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PubMed2004

Perioperative management of diabetes insipidus in children.

Managing children with diabetes insipidus (DI) in the perioperative period is complicated and frequently associated with electrolyte imbalance compounded by over- or underhydration. In this study the authors developed and prospectively evaluated a multidisciplinary approach to the perioperative management of DI with a comparison to 19 historical control children. Eighteen children either with preoperative DI or undergoing neurosurgical operations associated with a high risk for developing postoperative DI were identified and managed using a standardized protocol. In all patients in whom DI occurred during or after surgery, a continuous intravenous infusion of aqueous vasopressin was initiated and titrated until antidiuresis was established. Intravenous fluids were given as normal saline and restricted to two thirds of the estimated maintenance rate plus amounts necessary to replace blood losses and maintain hemodynamic stability. In all children managed in this fashion, perioperative serum sodium concentrations were generally maintained between 130 and 150 mEq/L, and no adverse consequences of this therapy developed. In the 24-hour period evaluated, the mean change in serum sodium concentrations between the historical controls was 17.6 +/- 9.2 mEq/L versus 8.36 +/- 6.43 mEq/L in those children managed by the protocol. Hyponatremia occurred less frequently in the children managed with this protocol compared with historical controls.

Adolescent↗
PubMed2006

Novel mutations underlying nephrogenic diabetes insipidus in Arab families.

PURPOSE: Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab families. METHODS: Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions. RESULTS: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion. CONCLUSIONS: Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing.

Aquaporin 2↗
PubMed1999

An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus.

Autosomal recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, are caused by mutations in the aquaporin-2 (AQP2) gene. Missense AQP2 proteins in recessive NDI have been shown to be retarded in the endoplasmic reticulum, whereas AQP2-E258K, an AQP2 mutant in dominant NDI, was retained in the Golgi complex. In this study, we identified the molecular mechanisms underlying recessive and dominant NDI. Sucrose gradient centrifugation of rat and human kidney proteins and subsequent immunoblotting revealed that AQP2 forms homotetramers. When expressed in oocytes, wild-type AQP2 and AQP2-E258K also formed homotetramers, whereas AQP2-R187C, a mutant in recessive NDI, was expressed as a monomer. Upon co-injection, AQP2-E258K, but not AQP2-R187C, was able to heterotetramerize with wild-type AQP2. Since an AQP monomer is the functional unit and AQP2-E258K is a functional but misrouted water channel, heterotetramerization of AQP2-E258K with wild-type AQP2 and inhibition of further routing of this complex to the plasma membrane is the cause of dominant NDI. This case of NDI is the first example of a dominant disease in which the 'loss-of-function' phenotype is caused by an impaired routing rather than impaired function of the wild-type protein.

Animals↗
PubMed1991

Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus.

In mice with hereditary nephrogenic diabetes insipidus (NDI), the inability of vasopressin to increase hydraulic water permeability is reflected in a lack of intramembranous particle (IMP) clusters in apical membranes of inner medullary collecting ducts. The lack arises from anomalously high activity of one or two isozymes of adenosine 3',5'-cyclic monophosphate-phosphodiesterase (cAMP-PDE). We asked whether inhibition of these isozymes with rolipram and cilostamide would raise not only the tissue content of cAMP but also and simultaneously restore IMP clusters. Inner medullary collecting ducts from NDI mice were incubated in vitro. Tissue content of cAMP (fmol of cAMP per bundle) and number of IMP clusters (per 100 microns 2 of principal cell apical membrane) were, respectively: control, 44.8 +/- 13.0 and 4.16 +/- 1.49; arginine vasopressin (AVP), 31.7 +/- 8.0 and 3.98 +/- 1.56; rolipram and cilostamide, 109.7 +/- 21.0 and 58.09 +/- 15.74; and AVP plus rolipram and cilostamide, 305.7 +/- 75 and 48.63 +/- 11.03 (with the last four values showing significant difference from control and AVP only, respectively). In addition, treating NDI mice with rolipram and cilostamide in vivo reduced their high fluid turnover. We conclude that failure by AVP to increase cAMP in cells of collecting ducts, which results from anomalously high activity of one or two specific isozymes of cAMP-PDE, is the major or sole cause for the excretion of hypotonic urine in NDI mice (DI +/+ Severe strain).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Dynamics of nucleotides in distal nephron of mice with nephrogenic diabetes insipidus.

