Nephrogenic diabetes insipidus: a comprehensive overview.

Nephrogenic diabetes insipidus (NDI) is characterized by the inability to concentrate urine that results in polyuria and polydipsia, despite having normal or elevated plasma concentrations of arginine vasopressin (AVP). In this study, we review the clinical aspects and diagnosis of NDI, the various etiologies, current treatment options and potential future developments. NDI has different clinical manifestations and approaches according to the etiology. Hereditary forms of NDI are mainly caused by mutations in the genes that encode key proteins in the AVP signaling pathway, while acquired causes are normally associated with specific drug exposure, especially lithium, and hydroelectrolytic disorders. Clinical manifestations of the disease vary according to the degree of dehydration and hyperosmolality, being worse when renal water losses cannot be properly compensated by fluid intake. Regarding the diagnosis of NDI, it is important to consider the symptoms of the patient and the diagnostic tests, including the water deprivation test and the baseline plasma copeptin measurement, a stable surrogate biomarker of AVP release. Without proper treatment, patients may developcomplications leading to high morbidity and mortality, such as severe dehydration and hypernatremia. In that sense, the treatment of NDI consists in decreasing the urine output, while allowing appropriate fluid balance, normonatremia, and ensuring an acceptable quality of life. Therefore, therapeutic options include nonpharmacological interventions, including sufficient water intake and a low-sodium diet, and pharmacological treatment. The main medications used for NDI are thiazide diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and amiloride, used isolated or in combination.

Updates and Perspectives on Aquaporin-2 and Water Balance Disorders.

Ensuring the proper amount of water inside the body is essential for survival. One of the key factors in the maintenance of body water balance is water reabsorption in the collecting ducts of the kidney, a process that is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and impermeable to ions or other small molecules. Impairments of AQP2 result in various water balance disorders, including nephrogenic diabetes insipidus (NDI), which is a disease characterized by a massive loss of water through the kidney and consequent severe dehydration. Dysregulation of AQP2 is also a cause of water retention with hyponatremia in heart failure, hepatic cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone vasopressin is an upstream regulator of AQP2. Its binding to the vasopressin V2 receptor promotes AQP2 targeting to the apical membrane and thus enables water reabsorption. Tolvaptan, a vasopressin V2 receptor antagonist, is effective and widely used for water retention with hyponatremia. However, there are no studies showing improvement in hard outcomes or long-term prognosis. A possible reason is that vasopressin receptors have many downstream effects other than AQP2 function. It is expected that the development of drugs that directly target AQP2 may result in increased treatment specificity and effectiveness for water balance disorders. This review summarizes recent progress in studies of AQP2 and drug development challenges for water balance disorders.

Molecular Characterization of an Aquaporin-2 Mutation Causing Nephrogenic Diabetes Insipidus.

The aquaporin 2 (AQP2) plays a critical role in water reabsorption to maintain water homeostasis. AQP2 mutation leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, polydipsia, and hypernatremia. We previously reported that a novel AQP2 mutation (G215S) caused NDI in a boy. In this study, we aimed to elucidate the cell biological consequences of this mutation on AQP2 function and clarify the molecular pathogenic mechanism for NDI in this patient. First, we analyzed AQP2 expression in Madin-Darby canine kidney (MDCK) cells by AQP2-G215S or AQP2-WT plasmid transfection and found significantly decreased AQP2-G215S expression in cytoplasmic membrane compared with AQP2-WT, independent of forskolin treatment. Further, we found co-localization of endoplasmic reticulum (ER) marker (Calnexin) with AQP2-G215S rather than AQP2-WT in MDCK cells by immunocytochemistry. The functional analysis showed that MDCK cells transfected with AQP2-G215S displayed reduced water permeability compared with AQP2-WT. Visualization of AQP2 structure implied that AQP2-G215S mutation might interrupt the folding of the sixth transmembrane α-helix and/or the packing of α-helices, resulting in the misfolding of monomer and further impaired formation of tetramer. Taken together, these findings suggested that AQP2-G215S was misfolded and retained in the ER and could not be translocated to the apical membrane to function as a water channel, which revealed the molecular pathogenic mechanism of AQP2-G215S mutation and explained for the phenotype of NDI in this patient.

