Central Diabetes Insipidus in the Background of Lithium Use: Consider Central Causes Despite Nephrogenic as the Most Common.

BACKGROUND Nephrogenic diabetes insipidus is a well-known adverse effect of lithium use. Albeit rare, there have also been documented cases of central diabetes insipidus (CDI) associated with lithium use. CASE REPORT A 31-year-old woman with a past medical history of bipolar disorder, managed with lithium 300 mg by mouth every day for 3 years, was assessed for a 1-year history of polyuria with accompanying polydipsia. During her initial hospital stay, her estimated urine output was more than 4 L per day. Initial labs showed elevated serum sodium (149 mmol/L; reference range 135-145), elevated serum osmolality (304 mOsm/kg; reference range 275-295), urine osmolality of 99 mOsm/kg (reference range 50-1200), and urine specific gravity (1.005; reference range 1.005-1.030). Lithium was at a subtherapeutic level of 0.05 mEq/L (reference range 0.6-1.2). Magnetic resonance imaging of the brain revealed no abnormalities of the pituitary gland. Two different occasions of desmopressin administration resulted in >50% increase in urine osmolality, confirming the diagnosis of CDI. Common causes of CDI, including trauma, tumors, and familial CDI, were ruled out and chronic lithium use was determined as the most probable cause for the patient's CDI. CONCLUSIONS CDI in the background of chronic lithium use is rarely reported. We present this case to consider CDI as a differential diagnosis when evaluating polyuria and hypernatremia in patients with long-term lithium use. These presentations warrant the consideration of both types of diabetes insipidus in the differential diagnoses.

Drugs Showing Real-world Efficacy for Nocturia in Patients With Bladder Storage Symptoms.

BACKGROUND/AIM: Nocturia is defined as the symptom that an individual has to disrupt their sleep at night, for one or several times, in order to void. Nocturia is a bothersome event that markedly reduces a patient's quality of life. The aim of the study was to elucidate which drugs, prescribed to reduce nocturia, show real-world efficacy in patients with bladder storage symptoms. PATIENTS AND METHODS: One hundred consecutive patients who visited the Fukuoka University Medical Center were evaluated between May and July 2022. Anticholinergic drugs, ß3 adrenoceptor agonists, α1 blockers, desmopressin, and other medicines were prescribed for relieving nocturia. Desmopressin was used as second-line treatment of nocturia only in males with nocturnal polyuria. The association between each drug and actual decrease in nocturia was investigated using multivariate analysis. RESULTS: The number of nocturia episodes was reduced in patients using anticholinergic drugs, ß3 adrenoceptor agonists, and desmopressin (-1.4±0.9, -1.3±0.9, -2.0 ±0.8 episodes/night, respectively). Multivariate analysis for the entire cohort showed that anticholinergic drugs and ß3 adrenoceptor agonists were associated with significantly decreased nocturia episodes (p=0.01 and p=0.04, respectively). In males, only desmopressin was associated with a significant decrease in nocturia (p=0.03), and combination therapy significantly decreased the number of nocturia episodes compared to monotherapy (p=0.001). CONCLUSION: In a real-world clinical setting, anticholinergic drugs and ß3 adrenoceptor agonists were similarly effective in reducing nocturia. Administration of desmopressin combined with anticholinergic drugs and/or ß3 adrenoceptor agonists is the most effective method for reducing nocturia in male patients with both storage symptoms and nocturnal polyuria.

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.

BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone. CONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats.

BACKGROUND: Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. METHODS: Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. RESULTS: Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. CONCLUSION: HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.

Case report: a thiazide diuretic to treat polyuria induced by tolvaptan.