In mice with hereditary nephrogenic diabetes insipidus (NDI), the high activity of cAMP-phosphodiesterase (cAMP-PDIE) in medullary collecting tubules (MCT) prevents the increase in cAMP content in response to vasopressin [Arg8]vasopressin (AVP). Even when the cAMP response to AVP is partly corrected by cAMP-PDIE inhibitor 1-methyl-3-isobutylxanthine (MIX), under all tested conditions the cAMP levels in MCT of NDI mice remained much lower than in controls (B. A. Jackson, R. M. Edwards, H. Valtin, and T. P. Dousa, J. Clin. Invest. 66: 110-122, 1980). In the present study, we explored which factors may account for this defect. We determined contents of ATP, nicotinamide adenine dinucleotide (NAD), and the levels of cAMP in MCT and in medullary thick ascending limb of Henle's loop (MAL) microdissected from control and NDI mice. In the presence of 1 microM AVP and 0.05 mM MIX, the cAMP levels accumulated in MCT of NDI mice were four times lower compared with controls, but the levels of ATP and NAD were not different. ATP levels in MAL of NDI mice were slightly (delta -23%) lower than in MAL from controls, and in distal convoluted tubules (DCT) of NDI mice the ATP levels were also decreased (delta -49%). Although AVP alone had little effect on cAMP levels in mouse MAL in the presence of 0.1 mM forskolin, the AVP elicited a 20-fold increase of cAMP of both the control and NDI mice. Addition of 0.1 mM forskolin further increased the cAMP accumulation in MCT incubated with AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed2006

Risk factors for diabetes insipidus in langerhans cell histiocytosis.

BACKGROUND: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied. RESULTS: Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI. CONCLUSIONS: Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.

Clinical Trials as Topic↗
PubMed1982

Impaired brain development of the diabetes insipidus Brattleboro rat.

The Brattleboro homozygous diabetes insipidus (HOM-DI) mutant rat, incapable of synthesizing the neuropeptide vasopressin, has an impaired body growth of which the severity depends upon the conditions of reproduction. The comparison of homogeneously genotyped litters of HOM-DI and heterozygous (HET-DI) control pups, delivered and nursed by HOM-DI females, was regarded to be the only experimental design that practically excludes other influences on growth differences than the mutation itself. In this breeding scheme the postnatal growth of the HOM-DI brain is impaired, and the weight deficit persists into adulthood. Regionally, the neonatal development of cerebellum and medulla oblongata is most affected, and only slightly that of the cerebral cortex. The other separately isolated parts of the the brain seem to be unaffected (olfactory bulbs, hypothalamus, hippocampus, colliculi and thalamus plus basal ganglia). Cerebellum appeared to be the most consistently affected brain area of the HOM-DI Brattleboro rat since, unlike in the case of cerebral cortex and medulla oblongata, the weight deficit persisted throughout life. Olfactory bulb growth, on the other hand, appeared to continue after the first month of life, resulting in an increased weight at day 180. Water content of cerebral cortex and cerebellum of HOM-DI adults appeared slightly higher and might be explained by the generation of different brain water regulation systems for HET- and HOM-DI Brattleboro rats. Protein and DNA estimations of cerebral cortex, cerebellum and olfactory bulbs of male brains during development and in adulthood reflect the differences as found for weight, indicating no obvious changes in cell densities. It is concluded after comparison with other types of brain growth malformations, that the HOM-DI Brattleboro brain has its own particular etiology. The possible involvement of the action of vasopressin is postulated and discussed.

Aging↗
PubMed1987

Post-traumatic diabetes insipidus combined with primary polydipsia.

We describe a case of diabetes insipidus after head injury in which thirst persisted despite treatment with DDAVP and normal plasma osmolality. Symptoms were only completely relieved when plasma osmolality was below 270 mosmol/kg. We believe that this might have been due to hypothalamic injury causing resetting of the thirst osmostat. To our knowledge, this type of primary polydipsia has not been described before in association with diabetes insipidus following head injury.

Adult↗
PubMed1992

Evidence for intact V1-vasopressin receptors in congenital nephrogenic diabetes insipidus.

The binding of tritium-labelled arginine vasopressin to human platelet vasopressin receptors was investigated in patients with congenital nephrogenic diabetes insipidus. Binding characteristics, that is receptor affinity and the maximum number of binding sites, were not significantly different from those found in normal control individuals. The findings confirm the concept of intact V1 receptors in congenital nephrogenic diabetes insipidus. The defect in nephrogenic diabetes insipidus apparently only affects the cyclic adenosine monophosphate dependent V2 receptors.

Adolescent↗
PubMed1976

Management of diabetes insipidus in neurosurgical patients.

The authors present a brief review of the problem of diabetes insipidus in neurosurgical patients, with particular emphasis on the differential diagnosis of postoperative and posttraumatic polyuria and the management of diabetes insipidus in these periods. A listing of drugs currently used in its treatment is given.

Administration, Intranasal↗
PubMed1992

[Effectiveness of and tolerability to oral desmopressin in the treatment of central diabetes insipidus].

