Nonosmotic Release Of Vasopressin Research Articles

Chapter 18 - The vasopressin–aquaporin-2 pathway syndromes

Vasopressin is the key hormone involved in water conservation and regulation of water balance, essential for life. In the renal collecting duct, vasopressin binds to the V2 receptor, increasing water permeability through activation of aquaporin-2 redistribution to the luminal membrane. This mechanism promotes rapid water reabsorption, important for immediate survival; however, only recently it has become clear that long-term adverse effects are associated with alterations of the vasopressin-aquaporin-2 pathway, leading to several syndromes associated with water balance disorders. The kidney resistance to the vasopressin action may cause severe dehydration for patients and, conversely, nonosmotic release of vasopressin is associated with water retention and increasing the circulatory blood volume. This chapter discusses the relevance of the altered vasopressin-aquaporin-2 pathway in some diseases associated with water balance disorders, including congenital nephrogenic diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The emerging picture suggests that targeting the vasopressin-AQP2 axis can provide therapeutic benefits in those patients.

Prevalence and Impact of Hyponatremia in Patients With Coronavirus Disease 2019 in New York City.

Hyponatremia occurs in up to 30% of patients with pneumonia and is associated with increased morbidity and mortality. The prevalence of hyponatremia associated with coronavirus disease 2019 and the impact on outcome is unknown. We aimed to identify the prevalence, predictors, and impact on outcome of mild, moderate, and severe admission hyponatremia compared with normonatremia among coronavirus disease 2019 patients. Retrospective, multicenter, observational cohort study. Four New York City hospitals that are part of the same health network. Hospitalized, laboratory-confirmed adult coronavirus disease 2019 patients admitted between March 1, 2020, and May 13, 2020. None. Hyponatremia was categorized as mild (sodium: 130-134 mmol/L), moderate (sodium: 121-129 mmol/L), or severe (sodium: ≤ 120 mmol/L) versus normonatremia (135-145 mmol/L). The primary outcome was the association of increasing severity of hyponatremia and in-hospital mortality assessed using multivariable logistic regression analysis. Secondary outcomes included encephalopathy, acute renal failure, mechanical ventilation, and discharge home compared across sodium levels using Kruskal-Wallis and chi-square tests. In exploratory analysis, the association of sodium levels and interleukin-6 levels (which has been linked to nonosmotic release of vasopressin) was assessed. Among 4,645 patient encounters, hyponatremia (sodium < 135 mmol/L) occurred in 1,373 (30%) and 374 of 1,373 (27%) required invasive mechanical ventilation. Mild, moderate, and severe hyponatremia occurred in 1,032 (22%), 305 (7%), and 36 (1%) patients, respectively. Each level of worsening hyponatremia conferred 43% increased odds of in-hospital death after adjusting for age, gender, race, body mass index, past medical history, admission laboratory abnormalities, admission Sequential Organ Failure Assessment score, renal failure, encephalopathy, and mechanical ventilation (adjusted odds ratio, 1.43; 95% CI, 1.08-1.88; p = 0.012). Increasing severity of hyponatremia was associated with encephalopathy, mechanical ventilation, and decreased probability of discharge home (all p < 0.001). Higher interleukin-6 levels correlated with lower sodium levels (p = 0.017). Hyponatremia occurred in nearly a third of coronavirus disease 2019 patients, was an independent predictor of in-hospital mortality, and was associated with increased risk of encephalopathy and mechanical ventilation.

Hyponatremia in a Patient With Cancer

Hyponatremia in a Patient With Cancer

Vasopressin-aquaporin-2 pathway: recent advances in understanding water balance disorders.