BACKGROUND: Currently, the vasopressin V2 receptor antagonist tolvaptan is the only available treatment for autosomal dominant polycystic kidney disease (ADPKD), but there are tolerability issues due to aquaretic side-effects such as polyuria. A possible strategy to ameliorate these side-effects may be addition of a thiazide diuretic, this is an established treatment in nephrogenic diabetes insipidus, a condition where vasopressin V2 receptor function is absent. CASE PRESENTATION: We describe a 46-year-old male ADPKD-patient, who was prescribed tolvaptan, which caused polyuria of around 5 l per day. Hydrochlorothiazide was added to treat hypertension, which resulted in a marked decrease in urine production. While using tolvaptan, rate of eGFR decline was - 1.35 mL/min/1.73m2 per year, whereas after hydrochlorothiazide was initiated this was - 3.97 mL/minute/1.73m2 per year. CONCLUSIONS: This case report indicates that while addition of hydrochlorothiazide may improve tolerability of vasopressin V2 receptor antagonists, co-prescription should only be used with great scrutiny as it may decrease tolvaptan effect on rate of ADPKD disease progression.

Combination exposure of melamine and cyanuric acid is associated with polyuria and activation of NLRP3 inflammasome in rats.

The molecular mechanisms of melamine-induced renal toxicity have not been fully understood. The purpose of the study aimed to investigate whether melamine and cyanuric acid induced NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in the kidney, which may contribute to abnormal water and sodium handling in a rat model. Wistar rats received melamine (Mel; 200 mg·kg body wt-1·day-1), cyanuric acid (CA; 200 mg·kg body wt-1·day-1), or Mel plus CA (Mel + CA; 100 mg·kg body wt-1·day-1, each) for 2 wk. Mel + CA caused damaged tubular epithelial structure and organelles, dilated tubular lumen, and inflammatory responses. Crystals were observed in urine and serum specimen, also in the lumen of dilated distal renal tubules. The combined ingestion of Mel and CA in rats caused a markedly impaired urinary concentration, which was associated with reduced protein expression of aquaporin (AQP)1, 2, and 3 in inner medulla and α-Na-K-ATPase and Na-K-2Cl transporters in cortex and outer medulla. Mel + CA treatment was associated with increased protein expression of CD3 and mRNA levels of CD68 and F4/80 as well as phosphorylation of NF-κB in the kidney. Mel + CA treatment increased protein and mRNA expression of NLRP3 inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1ß in the inner medulla of rats. NF-κB inhibitor Bay 11-7082 reduced IL-1ß expression induced by Mel + CA and prevented downregulation of AQP2 in inner medullary collecting duct cell suspensions. In conclusion, Mel + CA treatment caused urinary-concentrating defects and reduced expression of renal AQPs and key sodium transporters, which is likely due to the inflammatory responses and activation of NLRP3 inflammasome induced by crystals formed in the kidney.

Tamoxifen attenuates development of lithium-induced nephrogenic diabetes insipidus in rats.

Lithium is widely used in treatment of bipolar affective disorders but often causes nephrogenic diabetes insipidus (NDI), a disorder characterized by severe urinary-concentrating defects. Lithium-induced NDI is caused by lithium uptake by collecting duct principal cells and altered expression of aquaporin-2 (AQP2), which are essential for water reabsorption of tubular fluid in the collecting duct. Sex hormones have previously been shown to affect the regulation of AQP2, so we tested whether tamoxifen (TAM), a selective estrogen receptor modulator, would attenuate lithium-induced alterations on renal water homeostasis. Rats were treated for 14 days with lithium, and TAM treatment was initiated 1 wk after onset of lithium administration. Lithium treatment resulted in severe polyuria and reduced AQP2 expression, which were ameliorated by TAM. Consistent with this, TAM attenuated downregulation of AQP2 and increased phosphorylation of the cAMP-responsive element-binding protein, which induced AQP2 expression in freshly isolated inner-medullary collecting duct suspension prepared from lithium-treated rats. In conclusion, TAM attenuated polyuria dose dependently and impaired urine concentration and downregulation of AQP2 protein expression in rats with lithium-induced NDI. These findings suggest that TAM is likely to be a novel therapeutic option for lithium-induced NDI.

