Nephrogenic Diabetes Insipidus Research Articles

International expert consensus statement on the diagnosis and management of congenital nephrogenic diabetes insipidus (arginine vasopressin resistance).

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehydration. The diagnosis and management of NDI are very challenging and require an integrated, multidisciplinary approach. Here, we present 36 recommendations for diagnosis, treatment and follow-up in both children and adults, as well as emergency management, genetic counselling and family planning, for patients with NDI. These recommendations were formulated and graded by an international group of experts in NDI from paediatric and adult nephrology, urology and clinical genetics from the European Rare Kidney Disease Reference Network and the European Society of Paediatric Nephrology, as well as patient advocates, and were validated by a voting panel in a Delphi process. The goal of these recommendations is to provide guidance to health care professionals who care for patients with NDI and to patients and their families. In addition, we emphasize the need for further research on different aspects of this potentially life-threatening disorder to support the development of evidence-based guidelines in the future.

Diagnosing a genetic disease in a donor-conceived child: case report and discussion of the ethical, legal, and practical issues.

We describe the unexpected challenges pediatricians may experience when children conceived with assisted reproduction are diagnosed with a rare genetic condition. A local case series triggered a dialogue between many stakeholders with varied expertise. Indeed, diagnosing a genetic disease in a child conceived by embryo, egg, or sperm donation is becoming more common now that genetic testing and in vitro fertilization (IVF) are readily accessible. However, how and whether to share that information with other stakeholders in the gamete donation process has not been fully explored, and the clinical responsibilities of the treating clinician remain ill-defined. This work centers on a patient with a confirmed diagnosis of X-linked nephrogenic diabetes insipidus. Ultimately, we found the same AVPR2 mutation in two children from two families conceived by egg donation. It led to multigenerational cascade diagnoses in the family of the shared, anonymous egg donor. First, we review current genetic testing practices in gamete donation and third-party reproduction. Then, we provide an overview of relevant genomic, ethical, legal, and psychosocial considerations for sharing relevant genomic information. Finally, and to maximize the best interests of genetic relatives, we discuss how a pediatrician can play a role in the early disclosure of relevant clinical information to all stakeholders in the gamete donation process, starting with the fertility clinic. While these clinical cases are cast in a Canadian context, we submit that its important lessons generally apply to medical systems of nearly all developed countries, broadly defined.

12227 The Battle Between Central And Nephrogenic Diabetes Insipidus

Abstract Disclosure: A.A. Luzuriaga Chavez: None. J.P. Hidalgo: None. A. Rao: None. N. Patel: None. Diabetes insipidus (DI) is a rare disorder characterized by excessive polyuria and polydipsia. The two main types include central diabetes insipidus (CDI), which results from antidiuretic hormone (ADH) deficiency and nephrogenic diabetes insipidus (NDI), defined by ADH resistance in the renal tubules. It can be challenging to distinguish between different types of DI in a critically ill patient. A 68-year-old female with a past medical history of hypertension, bipolar disorder came to the ER for complaints of chills and shortness of breath. She was transferred to the intensive care unit (ICU) for septic shock secondary to pneumonia and left pleural effusion. A chest tube was placed with improvement in her breathing and she was transferred out of the ICU. Four days later, the patient developed altered mental status, fevers and ICU was reconsulted due to concern for meningitis. A lumbar puncture was done with negative results but the brain MRI revealed ischemic sites involving both medial parietal cortices extending into both occipital poles, consistent with acute ischemia. Furthermore, the patient developed an increased urine output of 200ml per hour with a negative balance of 2.7L, increased sodium of 150, serum osmolality of 313 and urine osmolality of 196. The patient received desmopressin 1 mcg q 6 hrs with the persistence of hypernatremia. Upon further questioning, the patient had been on lithium therapy in the past for bipolar disorder. Amiloride 2.5mg BID was added to the treatment regimen. The patient’s hypernatremia and urine output improved and she was discharged on both amiloride and desmopressin to follow up for dose adjustments as needed. DI has a prevalence of 1 in 25000. Acquired CDI secondary to lesions in the hypophysis or hypothalamus highlights the major role of the central nervous system in regulating water homeostasis. This case report describes CDI developing after a stroke. Ischemia can cause hypoperfusion of osmoreceptors in the hypothalamus and posterior pituitary. Lithium can be frequently associated with NDI, usually seen in 20 to 40% of patients. Different mechanisms of action include lithium interference in renal collecting tubules by increasing cAMP in response to ADH and down-regulation of aquaporin-2 expression, which is accepted to be reversible with the cessation of the therapy. However, long-term treatment with lithium likely results in permanent NDI. Our patient had a history of lithium therapy which contributed to the development of symptoms of NDI and responded to a combination of desmopressin and amiloride. The successful therapy enforces the diagnosis of both a central and a peripheral pathology. Central and nephrogenic DI, despite stemming from distinct underlying causes, may concurrently manifest in critically ill patients. This case report emphasizes the need for physicians to evaluate for multiple causes of DI in a patient with water disturbances. Presentation: 6/1/2024