Rapid development of vasopressin resistance in dietary K+ deficiency.

The association between diabetes insipidus (DI) and chronic dietary K+ deprivation is well known, but it remains uncertain how the disorder develops and whether it is influenced by the sexual dimorphism in K+ handling. Here, we determined the plasma K+ (PK) threshold for DI in male and female mice and ascertained if DI is initiated by polydipsia or by a central or nephrogenic defect. C57BL6J mice were randomized to a control diet or to graded reductions in dietary K+ for 8 days, and kidney function and transporters involved in water balance were characterized. We found that male and female mice develop polyuria and secondary polydipsia. Altered water balance coincided with a decrease in aquaporin-2 (AQP2) phosphorylation and apical localization despite increased levels of the vasopressin surrogate marker copeptin. No change in the protein abundance of urea transporter-A1 was observed. The Na+-K+-2Cl- cotransporter decreased only in males. Desmopressin treatment failed to reverse water diuresis in K+-restricted mice. These findings indicate that even a small fall in PK is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low PK as a causal trigger of NDI. We found that PK decreased more in females, and, consequently, females were more prone to develop NDI. Together, these data indicate that AQP2 regulation is disrupted by a small decrease in PK and that the response is influenced by sexual dimorphism in K+ handling. These findings provide new insights into the mechanisms linking water and K+ balances and support defining the disorder as "potassium-dependent NDI."NEW & NOTEWORTHY This study shows that aquaporin-2 regulation is disrupted by a small fall in plasma potassium levels and the response is influenced by sexual dimorphism in renal potassium handling. The findings provided new insights into the mechanisms by which water balance is altered in dietary potassium deficiency and support defining the disorder as "potassium-dependent nephrogenic diabetes insipidus."

Distal Renal Tubular Acidosis due to Primary Sjögren's Syndrome: Presents as Hypoakalemic Paralysis with Hypokalemia-Induced Nephrogenic Diabetes Insipidus.

Classic distal renal tubular acidosis (dRTA) is characterized by inability to acidify the urine maximally (to

Acute interstitial nephritis and nephrogenic diabetes insipidus following treatment with sulfamethoxazole-trimethoprim and temozolomide.

We report a case of acute interstitial nephritis with associated nephrogenic diabetes insipidus in a patient treated with temozolomide and sulfamethoxazole-trimethoprim for glioblastoma multiforme. Kidney biopsy demonstrated focal tubulointerstitial change with tubular dilatation, epithelial change and interstitial inflammation. The patient's kidney function improved with cessation of sulfamethoxazole-trimethoprim and treatment with hydrochlorothiazide for nephrogenic diabetes insipidus. Recommencement of temozolomide did not result in further deterioration in kidney function. In this case report, we discuss the novel association between sulfamethoxazole-trimethoprim-induced acute interstitial nephritis and nephrogenic diabetes insipidus, and suggest possible mechanisms involved.

Nephrogenic diabetes insipidus induced by ureter obstruction due to benign prostatic hyperplasia: A case report.

INTRODUCTION: Diabetes insipidus can be a common cause of polyuria and hydronephrosis in the kidneys. However, there is few reported case of urinary obstruction induced nephrogenic diabetes insipidus. PATIENT CONCERNS: A 60-year-old Chinese man came to our hospital with the complaints of polydipsia and polyuria for 1 month. His examination showed chronic kidney disease stage III with eGFR of 48.274 ml/min, and the plasma osmolality was 338.00 mOsm/(kg·H2O) with a urinary osmolality of 163.00 mOsm/(kg·H2O). Moreover, imagological examination of the urinary system showed benign prostatic hyperplasia and hydronephrosis. DIAGNOSIS: He was considered with benign prostatic hyperplasia induced ureter hydronephrosis and nephrogenic diabetes insipidus. INTERVENTIONS: He got the transurethral resection of the prostate to alleviate urinary retention. OUTCOMES: After that, the urine output gradually decreased, and the administered hydrochlorothiazide was stopped due to the improved renal function. CONCLUSION: Our study presents a case of nephrogenic diabetes insipidus caused by urinary obstruction. Differential diagnoses for diabetes insipidus as well as the relationship between nephrogenic diabetes insipidus and urinary obstruction are also considered in this study.

