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Concept: Nephrogenic diabetes insipidus


Background: The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. Methods: The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results to the final clinical diagnosis, i.e., no DI, central DI or nephrogenic DI. Median length of follow up was 8 years. In a subset of 10 patients, the novel marker copeptin (CP) was measured in plasma. Results: Using the final diagnosis as gold standard, a threshold for urine osmolality of > 800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96% and 100% for diagnosing PP. Sensitivity increased to 100% if the cut off value for urine osmolalilty was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate between central DI, nephrogenic DI or PP. In all three patients with central DI, plasma CP was <2.5 pmol/L with plasma osmolality > 290 mOsmol/kg, and >2.5 pmol/L in patients without DI. Conclusions: The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality > 680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgement since AVP levels did not discriminate.

Concepts: Cohort study, Diabetes mellitus, Type I and type II errors, Sensitivity and specificity, Diabetes insipidus, Nephrogenic diabetes insipidus


Abstract Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, mostly caused by AVPR2 mutations. Less than 10% of cases are due to mutations in the aquaporin-2 (AQP2) gene. Diagnosis and management of this condition remain challenging especially during infancy. Here, we report two unrelated patients, a 6-month-old Thai boy and a 5-year-old Emirati girl, with a history of failure to thrive, chronic fever, polydipsia, and polyuria presented in early infancy. The results of water deprivation test were compatible with a diagnosis of NDI. The entire coding regions of the AVPR2 and AQP2 gene were amplified by polymerase chain reaction and sequenced. Patient 1 was homozygous for a novel missense AQP2 mutation p.G96E, inherited from both parents. Patient 2 harbored a previously described homozygous p.T126M mutation in the AQP2 gene. Both patients were treated with a combination of thiazide diuretics and amiloride. Patient 1 developed paradoxical hyponatremia and severe dehydration 2 weeks after medical treatment began. In conclusion, we report a novel mutation of the AQP2 gene and highlight an important role of genetic testing for definite diagnosis. Vigilant monitoring of the fluid status and electrolytes after beginning the therapy is mandatory in infants with NDI.

Concepts: DNA, Genetics, Mutation, Diabetes mellitus, Dehydration, Diabetes insipidus, Nephrogenic diabetes insipidus, Water intoxication


Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments.

Concepts: Nephrology, Urine, Diabetes, Vasopressin, Diabetes insipidus, Nephrogenic diabetes insipidus, Arginine vasopressin receptor 2, Aquaporin 2


Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations.

Concepts: DNA, Protein, Nephrology, Mutation, Diabetes, Diabetes insipidus, Nephrogenic diabetes insipidus, Aquaporin 2


While lithium remains the most efficacious treatment for bipolar disorder, it can cause significant nephrotoxicity. The molecular mechanisms behind both this process and the development of nephrogenic diabetes insipidus still remain to be fully elucidated but appear to involve alterations in glycogen synthase kinase 3 signalling, G2 cell cycle progression arrest, alterations in inositol and prostaglandin signalling pathways, and dysregulated trafficking and transcription of aquaporin 2 water channels. The end result of this is a tubulointerstitial nephropathy with microcyst formation and relative glomerular sparing, both visible on pathology specimens and increasingly noted on non-invasive imaging. This paper will elucidate on the current evidence pertaining to the pathophysiology of lithium induced nephrotoxicity.

Concepts: Nephrology, Enzyme, Diabetes, The Current, Diabetes insipidus, Nephrogenic diabetes insipidus, Aquaporin 2, Aquaporin


Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by resistance of the kidney to the action of antidiuretic hormone (ADH), resulting in a decrease in the capacity of the kidney to concentrate the urine. NDI can be inherited or acquired due to, for example, chronic lithium therapy. Current treatment options are limited to attempts to lower urine output by a low-solute diet and the use of diuretics or anti-inflammatory drugs. These measures are only partially effective. Recent reports suggested that sildenafil, metformin, and simvastatin might improve ADH-independent urine concentration. If confirmed, this would provide interesting additional therapeutic options for patients with NDI. We, therefore, tested the effect of these drugs on ADH-independent urine concentrating capacity in healthy volunteers. We included 36 healthy volunteers who received sildenafil 20 mg thrice daily, metformin 500 mg thrice daily or simvastatin 40 mg once daily during 1 week. At baseline and at the end of treatment, a water loading test was performed. No significant increase in lowest urine osmolality was seen after the use of metformin or sildenafil (P = 0.66 and P = 0.09 respectively). Lowest urine osmolality increased modestly but significantly after the use of simvastatin (70 mOsm/kg to 85 mOsm/kg, P = 0.05). Our data suggest that only simvastatin has an effect on urine osmolality in healthy volunteers. Validation studies are needed and, most importantly, these drugs should be tested in patients with NDI.