8142 Endocrine Considerations Prior to Pituitary Tumor Resection

Abstract Disclosure: P. Einafshar: None. T. Delibasi: None. Endocrine Considerations in Pituitary Tumor Resection Introduction: Diabetes Insipidus (DI) is an endocrine condition involving a disturbance to the action of Anti-Diuretic Hormone (ADH) resulting in polyuria, and polydipsia with complications such as severe water and electrolyte disturbances. It can be classified into Central DI which affects the secretion of ADH or Nephrogenic DI which affects peripheral ADH receptors in Distal Convoluted Tubules (DCTs) in the renal system. Both subtypes however present similarly and are usually known to be transient. It is important to consider the most common etiologies contributing to both central and nephrogenic DI as severe complications may arise if not diagnosed and treated promptly. The most important step is to monitor and manage water and electrolytes and avoid excessive water loss which can lead to irreversible complications. This can be accomplished by introducing synthetic ADH called DDAVP or Desmopressin. Case Description: A 57-year-old female was admitted in preparation for a supra-orbital resection of a suprasellar mass. Two hours post-procedure, she was found to have an increase in urine output with her labs notable for a significant acute increase in serum sodium and a decrease in urine osmolality. Upon emergent Endocrinology evaluation, due to concerns of Acute Diabetes Insipidus in the setting of insult to the pituitary stalk, she was started on emergent treatment with IV DDAVP. Her course was complicated with persistent DI resulting in a case of permanent DI requiring out-patient daily treatments with DDAVP. Discussion: Injury to the pituitary stalk resulting in various endocrine abnormalities has been studied involving a trans-sphenoidal resection of pituitary tumors, but there is a paucity of cases reported when patients undergo a supra-orbital surgical approach. It is vital for Endocrinology and Neurosurgical services to be aware of this phenomenon, and a multi-disciplinary approach to patient management should be considered. Furthermore, close follow-up of pituitary hormones in the post-operative setting is imperative in order to avoid severe complications, such as brain damage or poor mental status. We hope to educate residents and fellows about this phenomenon that is rarely reported in the literature but can have profound effects on patient’s quality of life if not considered by the consulting Endocrinology team. References Christ-Crain, M., Winzeler, B., & Refardt, J. (2021). Diagnosis and management of diabetes insipidus for the internist: an update. Journal of internal medicine, 290(1), 73-87. Mutter, C. M., Smith, T., Menze, O., Zakharia, M., & Nguyen, H. (2021). Diabetes insipidus: pathogenesis, diagnosis, and clinical management. Cureus, 13(2). Presentation: 6/1/2024

Diagnostic Utility of Copeptin in Pediatric Patients with Polyuria-Polydipsia Syndrome: A Systematic Review and Meta-Analysis.

Pediatric patients with polyuria polydipsia syndrome (PPS) represent a diagnostic challenge for clinicians because of the technical difficulties in performing the gold standard water deprivation test (WDT). Copeptin, a stable biomarker representing the C-terminal portion of the polypeptide chain of the antidiuretic hormone, is a reliable diagnostic tool. To assess the diagnostic accuracy of baseline copeptin dosing, arginine/hypertonic saline copeptin stimulation tests, and WDT. This study aimed to establish the diagnostic utility of copeptin in pediatric patients by distinguishing between central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. Comparative and non-comparative primary studies published between January 2018 and August 2024 focusing on children were searched and included in PubMed, Cochrane Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. The QUADAS-2 tool was used to assess the risk of bias and applicability. Meta-analyses used fixed effects models because of low heterogeneity and the HSROC model. Eleven studies were included with an overall low bias and no significant applicability concerns. The mean pooled sensitivity = 0.98 (95% CI: 0.936-1.025), pooled specificity = 0.947 (95% CI: 0.920-0.973), and AUC = 0.972 (95% CI: 0.952-0.992), indicating excellent diagnostic accuracy. Stimulation methods for copeptin dosing represent an effective and less invasive diagnostic test for children with PPS, and future development of standard copeptin testing protocols is needed.

7320 A Case Of Concurrent Lithium-Associated Hyperthyroidism, Nephrogenic Diabetes Insipidus, Primary Hyperparathyroidism, And Acute Pancreatitis

Abstract Disclosure: C. Buchanan: None. C. Ellenburg: None. M. Beasey: None. Background: Hyperthyroidism, nephrogenic diabetes insipidus, and hyperparathyroidism are all well-documented adverse effects of long-term lithium therapy. This report highlights a rare case of these three endocrinologic adverse effects occurring concurrently. Clinical Case: A 47-year-old man on long-term lithium therapy for bipolar disorder presented with slurred speech, fatigue, new tremor, and generalized muscle weakness. Laboratory testing was consistent with lithium toxicity with serum lithium level of 2.22 mmol/L (0.60-1.50). Thyrotoxicosis was present with a free T4 of 3.2 ng/dL (0.6-1.1) and TSH of 0.04 µlU/mL (0.24-5.60). CT of the neck revealed mild enlargement and heterogeneity of the left lobe of the thyroid gland. Methimazole was started. Calcium corrected for albumin was elevated at 12.4 mg/dL (8.6-10.0) and PTH was also elevated at 146.0 pg/mL (12.0-88.0). Serum sodium was elevated at 160 mmol/L (136-145) with urine osmolality of 327 mOsm/kg. DDAVP was trialed in addition to IV hypotonic fluids, although it had little effect. Acetazolamide was started a few days later with subsequent normalization of the serum sodium level. Acetazolamide was later discontinued in favor of hydrochlorothiazide because of the development of non-anion-gap metabolic acidosis. A dose of zoledronic acid was given and cinacalcet was started. Serum calcium normalized over the following week. The patient acutely developed right upper quadrant abdominal pain, nausea, and emesis on hospital day 13. Lipase was elevated at 575 u/L (11-82). CT of the abdomen demonstrated moderate inflammatory changes along the pancreas and duodenum. Acute pancreatitis was diagnosed. There were no gallstones or acute biliary tract abnormalities seen on ultrasound. The patient’s symptoms gradually improved and he was discharged from the hospital after a total of 18 days. Lithium was discontinued indefinitely. TSH and free T4 normalized within 3 months. He had continued to require hydrochlorothiazide, methimazole, and cinacalcet at the time of his 3-month primary care follow-up appointment. Conclusion: Despite its efficacy and widespread use in mood stabilization, lithium has a narrow therapeutic window and is strongly associated with several serious, sometimes irreversible, adverse effects. Routine monitoring of lithium levels, serum calcium, and thyroid hormone levels is required. Lapses in routine monitoring may, as in this case, result in significant morbidity and prolonged hospitalization. Presentation: 6/1/2024

6616 Copeptin Use To Reduce Hospital Stay In A Complicated DI Case

Abstract Disclosure: S.S. Kowsika: None. H. Moran: None. Introduction: While there is literature describing the use of copeptin for the diagnosis of polyuria-polydipsia syndrome, its utilization remains very limited in many hospitals. We present a case where the patient, initially misdiagnosed with central diabetes insipidus (DI), was appropriately diagnosed with partial nephrogenic DI through the use of copeptin. Case: A 48-year old female with a history of cardiac arrest, anoxic brain injury and diabetes insidious (DI) presented to the emergency department with hypernatremia (Na 154 mmol/L). The patient had been initiated on desmopresin (DDAVP) at an outside facility prior to her current admission. Despite receiving high doses of DDAVP, her sodium levels remained elevated, prompting further investigation. DDAVP administration was discontinued. A water deprivation test was subsequently performed, followed by IV administration of 2 mcg of DDAVP, which resulted in an increase in urine osmolality from 191 to 331 mosm/kg, which was less than the expected 50% increase observed in central DI. Additionally, a baseline copeptin level was obtained and noted to be 31 pmol/L, confirming the diagnosis of partial nephrogenic DI. The patient was started on Amiloride, leading to normalization of sodium levels. Discussion: Many patients with polyuria-polydipsia syndrome are frequently misdiagnosed and receive incorrect treatment, potentially worsening their clinical condition. Copeptin (Carboxy-Terminal-Pro-vasopressin) is the C-terminal peptide of pro-vasopressin, co-secreted with arginine vasopressin (AVP). It has been proposed as a direct test for diagnosing polyuria-polydipsia syndrome. Baseline Copeptin testing without stimulation can accurately diagnose nephrogenic DI if elevated (>21.4, pmol/L). To differentiate between central DI and chronic polyuria, prior thirsting with hypertonic saline or glucagon stimulation is necessary, with stimulated copeptin <4.9 pmol/L diagnosing central DI. Despite its diagnostic potential, Copeptin is underutilized in many settings. In this case, using Copeptin to accurately diagnose our patient led to appropriate treatment and the resolution of hypernatremia. Presentation: 6/1/2024

Downregulation of the Vasopressin-AQP2 Pathway Explains Secondary Nephrogenic Diabetes Insipidus Associated with Cystinosis: In Vivo and In Vitro Evidence

Downregulation of the Vasopressin-AQP2 Pathway Explains Secondary Nephrogenic Diabetes Insipidus Associated with Cystinosis: In Vivo and In Vitro Evidence

Genotype, Phenotype, and Follow-Up in Taiwanese Patients with Congenital Nephrogenic Diabetes Insipidus

Genotype, Phenotype, and Follow-Up in Taiwanese Patients with Congenital Nephrogenic Diabetes Insipidus

Can Acetylation of Lysine 282 of Aquaporin 3 Improve Urinary Concentration in Mice with Lithium-Induced Nephrogenic Diabetes Insipidus?

Can Acetylation of Lysine 282 of Aquaporin 3 Improve Urinary Concentration in Mice with Lithium-Induced Nephrogenic Diabetes Insipidus?

A novel mutation in the AVPR2 gene causing congenital nephrogenic diabetes insipidus

A novel mutation in the AVPR2 gene causing congenital nephrogenic diabetes insipidus

Acute lymphoblastic leukemia with nephrogenic diabetes insipidus as the first symptom: a case report

BackgroundAcute lymphoblastic leukemia is the most common pediatric malignancy, characterized by fever, anemia, hemorrhage, and symptoms brought on by blasts infiltrating organs.Case presentationThis is a case report of a 9-year-old Asian patient with acute lymphoblastic leukemia who presented with polyuria alone as a presenting feature without any other clinical manifestation; primary renal disease or inherited metabolic disease was highly suspected. However, the water deprivation test and water deprivation pressurization test suggested nephrogenic diabetes insipidus, and the renal biopsy displayed diffuse lymphocytic infiltration in the renal interstitium. Bone marrow aspiration was performed immediately, and a comprehensive diagnosis of B-lymphoblastic leukemia was finally made.ConclusionsRenal infiltration with leukemic blasts mostly remains asymptomatic, but our case suggests that it can present with nephrogenic diabetes insipidus. This case fully demonstrates that the presentation of extramedullary infiltration in acute lymphoblastic leukemia is varied. When the patient has renal diabetes insipidus as the first symptom, the possibility of hematological tumor infiltration should be considered when finding the cause, and timely bone marrow cytology should be performed.

Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials.

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

Hypokalemic paralysis and proximal renal tubular acidosis secondary to tenofovir-induced Fanconi syndrome: A contributing cause of death

Nucleotide reverse transcriptase inhibitors (NRTIs, primarily cidofovir and adefovir, less likely tenofovir) pose a well-known risk of nephrotoxicity. Acute renal failure, nephrogenic diabetes insipidus (NDI), and Fanconi syndrome (FS) are the primarily reported renal adverse effects associated with NRTIs. In this report, we describe a case of a 52-year-old female who presented to the outpatient department of a tertiary-care facility with polyuria, polydipsia, convulsions, myalgias, and hypokalemic paralysis (quadriparesis) after 10 months exposure to tenofovir disoproxil fumarate (TDF), which she was taking for HIV and Hepatitis-B virus coinfection. The patient developed hypokalemic paralysis and proximal renal tubular acidosis (pRTA) with normal anion gap hyperchloremic metabolic acidosis. On evaluation, renal tubulopathy was evident, which was resolved post-TDF discontinuation and therapeutic corrections. A diagnosis of TDF-induced FS, pRTA, and NDI were considered, as there were no clear alternative explanations. This report also highlights the characteristics of TDF-induced FS from the published case reports in the Indian context.

Effects of YM087 and VPA985 on the T237M mutant receptor functionality in nephrogenic diabetes insipidus

Abstract Objectives Mutations detected in the AVPR2 gene (arginine vasopressin type 2 receptor) are known to cause nephrogenic diabetes insipidus (NDI). Several pharmacological chaperones (PCs) target misfolded AVPR2 proteins and rescue them from the quality control system of the cell. In this study, we investigated the effect of YM087 and VPA985, which are PCs, on T273M-AVPR2 mutant that are known to cause NDI. Methods The total and cell surface expressions of T273M in COS-1 cells were measured by sandwich ELISA and flow cytometry after the cells were treated with YM087 and VPA985 separately. In addition, the cAMP accumulation assay was performed. Results It was observed that VPA985 treatment significantly increased the cell surface expression and slightly increased the maximum cAMP response of T273M. Both YM087 and VPA985 decreased the ligand concentrations which were responsible for making half of the maximum response of the T273M mutant receptor. Conclusions PCs have different potential effects on different AVPR2 mutants. Therefore, studying the effectiveness of PCs in rescuing AVPR2 mutants and making them functional again may contribute to the development of new therapeutic strategies.

Approach to the patient with suspected hypotonic polyuria.

Investigation and management of hypotonic polyura is a common challenge in clinical endocrinology. The three main causes, recently renamed to arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus), AVP-resistance (AVP-R, formerly nephrogenic diabetes insipidus), and primary polydipsia (PP) require accurate diagnosis as management differs for each. This new nomenclature more accurately reflects pathophysiology, and has now been adopted by the Systemised Nomenclature of Medicine (SNOMED). Advances in diagnosis over the last few years have centered around the use of copeptin measurement. Here, we use three patient case histories to highlight the use of this approach, and to demonstrate how it can succeed where other approaches, such as the water deprivation test, sometimes fail. We discuss the overall approach to each type of patient and the strengths and limitations of diagnostic strategies, illustrating the use of the new nomenclature.

Duloxetine-Induced Antidiuresis in Rats with Lithium-Induced Nephrogenic Diabetes Insipidus.

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia.

Clinical manifestations and renal pathology of ethylene glycol.

Ethylene glycol (EG) poisoning is a critical medical emergency often associated with suicide attempts in adults. EG is metabolized by alcohol dehydrogenase, leading to the formation of toxic metabolites that cause metabolic acidosis, renal failure, hypocalcemia, aciduria, and disorders of the central nervous and cardiovascular systems. Calcium oxalate, a metabolite of EG, contributes to acute tubular necrosis. Despite limited reports on human renal pathology, we present a case detailing renal pathology following EG ingestion. A 44-year-old male, admitted due to loss of consciousness, had ingested a lethal dose of EG. Blood tests indicated metabolic acidosis, while urinary examination revealed calcium oxalate crystals. Continuous renal replacement therapy corrected the acidosis; however, nephrogenic diabetes insipidus subsequently developed. A renal biopsy on day 31 revealed calcium oxalate crystal deposition and tubulointerstitial damage. Notably, various stages of crystal deposition, adherence, and degradation were observed. This case underscores the importance of considering EG poisoning in cases of unexplained metabolic acidosis and renal dysfunction, with renal biopsy serving as a valuable diagnostic tool. Understanding the renal effects of EG is essential for timely intervention and effective management of poisoning cases.

Clinical management of unremitting nephrogenic diabetes insipidus.

The polyuria and polydipsia state in diabetes insipidus (DI) can be challenging to manage for patients and clinicians with significant impact on the patients' well-being. A review of literature shows that nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide and potassium-sparing diuretics, along with low dietary solute and protein, and high water intake remain the standard medical therapy. Although these therapeutic approaches improve symptoms, the urine-concentrating defect is still considerable, posing a serious risk to patient's life from hypovolemia if high fluid intake is not maintained. Our case describes the challenges faced with the medical management of a patient with nephrogenic DI that was only partially responsive to standard medical therapy, resulting in debilitating effects on the patient's quality of life.

Cannabinoid receptor type 1 activation causes a water diuresis by inducing an acute central diabetes insipidus in mice.

Cannabis and synthetic cannabinoid consumption are increasing worldwide. Cannabis contains numerous phytocannabinoids that act on the G protein-coupled cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 expressed throughout the body, including the kidney. Essentially every organ, including the kidney, produces endocannabinoids, which are endogenous ligands to these receptors. Cannabinoids acutely increase urine output in rodents and humans, thus potentially influencing total body water and electrolyte homeostasis. As the kidney collecting duct (CD) regulates total body water, acid/base, and electrolyte balance through specific functions of principal cells (PCs) and intercalated cells (ICs), we examined the cell-specific immunolocalization of CB1R in the mouse CD. Antibodies against either the C-terminus or N-terminus of CB1R consistently labeled aquaporin 2 (AQP2)-negative cells in the cortical and medullary CD and thus presumably ICs. Given the well-established role of ICs in urinary acidification, we used a clearance approach in mice that were acid loaded with 280 mM NH4Cl for 7 days and nonacid-loaded mice treated with the cannabinoid receptor agonist WIN55,212-2 (WIN) or a vehicle control. Although WIN had no effect on urinary acidification, these WIN-treated mice had less apical + subapical AQP2 expression in PCs compared with controls and developed acute diabetes insipidus associated with the excretion of large volumes of dilute urine. Mice maximally concentrated their urine when WIN and 1-desamino-8-d-arginine vasopressin [desmopressin (DDAVP)] were coadministered, consistent with central rather than nephrogenic diabetes insipidus. Although ICs express CB1R, the physiological role of CB1R in this cell type remains to be determined.NEW & NOTEWORTHY The CB1R agonist WIN55,212-2 induces central diabetes insipidus in mice. This research integrates existing knowledge regarding the diuretic effects of cannabinoids and the influence of CB1R on vasopressin secretion while adding new mechanistic insights about total body water homeostasis. Our findings provide a deeper understanding about the potential clinical impact of cannabinoids on human physiology and may help identify targets for novel therapeutics to treat water and electrolyte disorders such as hyponatremia and volume overload.