Post-cytokine-release Salt Wasting as Inverse Tumor Lysis Syndrome in a Non-cerebral Natural Killer-cell Neoplasm.

The pathogenesis of cerebral/renal salt-wasting syndrome remains unknown. We herein present a case of salt-wasting syndrome with a natural killer-cell neoplasm without cerebral invasion. A 78-year-old man with hemophagocytic syndrome received two cycles of chemotherapy that did not induce tumor lysis syndrome, but repeatedly caused polyuria and natriuresis. The expression of tumor necrosis factor-α in the neoplasm led us to hypothesize that an oncolysis-induced cytokine storm may have caused renal tubular damage and salt wasting. Our theory may explain the pathogenic mechanism of cerebral/renal salt-wasting syndrome associated with other entities, including cerebral disorders, owing to the elevation of cytokine levels after subarachnoid hemorrhage.

Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus.

The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food-1·day-1 for 4 days and 20 mmol·kg dry food-1·day-1 for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt-1·day-1 in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.

Polyuria due to vasopressin V2 receptor antagonism is not associated with increased ureter diameter in ADPKD patients.

BACKGROUND: Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients. METHODS: 70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5). RESULTS: In these patients [65.7 % male, age 41 ± 9 years, mGFR 74 ± 27 mL/min/1.73 m2 and TKV 1.92 (1.27-2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p < 0.001), but no differences were found in ureter diameter between both groups (renal pelvis: 4.2 vs. 4.4 mm, p = 0.4 and L5: 3.1 vs. 3.3 mm, p = 0.4). CONCLUSIONS: Tolvaptan-induced polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view.

Life threatening biphasic adverse reactions to desmopressin: case report and review of the literature.

Treatment with desmopressin diacetate arginine vasopressin (DDAVP) and its withdrawal are associated with side effects. We present a rare case of severe biphasic adverse reactions induced by DDAVP and its withdrawal in a 63-year-old female patient. A lump in the left axillary region was biopsied, and she received DDAVP after surgery. The following day, she lost consciousness, with foaming at the mouth and seizures. Hypotonic encephalopathy was considered. DDAVP was ceased, and she received electrolytes. On day 1, she displayed low blood pressure and increased urine output. She received DDAVP and dopamine as well as electrolytes. The patient was ambulatory on day 7 and was discharged without brain abnormalities on MRI. In conclusion, severe hyponatremia induced by DDAVP and massive polyuria and hypovolemic shock induced by DDAVP withdrawal are life-threatening conditions. This case underlines the need to be vigilant when administering DDAVP and to monitor for any side effects.

Osmotic diuresis with SGLT2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials.

OBJECTIVE: Dapagliflozin reduces hyperglycemia in type 2 diabetes mellitus (T2DM) and lowers blood pressure, at least in part, secondary to mild diuresis consequent to dapagliflozin-induced glucosuria. While blood-pressure lowering may contribute to cardiovascular risk reduction, dapagliflozin-induced diuresis may potentially contribute to adverse events (AEs) of volume reduction. The present analysis compared the frequency of AEs of volume reduction between dapagliflozin and placebo. METHODS: Pooled data were assessed from 13 placebo-controlled dapagliflozin clinical trials ≤24 weeks in patients with T2DM, overall, and in those at risk (aged ≥65y, estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2), or on antihypertensive therapy). Longer-term (≤104 weeks) data were available for 9 of these trials. RESULTS: The frequency of patients experiencing ≥1 AE of volume reduction over 24 weeks was low overall; 27/2360 (1.1%) with dapagliflozin 10 mg and 17/2295 (0.7%) with placebo; and slightly more frequent in patients ≥65 years (11/665 [1.7%] and 6/711 [0.8%], respectively) and in patients receiving loop diuretics (6/236 [2.5%] and 4/267 [1.5%], respectively). Over 104 weeks, AEs of volume reduction occurred in 38/2026 (1.9%) with dapagliflozin 10 mg and in 27/1956 (1.4%) with placebo; serious AEs of volume reduction in 4/2026 (0.2%) and 6/1956 (0.3%), respectively; and 2 patients in each group discontinued therapy due to these AEs. Dapagliflozin versus placebo incidence rate ratios did not suggest any meaningful increase in frequency of these AEs with dapagliflozin 10 mg, either overall or in those at risk. Although mean eGFR declined by 4.2 ml/min/1.73 m(2) within the first week of dapagliflozin therapy, thereafter eGFR gradually recovered to baseline levels by 104 weeks (mean change from baseline +0.02 mL/min/1.73 m(2); 95%CI: -0.9, 1.0). CONCLUSION: No meaningful increase in frequency of AEs of volume reduction occurred with dapagliflozin 10 mg in patients with T2DM, either overall, or in those at increased risk of these events. However, caution should nevertheless be exercised when prescribing dapagliflozin to elderly patients, those with reduced eGFR, and those receiving antihypertensive medication.

