Intracranial calcifications associated with nephrogenic diabetes insipidus

A 6-year-old boy with nephrogenic diabetes insipidus (NDI) and intracranial calcification is reported. The calcifications were symmetrical and located in the basal ganglia and in the subcortical regions of the frontal, temporal, parietal and occipital lobes. Episodes of hyperosmolality during infancy are considered to be one of the causes of intracranial calcification in NDI. However, other unknown factors may be involved, because up to now there have been no reports of intracranial calcification in patients with central diabetes insipidus.     

Congenital nephrogenic diabetes insipidus with marked hyponatremia

A 42-year-old man previously diagnosed with congenital diabetes insipidus (DI) developed polydipsia and polyuria (water intake and urine excretion, above 20 l per day). On admission, a serum sodium level of 124 mEq/l, a serum chloride level of 87 mEq/l, and plasma osmolality of 254 mOsm/kg H₂O were found, although urine osmolality was always less than 100 mOsm/kg H₂O, with daily urine excretion of more than 15 l. Creatinine clearance was 153 l/day. Initially, he had free access to water and his daily water intake was 20–27 l. Restriction of water intake (10 l/day) normalized his serum sodium levels and alleviated his general fatigue. Hyponatremia is a rare fluid electrolyte disturbance in DI. We found no reports of hyponatremia associated with congenital nephrogenic DI, presumably because the osmosensing mechanism is intact in such patients. The use of thiazides for the treatment of polyuria, in combination with potassium-sparing diuretics and salt restriction, may accelerate the genesis of hyponatremia caused by psychogenic polydipsia in nephrogenic DI. Received: March 30, 2001 / Accepted: July 4, 2001     

药物所致肾性尿崩症11例报道

目的为提高对药物所致肾性尿崩症的认识和防治水平。方法对ICU中资料完整的11例尿崩患者病例进行回顾性分析。结果11例患者中4例使用碳青霉烯类抗生素（美罗培南）、氨基糖肽类抗生素（万古霉素）;3例使用抗真菌药（氟康唑2例、两性霉素B1例）;2例使用酶抑制剂抗生素他唑巴坦＋哌拉西林钠（特治星）＋喹诺酮类抗生素（左氧氟沙星）;2例使用甘露醇。使用上述药物的过程中,患者尿量突然增多达4210-21000ml／d,将脱水药甘露醇或速尿停用后,近期内尿量不减少,对垂体加压素治疗后无反应,尿比重、尿渗透压、血渗透压、血钠降低。双肾B超均未见尿路梗阻。结论ICU中肾性尿崩发生率远高于其他病区,与长期大量使用各种药物有关,另外ICU中患者存在多脏器功能不全甚至衰竭,对药物的代谢和排泄存在障碍,应引起临床重视。     

Efficacy of COX-2 inhibitors in a case of congenital nephrogenic diabetes insipidus

A 17-month-old boy presented with failure to thrive, polyuria, and vomiting. He had been diagnosed clinically with nephrogenic diabetes insipidus and treated by amiloride and hydrochlorothiazide combination without a satisfactory outcome at another center since 1 year of age. The diagnosis was confirmed by genetic analysis (AVPR2mutation), and the treatment was modified to include rofecoxib (a selective cyclooxygenase-2 inhibitor) in addition to hydrochlorothiazide and amiloride. This combination along with a low-salt diet resulted in a dramatic decrease in urinary free-water loss, while no side effect was noted. Because of prohibition of rofecoxib, it had to be substituted first by indomethacin and then by ibuprofen. However, both drugs were ineffective in controlling water diuresis. Thus, we had to replace these drugs by celecoxib (another selective cyclooxygenase-2 inhibitor). We conclude that the combination hydrochlorothiazide/amiloride/cyclooxygenase-2 inhibitor could be successfully used to treat congenital nephrogenic diabetes insipidus.     