Acquired forms of central diabetes insipidus: Mechanisms of disease.

Most cases of acquired central diabetes insipidus are caused by destruction of the neurohypophysis by: 1) anatomic lesions that destroy the vasopressin neurons by pressure or infiltration, 2) damage to the vasopressin neurons by surgery or head trauma, and 3) autoimmune destruction of the vasopressin neurons. Because the vasopressin neurons are located in the hypothalamus, lesions confined to the sella turcica generally do not cause diabetes insipidus because the posterior pituitary is simply the site of the axon terminals that secrete vasopressin into the bloodstream. In addition, the capacity of the neurohypophysis to synthesize vasopressin is greatly in excess of the body's needs, and destruction of 80-90% of the hypothalamic vasopressin neurons is required to produce diabetes insipidus. As a result, even large lesions in the sellar and suprasellar area generally are not associated with impaired water homeostasis until they are surgically resected. Regardless of the etiology of central diabetes insipidus, deficient or absent vasopressin secretion causes impaired urine concentration with resultant polyuria. In most cases, secondary polydipsia is able to maintain water homeostasis at the expense of frequent thirst and drinking. However, destruction of the osmoreceptors in the anterior hypothalamus that regulate vasopressin neuronal activity causes a loss of thirst as well as vasopressin section, leading to severe chronic dehydration and hyperosmolality. Vasopressin deficiency also leads to down-regulation of the synthesis of aquaporin-2 water channels in the kidney collecting duct principal cells, causing a secondary nephrogenic diabetes insipidus. As a result, several days of vasopressin administration are required to achieve maximal urine concentration in patients with CDI. Consequently, the presentation of patients with central diabetes insipidus can vary greatly, depending on the size and location of the lesion, the magnitude of trauma to the neurohypophysis, the degree of destruction of the vasopressin neurons, and the presence of other hormonal deficits from damage to the anterior pituitary.

Diagnosis and differential diagnosis of diabetes insipidus: Update.

The two main differential diagnoses of central diabetes insipidus are nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between those entities is essential as treatment differs substantially with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the indirect water deprivation test had several pitfalls, resulting in a low diagnostic accuracy. With the introduction of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of diabetes insipidus was new evaluated. While unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, a stimulation test is needed to differentiate patients with central diabetes insipidus from patients with primary polydipsia. Stimulation can either be achieved through hypertonic saline infusion or arginine infusion. While the former showed high diagnostic accuracy and superiority over the indirect water deprivation test in a recent validation study, the diagnostic accuracy for arginine-stimulated copeptin was slightly lower, but superior in test tolerance. In summary of the recent findings, a new copeptin based diagnostic algorithm is proposed for the reliable diagnosis of diabetes insipidus.

Gestational diabetes insipidus: Diagnosis and management.

In the pregnant patient, hypotonic polyuria in the setting of elevated serum osmolality and polydipsia should narrow the differential to causes related to diabetes insipidus (DI). Gestational DI, also called transient DI of pregnancy, is a distinct entity, unique from central DI or nephrogenic DI which may both become exacerbated during pregnancy. These three different processes relate to vasopressin, where increased metabolism, decreased production or altered renal sensitivity to this neuropeptide should be considered. Gestational DI involves progressively rising levels of placental vasopressinase throughout pregnancy, resulting in decreased endogenous vasopressin and resulting hypotonic polyuria worsening through the pregnancy. Gestational DI should be distinguished from central and nephrogenic DI that may be seen during pregnancy through use of clinical history, urine and serum osmolality measurements, response to desmopressin and potentially, the newer, emerging copeptin measurement. This review focuses on a brief overview of osmoregulatory and vasopressin physiology in pregnancy and how this relates to the clinical presentation, pathophysiology, diagnosis and management of gestational DI, with comparisons to the other forms of DI during pregnancy. Differentiating the subtypes of DI during pregnancy is critical in order to provide optimal management of DI in pregnancy and avoid dehydration and hypernatremia in this vulnerable population.