The alteration of water balance and related disorders has emerged as being strictly linked to the state of activation of the vasopressin–aquaporin-2 (vasopressin–AQP2) pathway. The lack of responsiveness of the kidney to the vasopressin action impairs its ability to concentrate the urine, resulting in polyuria, polydipsia, and risk of severe dehydration for patients. Conversely, non-osmotic release of vasopressin is associated with an increase in water permeability in the renal collecting duct, producing water retention and increasing the circulatory blood volume. This review highlights some of the new insights and recent advances in therapeutic intervention targeting the dysfunctions in the vasopressin–AQP2 pathway causing diseases characterized by water balance disorders such as congenital nephrogenic diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The recent clinical data suggest that targeting the vasopressin–AQP2 axis can provide therapeutic benefits in patients with water balance disorders.

Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites?

Hyponatremia is a frequent complication of advanced cirrhosis with ascites associated with increased morbidity and mortality. It is caused by an impairment in the renal capacity to eliminate solute-free water and is considered to be related to persistent secretion of vasopressin despite low serum osmolality. This nonosmotic release of vasopressin is mediated by the autonomic nervous system, which senses the underfilling of arterial vascular component. This reduction of effective arterial blood volume is closely related to the development of ascites. Although the short-time effects of vasopressin V2 receptor antagonists (vaptans) on hyponatremia and ascites have been repeatedly reported, their effects on the long-term management of cirrhotic ascites have not been established yet. Considering that their effects on water diuresis and their safety are limited by severe underfilling state of patients, cautious approaches with adequate monitoring are needed to advanced cirrhosis. Proper indication, adequate doses and new possibility of combination therapy should be explored in the future controlled study. As hyponatremia is frequent obstacle to ascites management, judicious combination with low-dose diuretics may decrease the incidence of refractory ascites. Although vaptans show much promise in the treatment of advanced cirrhosis, the problem of high cost should be solved for the future.

Renal insufficiency in patients with hepatic insufficiency

Renal dysfunction is a common complication of cirrhosis, occurring in approximately 20 % of all hospitalized patients with cirrhosis and associated with increased mortality. In about two thirds of the patients, renal dysfunction is caused by prerenal disorders (e.g. gastrointestinal bleeding, diuretics, bacterial infection); one third is caused by intrarenal diseases (e.g. hepatitis associated glomerulonephritis). In most patients, prerenal failure can be successfully handled by volume therapy. In one third, volume replacement is not effective any more to improve kidney function. This kind of prerenal failure is called hepatorenal syndrome (HRS). The pathophysiology is based on an increased splanchic vasodilation, which cannot be compensated any more by an increased cardiac output. Therefore, patients with cardiac insufficiency are more at risk of developing HRS. The decompensation leads to a stimulation of the baroreceptors with consecutive activation of the sympathetic nerve system, the renin-angiotensin-aldosteron system (RAAS), and nonosmotic release of vasopressin. This results in renal vasoconstriction, which is strengthened by the activation of hepatorenal reflex secondary to an increase in intrahepatic pressure and/or decrease in sinusoidal blood flow. Several studies have shown that the vasopressin analogue terlipressin combined with albumin can reverse HRS in up to 50 % of patients. Long-term survival can only be achieved by liver transplantation. Improving kidney function before transplantation improves outcome after transplantation.

Physiopathology of hereditary polyuric states: a molecular view of renal function

Recent discoveries have shed new light on the understanding of water metabolism: (1.) in addition to hypothalamic osmoreceptor cells expressing a TRPV1 variant, there are peripheral TRPV4 receptors sensing tonicity in the portal vein and changing central vasopressin secretion and peripheral autonomic activity; (2.) the central osmoregulatory gain of angiotensin action participates in the non-osmotic release of vasopressin induced by hypovolaemia; (3.) prostaglandins EP2 receptors on principal cells of the collecting ducts positively regulate urine concentration mechanisms. These new developments are important clinically for the understanding of hereditary polyuric states. We recommend sequencing of the nephrogenic diabetes insipidus genes in all affected patients. This genomic information is key to the routine care of patients with congenital polyuria and, as in other genetic diseases, reduces health costs and confers psychological benefits on patients and families.

Salt and water imbalance in chronic heart failure

In chronic heart failure (CHF), neurohumoral systems, which help to maintain circulatory homeostasis, are maladaptive and responsible for disease progression and congestion in the long term. The activation of sympathetic hormones and renin-angiotensin-aldosterone system (RAAS), in addition to non-osmotic vasopressin release, up-regulation of aquoporine 2 and renal sodium transporters, and renal resistance to natriuretic peptide lead to a salt- and water-avid state. A primary decrease in cardiac output and arterial vasodilatation brings about arterial underfilling, which activates neuro-humoral reflexes and systems. The heart disease is the primum movens, but the kidney is the end organ responsible for increased tubular reabsorption of sodium and water. The most important hemodynamic alteration in the kidneys is constriction of glomerular efferent arterioles, which increases intraglomerular pressure and hence glomerular filtration rate. The resulting changes in intrarenal oncotic and hydrostatic pressures promote tubular reabsorption. Over time, a gradually falling glomerular filtration rate, due to CHF progression, medications or chronic kidney injury due to comorbidities, becomes more critical in sodium/water imbalance. Moreover, long-term use of diuretics can lead to a diuretic-resistant state, which necessitates the use of higher doses further activating RAAS, often at the expense of worsening renal function. However, every patient is a case in itself and the general pathophysiology of hydro-saline balance may be different in each subject. A mechanism can prevail over others and the kidney may have different responses to the same diuretic. So, it is necessary to customize each individual's long-term therapy, tailoring medical treatment according to clinical profiles, comorbidities and renal function, introducing active control of body weight by the patient himself, fluid restriction, a less restricted sodium intake, flexibility of diuretic doses, early and personalized ambulatory follow-up, and congestion monitoring by bioelectrical impedance vector analysis, BNP, inferior vena cava ultrasonography or echocardiographic e/e(1) ratio or pulmonary capillary wedge pressure.

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Water and Sodium Regulation in Heart Failure

Heart failure is the pathophysiological state characterized by ventricular dysfunction and associated clinical symptoms. Decreased cardiac output or peripheral vascular resistance lead to arterial underfilling. That is an important signal which triggers multiple neurohormonal systems to maintain adequate arterial pressure and peripheral perfusion of the vital organs. The kidney is the principal organ affected when cardiac output declines. Alterations of hemodynamics and neurohormonal systems in heart failure result in renal sodium and water retention. Activation of sympathetic nervous system, renin-angiotensin-aldosterone system and non-osmotic vasopressin release stimulate the renal tubular reabsorption of sodium and water. Dysregulation of aquaporin-2 and sodium transporters also play an important role in the pathogenesis of renal sodium and water retention.

Fluid retention in cirrhosis: pathophysiology and management

Accumulation of fluid as ascites is the most common complication of cirrhosis. This is occurring in about 50% of patients within 10 years of the diagnosis of cirrhosis. It is a prognostic sign with 1-year and 5-year survival of 85% and 56%, respectively. The most acceptable theory for ascites formation is peripheral arterial vasodilation leading to underfilling of circulatory volume. This triggers the baroreceptor-mediated activation of renin-angiotensin-aldosterone system, sympathetic nervous system and nonosmotic release of vasopressin to restore circulatory integrity. The result is an avid sodium and water retention, identified as a preascitic state. This condition will evolve in overt fluid retention and ascites, as the liver disease progresses. Once ascites is present, most therapeutic modalities are directed on maintaining negative sodium balance, including salt restriction, bed rest and diuretics. Paracentesis and albumin infusion is applied to tense ascites. Transjugular intrahepatic portosystemic shunt is considered for refractory ascites. With worsening of liver disease, fluid retention is associated with other complications; such as spontaneous bacterial peritonitis. This is a primary infection of ascitic fluid caused by organisms originating from large intestinal normal flora. Diagnostic paracentesis and antibiotic therapy plus prophylactic regimen are mandatory. Hepatorenal syndrome is a state of functional renal failure in the setting of low cardiac output and impaired renal perfusion. Its management is based on drugs that restore normal renal blood flow through peripheral arterial and splanchnic vasoconstriction, renal vasodilation and/or plasma volume expansion. However, the definitive treatment is liver transplantation.

Nonosmotic release of vasopressin and renal aquaporins in impaired urinary dilution in hypothyroidism

The purpose of this study was to examine protein expression of renal aquaporins (AQP) and ion transporters in hypothyroid (HT) rats in response to an oral water load compared with controls (CTL) and HT rats replaced with l-thyroxine (HT+T). Hypothyroidism was induced by aminotriazole administration for 10 wk. Body weight, water intake, urine output, solute and urea excretion, and serum and urine osmolality were comparable among the three groups at the conclusion of the 10-wk treatment period. One hour after oral gavage of water (50 ml/kg body wt), HT rats demonstrated significantly less water excretion, higher minimal urinary osmolality, and decreased serum osmolality compared with CTL and HT+T rats. Despite the hyposmolality, plasma vasopressin concentration was elevated in HT rats. These findings in HT rats were associated with an increase in protein abundance of renal cortex AQP1 and inner medulla AQP2. AQP3, AQP4, and the Na-K-2Cl cotransporter were also increased. Moreover, 1 h following the oral water load, HT rats demonstrated a significant increase in the membrane-to-vesicle fraction of AQP2 by Western blot analysis. The defect in urinary dilution in HT rats was reversed by the V(2) vasopressin antagonist OPC-31260. In conclusion, impaired urinary dilution in HT rats is primarily compatible with the nonosmotic release of vasopressin and increased protein expression of renal AQP2. The impairment of maximal solute-free water excretion in HT rats, however, appears also to involve diminished distal fluid delivery.

Presentation of the 2003 Jean Hamburger Award to Robert W. Schrier

Presentation of the 2003 Jean Hamburger Award to Robert W. Schrier

Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial

Background & Aims: Dilutional hyponatremia is a frequent complication of cirrhosis partly because of nonosmotic vasopressin release. No effective therapy exists for this complication. Therefore, we investigated the effects of VPA-985, an orally active vasopressin V2 receptor antagonist, in patients with cirrhosis and dilutional hyponatremia. Primary endpoint was normalization of serum sodium (serum sodium ≥136 mmol/L). Methods: Sixty patients with cirrhosis and dilutional hyponatremia were randomly assigned to 100 or 200 mg/day of VPA-985 or placebo in a double-blind study. Treatment was given with fluid restriction (1000 mL/day) until normalization of serum sodium or for 7 days. Results: Normalization of serum sodium concentration was achieved in 27% and 50% of patients in the VPA-985 100 mg/day and 200 mg/day groups, respectively, but in none of the patients in the placebo group (P < 0.05 and P < 0.001, respectively). Treatment with VPA-985 was associated with a significant reduction in urine osmolality and body weight. Thirst sensation increased significantly in the VPA 200 mg group but not in the VPA 100 mg or placebo group. Serious adverse events were similar among the 3 groups. Conclusions: An orally active vasopressin receptor antagonist can correct hyponatremia in patients with cirrhosis and ascites. This represents a novel therapy of water retention in cirrhosis.

Pathogenesis and management of sodium and water retention in cardiac failure and cirrhosis.

The kidneys play the crucial role in the maintenance of the body fluid volume homeostasis. Several hypotheses have been introduced to explain sodium and water retention leading to edematous states in such pathologic conditions as congestive heart failure (CHF) and cirrhosis. We have suggested a unifying arterial underfilling hypothesis, explaining the development of edema in these conditions. Arterial underfilling, caused by decreased cardiac output or peripheral arterial vasodilation, leads to activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, and nonosmotic vasopressin release. This review discusses the pathophysiologic mechanisms resulting in renal sodium and water retention, impaired mineralocorticoid escape, and resistance to atrial natriuretic peptide in patients with CHF and cirrhosis. Furthermore, the basis of current therapies in these disorders is discussed, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, and diuretics in CHF and cirrhosis, as well as new approaches to treatment of water retention with vasopressin V(2) receptor antagonists.

Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease

The pathogenesis of renal sodium and water retention in cirrhosis involves extrarenal mechanisms because when kidneys from cirrhotic patients are transplanted into persons with normal livers, renal sodium and water retention no longer occurs. Cirrhosis is accompanied by portal hypertension, which leads to a hyperdynamic circulatory state. The Peripheral Arterial Vasodilation Hypothesis incriminates a relative underfilling of the arterial vascular compartment, which leads to the same neurohumoral responses that occurs in low cardiac output. Activation of the renain-angiotensin-aldosterone axis and the sympathetic system as well as non-osmotic release of vasopressin are well documented in cirrhosis. This sequence of events results in renal water and sodium retention, failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. Dilutional hyponatremia is the strongest predictor of the occurrence of hepatorenal syndrome. The pathogenesis of the peripheral arterial vasodilation is not completely elucidated, but there is evidence for a major role of nitric oxide (NO). Increased vascular NO production has been demonstrated in cirrhosis. In the rat model of cirrhosis, normalization of vascular NO production with a NOS inhibitor corrects the hyperdynamic circulation, improves sodium and water excretion, and decreases neurohumoral activation. This insight into the mechanism(s) of the peripheral arterial vasodilation in cirrhosis should provide new tools in the treatment of edema and ascites, a major cause of morbidity and mortality in cirrhosis.

Smokeless nicotinergic stimulation of vasopressin secretion in patients with persisting nocturnal enuresis and controls.

This study aimed to evaluate the effect of nicotine stimulation on pituitary release of plasma arginine vasopressin (P(AVP)) in patients with primary monosymptomatic nocturnal enuresis (PMNE) and healthy control subjects. Postpubertal teenagers and adult enuretics as well as control subjects were enrolled into the study and admitted to hospital for measurements of P(AVP) in relation to intake of orally administered nicotine. Sixteen patients with PMNE (9 females, 7 males; aged 15-51 years, mean 23.5) and nine normal subjects (4 females, 5 males; aged 24-31 years, mean 27.3) were studied. The enuretics were characterized prior to investigation as either 1-desamino-8-D-arginine vasopressin (DDAVP) responders (n = 8; 16-51 years, mean 28.9) or DDAVP non-responders (n = 8; 15-24 years, mean 18.1) based on the reduction in the number of wet nights. P(AVP), mean arterial blood pressure (MAP) and heart rate (HR) were measured 0, 5, 10, 15 and 30 min, and plasma osmolality (P(osm)) 0 and 30 min after receiving 4 mg nicotine (Nicorette, Pharmacia & Upjohn) chewing gum. In the compiled material a slight but statistically significant increase was observed in P(AVP) at 30 min compared with baseline levels, concurrent with significant rises in MAP and HR above baseline levels at 15 and 30 min. No difference was seen in P(osm) before and after nicotine administration. No other significant variation over time, assessed by an ANOVA, was detected. No difference was encountered in any measured parameter between controls and enuretics or between DDAVP responders and non-responders. Smokeless nicotine chewing gum induces non-osmotic vasopressin release in humans. The secretory AVP capacity to this stimulation is normal in PMNE.

Update on peripheral arterial vasodilation, ascites and hepatorenal syndrome in cirrhosis.

In cirrhosis of the liver, according to the peripheral arterial vasodilation hypothesis, relative underfilling of the arterial tree triggers a neurohumoral response (activation of renin-angiotensin-aldosterone system, sympathetic nervous system, nonosmotic release of vasopressin) aimed at restoring circulatory integrity by promoting renal sodium and water retention. Evidence has accumulated for a major role of increased vascular production of nitric oxide as the primary cause of arterial vasodilation in cirrhosis. Ascites is a common complication in cirrhosis. Treatment of ascites consists of a low salt diet with diuretics, and paracentesis together with plasma volume expanders in diuretic-resistant patients. Progression of cirrhosis may result in hepatorenal syndrome, a state of functional renal failure that carries an ominous prognosis. Orthotopic liver transplantation has remained the only curative treatment for patients with advanced liver disease; other modalities such as transjugular intrahepatic portosystemic shunt or vasopressin analogues may serve as a bridge to transplantation. Another complication of decompensated cirrhosis is spontaneous bacterial peritonitis, the incidence of which can be reduced by primary or secondary antibiotic prophylaxis by using orally active antibiotics.