Molecular pathogenesis of nephrogenic diabetes insipidus

There have been significant advances recently in the understanding of the molecular causes of nephrogenic diabetes insipidus. The resistance of the collecting duct to the action of vasopressin in this disorder results from abnormalities in several of the intricate steps that mediate the increase in principal cell hydraulic conductivity in response to the hormone. In this article, we review the current understanding of the known genetic causes of nephrogenic diabetes insipidus that affect the binding of vasopressin to the V2 receptor and subsequent intracellular signaling events, as well as the translocation of aquaporin-2 water channels to the apical membrane. In addition, genetic diseases, which decrease collecting-duct water absorption by diminishing the interstitial medullary osmolarity, are discussed. Received: October 22, 2002 / Accepted: November 18, 2002 Acknowledgments This work was supported by NIH grants DK-63125, DK-07789, the Max Factor Family Foundation, and the Richard and Hinda Rosenthal Foundation. Correspondence to:M.K. Nguyen     

Molecular and cellular defects in nephrogenic diabetes insipidus

The identification of the different molecular causes of congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by renal insensitivity to the antidiuretic effect of arginine vasopressin, has been of indispensable importance for understanding the cellular processes involved in diuresis and antidiuresis. In most cases, NDI is X-linked and caused by mutations in the vasopressin type-2 receptor (V2R) gene. Mutations in the aquaporin-2 (AQP2) water channel gene are responsible for the autosomal recessive and rare dominant forms of NDI. By in vitro expression, it has been shown that the majority of V2R mutants and all AQP2 mutants found in recessive NDI are misfolded and retained within the endoplasmic reticulum (ER). Functional analysis of one of the mutations identified in dominant NDI showed that this mutant is properly folded and transported out of the ER, but is retained in the Golgi region. In addition, this mutant, in contrast to mutants found in recessive NDI, is able to heterotetramerize with wild-type AQP2. The resulting complex is hindered in its transport to the membrane, a finding that explains the dominant-negative effect of this mutation. Several new methodologies focused on the molecular defects causing NDI are presently being investigated in vitro and might eventually develop into useful therapeutic strategies. Received: 12 April 2001 / Revised: 6 July 2001 / Accepted: 6 July 2001     

Congenital nephrogenic diabetes insipidus — vasopressin and prostaglandins in response to treatment with hydrochlorothiazide and indomethacin

In four boys with congenital nephrogenic diabetes insipidus, plasma arginine-vasopressin (AVP) and urinary excretion of prostaglandins were studied in response to treatment with hydrochlorothiazide and indomethacin. An abnormal relationship between AVP and urine osmolality was demonstrated in all patients. In the first patient, treatment with indomethacin (3 mg/kg per day) resulted in a drop of the inulin and paraminohippurate clearances. In the other three patients urinary excretion of PGE₂ was raised, and fell during treatment with hydrochlorothiazide (2 mg/kg per day) and indomethacin (2 mg/kg per day). Urine flow, free water clearance and osmolar clearance decreased during treatment. A combination of both drugs is more effective than hydrochlorothiazide alone and the effect appears to be additive.     

Treatment of congenital nephrogenic diabetes insipidus by hydrochlorothiazide and cyclooxygenase-2 inhibitor

A 1-month-old male infant presented with failure to thrive, polyuria, and severe hypernatremic dehydration. Based on family history, lack of response to vasopressin, and normal sonography of the urinary system, the diagnosis of congenital nephrogenic diabetes insipidus (cNDI) was established. The infant responded well to indomethacin in combination with hydrochlorothiazide (HCTZ), but quickly developed gastrointestinal bleeding. The substitution of indomethacin by amiloride and later by tolmetin was found to be ineffective. Treatment with HCTZ (3 mg/kg per day) and rofecoxib (1 mg/kg per day, both divided into three doses) combined with a low-salt formula resulted in a dramatic decrease in urinary free water losses. No side effects of the combination were noted. At age 8.5 months, the infant demonstrated catch-up growth and normal neurodevelopmental milestones. We conclude that the combination HCTZ/cyclooxygenase-2 inhibitor could be successfully used to treat infantile cNDI.     