Renal Tubular Acidosis Presenting as Nephrogenic Diabetes Insipidus.

BACKGROUND: Nephrogenic diabetes insipidus (DI) can be primary or secondary to various causes. CASE CHARACTERISTICS: One child with Fanconi syndrome with proximal renal tubular acidosis (RTA) due to nephropathic cystinosis, and other with Distal RTA with hearing loss. OBSERVATION: Both cases showed features of nephrogenic DI, which resolved after treating the primary pathology. MESSAGE: Renal Tubular acidosis may cause nephrogenic DI.

Nephrogenic Diabetes Insipidus.

Nephrogenic diabetes insipidus (NDI) results from the inability of the late distal tubules and collecting ducts to respond to vasopressin. The lack of ability to concentrate urine results in polyuria and polydipsia. Primary and acquired forms of NDI exist in children. Congenital NDI is a result of mutation in AVPR2 or AQP2 genes. Secondary NDI is associated with electrolyte abnormalities, obstructive uropathy, or certain medications. Management of NDI can be difficult with only symptomatic treatment available, using low-solute diet, diuretics, and prostaglandin inhibitors.

Double Trouble - Severe Hypernatremia Secondary to Central Diabetes Insipidus Complicated by Hypercalcemic Nephrogenic Diabetes Insipidus: A Case Report.

BACKGROUND Patients with malignancies often have electrolyte abnormalities. We present a case of a patient with central diabetes insipidus secondary to metastatic pituitary invasion complicated by hypercalcemic nephrogenic diabetes insipidus. CASE REPORT We present a case of 40-year-old female with a history of stage IV breast cancer with skeletal and leptomeningeal metastasis, who was admitted with polyuria, polydipsia, and recent onset of confusion. The patient was found to have profound hypernatremia and severe hypercalcemia with normal parathyroid and vitamin D serum levels. Urine studies showed low urine osmolality and high urine output, despite the higher serum osmolality. The patient received 5% dextrose for rehydration, 1 dose of intravenous (IV) pamidronate, 1 dose of IV desmopressin, and 4 days of subcutaneous calcitonin 200 international units Q12H. Initially, her urine output in the hospital was in the range of 350-400 milliliters/hour, which responded well to 1 dose of 1-desamino-8d-arginine vasopressin (DDAVP). In the subsequent days, her confusion resolved with normalization of serum sodium and calcium, but she died because of the extensive malignancy. CONCLUSIONS Our case emphasizes the importance of identification of causes and complications of electrolyte abnormalities associated with metastatic cancers. These electrolyte abnormalities can be primary or paraneoplastic and should be actively pursued and treated in such cases.

Nephrogenic diabetes insipidus in initial stage of acute lymphoblastic leukemia and relapse after haploidentical hematopoietic stem-cell transplantation: A case report.

RATIONALE: Nephrogenic diabetes insipidus (NDI) rarely presents in the initial stage of acute lymphoblastic leukemia (ALL) and relapse due to renal infiltration is also rare. PATIENT CONCERNS: A 19-year-old man presented with weakness, polydipsia, and polyuria for 1 month. DIAGNOSES: NDI was diagnosed with insignificant response to a water deprivation test after stimulation with vasopressin injection. Bone marrow examination combined with immunophenotypic analysis, cerebrospinal cytology, and abdominal ultrasonography confirmed the diagnoses of precursor B cell ALL with renal infiltration. INTERVENTIONS: The patient accepted standardized combination chemotherapy and ultimately had sustained remission, and his polydipsia and polyuria disappeared after 3 days of treatment. The ALL relapsed 1 year later and he received haploidentical stem cell transplantation (haplo-SCT) from his father. OUTCOMES: One year later, he again developed NDI, with bilateral renal enlargement because of extramedullary relapse, leading to subsequent death. LESSONS: This case demonstrates unusual early renal involvement in ALL presenting with initial NDI. Interestingly, the NDI returned with the relapse of renal infiltration 1 year after haplo-SCT. This case suggests that NDI was probably secondary to renal leukemic infiltration.