Increased Norepinephrine Secretion in Patients with the Nephrotic Syndrome and Normal Glomerular Filtration Rates: Evidence for Primary Sympathetic Activation

Considerable controversy exists in regard to the state of arterial circulatory integrity in patients with the nephrotic syndrome. Increased sympathetic nervous system activity, along with activation of the renin-angiotensin-aldosterone system and the nonosmotic release of vasopressin, is seen in other states of arterial underfilling. Thus, in the present study, sympathetic nervous system activity was assessed by determining plasma norepinephrine secretion and clearance rates using a whole-body steady-state radionuclide tracer method in 6 edematous patients with the nephrotic syndrome of various parenchymal etiologies and 6 normal control subjects in the supine position. Patients were withdrawn from all medications 7 days prior to study. Mean creatinine clearances and serum creatinine concentrations were normal in both the nephrotic syndrome patients and controls (99 +/- 13 vs. 112 +/- 15 ml/min, p = NS, 1.1 +/- 0.1 vs. 0.8 +/- 0.0 mg/dl, p = 0.03, respectively). However, the nephrotic syndrome patients exhibited significant hypoalbuminemia (2.0 +/- 0.4 vs. 3.8 +/- 0.1 g/dl, p < 0.01). The supine plasma norepinephrine level was elevated in the patients with the nephrotic syndrome as compared with controls (240 +/- 58 vs. 119 +/- 22 pg/ml, p = 0.07). More significantly, the secretion rate of norepinephrine was markedly increased in nephrotic patients (0.30 +/- 0.07 vs. 0.13 +/- 0.02 micrograms/m2/min, p < 0.05), whereas the clearance rate of norepinephrine was similar in the two groups (2.60 +/- 0.29 vs. 2.26 +/- 0.27 l/min, p = NS). Plasma renin activity and plasma aldosterone, arginine vasopressin and atrial natriuretic peptide concentrations were not different in nephrotic syndrome patients compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Unifying hypothesis of sodium and water regulation in health and disease.

Sodium and water retention is characteristic of edematous disorders including cardiac failure, cirrhosis, nephrotic syndrome, and pregnancy. Nonosmotic vasopressin release has been implicated in the water retention of these edematous disorders. The nonosmotic release of vasopressin is consistently associated with activation of the sympathetic nervous and renin-angiotensin-aldosterone systems in both experimental animals and in edematous patients. Moreover, the sympathetic nervous system has been shown to be involved in the nonosmotic release of vasopressin and activation of the renin-angiotensin system. These findings have led to our proposal that body fluid volume regulation involves the dynamic interaction between cardiac output and peripheral arterial resistance. Neither total extracellular fluid volume nor blood volume is a determinant of renal sodium and water excretion. Rather, renal sodium and water retention is initiated by a decrease in effective arterial blood volume (EABV) due to either a fall in cardiac output or peripheral arterial vasodilation. The acute response to a decrease in EABV involves vasoconstriction mediated by angiotensin, sympathetic mediators, and vasopressin. The slower response to restoring EABV involves vasopressin-mediated water retention and aldosterone-mediated sodium retention. The resultant renal vasoconstriction limits the distal tubular delivery of sodium and water, thus maximizing the water-retaining effect of vasopressin and impairing the normal escape from the sodium-retaining effects of aldosterone. The elevated glomerular filtration rate and filtered sodium load in pregnancy allows increased distal sodium and water delivery in spite of a decrease in EABV, thus limiting edema formation during gestation.