An updated review of the optimal lithium dosage regimen for renal protection.

OBJECTIVE: Despite several decades of research, there is still uncertainty regarding the optimal lithium dosage regimen associated with a decreased risk of renal effects, such as polyuria, in patients with bipolar affective disorder. We present an updated review of the literature to provide an informed dosing regimen recommendation for prescribers. METHOD: Major databases MEDLINE and Embase were searched using terms, such as lithium, drug administration schedule, dose-response relationship, once daily, twice daily, and sustained release. In addition, the bibliographies of related publications were manually searched. RESULTS: A total of 20 trials were included. Some trials showed a reduction in urine volume with single daily dosing (SDD), while others showed no change. The only trial evaluating patients newly started on lithium found a reduction in urinary frequency with SDD after 21 days. Trials examining renal biopsy results found that multiple daily doses were associated with more pathologic damage to the kidneys. SDD regimens were generally well tolerated, and no reduction in efficacy was noted in any of the trials. CONCLUSIONS: The available evidence is contradictory as to whether SDD of lithium reduces polyuria; however, no trial has demonstrated any downfall of SDD in terms of prophylactic efficacy or adverse effects. Given the added benefits of SDD, such as improved compliance, we recommend patients newly started on lithium should be converted to a SDD of lithium at bedtime once an appropriate daily dose is determined.

Objectif : Malgré plusieurs décennies de recherche, il y a encore de l'incertitude concernant la posologie optimale du lithium associée au risque réduit d'effets rénaux, comme la polyurie, chez les patients souffrant du trouble bipolaire affectif. Nous présentons une revue mise à jour de la littérature afin d'offrir aux prescripteurs une recommandation éclairée de régime posologique. Méthode : Cette recherche a été menée à partir des grandes bases de données MEDLINE et Embase à l'aide de termes comme : lithium, horaire d'administration des médicaments, relation dose­réponse, une fois par jour, deux fois par jour, et libération prolongée. En outre, les bibliographies de publications connexes ont fait l'objet d'une recherche manuelle. Résultats : Un total de 20 essais ont été inclus. Certains essais montraient une réduction du volume d'urine avec une dose unique quotidienne (DUQ), alors que d'autres n'indiquaient aucun changement. Le seul essai qui évaluait les patients qui commençaient le lithium a observé une réduction de la fréquence urinaire avec la DUQ après 21 jours. Les essais examinant les résultats de biopsie rénale ont constaté que les doses multiples quotidiennes étaient associées à plus de dommages pathologiques aux reins. Les posologies de DUQ étaient généralement bien tolérées, et aucune réduction d'efficacité n'a été notée dans tous les essais. Conclusions : Les données probantes disponibles sont contradictoires sur le fait que la DUQ de lithium réduise la polyurie; cependant, aucun essai n'a démontré un désavantage de la DUQ en ce qui concerne l'efficacité prophylactique ou les effets indésirables. Étant donné les avantages ajoutés de la DUQ, comme une meilleure observance, nous recommandons aux patients qui commencent le lithium de se convertir à une DUQ de lithium au coucher, une fois que la dose quotidienne appropriée est déterminée.

