, 3 In contrast, acquired NDI isgenerally an adverse effect to drugs including lithium,demeclocycline, and amphotericin. As can be expectedfrom their different etiologies, most patients with CNDI
are diagnosed in infancy,5, 10 and most of acquired NDI
are diagnosed in adulthood. In our extensive study, we
also found that 7.0% of patients with CNDI were diagnosed after the age of 3 years, including 3 patients who
were diagnosed in their 20s. In general, patients with
CNDI show polyuria and polydipsia from birth, as well
as fever, poor weight gain and vomiting within the 1st
week of life.11, 12 However, polyuria and polydipsia are
not always the chief complaints associated with CNDI,5,10
and other various symptoms are usually found during
infancy, such as fever, poor weight gain, failure to thrive,
vomiting and anorexia. Furthermore, the results of oursurvey have revealed that 21% of CNDI patients present
no symptoms except for fever at the time of onset. Ourfindings suggest that many clinicians already consider
CNDI when facing a fever of unknown etiology in an
infant, but that all clinicians should do so.
As of October 2012, more than 220 mutations in the
AVPR2 gene and more than 50 mutations in the AQP2
gene have been identified as causing NDI.2, 7, 9, 13 Spanakis et al.7 found 13 hotspot mutations in the AVPR2 gene.
These mutations were reported in more than 6 families
with NDI.7 To evaluate whether there are clusteredmutations among patients with CNDI in Japan, we conducted a survey concerning the detection of mutations in
the AVPR2 and AQP2 genes. Although some mutations
were especially common (AVPR2 gene: p.D85N, 11% of
patients with the gene; p.R106C, 7.7% of patients withthe gene), we could not find clearly clustered mutations.
However, analyses of mutations in AVPR2 and AQP2
were not performed in 1/3 of the CNDI patients in ourstudy. If all CNDI patients had received gene analyses,
it is possible that p.D85N and p.R106C would have appeared as more common mutations in the AVPR2 gene.
Moreover, it has been reported that 14 mutations in the
AVPR2 gene (p.D85N, p.V88M, p.R104C, p.R106C,
p.Y128S, p.G201D, p.F287L, p.M311V, p.N317K,
p.N317S, p.N321Y, p.P322S, p.S329R, p.S333del) areassociated with partial CNDI, in which mild dysfunction of AVPR2 is exhibited in vitro.8 In our survey, thesewere detected in 22 (34%) of the 65 patients. Eleven (50%)

Number of patients
0

30

60

90

120

Thiazide
diuretics

TherapyLow-sodium
diet
DDAVP
NSAIDsAldosterone
antagonists
Effectiveb

Not effective

Number of patients
0

5

10

15

20

Thiazide
diuretics

TherapyLow-sodium
diet
DDAVP
NSAIDsAldosterone
antagonists

Fig. 2. The efficacy of therapy for CNDI (a) and acquired NDI(b). The patients in whom the treatment reduced urine volume are
depicted with an open bar, and patients in whom treatment did not
reduce urine volume are depicted with a closed bar. CNDI, congenital NDI; DDAVP, desmopressin acetate; NDI, nephrogenic
diabetes insipidus; NSAID, non-steroidal anti-inflammatory agent.

diuretics. A low-sodium diet was useful for 32 (65%) of
49 patients with CNDI. Desmopressin acetate (DDAVP)
was provided in 32 patients (28 males and 4 females),which was effective in 8 patients [6 males (21%) and 2
females (50%)] of them. The dose of DDAVP was not investigated in the questionnaire. All 8 patients who wereeffectively treated with DDAVP had AVPR2 gene mutations (p.A37P, p.D85N, p.R104C, and p.Y128S) or AQP2
gene mutations (p.R254Q and c.763_722del).
DISCUSSION
To our knowledge, we have conducted the nationwide
survey of NDI in Japan, which has allowed us to evaluate the characteristics of NDI—especially CNDI—in89

M. Fujimoto et al.

of the 22 were early diagnosed at age less than 6 months.
Because of the small sample size, we could not analyze
the relationship between age of diagnosis and genotype.
However, AVPR2 gene mutations (p.A37P, p.D85N,
p.R104C, and p.Y128S) or AQP2 gene mutations(p.R254Q and c.763_722del) were present in each of the
8 patients with CNDI who were effectively treated with
DDAVP. These AVPR2 gene mutations have previously
been reported as being associated with a mild phonotypeof CNDI.7, 8 It has been reported that the majority of thesubjects with AQP2 gene mutations did not respond to
DDAVP. Surprisingly, 4 (50%) of 8 patients with AQP2
gene mutation had response to DDAVP.14 Accordingly,
we suggest that gene analysis can play important roles intreatment selection and early detection of CNDI in siblings.
Commonly, female patients who have CNDI with
the AVPR2 mutation are asymptomatic because the mutation is heterozygous. However, our survey surprisingly
included 10 female patients with CNDI and the AVPR2
mutations (10 of 86 cases; 12%). Some studies havefound that female carriers show a clinical phenotype
similar to that of male carriers because of skewed Xinactivation or Turner syndrome.15–17 Because our form
questionnaires did not include details of genotype or Xinactivation, we could not compare clinical form withgenotype. However, our survey might reveal that there
are more female cases with the AVPR2 mutation thanhas previously been expected. Further investigation isneeded to clarify this issue.
The optimal goals of treatments for NDI are to
reduce urine volume and adequately replace lost water through increased water intake. These goals areachieved to some extent by using low-sodium diets,
thiazide diuretics, potassium-sparing diuretics (such as
amiloride and aldosterone antagonists) and NSAIDs(such as indomethacin and selective cyclooxygenase-2
inhibitors).11, 18–20 In some reports,18–21 urine volume
decreased by 30% to 70% among patients who received
diuretic therapy. If sufficient control of urine volume is
not achieved through a single treatment, different treatments are often combined. Although treatment of NDI
with DDAVP is generally considered to be ineffective, it
has been reported that high doses of DDAVP (10–40 μg)
are effective for p.D85N, p.V88M, or p.R104C AVPR2
gene mutations,5, 11, 21 which have mild phenotypes7, 8 asa consequence of the retained function of the AVPR2 receptor. In our study, DDAVP was effective in 4 patientswith AVPR2 mutations that caused mild phenotypes(p.A37P, p.D85N, p.R104C, and p.Y128S), and in 4 patients with AQP2 mutations (p. R254Q, c.763_722del).
Accordingly, if one of the above mutations is detected,
treatment with DDAVP should be considered.