Amphotericin B-induced partial nephrogenic diabetes insipidus in a child

The case of a 12-year-old boy who developed polyuria and polydipsia while on amphotericin B treatment is discussed. The clinical and laboratory features are most consistent with partial nephrogenic diabetes insipidus. Several adult patients have been reported with amphotericin B-induced nephrogenic diabetes insipidus. To the knowledge of the authors, this is the first pediatric patient described with this condition. Pharmacological doses of antidiuretic hormone in conjunction with diure-tic treatment significantly reduced the polyuria and alleviated the associated symptoms. The authors propose that in amphotericin B-induced partial nephrogenic diabetes insipidus, pharmacological doses of antidiuretic hormone may offer an additional benefit to commonly used diuretic therapy. Received: 4 August 2000 / Revised: 31 January 2001 / Accepted: 31 January 2001     

Long-term growth of children with nephrogenic diabetes insipidus

Primary nephrogenic diabetes insipidus (NDI) is a genetic, chronic disease characterised by lack of distal renal tubule to antidiuretic hormone. The condition produces polyuria, polydipsia, and consequently, reduced caloric intake and growth failure. There is very scarce information on physical growth of affected children. The objective of the paper is to describe long-term growth of 14 patients from 11 families, studied retrospectively and followed for 3–16 years (median 11.6 years). Diagnosis was made on the basis of clinical and laboratory data and concentration test under pitressin. Patients were treated with indomethacin, thiazides, and amiloride. Weight and standing height was measured periodically at the Laboratory of Anthropometry, following standardised techniques. Information was obtained from clinical notes. The majority of children grew below the third centile of local standards, and many showed improvement of weight, height, and body mass index (BMI) over time. Mean height, weight, and BMI gain during follow-up was 1.72, 1.06, and 1.46 standard deviations (SDs), respectively. Three children who did not adhere to treatment showed growth delay. Height gain during the first 2 years of follow-up was inversely associated with height deficit at diagnosis. Further studies on growth at adolescence and in different mutations are recommended.     

Transient nephrogenic diabetes insipidus caused by fetal exposure to haloperidol

Haloperidol is commonly used in the treatment of psychiatric disorders. Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. For the first time, we report a neonate with transient nephrogenic diabetes insipidus (DI) caused by fetal exposure to haloperidol. The magnitude of risk associated with the use of haloperidol during pregnancy appears to be small, but nephrogenic DI secondary to haloperidol is a serious condition with the risk of hypernatremic dehydration. Haloperidol can have adverse effects on the fetus and newborn infant, that’s why one should prevent the use of haloperidol during pregnancy and lactation.     

Nephrogenic diabetes insipidus due to hydronephrosis in a patient with a solitary kidney

A 68-year-old man with a history of nephrectomy of the right kidney was admitted to our hospital with a 1-month history of polyuria (4l per day). He also exhibited hyposthenuria, which was unresponsive to treatment with exogenous vasopressin. Radiographic examination revealed partial obstruction of the left ureter and moderate hydronephrosis. The cause of the obstruction was cancer of the ureter. After drainage using a nephrostomy tube, the polyuria and hyposthenuria were gradually resolved. This is the first known case of nephrogenic diabetes insipidus due to hydronephrosis in a patient with a solitary kidney.     

Nephrogenic diabetes insipidus: identification of the genetic defect

Congenital nephrogenic diabetes insipidus (NDI) is an X-linked inherited disorder characterized by renal resistance to the antidiuretic hormonal action of arginine vasopressin. The disease gene has been assigned to the subtelomeric region of the X chromosome long arm by demonstrating close linkage between NDI and several X-chromosomal DNA markers. The finding of closely linked genetic markers is useful in the diagnosis of NDI. Receptor studies in patients have indicated that NDI might be due to the absence or an abnormality of the adenylate cyclase-bound vasopressin type 2 receptor. This assumption was supported by the discovery of functional vasopressin V2 receptor activity in somatic cell hybrid cell lines that carried at least the distal part of the human X chromosome long arm. Definite evidence for a V2 receptor defect being the cause of NDI was found in a recent study demonstrating point mutations in the V2 receptor gene from affected individuals. Direct mutation analysis is now applicable for accurate carrier detection and early (prenatal) diagnosis.     

Successful treatment with hydrochlorothiazide and amiloride in an infant with congenital nephrogenic diabetes insipidus

We report a 9-month-old male latino infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypernatremic dehydration aggravated by severe gastroenteritis. Initially, the infant was managed with intravenous fluids followed by standard 20 cal/ounce formula and pharmacological therapy, resulting in normalization of his serum sodium level. While hydrochlorothiazide therapy alone or in combination with prostaglandin inhibitors or amiloride has been successful in children and adolescents, this is the first report of the successful use of hydrochlorothiazide and amiloride in an infant with congenital NDI.     

A case of nephrogenic diabetes insipidus with a novel missense mutation in the <Emphasis Type="BoldItalic">AVPR2</Emphasis> gene

We describe a pediatric case of nephrogenic diabetes insipidus (NDI) with a novel missense mutation in the arginine vasopressin receptor 2 (AVPR2) gene. The patient, a 3-year-old boy, had polyuria (4357 ml/day, 7230 ml/m²/day) and polydipsia. Water deprivation testing demonstrated no decrease of urine volume, and urinary volume did not respond to subcutaneous injection of 0.1 U/kg pitressin. Molecular genetic analysis demonstrated that the patient had an AVPR2 missense mutation involving substitution of phenylalanine for tyrosine at position 205 (Y205F). It was also found that the patient’s mother was heterozygous for this Y205F mutation. Analysis of the intermolecular interaction of the Tyr-205 hydrogen group by molecular modeling showed that Tyr-205 was located in transmembrane domain (TM) 5, and that its hydroxy group formed a hydrogen bond with Leu-169 main-chain =O located in TM 4. The mutation of Tyr-205 to phenylalanine would cause loss of this hydrogen bond and decrease or change the interaction between these TM coils, thus affecting the ability of AVP to bind to the receptor. According to this molecular model of AVPR2, the Y205F mutation would cause nephrogenic diabetes insipidus.     

Nephrogenic diabetes insipidus: treat with caution

Current therapy for congenital nephrogenic diabetes insipidus consists of appropriate water intake coupled with decreased urine output obtained by means of a low-sodium diet and a combination of thiazide diuretics with renal prostaglandins inhibitors or amiloride. We report a case of congenital nephrogenic diabetes insipidus that was complicated by paradoxical water intoxication secondary to liberal water intake and the initiation of hydrochlorothiazide and indomethacin combination therapy. This report emphasizes the importance of evaluating the water balance and of a quick response with strict protocols following the initiation of indomethacin and thiazide diuretics in nephrogenic diabetes insipidus.     

Wilms tumor arising in a child with X-linked nephrogenic diabetes insipidus

We report on a child with X-linked nephrogenic diabetes insipidus (NDI) who developed Wilms tumor (WT). Nephrogenic diabetes insipidus is caused by mutations of the arginine vasopressin receptor (AVPR2) or aquaporin-II (AQP2) genes. Wilms tumor is also genetically heterogeneous and is associated with mutations of WT1 (15–20%), WTX (20–30%) and other loci. The boy presented at 5 months with failure to thrive, polyuria, hypernatremia and abdominal mass. Analysis of leukocyte DNA showed a novel missense mutation (Q174H) of the AVPR2 gene, which was not present in his mother. In cells (WitS) isolated from the tumor, WTX mRNA expression and coding sequence were intact. However, we identified a 44-kb homozygous deletion of the WT1 gene spanning exons 4 to 10. The WT1 deletion was not present in leukocyte DNA from the patient or his mother. We also noted strong β-catenin (CTNNB1) expression in the tumor cells and identified a heterozygote missense Ser45Cys mutation of exon 3 of CTNNB1. However, the mutation was absent both in the constitutional DNA of the patient and his mother. The concurrence of WT and NDI has not been previously reported and may be unrelated. Nevertheless, this case nicely illustrates the sequence of events leading to sporadic Wilms tumor.