Intranasal desmopressin represents the treatment of choice in Central Diabetes Insipidus. Nevertheless, this route of administration bears some practical disadvantage, linked to either difficult delivering technique, or the status of nasal mucose. The antidiuretic effectiveness of oral desmopressin has been recently demonstrated, both in experimental animals and in man. In our study we compared oral vs. intranasal desmopressin efficacy in 13 patients affected by Central Diabetes Insipidus. The results show that the peroral administration of Desmopressin at a mean dose of 500-600 micrograms/die determines an antidiuretic effect comparable to that of intranasal route, without affecting body weight, arterial pressure and chemical analysis. Side effects, generally limited to the first week of treatment, were described (nausea, vomiting, headache, dizziness [corrected], bitter taste, epygastralgia, asthenia, epystassis), inducing 4/13 patients to withdrawal the trial.

Administration, Intranasal↗
PubMed1979

Cushing's disease with cyclic hormonogenesis and diabetes insipidus.

A cyclic excess of cortisol secretion was detected in a patient with diabetes insipidus and diabetes mellitus. The cycles of hypercortisolism were of 7 days' duration, but during the nadir of these cycles urinary excretion of corticosteroids and 17-ketosteroids was within the normal range. The radiological appearance of the sella turcica was normal; however, computerized axial tomography of the head revealed a small tumor immediately superior to the sella turcica. At operation a small chromophobe adenoma superior to the diaphragma sellae and involving the hypophysial stalk was partially resected. Postoperatively, the patient continued to have 7-day cycles of increased corticosteroid excretion, but the amounts excreted were less than they had been preoperatively. Other patients have been described in whom Cushing's disease has been due to cyclic hypercortisolism. These cycles have been remarkably regular in individual patients, but of variable duration in different patients. Furthermore, cyclic hormonogenesis probably occurs in a variety of endocrinopathies. (Neurosurgery, 5: 598--603, 1979).

17-Hydroxycorticosteroids↗
PubMed1988

In situ hybridization demonstrates vasopressin gene transcription in hypothalamic neurons of crossbred hypertensive x diabetes insipidus rats.

In situ hybridization, Northern blotting, and solution hybridization assay were used to examine vasopressin-gene messenger ribonucleic acid (mRNA) transcripts in hypothalamic tissue from five strains of rats: Long-Evans, Wistar-Kyoto, and diabetes insipidus (Brattleboro) rats, spontaneously hypertensive-stroke-prone rats, and cross-bred diabetes insipidus x spontaneously hypertensive-stroke-prone rats. A 290 base-pair, single-stranded RNA probe, with 221 bases complementary to exon C of the vasopressin gene was synthesized by the SP6 transcription vector system. This probe labeled appropriate neurohypophysial hypothalamic neurons, as well as suprachiasmatic nucleus cells, in tissue samples from all five strains of rats. Confirming other recent hybridization results with diabetes insipidus rat brain tissue, diabetic animals were found to transcribe their mutated vasopressin gene. In addition, this investigation found that the cross-bred diabetic-hypertensive rat also synthesizes a vasopressin-gene messenger ribonucleic acid transcript. Quantitative analyses of solution and in situ hybridization results suggested the cross-bred diabetic-hypertensive rat exhibits a level of vasopressin-gene messenger ribonucleic acid similar to diabetes insipidus rats. This observation is consistent with previous data on the cross-bred diabetic-hypertensive rat which suggests they inherit the mutant vasopressin gene from Brattleboro rats.

Animals↗
PubMed2003

Gene therapy for central diabetes insipidus: effective antidiuresis by muscle-targeted gene transfer.

Central diabetes insipidus, characterized by severe polyuria and polydipsia, is a disorder resulting from deficient secretion of the small neuropeptide hormone vasopressin in the neurohypophysis. The standard therapy is daily and life-long administration of vasopressin analog (desmopressin acetate), but gene therapy is potentially alternative to the conventional replacement therapy. To obtain the therapeutic neuropeptide more feasibly, we tried to express vasopressin in nonneuronal tissues using nonviral gene transfer techniques. We found that the unprocessed large precursor form, provasopressin, was predominantly produced in nonendocrine cells transfected with the wild-type vasopressin gene, because of the lack of neuroendocrine cell-specific endopeptidases. In sharp contrast, appropriately processed bioactive vasopressin can be efficiently produced even in nonendocrine cells with a modified vasopressin gene containing a ubiquitous endoprotease furin cleavage site. We also succeeded in maintaining a long-term antidiuretic effect on vasopressin-deficient (Brattleboro) rats by direct introduction of the furin-processible gene into skeletal muscle by electroporation. Altogether, our data clearly show that skeletal muscle is a useful target tissue for continuous delivery of bioactive neuropeptide. Furthermore, our strategies may be applicable to future gene therapies for central diabetes insipidus and other peptide hormone deficiencies.

Animals↗