MR is considered as a major complication of NDI,
and is critically related to prognosis. In the original
studies of NDI, it was reported that MR was prevalent
in 70% to 90% of the patients.3 On the other hand, areport demonstrated that the majority of patients with
NDI have normal intelligence.5, 22 In the present study,
we found that 14% of CNDI patients are accompanied
by MR. The results suggest that the actual prevalenceof this complication is located between the findings ofthese 2 studies,3, 5 and MR may be avoided throughtreatment. Indeed, it has been reported that NDI leads torecurrent severe hyperosmotic dehydration1, 11 and brain
edema brought about by attempts to rehydrate too quickly.11 These events damage both endothelial and otherbrain cells, and deposit calcium phosphate and othersubstances, particularly within or around the wall ofsmall vessels,23 resulting in MR. In our study, 8 patients(5%) already had MR at the time of CNDI diagnosis.
Moreover, patients with CNDI and MR at onset tend to
be diagnosed at an age that is older than the mean age of
CNDI diagnosis. These findings indicate that the early
diagnosis and careful treatment play an important role inpreventing MR.
Megacystis, trabeculated bladder wall, hydroureter,hydronephrosis and other urinary tract abnormalities aremajor complications of NDI that result from persistentpolyuria.12 Although Uribarri et al. reported that urinary
tract abnormalities were found in 67% of patients with
NDI in the United States,24 such abnormalities were
found in only 73 patients (42%) in our study. Elevenpatients (6.4%) experience renal failure in our study.
Because ultrasonic examination is widely recognized asimportant tool for the early detection of urologic complications, we suggest that ultrasonographic follow-up
should be performed for all NDI patients. Further, adequate treatment and control of NDI should be performed
to prevent the complication of urinary tract abnormalities. Additionally, adequate treatment of urinary tract
abnormalities is also needed to prevent acquired NDI.
It is widely recognized that several drugs can cause
acquired NDI, including lithium, demeclocycline andamphotericin. Of the drugs that are capable of inducing
NDI, lithium is prescribed most frequently.18 It is reported that over 40% of patients treated with lithium develop
NDI as an adverse effect.25 In our study, 15 patients (50%)
with lithium-induced NDI were detected. Our sample
size was too limited to investigate the actual conditionsof acquired NDI because we were unable to provide thissurvey to members of the Japanese Society of Psychiatry
and Neurology. However, our findings suggest that all
patients receiving lithium treatment should be checked
for acquired NDI.
90

Nephrogenic diabetes insipidus in Japan

In conclusion, we have presented the results of thenationwide survey of NDI in Japan. Our findings suggest
the existence of a form of CNDI with mild symptoms,
which is often diagnosed at older ages. We suggest that
adequate diagnosis and treatment are the most importantfactors for improving prognoses. We further suggest thatgene analysis should be performed for optimal treatment
selection and the early detection of NDI among siblings.

9 Oksche A, Rosenthal W. The molecular basis of nephrogenic
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9587067.
10 Mizuno H, Sugiyama Y, Ohro Y, Imamine H, Kobayashi
M, Sasaki S, et al. Clinical characteristics of eight patientswith congenital nephrogenic diabetes insipidus. Endocrine.
2004;24:55-9. PMID: 15249704.
11 Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essential insights into the molecular background andpotential therapies for treatment. Endocr Rev. 2013;34:278301. PMID: 23360744.
12 Wesche D, Deen PM, Knoers NV. Congenital nephrogenic
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2012;27:2183-204. PMID: 22427315.
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Oiso Y. A novel deletion mutation in the arginine vasopressin
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J Endocrinol Invest. 2004;27:167-70. PMID: 15129813.
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Acknowledgments: We thank the members of the Japan Endocrine Society, the Japanese Urological Association, the JapaneseSociety for Pediatric Endocrinology, the Japanese Society for
Pediatric Nephrology, the Japanese Society of Nephrology, theJapanese Society of Neurology and the Japanese Society of Pediatric Urology.
This work was supported in part by a Grant-in-Aid for
Health Labour Sciences Research Grants (Number: 21211001)
from the Ministry of Health, Labour and Welfare of Japan. This
work was supported in part by Grans-in-Aid for Scientific Research, Japan Society for the Promotion of Science (Grant Number: 24591512 and 23591568).
The authors declare no conflict of interest.
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