Syndrome of inappropriate antidiuresis (SIAD) is one of the most frequent causes of euvolemic hyponatremia (serum sodium levels < 135 mEq/L) and it represents more than 35% of hyponatremia cases in hospitalized patients. It is characterized by an inappropriate vasopressin (AVP)/antidiuretic hormone (ADH) secretion, which occurs independently from effective serum osmolality or circulating volume, leading to water retention via its action on type 2 vasopressin receptor in the distal renal tubules. Corpus callosum agenesis (CCA) is one of the most common congenital brain defects, which can be associated to alterations in serum sodium levels. This report presents a rare case of chronic hyponatremia associated with SIAD in a woman with CCA, whose correction of serum sodium levels only occurred following twice-daily tolvaptan administration.
A 30-year-old female was admitted to our hospital for non-acute hyponatremia with dizziness, headache, distal tremors, and concentration deficits. She had profound hyponatremia (Na 121 mmol/L) with measured plasma hypo-osmolality (259 mOsm/Kg) and urinary osmolality greater than 100 mOsm/Kg (517 mOsm/Kg). She presented clinically as normovolemic. After the exclusion of other causes of normovolemic hyponatremia, such as hypothyroidism and adrenal insufficiency, a diagnosis of SIAD was established. We have ruled out paraneoplastic, inflammatory, and infectious causes, as well as ischemic events. Her medical history showed a CCA and frontal teratoma. We administered tolvaptan initially at a low dosage (15 mg once a day) with persistence of hyponatremia. Therefore, the dosage was first doubled (30 mg once a day) and then increased to 45 mg once a day with an initial improvement in serum sodium levels, although not long-lasting. We therefore tried dividing the 45 mg tolvaptan administration into two doses of 30 mg and 15 mg respectively, using an off-label treatment schedule, thus achieving long-lasting serum sodium levels in the low-normal range associated with a general clinical improvement.
This report underlines the importance of the correct diagnosis, management and treatment of SIAD, as well as the need for further studies about the pharmacokinetics and pharmacodynamics of vasopressin receptor antagonists.

Although diuretics play an important role in triple-whammy acute kidney injury (AKI), it is unclear whether the type of diuretic influences the risk of triple-whammy AKI. The aim of this study was to evaluate whether vasopressin receptor antagonists affect triple-whammy AKI. This cross-sectional study used disproportionality analysis of VigiBase data to assess the risk of AKI with various diuretics. Although multiple logistic regression analysis showed that aldosterone antagonists (odds ratio [OR] 2.19, 95% CI 2.01-2.37), loop diuretics (OR 4.40, 95% CI 4.07-4.76) and thiazide diuretics (OR 1.98, 95% CI 1.83-2.15) increased the risk of AKI in patients who received non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system inhibitors (RASi), vasopressin receptor antagonists did not increase the risk of AKI in those patients. Vasopressin receptor antagonists might not influence the development of triple-whammy AKI.

Volume management in acute decompensated and chronic heart failure (HF) remains a significant challenge. Although progress has been made in the development of mortality-reducing neurohormonal regimens in the reduced ejection fraction population, no clinical trial has yet demonstrated anything more than symptomatic relief or biomarker reduction with pharmacotherapeutic volume-based interventions made in the acutely decompensated individual or those with evolving outpatient congestion. As the number of patients with HF continues to grow, in addition to HF-related hospitalizations, identifying therapies that have the potential to aid in diuresis more safely and efficaciously is paramount to decreasing inpatient length of stay and preventing unnecessary admissions. More recently, a significant amount of research has been dedicated to the use of vasopressin antagonists, specifically tolvaptan, as adjunctive therapy to loop and thiazide diuretics. Although these agents do not seem to have a pervasive role in fluid management in the acute decompensated and chronic HF populations, they are effective tools to have available for specific clinical situations. This review summarizes the literature surrounding the use of tolvaptan for volume management in congestive HF, as well as offering practical guidance for use of this agent.

Heart and kidney failure continued to be of increasing prevalence in today\'s society, and their comorbidity has synergistic effect on the morbidity and mortality of patients. Cardiorenal syndrome (CRS) is a complex disease with multifactorial pathophysiology. Better understanding of this pathophysiological network is crucial for the successful intervention to prevent advancement of the disease process. One of the major factors in this process is neurohormonal activation, predominantly involving renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP). Heart failure causes reduced cardiac output/cardiac index (CO/CI) and fall in renal perfusion pressures resulting in activation of baroreceptors and RAAS, respectively. Activated baroreceptors and RAAS stimulate the release of AVP (non-osmotic pathway), which acts on V2 receptors located in the renal collecting ducts, causing fluid retention and deterioration of heart failure. Effective blockade of AVP action on V2 receptors has emerged as a potential treatment option in volume overload conditions especially in the setting of hyponatremia. Vasopressin receptor antagonists (VRAs), such as vaptans, are potent aquaretics causing electrolyte-free water diuresis without significant electrolyte abnormalities. Vaptans are useful in hypervolemic hyponatremic conditions like heart failure and liver cirrhosis, and euvolemic hyponatremic conditions like syndrome of inappropriate anti-diuretic hormone secretion. Tolvaptan and conivaptan are pharmaceutical agents that are available for the treatment of these conditions.