Central diabetes insipidus: a previously unreported side effect of temozolomide.

CONTEXT: Temozolomide (TMZ) is an alkylating agent primarily used to treat tumors of the central nervous system. We describe 2 patients with apparent TMZ-induced central diabetes insipidus. Using our institution's Research Patient Database Registry, we identified 3 additional potential cases of TMZ-induced diabetes insipidus among a group of 1545 patients treated with TMZ. CASE PRESENTATIONS: A 53-year-old male with an oligoastrocytoma and a 38-year-old male with an oligodendroglioma each developed symptoms of polydipsia and polyuria approximately 2 months after the initiation of TMZ. Laboratory analyses demonstrated hypernatremia and urinary concentrating defects, consistent with the presence of diabetes insipidus, and the patients were successfully treated with desmopressin acetate. Desmopressin acetate was withdrawn after the discontinuation of TMZ, and diabetes insipidus did not recur. Magnetic resonance imaging of the pituitary and hypothalamus was unremarkable apart from the absence of a posterior pituitary bright spot in both of the cases. Anterior pituitary function tests were normal in both cases. Using the Research Patient Database Registry database, we identified the 2 index cases and 3 additional potential cases of diabetes insipidus for an estimated prevalence of 0.3% (5 cases of diabetes insipidus per 1545 patients prescribed TMZ). CONCLUSIONS: Central diabetes insipidus is a rare but reversible side effect of treatment with TMZ.

Angiotensin type 1a receptors in the subfornical organ are required for deoxycorticosterone acetate-salt hypertension.

Although elevated renin-angiotensin system activity and angiotensinergic signaling within the brain are required for hypertension, polydipsia, and increased metabolic rate induced by deoxycorticosterone acetate (DOCA)-salt, the contribution of specific receptor subtypes and brain nuclei mediating these responses remains poorly defined. We hypothesized that angiotensin type 1a receptors (AT(1a)R) within the subfornical organ (SFO) mediate these responses. Transgenic mice carrying a conditional allele of the endogenous AT(1a)R (AT(1a)R(flox)) were administered an adenovirus encoding Cre-recombinase and enhanced green fluorescent protein (eGFP) or adenovirus encoding eGFP alone into the lateral cerebral ventricle. Adenovirus encoding Cre-recombinase reduced AT(1a)R mRNA and induced recombination in AT(1a)R(flox) genomic DNA specifically in the SFO, without significant effect in the paraventricular or arcuate nuclei, and also induced SFO-specific recombination in ROSA(TdTomato) reporter mice. The effect of SFO-targeted ablation of endogenous AT(1a)R was evaluated in AT(1a)R(flox) mice at 3 time points: (1) baseline, (2) 1 week after virus injection but before DOCA-salt, and (3) after 3 weeks of DOCA-salt. DOCA-salt-treated mice with deletion of AT(1a)R in SFO exhibited a blunted increase in arterial pressure. Increased sympathetic cardiac modulation and urine copeptin, a marker of vasopressin release, were both significantly reduced in DOCA-salt mice when AT(1a)R was deleted in the SFO. Additionally, deletion of AT(1a)R in the SFO significantly attenuated the polydipsia, polyuria, and sodium intake in response to DOCA-salt. Together, these data highlight the contribution of AT(1a)R in the SFO to arterial pressure regulation potentially through changes on sympathetic cardiac modulation, vasopressin release, and hydromineral balance in the DOCA-salt model of hypertension.

Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla.

Chloroquine, a widely used anti-malaria drug, has gained popularity for the treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV). Unfortunately, chloroquine may also negatively impact renal function for patients whose fluid and electrolyte homeostasis is already compromised by diseases. Chronic administration of chloroquine also results in polyuria, which may be explained by suppression of the antidiuretic response of vasopressin. Several of the transporters responsible for concentrating urine are vasopressin-sensitive including the urea transporters UT-A1 and UT-A3, the water channel aquaporin-2 (AQP2), and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). To examine the effect of chloroquine on these transporters, Sprague-Dawley rats received daily subcutaneous injections of 80 mg·kg(-1)·day(-1) of chloroquine for 4 days. Twenty-four hour urine output was twofold higher, and urine osmolality was decreased by twofold in chloroquine-treated rats compared with controls. Urine analysis of treated rats detected the presence chloroquine as well as decreased urine urea and cAMP levels compared with control rats. Western blot analysis showed a downregulation of AQP2 and NKCC2 transporters; however, UT-A1 and UT-A3 abundances were unaffected by chloroquine treatment. Immunohistochemistry showed a marked reduction of UT-A1 and AQP2 in the apical membrane in inner medullary collecting ducts of chloroquine-treated rats. In conclusion, chloroquine-induced polyuria likely occurs as a result of lowered cAMP production. These findings suggest that chronic chloroquine treatment would exacerbate the already compromised fluid homeostasis observed in diseases like chronic kidney disease.

Tumor necrosis factor-alpha induces renal cyclooxygenase-2 expression in response to hypercalcemia.

The effect of tumor necrosis factor-alpha (TNF) on cyclooxygenase-2 (COX-2) expression in the renal outer medulla (OM) was determined in a model of dihydrotachysterol (DHT)-induced hypercalcemia. Increases in serum calcium and water intake were observed during ingestion of a DHT-containing diet in both wild type (WT) and TNF deficient mice (TNF(-/-)). Polyuria and a decrease in body weight were observed in response to DHT treatment in WT and TNF(-/-) mice. A transient elevation in urinary TNF was observed in WT mice treated with DHT. Moreover, increased urinary levels of prostaglandin E(2) (PGE(2)) and a corresponding increase in COX-2 expression in the OM were observed in WT mice fed DHT. Increased COX-2 expression was not observed in TNF(-/-) mice fed DHT, and the characteristics of PGE(2) synthesis were distinct from those in WT mice. This study demonstrates that COX-2 expression in the OM, secondary to hypercalemia, is TNF-dependent.

Genetic deletion of the P2Y2 receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2 signaling.

Lithium (Li)-induced polyuria is due to resistance of the medullary collecting duct (mCD) to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE(2). We previously reported that the P2Y(2) receptor (P2Y(2)-R) antagonizes the action of AVP on the mCD and may play a role in Li-induced polyuria by enhancing the production of PGE(2) in mCD. Hence, we hypothesized that genetic deletion of P2Y(2)-R should ameliorate Li-induced polyuria. Wild-type (WT) or P2Y(2)-R knockout (KO) mice were fed normal or Li-added diets for 14 days and euthanized. Li-induced polyuria, and decreases in urine osmolality and AQP2 protein abundance in the renal medulla, were significantly less compared with WT mice despite the lack of differences in Li intake or terminal serum or inner medullary tissue Li levels. Li-induced increased urinary excretion of PGE(2) was not affected in KO mice. However, prostanoid EP(3) receptor (EP3-R) protein abundance in the renal medulla of KO mice was markedly lower vs. WT mice, irrespective of the dietary regimen. The protein abundances of other EP-Rs were not altered across the groups irrespective of the dietary regimen. Ex vivo stimulation of mCD with PGE(2) generated significantly more cAMP in Li-fed KO mice (130%) vs. Li-fed WT mice (100%). Taken together, these data suggest 1) genetic deletion of P2Y(2)-R offers significant resistance to the development of Li-induced polyuria; and 2) this resistance is apparently due to altered PGE(2) signaling mediated by a marked decrease in EP3-R protein abundance in the medulla, thus attenuating the EP3-mediated decrease in cAMP levels in mCD.