Concepts: Kidney, Nephrology, Diabetes mellitus, Endocrinology, Diabetes, Vasopressin, Diabetes insipidus, Nephrogenic diabetes insipidus


Keap1 is a negative regulator of Nrf2, a master transcription factor that regulates cytoprotection against oxidative and electrophilic stresses. Although several studies have suggested that the Keap1-Nrf2 system contributes to bone formation besides the maintenance of redox homeostasis, how Nrf2 hyperactivation by Keap1 deficiency affects the bone formation remains to be explored, as the Keap1-null mice are juvenile lethal. To overcome this problem, we used viable Keap1-deficient mice that we have generated by deleting the esophageal Nrf2 in Keap1-null mice (NEKO mice). We found that the NEKO mice exhibit small body size and low bone density. Although nephrogenic diabetes insipidus has been observed in both the NEKO mice and renal-specific Keap1-deficient mice, the skeletal phenotypes are not recapitulated in the renal-specific Keap1-deficient mice, suggesting that the skeletal phenotype by Nrf2 hyperactivation is not related to the renal phenotype. Experiments with primary culture cells derived from Keap1-null mice showed that differentiation of both osteoclasts and osteoblasts was attenuated, showing that impaired differentiation of osteoblasts rather than osteoclasts is responsible for bone hypoplasia caused by Nrf2 hyperactivation. Thus, we propose that the appropriate control of Nrf2 activity by Keap1 is essential for maintaining bone homeostasis.

Concepts: Nephrology, Bone, Gene, Skeletal system, Diabetes, Diabetes insipidus, Nephrogenic diabetes insipidus, Intramembranous ossification


Lithium-induced nephrogenic diabetes insipidus (Li-NDI) is a rare and difficult-to-treat condition. A study in mice and two recent papers describe the use of acetazolamide in Li-NDI in 7 patients (a case report and a 6 patient series). We describe the case of a 63-year-old woman with bipolar disorder treated with lithium and no previous history of diabetes insipidus. She was hospitalized due to a bowel obstruction and developed severe dehydration after surgery when she was water deprived. After desmopressin administration and unsuccessful thiazide and amiloride treatment, acetazolamide was administrated to control polyuria and hydroelectrolytic disorders without significant side effects. To our knowledge, this is the third publication on acetazolamide use in Li-NDI patients.

Concepts: Diabetes mellitus, Hospital, Diabetes, Dehydration, Bipolar disorder, Diabetes insipidus, Nephrogenic diabetes insipidus, Polyuria


Congenital nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentrating ability. Symptomatic polyuria is present from birth, even with normal release of the antidiuretic hormone vasopressin by the pituitary. Over the last two decades, the aquaporin-2 (AQP2) gene has been cloned and the molecular mechanisms of urine concentration have been gradually elucidated. Vasopressin binds to the vasopressin type II receptor (V2R) in the renal collecting ducts and then activates AQP2 phosphorylation and trafficking to increase water reabsorption from urine. Most cases of congenital NDI are caused by loss-of-function mutations to V2R, resulting in unresponsiveness to vasopressin. In this article, we provide an overview of novel therapeutic molecules of congenital NDI that can activate AQP2 by bypassing defective V2R signaling with a particular focus on the activators of the calcium and cAMP signaling pathways.

Concepts: Diabetes mellitus, Hormone, Endocrinology, Oxytocin, Vasopressin, Diabetes insipidus, Nephrogenic diabetes insipidus, Aquaporin 2


It has been reported that mutations in arginine vasopressin type 2 receptor (AVPR2) cause congenital X-linked nephrogenic diabetes insipidus (NDI). However, only a few cases of AVPR2 deletion have been documented in China.

Concepts: Genetics, Hormone, Endocrinology, Diabetes, Vasopressin, Diabetes insipidus, Nephrogenic diabetes insipidus, Desmopressin