In the congestive heart failure (CHF) setting, chronic hyponatremia is very common. The present review aims at addressing topics relevant to the pathophysiology of hyponatremia in the course of CHF as well as its optimal treatment, including the main advantages and the limitations resulting from the use of the available dietary and pharmacological measures approved for the treatment of this electrolytic trouble. A narrative review is carried out in order to represent the main modalities of therapy for chronic hyponatremia that frequently complicates CHF. The limits of usual therapies implemented for CHF-related chronic hyponatremia are outlined, while an original analysis of the main advancements achieved with the use of vasopressin receptor antagonists (VRAs) is also executed. The European regulatory restrictions that currently limit the use of VRAs in the management of CHF are substantially caused by financial concerns, i.e., the high costs of VRA therapy. A thoughtful reworking of current restrictions would be warranted in order to enable VRAs to be usefully associated to loop diuretics for decongestive treatment of CHF patients with hyponatremia.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end-stage renal disease (ESRD) worldwide. Its prevalence is evaluated according to studies and population between 1/1000 and 1/4000 live births and it accounts for 6 to 8% of incident ESRD patients in developed countries. ADPKD is characterized by numerous cysts in both kidneys and various extrarenal manifestations that are detailed in this review. Clinico-radiological and genetic diagnosis are also discussed. Mutations in the PKD1 and PKD2 codifying for polycystin-1 (PC-1) and polycystin-2 (PC-2) are responsible for the 85 and 15% of ADPKD cases, respectively. In primary cilia of normal kidney epithelial cells, PC-1 and PC-2 interact forming a complex involved in flow- and cilia-dependant signalling pathways where intracellular calcium and cAMP play a central role. Alteration of these multiple signal transduction pathways leads to cystogenesis accompanied by dysregulated planar cell polarity, excessive cell proliferation and fluid secretion, and pathogenic interactions of epithelial cells with an abnormal extracellular matrix. The mass effect of expanding cyst is responsible for the decline in glomerular filtration rate that occurs late in the course of the disease. For many decades, the treatment for ADPKD aims to lessen the condition\'s symptoms, limit kidney damage, and prevent complications. Recently, the development of promising specific treatment raises the hope to slow the growth of cysts and delay the disease. Treatment strategies targeting cAMP signalling such as vasopressin receptor antagonists or somatostatin analogs have been tested successfully in clinical trials with relative safety. Newer treatments supported by preclinical trials will become available in the next future. Recognizing early markers of renal progression (clinical, imaging, and genetic markers) to identify high-risk patients and multidrug approaches with synergistic effects may provide new opportunities for the treatment of ADPKD.

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. The development of ascites in patients with cirrhosis is multi-factorial. Portal hypertension and the associated systemic vasodilation lead to activation of the sodium-retaining neurohumoral mechanisms which include the renin-angiotensin-aldosterone system, sympathetic nervous system and antidiuretic hormone (ADH). The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume resulting in the development of ascites. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and ascites leads to impairment of the kidneys to eliminate solute- free water. This leads to additional compensatory mechanisms including non-osmotic secretion of ADH, also known as arginine vasopressin, further worsening excess water retention and thereby hyponatremia. Hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic marker both before and after liver transplant. The management of hyponatremia in this setting is a challenge as conventional therapy for hyponatremia including fluid restriction and loop diuretics are frequently inefficacious. In this review, we discuss the pathophysiology and various treatment modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with cirrhosis.

OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disorder that leads to kidney failure. Our aim was to undertake a meta-analysis of randomized trials of interventions that have been hypothesized to reduce the progression of total kidney volume (TKV) and renal function in ADPKD.
METHODS: Relevant trials were identified, and outcomes were: change in TKV, total cyst volume (TCV), renal function and adverse events. Meta-analysis used random effects, with results expressed as mean difference and risk ratio both with 95% confidence intervals (CI).
RESULTS: Eleven trials (2262 patients) were included. Compared with placebo, Target of Rapamycin complex 1 (TORC1) inhibitors (5 trials, n = 619), showed no significant change in TKV (P = 0.21), TCV (P = 0.06) or eGFR (P = 0.22). Somatostatin analogues (3 trials, n = 157) reduced TKV by 9% (95% CI -10.33 to -7.58%) but did not alter eGFR. The vasopressin receptor antagonist (n = 1455) attenuated TKV increase to 3%/year (95% CI -3.48 to -2.52) and slowed kidney function decline over a 3-year period. A single trial (n = 41) of eicosapentaenoic acid did not alter the progression of either TKV (P = 0.9) or renal dysfunction (P = 0.78). Adverse events were significant for interventions in all trials compared with placebo.
CONCLUSIONS: These data suggest that somatostatin analogues and vasopressin receptor antagonists attenuate TKV increase. The neutral effects of TORC1 inhibitors on TKV could be true, or due to heterogeneity in study population, drug efficacy and follow-up duration. In the future, further well-designed and powered trials of longer duration using new biomarkers or therapeutic agents with better tolerance are required.

Arginine vasopressin (AVP) plays an important role in water and sodium homeostasis. It acts via three receptor subtypes-V1a, V1b, and V2-distributed widely throughout the body. Vaptans are nonpeptide vasopressin receptor antagonists (VRA). By property of aquaresis, VRAs offer a novel therapy of water retention. Conivaptan is a V1a/V2 nonselective VRA approved for euvolemic and hypervolemic hyponatremia. Tolvaptan is the first oral VRA. Other potential uses of this new class of drugs include congestive heart failure (CHF), cirrhosis of liver, syndrome of inappropriate secretion of antidiuretic hormone, polycystic kidney disease, and so on. These novel drugs score over diuretics as they are not associated with electrolyte abnormalities. Though much remains to be elucidated before the VRAs are applied clinically, the future holds much promise.