Systemic lupus erythematosus with Sjögren's syndrome and renal tubular acidosis presenting as nephrogenic diabetes insipidus.

Systemic lupus erythematosus (SLE) presenting as diabetes insipidus (DI) is a rare association; there is a case report of neurogenic DI in patients of SLE; however, SLE and nephrogenic DI has not been reported in literature. We present a case of SLE presenting as nephrogenic DI. We report a case who presented with DI (nephrogenic) and fulfilled criteria for SLE and Sjögren's syndrome with renal tubular acidosis.

Value of Renal Biopsy in Diagnosing Infantile Nephropathic Cystinosis Associated With Secondary Nephrogenic Diabetes Insipidus.

Cystinosis is the most common cause of inherited renal Fanconi syndrome in young children, and typically presents with laboratory findings of a proximal tubulopathy and corneal crystals by one year of age. We describe here renal biopsy findings in a 20-month-old patient with an atypical presentation of distal renal tubular acidosis, diabetes insipidus, and the absence of corneal crystals. Although renal biopsy is usually not necessary to establish the diagnosis of cystinosis, when the patient presents with atypical signs and symptoms, a renal biopsy may be extremely valuable. A 20-month-old boy presented with failure to thrive, polyuria, polydipsia, and rickets. He initially showed evidence of a renal tubular acidosis, mild renal insufficiency, and nephrogenic diabetes insipidus. His initial ophthalmologic examination did not demonstrate corneal crystals. His subsequent workup revealed phosphaturia, suggesting a partial proximal tubulopathy. Concomitantly, a renal biopsy revealed prominent podocytes with an immature glomerular appearance, and electron microscopy analysis showed numerous intracellular crystals within tubular epithelial cells. Subsequent laboratory and genetic testing confirmed a diagnosis of infantile nephropathic cystinosis. This case highlights the variability in the clinical presentation of cystinosis, resulting in an uncommon clinical picture of a rare disease. Given that treatment is available to prolong renal function and minimize the extra-renal manifestations of this disorder, early diagnosis is essential. It is important to raise the index of suspicion of cystinosis by recognizing its subtle morphological changes in young patients, and that nephrogenic diabetes insipidus can be secondary to this disorder.

Hypercalcemia induces targeted autophagic degradation of aquaporin-2 at the onset of nephrogenic diabetes insipidus.

Hypercalcemia can cause renal dysfunction such as nephrogenic diabetes insipidus (NDI), but the mechanisms underlying hypercalcemia-induced NDI are not well understood. To elucidate the early molecular changes responsible for this disorder, we employed mass spectrometry-based proteomic analysis of inner medullary collecting ducts (IMCD) isolated from parathyroid hormone-treated rats at onset of hypercalcemia-induced NDI. Forty-one proteins, including the water channel aquaporin-2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the downregulated proteins were associated with cytoskeletal protein binding, regulation of actin filament polymerization, and cell-cell junctions. Targeted LC-MS/MS and immunoblot studies confirmed the downregulation of 16 proteins identified in the initial proteomic analysis and in additional experiments using a vitamin D treatment model of hypercalcemia-induced NDI. Evaluation of transcript levels and estimated half-life of the downregulated proteins suggested enhanced protein degradation as the possible regulatory mechanism. Electron microscopy showed defective intercellular junctions and autophagy in the IMCD cells from both vitamin D- and parathyroid hormone-treated rats. A significant increase in the number of autophagosomes was confirmed by immunofluorescence labeling of LC3. Colocalization of LC3 and Lamp1 with aquaporin-2 and other downregulated proteins was found in both models. Immunogold electron microscopy revealed aquaporin-2 in autophagosomes in IMCD cells from both hypercalcemia models. Finally, parathyroid hormone withdrawal reversed the NDI phenotype, accompanied by termination of aquaporin-2 autophagic degradation and normalization of both nonphoshorylated and S256-phosphorylated aquaporin-2 levels. Thus, enhanced autophagic degradation of proteins plays an important role in the initial mechanism of hypercalcemic-induced NDI.

Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus.

Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split-open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR-A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling.