Antidiuretic Hormone and Serum Osmolarity Physiology and ...

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Antidiuretic Hormone and Serum OsmolarityPhysiology and Related Outcomes: What Is Old,What Is New, and What Is Unknown?

Mehmet Kanbay,1 Sezen Yilmaz,2 Neris Dincer,2 Alberto Ortiz,3 Alan A. Sag,4

Adrian Covic,5 Laura G. Sanchez-Lozada,6 Miguel A. Lanaspa,7 David Z. I. Cherney,8

Richard J. Johnson,7 and Baris Afsar9

1Division of Nephrology, Department of Medicine, Koc University School of Medicine, 34450 Istanbul,Turkey; 2Department of Medicine, Koc University School of Medicine, 34450 Istanbul, Turkey; 3Dialysis Unit,School of Medicine, IIS–Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, 28040 Madrid, Spain;4Division of Vascular and Interventional Radiology, Department of Radiology, Duke University MedicalCenter, Durham, North Carolina 27710; 5Nephrology Department, Dialysis and Renal Transplant Center,“Dr. C. I. Parhon” University Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi,Romania; 6Laboratory of Renal Physiopathology, Department of Nephrology, INC Ignacio Chavez, 14080Mexico City, Mexico; 7Division of Renal Diseases and Hypertension, School of Medicine, University ofColorado Denver, Aurora, Colorado 80045; 8Department of Medicine, Division of Nephrology, TorontoGeneral Hospital, University of Toronto, Toronto, Ontario M5G 2C4, Canada; and 9Division of Nephrology,Department of Medicine, Suleyman Demirel University School of Medicine, 32260 Isparta, Turkey

ORCiD numbers: 0000-0002-1297-0675 (M. Kanbay).

Context: Although the physiology of sodium, water, and arginine vasopressin (AVP), also known asantidiuretic hormone, has long been known, accumulating data suggest that this system operatesas a more complex network than previously thought.

Evidence Acquisition: English-language basic science and clinical studies of AVP and osmolarity onthe development of kidney and cardiovascular disease and overall outcomes.

Evidence Synthesis: Apart from osmoreceptors and hypovolemia, AVP secretion is modified bynovel factors such as tongue acid-sensing taste receptor cells and brain median preoptic nucleusneurons. Moreover, pharyngeal, esophageal, and/or gastric sensors and gut microbiota modulateAVP secretion. Evidence is accumulating that increased osmolarity, AVP, copeptin, and dehydrationare all associated with worse outcomes in chronic disease states such as chronic kidney disease(CKD), diabetes, and heart failure. On the basis of these pathophysiological relationships, an AVPreceptor 2 blocker is now licensed for CKD related to polycystic kidney disease.

Conclusion: From a therapeutic perspective, fluid intake may be associated with increased AVPsecretion if it is driven by loss of urine concentration capacity orwith suppressed AVP if it is driven byvoluntary fluid intake. In the current review, we summarize the literature on the relationshipbetween elevated osmolarity, AVP, copeptin, and dehydration with renal and cardiovascularoutcomes and underlying classical and novel pathophysiologic pathways. We also review recentunexpected and contrasting findings regarding AVP physiology in an attempt to explain andunderstand some of these relationships. (J Clin Endocrinol Metab 104: 5406–5420, 2019)

ISSN Print 0021-972X ISSN Online 1945-7197Printed in USACopyright © 2019 Endocrine SocietyReceived 10 May 2019. Accepted 25 July 2019.First Published Online 31 July 2019

Abbreviations: ADPKD, autosomal-dominant type of polycystic kidney disease; AQP,aquaporin; AVP, arginine vasopressin; CKD, chronic kidney disease; eGFR, estimatedglomerular filtration rate; ESRD, end-stage renal disease; GFR, glomerular filtration rate;HF, heart failure; MACE, major cardiovascular event; MI, myocardial infarction; PKD,polycystic kidney disease; RAAS, renin-angiotensin-aldosterone system.

5406 https://academic.oup.com/jcem J Clin Endocrinol Metab, November 2019, 104(11):5406–5420 doi: 10.1210/jc.2019-01049

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Plasma osmolarity is proportional to the number ofmolecules per liter of solution. Plasma osmolarity is

set within certain limits by homeostatic mechanismsgiven its vital importance for the organism. Increasedosmolarity activates various physiological systems in aneffort to lower plasma osmolarity toward normal,baseline levels (1). The key systems activated by hyper-osmolarity are thirst and arginine vasopressin (AVP),which is also known as antidiuretic hormone. The reasonto specify AVP is because pig vasopressin substituteslysine for arginine at position 8 and is termed lysinevasopressin (2).

AVP is considered a beneficial hormone, because itsprimary action is to increase water reabsorption in thecollecting duct under conditions of hyperosmolarity orextracellular volume depletion, thus decreasing urinarywater losses and restoring homeostasis (3). However,recent evidence suggests that there is a “tradeoff” inwhich elevated AVP levels can be detrimental. Indeed,increased plasma osmolarity and AVP levels and de-hydration were associated with worse renal and car-diovascular outcomes (1). In this review, we summarizethe literature on the relationship of elevated osmolarityand AVPwith renal and cardiovascular outcomes and theunderlying pathophysiology.

Overview of AVP Physiology

AVP is not generated as a final product but rather firstas a prepro-protein named prepro-vasopressin that istranscribed from the AVP gene. This preprotein thenneeds to be proteolysed, which yields AVP as well ascopeptin and neurophysin II (as seen in Fig. 1). Bio-chemically, AVP is cyclical, a nonapeptide with a criticaldisulfide bridge that determines biological activity. AVPis mainly created in large (magnocellular) supraoptic andparaventricular neurons in the hypothalamus and arereleased arterially in the posterior pituitary. AVP isescorted by a carrier protein that is appropriately namedneurophysin. The trip courses along the supraoptic hy-pophyseal tract to reach the posterior pituitary gland

axonal terminals of the magnocellular neurons. Releaseof AVP can be stimulated physically (nausea, vomiting,pain, stress) or chemically (hypoxemia, acidosis). Sepa-rately, catecholamines can stimulate central adrenergicreceptors to modulate AVP release with a variety of ef-fects on vasopressin release. Most importantly, and tel-eologically most logically related to dietary intake,osmolarity is the major stimulus for AVP. Regardless ofthe stimulus, AVP is functionally a neurotransmitteracting upon AVP-sensitive neurons downstream ofneurons sensing the above-mentioned stimuli (Fig. 2).

AVP release and osmolarityPlasma osmolarity and AVP have a linear relationship,

with a threshold for AVP release (4, 5). This threshold (6)determines when a reduced circulating volume and bloodpressure modulate the osmoregulatory threshold. Thethreshold is more permissive in states of hypovolemia,and as hypovolemia progresses, nonosmotically regu-lated AVP release can persist despite significant hypo-natremia (7).

Special vascular organ of lamina terminalis neuronsare able to sense osmolarity of blood and cerebrospinalfluid by using aquaporin (AQP) 4 receptors. In hyper-osmolar states, water flow through the aquaporinstretches the membrane and depolarizes the vascularorgan of lamina terminalis neuron, sending a depolar-ization downstream that releases AVP. As water leavesthe cell, TRPV (a family of transient receptor potentialcation channels) cation channels sense the mechanicalstretch and allow cation influx, which leads to stimula-tion of thirst and, again, AVP release (8).

In fact, AQP4 is abundant in the brain especially at theblood–brain barrier (which is logical, as it must senseosmolar changes in the bloodstream). AQP4 acts uponpresynaptic glial cells to regulate water transport throughAQP1 (which can be detected and is a surrogate markerof synaptic activation) (9) and helps control brain volumevia its water content (10–12). AVP has a half-life of 5 to25 minutes not regulated by osmolality. The molecule isdegraded peripherally in the bloodstream (13).

Figure 1. Preprovasopressin, AVP, and copeptin.

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AVP release and thirstThe physiology of AVP is closely linked to thirst.

Serum osmolarity of 285 mOsm/L has been determinedas the threshold for both thirst perception and AVP re-lease (13). Drinking water reduces thirst and reducesosmolarity slightly, but it results in a disproportionatelylarge drop in serum osmolarity that raises the possibilityof a nonosmotic-dependent response (14).

Interestingly, recent evidence supports the existenceof additional novel regulatory pathways of AVP se-cretion. For example, the “sour” receptors for taste inthe tongue, the type 3 presynpatic acid-sensing tastereceptor cells, express otopetrin 1, which mediates adownstream responses to water intake.Median preopticnucleus neuron activity in the lamina terminalis is alsoproportional to the intensity of dehydration. It is pos-sible that oropharyngeal gulp motions are sensed by theneurons and provide liquid-specific thirst modulation(15). Pharyngeal, esophageal, and/or gastric sensorscould additionally convey organ-specific information ofwater ingestion by the sensory vagus nerve (16). Ad-ditionally, both dietary and endogenously producedfructose has recently been recognized as a nutrient thatstimulates AVP synthesis and secretion as a consequenceof its metabolism (17–20). Thus, AVP secretion is re-duced before osmolality returns to normal limits: Itdecreases immediately after water comes into contactwith the oral mucosa through afferent nerves signalingto the brain (21).

AVP release and gut microbiotaThere are also data regarding the regulation of AVP

secretion by gut microbiota. Indeed, antibiotic treatmentof mice, which disrupts and depletes the gut microbiota,decreases hypothalamic AVP expression (22). The hy-pothalamus and gut microbiota may have a bidirectionalmodulation. When AVP is expressed, there are effects onstress response, inflammatory response, and behaviorsthat may alter gut microbiota. Heterozygous AVP knock-out rats have different gut microbiota in between thehomozygous mutant and wild-type rats, in a sex-specificfashion, possibly via antigenic mimicry of host neuro-peptides to microbiotic receptors (23, 24). In vitro, AVP isstable in colonic environments without normal fecalmicrobiota (25), suggesting that microbiota may metab-olize AVP (23). However, it is still unclear how or whetherhypothalamus-secreted AVP reaches the gut lumen.

Overall, recent data suggest that thirst and AVP re-lease are regulated by factors beyond osmoreceptors,including the gastrointestinal system.

AVP actions

Renal actionsAVP regulates renal water resorption (Fig. 2). The

nephrons are bathed in a gradient of osmolarity andexpress aquaporins that allow concentration of the urineas needed, based on osmolarity-dependent AVP action.Whereas basolateral membrane AQP3 and AQP4 are

Figure 2. Regulation of thirst and AVP secretion and pathways engaged to restore plasma osmolarity. Novel regulators of thirst and AVPsecretion are shown in bold blue. Copeptin is cosecreted with AVP, but its function remains unclear. TRC, taste receptor cell.

5408 Kanbay et al Antidiuretic Hormone, Copeptin, and Serum Osmolarity J Clin Endocrinol Metab, November 2019, 104(11):5406–5420

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constitutively expressed, hypertonicity regulates AQP2expression on the luminal collecting duct, which is re-sponsive toAVP concentrations. Specifically, AVP-derivedcAMP activates protein kinase A to phosphorylate vesiclesthat have preprepared AQP, sending them to the apicalmembrane. Water is recaptured, causing concentration ofthe urine. When vasopressin is not present, the urine is notconcentrated via this pathway (8).

Additional kidney effects of AVP include the decreaseof medullary blood flow and stimulation of urea re-capture to the medullary interstitium (26–28). Sodium isalso concentrated here, allowing a hypertonic gradientthrough which the loop of Henle passes (29), allowingwater countercurrent exchange for water reabsorptionmodulation (13). Epithelial sodium channels also re-absorb water in response to AVP (30).

Glucose metabolism actionsAVP increases blood glucose concentration, leading to

speculation about its metabolic value (31). When AVPbinds V1a receptors in the liver, this initiates glycogen-olysis by glycogen phosphporylase (32). In the liver, AVPacts through calcium-dependent pathways, distinguish-ing it from glucagon (33), although rat studies have alsosuggested that AVP actually stimulates glucagon secre-tion (34) to reach its metabolic endpoint.

AVP also causes release of ACTH from the anteriorpituitary gland, stimulates corticotropin-releasing factorrelease from the hypothalamus via V1bR activation, andalso stimulates cortisol release directly (35, 36). Both thea- and b-cells in the islets of Langerhans contain V1breceptors, so both insulin and glucagon are at playdepending on the glucose concentration in the extra-cellular space. For example, normoglycemic individualsbecome hyperglycemic with AVP infusion (37). In sum,AVP may be a risk factor for hyperglycemia/metabolicsyndrome/diabetes spectrum metabolic derangements.

Separately, AVP decreases circulating ketones (31)and suppresses lipolysis using the AVP V1A receptor in acalcium-dependent fashion (38). The exact mechanism ofAVP-induced lipid metabolism remains understudied(39); however, V1A knockout mice hypermetabolize fat,possibly due to insulin-mediated effects on hormone-sensitive lipase activity (40).

Teleologically, blood loss is an important cause ofhypovolemia, and it is logical that AVP stimulates release ofprocoagulant factors from endothelial cells (41). Vasopressincorrals platelets for aggregation using its V1a receptor (42).Divalent cations (calcium and magnesium) regulate thethrombotic effects of AVP to a lesser and greater extent,respectively. Desmopressin (DDAVP) is another osmolarity-relatedmolecule that regulates platelet function via P-selectinexpression at the endothelial level (41).

Hypertensive actionsAVP increases blood pressure via vasoconstriction and

antidiuretic effects, and it is therefore complementary tothe renin-angiotensin-aldosterone system (RAAS). Syn-dromes such as neurogenic hypertension, angiotensinII–related hypertension, and salt-sensitive hypertensionas well as obesity-induced hypertension have all beenseen to have elevated vasopressin activity (43). AVPstimulates aldosterone release directly and via RAASstimulation, increases sympathetic activity and barore-flex sensitivity, and increases renal collecting ductal ep-ithelial sodium channel activity (44, 45). Urine sodiumexcretion decreases after urine flow drops below 1 L,implying a threshold for sodium-specific AVP actions(46). AVP regulates glomerular filtration rate (GFR) viathe V1a receptor using RAAS and vasopressin 2 receptor–AQP2 to determine fluid homeostasis (47).

AVP and copeptinGiven the very short half-life of AVP, it is not practical

to measure plasma AVP as a prognostic marker. Instead,copeptin is used for this purpose because it has a longerhalf-life (48). Copeptin is created at the same time asAVP, as described above (49, 50) (Fig. 1). Copeptin levelsare also correlated with osmolarity. A recent study ex-plored the impact of water intake on plasma copeptin in82 healthy adults stratified by daily fluid intake volumes:50% to 80%, 81% to 120%, or 121% to 200% ofdietary reference values from the European Food SafetyAuthority. Following a baseline visit, those drinking lesswater were instructed to increase their water intake for6 weeks to match those drinking more water. This wasassociated with a significant decrease of copeptin, urineosmolality, and urine specific gravity (51). Copeptinproperties stimulated research into the significance ofcopeptin levels as a surrogate for AVP synthesis in var-ious clinical conditions, including cardiovascular andkidney diseases (52). As discussed below, despite thephysiological role of AVP, increased osmolarity andcopeptin are associated with adverse outcomes (53).

Clinical Evidence

Preclinical and human observational studies have linkedsituations of higher AVP secretion to progression ofchronic kidney disease (CKD) or adverse cardiovascularoutcomes and, more recently, the vasopressin receptor 2blocker tolvaptan was shown to slow the renal damage inthe autosomal-dominant type of polycystic kidneydisease (ADPKD). As summarized in Table 1, the im-plications of some of these different variables are context-dependent.


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Increased osmolarity, dehydration, andcardiorenal outcome

In recent years, various studies have examined therelationship between variables such as serum and urineosmolarity, fluid or water intake and diuresis, and car-diorenal outcomes. Dehydration is traditionally acceptedas a risk factor for conditions such as nephrolithiasis andelevated blood urea nitrogen. A recent comprehensivereview investigated the relationship between hydrationstatus and kidney diseases. The authors concluded thatincreasing water intake reduces AVP secretion, especiallyrelevant in patients with ADPKD and in those at risk forCKD (54). Previous studies demonstrated that doublingwater intake halved AVP levels in rats with CKD andslowed proteinuria and hypertension (55). However, lowfluid intake (which may potentially result in increasedplasma and urine osmolarity) could beget CKD and itsprogression (56–58). A relationship between serum os-molarity and development of CKD was observed in aretrospective 5-year cohort study of 12,041 Japanesesubjects. Kuwabara et al. (53) demonstrated that serumosmolarity predicts CKD development with an increasedrisk of 24% for every 5 mOsm/L increase.

Urine osmolarity independently predicted dialysisinitiation in a retrospective analysis of 273 patients withCKD, of whom 105 initiated dialysis after a median of92 months, with a threshold time point of 72 months,after which maximal dialysis initiation was observed(59). Prevalence of dialysis initiation increased with os-molarity at 72 months.

Mesoamerican nephropathy or heat stress nephropathyhas been proposed to depend on dehydration and increasedosmolarity. This primarily occurs in male field laborers inhumid conditions. There is high creatinine level, mildproteinuria, mild hypertension, and normal blood glucoseand urinary sediment, arguing against glomerular injury.The predominant pathology is tubulointerstitial injury, andthe major pathophysiologic mechanism is thought to beincreased serum osmolarity (1, 58).

Regarding blood pressure, we recently investigated 10healthy individuals not taking any medications with fourseparate soup challenges with increasing salt content. Ateach visit, plasma osmolarity, sodium and copeptinlevels, and blood pressure were measured at baseline andhourly for 4 hours. Intake of 3 g of salt was associatedwith increased plasma osmolality (16 mOsm/L) andsodium (2.5 mmol/L) and systolic blood pressure (10 mmHg) at 2 hours. The concomitant intake of water pre-vented these changes. Thus, the acute increase in bloodpressure following salt ingestion depends on the osmo-larity change, not the absolute salt amount. This impliesthat concurrent intake of enoughwater to prevent the risein serum osmolarity may protect from blood pressureelevation after salt intake. Clinically, increasing waterintake may be an alternative to salt restriction (60). Thisissue is particularly important given the low adherence(10% to 20%) to low-salt diets (61). In health, the kidneyexcretes more sodium as the patient drinks more water,whereas conversely, AVP retains sodium (30). Despitethese observations, studies are needed to explore whetherconcomitant water intake may have protective effectsover salt-induced changes in blood pressure in the longterm.

However, some contrary data exist. A population-based prospective study of ;4000 patients $49 yearsof age was performed using a food questionnaire. After13.1 years, estimated glomerular filtration rate (eGFR)was found to decrease 2.2 mL/min/1.73 m2 in the 1207patients who had data available for this analysis. Im-portantly, this was not associated with fluid intake,raising the question of whether fluid intake is trulynephroprotective (62). However, the rate of eGFR losswith aging was slower than the expected rate of1.0 mL/min per 1.73 m2/y, raising questions about therepresentativeness of the sample. Additionally, water wasnot included, which would be expected to have a highervasopressin-lowering effect than electrolyte-containing

Table 1. Plasma and Urine Osmolarity, Diuresis and Plasma AVP, and Copeptin in Diverse PathophysiologicalSituations

PlasmaOsmolarity

UrineOsmolarity

UrineVolume

PlasmaAVP

PlasmaCopeptin

Defective urine concentrating ability(e.g., CKD)

↑ ↔ ↑ ↑ ↑

↓ Water intake ↑ ↑ ↓ ↑ ↑↑ Solute intake ↑ ↑ ↓ ↑ ↑↑ Fluid intake in response to thirst ↑ ↑ ↓ ↑ ↑↑ Spontaneous fluid intake ↓ ↓ ↑ ↓ ↓Taste receptor cells (tongue type IIIpresynaptic acid-sensing taste receptorcells)

↓ (?)

Gut microbiota ↑ (?)


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food or beverages. Finally, the https://vwp-psapp01.dhe.duke.edu/RadPortal/ study assessed spontaneous fluidintake, which may be in response to thirst (and, thus,increased vasopressin levels) triggered by prior waterlosses and dehydration. Thus, a high fluid intake maynot necessarily imply suppressed vasopressin secretion.

ADPKD has been a topic of research, given the pre-clinical and clinical evidence of beneficial effects of vaso-pressin signaling blockade that results in decreased cystgrowth and other nephroprotective actions (63). In aretrospective analysis of 139 CKD patients with PKD and442 without PKD during a follow-up period of 2.3 years, ahigher mean 24-hour urine volume and lower urine os-molarity were associated with more rapid GFR decline.PKD increased this rate of decline mildly, but fluid intakedid not slow renal decompensation (64). Given this, weshould again differentiate between a high fluid intakesecondary to prior fluid losses (e.g., secondary to partialnephrogenic diabetes insipidus associated with the urineconcentration defect that may be found in CKD and,specially, in PKD), which is associated with a high vaso-pressin secretion, and preemptive fluid ingestion that alsoincreases urinary losses and decreases urine osmolarity, butis associated with suppressed vasopressin secretion.

A very recent prospective study assessed the re-lationship between fasting urinary osmolality, CKDprogression, and mortality in 2084 adults with CKDstages 1 to 4. At a median of 6 years, 225 patients diedbefore end-stage renal disease (ESRD) occurred, and 380ESRD events occurred. Having a lower baseline urineosmolality protected against ESRD but not death. Again,lower fasting urine osmolality may reflect a suboptimalurine concentration ability, a condition associated withhigher vasopressin secretion.

Any study of nephroprotective water intake has manyconfounders (1). A randomized clinical trial of watersupplementation vs control therapy in 631 patients with

CKD (mean eGFR, 43 mL/min/1.73 m2) from differentcauses tested whether adding 1.0 to 1.5 L water daily tousual beverage intake for 12 months may significantlyreduce the decline of GFR (65). Hydrated patients had aworse mean change in eGFR (22.2 vs 21.9 mL/min/1.73 m2) despite having mean urine volumes change of10.6 L/d (66). Thus, intervention patients did notcomply with the 1.0 to 1.5 L additional water intake,although plasma copeptin decreased by 1.4 pmol/L (8%)from baseline. Unfortunately, drinking water withoutthirst is not easy, and noncompliance is expected to be amajor obstacle for studies of similar design. Etiology-specific water intake trials are ongoing or have beenrecently completed, but results not yet reported, sucha DRINK feasibility trial (NCT02933268) and thePREVENT-ADPKD (ANZCTR12614001216606) trialson ADPKD (67, 68).

AVP, copeptin, and cardiorenal outcomesAs observational studies of fluid intake or urine vol-

ume or osmolarity may be marred by the factors drivingfluid intake or urine volume (e.g., voluntary fluid intakevs thirst-driven fluid intake or CKD-associated sponta-neous polyuria), assessment of copeptin as a surrogate forAVP may provide better insight into pathophysiologicalmechanisms. In this regard, copeptin levels have beenassociated with adverse clinical outcomes in kidney andcardiovascular disease (Fig. 3).

Experimentally, AVP accelerated CKD progression bycausing glomerular hyperfiltration and albuminuria (55,69). There are clinical data pointing in the same direction.High copeptin was associated with left ventricular hy-pertrophy and carotid intima thickening in a multivariateanalysis among 86 patients with CKD not on renal re-placement (70). A French study during 9 years of;1200patients confirmed that copeptin elevations were asso-ciated with CKD development (71). Approximately 3200

Figure 3. Clinical associations of high copeptin levels with negative outcomes in kidney and cardiovascular disease.


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patients in the Malmo Diet and Cancer–CardiovascularCohort demonstrated that copeptin was independentlyassociated with eGFR decline (72). In three Europeangeneral population cohorts (France, Sweden, and theNetherlands with median follow-up of 8.5, 16.5, and11.3 years, respectively), the upper tertile of plasmacopeptin levels was significantly and independently as-sociated with higher risk for stage 3 CKD, kidneyfunction decline in accordance with KDIGO criteria,rapid kidney function decline, and microalbuminuria(49%, P, 0.0001; 64%, P, 0.0001; 79%, P, 0.0001;and 24%, P, 0.0001, respectively.) This was one of thelargest studies demonstrating copeptin as a risk factor forCKD (73).

Serum copeptin correlated positively with the albumin/creatinine ratio and negatively with eGFR in a study of979 patients with diabetes (74). Copeptin correlatedpositively with GFR in 80 patients with type 1 diabetes(R 5 0.86, P 5 0.021) and in healthy controls (n 5 61,R5 0.61, P5 0.034). Multivariate analysis showed thatGFR was associated with copeptin in the patients withtype 1 diabetes only (b5 0.23, P5 0.032) (75). Copeptinelevation was associated with creatinine concentrationand ESRD in diabetes (76, 77).

Copeptin was associated with the size of the kidneysin a general population study (78). In patients withADPKD, copeptin was associated with markers of dis-ease severity, including GFR and albuminuria (79, 80).Additionally, the ratio of copeptin to creatinine is as-sociated with kidney size in ADPKD (81). Randomizedtrial data demonstrate that patients with higher baselinecopeptin levels have superior nephroprotection fromtolvaptan. A greater copeptin rise at treatment week 3predicted less eGFR decline at 3 years (82). Copeptinelevation was associated with microalbuminuria andCKD progression in renal transplant patients (83).

Copeptin is also associated with blood pressure. Pa-tients with resistant hypertension had approximatelytwofold higher copeptin levels than did patients withadequate blood pressure control. This suggests that hy-pertensives have elevated homeostatic levels of copeptinregarding the osmolarity thresholds leading to AVP re-lease (84). A recent study observed increased AVP levelsin women with preeclampsia as early as at 6 weeks ofgestation (85). Pregnant C57BL/6J mice receiving AVPinfusion become hypertensive and have renal glomerularendotheliosis and pregnancy complications in the ab-sence of placental hypoxia. This suggests that AVP isitself capable of inducing clinical phenotypes of pre-eclempsia independent from hypoxia-mediated mecha-nisms (86).

In patients with heart failure (HF), higher copeptinlevels are associated with death (63.4% vs 33.0% at 1

year, P 5 0.03) after adjusting for confounding factors(87). A study of 340 patients in Denmark who had leftventricular dysfunction found that copeptin levels pre-dicted hospitalization or death at median follow-up of55 months (hazard ratio, 1.4; 95% CI, 1.1 to 1.9; P ,0.019). However, copeptin did not predict mortalityindependently of N-terminal pro–B-type natriuretic pep-tide (88). These studies are in line with prior reports of asignificant association of copeptin with HF outcomes(89–92) and of high AVP levels with HF severity (93–95).

Copeptin has also prognostic implications inatherosclerosis-related cardiovascular events, includingacute coronary syndromes and stroke. Copeptin plushigh-sensitivity cardiac troponin T compared favorablyto an algorithm based only on high-sensitivity cardiactroponin T to rule out myocardial infarction (MI) (96).The prognostic value of serum copeptin for a combinedendpoint of major cardiovascular events (MACEs)(death, repeat percutaneous coronary intervention, re-current MI, or coronary artery bypass grafting) wasstudied retrospectively in 149 patients who successfullyreceived percutaneous coronary intervention after anacute MI. Copeptin was positively associated withMACEs. In multiple logistic regression analyses, higherserum copeptin levels were independently associatedwithan increased risk of MACEs (OR, 1.6) (97). In otherwork, copeptin levels are associated with other poorclinical outcomes after acute MI, including HF (98–100).

Another study explored copeptin and renal/cardiovascular morbidity/mortality in two cohorts to-taling 4505 patients with type 2 diabetes. As sex-specifictertiles of copeptin increased, the cumulative incidenceof cardiovascular events also increased after adjustingfor covariates. Pooled cohort analyses including pa-tients with albuminuria found no interaction be-tween copeptin levels and eGFR with cardiovascularevents (101).

When HF induces renal failure, or vice versa, this istermed cardiorenal syndrome (102). AVP is implicatedin this process. HF is associated with elevated AVP(released nonosmotically), causing fluid retention andperipheral vasoconstriction via V2 and V1 AVP re-ceptors, respectively. HF-derived low cardiac outputcauses renal ischemia and activation of RAAS tostimulate further AVP, completing the cycle thatultimately leads to cardiorenal syndrome (103).Diuresis-dependent strategies in management of HFare challenged by the inappropriate elevation of AVP.In fact, AVP-directed diuresis-focused strategies havebeen studied as a result. For example, conivaptanallows dose-dependent diuresis in symptomatic pa-tients with heart failure without changes in BP, heartrate, or electrolyte balance (104, 105). Tolvaptan


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increases urine volume significantly from a mean of;1 L/d to 1.5 L/d (P , 0.01) with stable creatininelevels, giving value in volume-overloaded patientswith CKD (106).

Studies on copeptin and stroke have not been con-cordant. In a case-control study that included 119healthy controls and 119 patients with stroke, copeptinwas associated with ischemic stroke, and unexpectedlynegatively associated with hemorrhagic stroke. Strokeprevalence increased with copeptin (5% ischemic, 8%hemorrhagic) (107) in one study whereas ischemic strokedid not increase with copeptin in another study (108),and in yet another study, the association occurred only inpatients with diabetes (109).

Copeptin may have prognostic value in pulmonaryembolism. Within the first 30 days, 843 normotensivepatients with pulmonary embolism demonstrated a 7.6-fold increased risk of death (P 5 0.001) with elevatedcopeptin levels (110).

All of the above association data suggest that copeptinis associated with outcomes in various pathologic statesrelated to kidney and cardiovascular disease, and this listis increasing. However, the leap from associations andbiomarker potential of copeptin to causality and, thus,therapeutic target potential of AVP requires interven-tional studies that so far have only been performedsuccessfully, outside the context of hyponatremia, forADPKD (111).

AVP Pathophysiology BeyondOsmolarity Control

Although it is a very “old” hormone, the full extent ofAVP pathophysiological implications is only now beingrecognized. Besides its traditional role to regulate waterhomeostasis (Fig. 2) and systemic vasoconstrictive ef-fects, there are several pathophysiological mechanismsthat directly link AVP to kidney disease (Fig. 4).

In rats, AVP causes glomerular hypertension andkidney hypertrophy, and the reverse occurs when AVP isdecreased with water intake (112), with similar findingsin healthy humans (113). In this regard, AVP increasesurinary albumin excretion in a dose-dependent manner(69). In rats with subtotal nephrectomy, tripling waterintake reduced AVP secretion, osmolairy, proteinuria,renal hypertrophy, and mortality (55). These findingswere reproduced in diabetic animal studies (114, 115).AVP infusion also accelerated CKD progression insubtotally nephrectomized AVP-deficient rats (116). Inpatients with ADPKD, the AVP V2 receptor blockertolvaptan reversibly decreased hyperfiltration and alsodecreased albuminuria in randomized clinical trials(111, 117). Thus, AVP may be involved in glomerularhyperfiltration and may help increase urinary albuminexcretion for humans and rats (114). However, furtherhuman studies are needed to demonstrate that these ef-fects are also evident in disease conditions other than

Figure 4. Postulated mechanisms for kidney injury triggered by dehydration. In the renal medulla, the presence of sorbitol and other osmolytesprotects from hyperosmolarity (green).


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ADPKD. There are several potential mechanisms linkingvasopressin to hyperfiltration, a driver of albuminuriaand CKD progression. Vasopressin-induced hyper-filtration may be related to macula densa sodium con-centration reducing feedback from the tubule to theglomerulus via complex AVP-dependent intrarenalhandling of urea, whereby there is more urea in the loopof Henle (57, 118). Additionally, AVP V2 receptors(those blocked by tolvaptan) induce vasodilation inrabbit afferent arterioles (119).

There is preclinical evidence that AVP, likely via a V2receptor–dependent pathway, may directly cause kidneyinjury (3). Thus, dehydration-induced hyperosmolarityand chronic stimulation of the V2 receptor may lead tokidney damage (54, 118). Experimental heat stress ne-phropathy in male mice induced by recurrent heat ex-posure with limited water availability was characterizedby evidence of glomerular (albuminuria, mesangiolysis,matrix expansion) and tubulointerstitial injury (elevatedurinary neutrophil gelatinase-associated protein, fibrosis,inflammation). Desmopressin, a V2 receptor agonist,twice daily for 5 weeks was associated with albuminuriaand tubulointerstitial fibrosis in mice, which was worsein heat-stress mice.

Stress and desmopressin activate the polyol–fructokinase pathway in the renal cortex, likely via in-terstitial osmolarity, which is another potential driver ofkidney injury (1, 3). Hyperosmolarity activates the en-zyme aldose reductase, which is normally active in thehyperosmolar renal medulla where it metabolizes glucoseinto sorbitol (120), an intracellular osmolyte that pro-tects medullary cells from hypertonicity-induced injury(121). Although sorbitol is the end product of the polyolpathway in the renal medulla, sorbitol dehydrogenase inthe outer medulla and renal cortex sorbitol can furtherdegrade sorbitol to fructose, a substrate for the proximaltubular enzyme fructokinase. Fructokinase activationmay lead to a fall in ATP levels and increases in adeninenucleotide turnover, uric acid production, oxidative stress,and chemokine (monocyte chemoattractant protein-1)release, processes that can cause local renal injury (122,123). Sodas may worsen the effect.

Uric acid is another potential link between AVP andkidney injury. Heat stress causing nephropathy has beentheorized since the 1970s (124). Hyperuricemia is as-sociated with effective circulating volume depletion inheat-stress nephropathy. Hard physical work in hotenvironments with inadequate hydration results in in-creased serum osmolarity and in increased serum uricacid levels derived from muscle turnover. Additionally,concentrated urines in this setting may exceed the uricacid insolubility threshold, a process further facilitated byurine acidity. Serum uric acid may cause glomerular

hypertension, whereas urinary uric acid may cause injuryin tubules through crystalline and noncrystalline effects.In a study of male sugarcane workers, the daily work shiftwas associated with increased serum creatinine and uricacid, urine concentration and acidification, and uric acidcrystalluria, supporting the concept that repetitive sub-clinical kidney injury through recurrent exposure to heat,exercise, and dehydration may favor the developmentand progression of CKD (125).

In spontaneously hypertensive rats, chronic recurrentdehydration induced by restricting drinking to a 2-hourperiod each day for 4 weeks exacerbated hypertensionand promoted renal damage, as assessed by decreasedGFR, increased urinary neutrophil gelatinase-associatedlipocalcin, and more severe renal fibrosis and an in-creased Th1/Th2 cell ratio. Thus, recurrent dehydrationwas associated with kidney damage even in the absenceof heat exposure or strenuous physical exercise (126).Several previous studies had reported a protective effectof increasing water intake to reduce urine concentration,or administering AVP receptor antagonists, on CKDprogression in rats (127, 128). The amount of water usedfor this purpose was roughly equivalent to 2 to 2.5 L/d inhumans.

CKD progression via renal injury and inflammationis associated with recurrent dehydration and hyper-osmolarity (129). Regarding osmolytes, in a cohort of227 patients with CKD, urine metabolomics identifiedincreased urine concentrations of the osmolytes betaineand myo-inositol to predict CKD progression (130).Interestingly, kidney transcriptomics identified decreasedexpression of osmolyte transporters Slc6a12 and Slc5a11mRNA in injured renal tissue, consistent with a role ofosmolyte disturbances in CKD progression (130).

Hyperosmolarity promotes CKD (131) via cytokinesfrom monocytes (132, 133) as seen in a prospective studyshowing that dialysate sodium reduction reduced cyto-kine levels (134). There is also evidence that a high so-dium intake is associated with a proinflammatory state(135). AVP secretion is also closely related with immuneactivity (136, 137). The relationship between AVP andthe immune response may be bidirectional because nucleithat make AVP also respond to inflammation (138), andAVP receptors are found on immune cells (139). Tomakethings more complicated, both AVP and the gut micro-biota regulate and are potentially regulated by immune-related pathways (140, 141). Therefore, the interactionbetween gut microbiota and AVP expression may be inpart mediated by the immune system.

Other potential deleterious mechanisms of increasedosmolarity include activation of the sympathetic (142) andintracerebral angiotensin II activation (143, 144). Addi-tionally, AVP causes mitochondrial dysfunction (145).


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Paradoxical Impact of Sodium Intake onWater Balance

In classical physiology, ingestion of a salty meal leads tohypertonicity, which stimulates fluid intake with re-sultant expansion of extracellular fluid volume (146).However, this concept has been challenged by recentfindings. In contrast to traditional belief, a long-termhigh-salt intake decreased fluid intake in humans. Al-though the mechanisms are unclear, this may be partlyattributed to reduced urinary osmolyte-free water (147).In mice, increased salt intake stimulated catabolism,resulting in urea production that was partly mediated byincreased plasma cortisol levels. Furthermore, mice withhigh dietary salt intake chose to eat more overall, pos-sibly to counter catabolism. High salt intake increasesrenal medullary urea transporters, and a higher pro-duction of urea and reduced urea excretion results inmedullary urea concentration with the ability to con-centrate the urine. However, surprisingly, urine volumedid not increase with salt intake. Thus, increased urinewater excretion likely depends on additional watersources, such as increased endogenous water production.Taken together, decreased free water excretion in urineand elevated endogenous water production were asso-ciated with lower fluid intake without a rise in tonicity(148). Increasing salt intake for 7 days in healthy menwas not associated with changes in fluid intake or urinevolume (149). When dietary sodium is increased to 15g/d, healthy male subjects demonstrated net negativefluid balance with stable extracellular fluid balance. Thismeans that water was recruited from intracellular spaces,protected from insensible losses, or protected frommetabolic losses (150). Potential explanations for thesediverse findings include patient characteristics, endo-crine and other physiologic perturbations, and theamount and chronological pattern of ingested salt (151).An improved understanding of these systems may helptackle the contribution of hyperosmolarity and AVPto disease by designing approaches that do not have torely on difficult-to-implement dietary or drinking habitmodifications.

Conclusion and Research Ahead

Recent evidence suggests that the regulation and impactof AVP and hyperosmolarity are more complex thanpreviously thought and include regulation of AVP se-cretion by acid-sensing taste receptor cells, medianpreoptic nucleus neurons in the brain, pharyngeal,esophageal, and/or gastric sensors, and gut microbiota.Surprisingly, and contrary to prior literature, long-termsalt intake decreased fluid consumption in humans.

Copeptin and AVP levels are associated with chronicdisease outcomes. There is also recent data on the directrelationship between sodium, hyperosmolarity, and AVPwith the immune system. Several underlying mechanismsmay be involved in the novel observations regarding saltintake, hyperosmolarity, and AVP secretion and actions,and it is important to clarify them to develop noveltherapeutic approaches. Some controversy exists re-garding fluid intake and progression of CKD. Whereassome studies suggested an association between higherfluid intake and slower CKD progression, others did not.The nature of fluid intake in response to hypertonicitydriven by urinary concentrating defects, or as a proactiveaction leading to lower AVP levels, may underlie thecontroversial results. In this regard, although fluid intakemay be of the same magnitude in both scenarios, therelationship to AVP levels and tonicity would be theopposite. Definitive proof may come from clinical trialsof increased water intake or other approaches. How-ever, novel imaginative ways to effortlessly increaseelectrolyte-free water intake are required. In any case, therecent demonstration of nephroprotection by tolvaptanin ADPKD and the surprising finding that this is asso-ciated with decreased hyperfiltration and albuminuria (apotential universal nephroprotective mechanism) on topof direct effects on cyst size (a disease-specific mecha-nism) emphasize the need to further understand the AVPsystem and its therapeutic implications for chronic car-diovascular and renal diseases.

Acknowledgments

Financial Support: M.K. gratefully acknowledges use of theservices and facilities of the Koç University Research Centerfor Translational Medicine (KUTTAM), funded by thePresidency of Turkey, Presidency of Strategy and Budget.The content is solely the responsibility of the authors anddoes not necessarily represent the official views of thePresidency of Strategy and Budget. A.O. was supported byInstituto de Salud Carlos III (ISCIII) and Fonds Europeende Developpement Economique et Regional (FEDER)Grant PI16/02057, Sociedad Española de Nefrologia,Fundacion Renal Iñigo Alvarez de Toledo (FRIAT), and byISCIII Red de Investigacion Renal (REDinREN) GrantRD016/009.

Correspondence and Reprint Requests: Mehmet Kanbay,MD, Division of Nephrology, Department of Medicine, KocUniversity School ofMedicine, 34010 Istanbul, Turkey. E-mail:[email protected].

Disclosure Summary: The authors have nothing todisclose.

Data Availability: Data sharing is not applicable to thisarticle as no datasets were generated or analyzed during thecurrent study.


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