Vasopressin in Chronic Kidney Disease: an Elephant in the Room?

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proteinuria, renal hypertrophy, glomeru- Vasopressin in chronic kidney losclerosis, and tubulointerstitial fi brosis in 5 / 6 nephrectomized rats.6,7 Compensa- disease: an elephant in the room? tory renal hypertrophy and CKD progression following 5 / 6 nephrectomy are 1 Vicente E. Torres attenuated in Brattleboro rats, which can- not secrete AVP, although a study of Perico et al. report that a dual arginine vasopressin (AVP) V2 and V 1a shorter duration (3 versus 13 weeks) did receptor antagonist lowers blood pressure, proteinuria, and not detect this eff ect.8,9 Brattleboro rats glomerulosclerosis in 5/ 6 nephrectomized rats, pointing to its potential with diabetes mellitus exhibit no or mark- value in the treatment of chronic kidney disease (CKD). AVP likely edly reduced glomerular hyperfi ltration, contributes to CKD progression by its effects on renal hemodynamics, albuminuria, and renal hypertrophy compared with wild-type controls.4 These blood pressure, and mesangial and/ or epithelial cells, but the relative observations seem to contradict a post hoc contributions of V2 and V1a receptors and potential usefulness of V2 and analysis of the Modification of Diet in V 1a receptor antagonists remain ill defined. Renal Disease (MDRD) study in which an Kidney International (2009) 76, 925 – 928. doi: 10.1038/ki.2009.325 association between high urine volumes and rates of GFR decline was thought to refl ect a deleterious eff ect of increased In this issue of Kidney International , increases in single-nephron perfusion, water intake on disease progression. 10 Perico et al.1 report that treatment with glomerular capillary hydraulic pressure, However, it is impossible to conclude from RWJ-676070, a dual V1a and V2 arginine and filtration rate; resetting of tubu- this analysis whether high urine fl ow rate vasopressin receptor antagonist (V1 / loglomerular feedback, allowing persist- was a cause or a consequence of GFR V 2 RA), initiated 3 weeks after 5/ 6 ent glomerular hyperfi ltration; and failure decline, or whether another independent nephrectomy, signifi cantly lowers blood of autoregulation, exposing glomerular factor infl uenced the two variables simul- pressure, proteinuria, and glomeruloscle- capillaries to systemic hypertension. Th e taneously. Furthermore, this association rosis in rats. Combined treatment with superiority of ACEIs and ARBs in treating is not unexpected, since defective urine- RWJ-676070 and an angiotensin-convert- glomerular capillary hypertension, as concentrating capacity is a manifestation ing enzyme inhibitor (ACEI) or an angi- compared with antihypertensive agents of CKD. In the study by Perico et al. , 1 otensin II type 1 receptor blocker (ARB) that mainly dilate preglomerular vessels urine output more than doubled in the 5 / 6 has eff ects on proteinuria, renal function, or activate the renin – angiotensin system, nephrectomized as compared with the and structure that are numerically, but not has established the central role of angi- control rats and did not increase further significantly, greater than those of an otensin II in this pathway. In addition, following V 1a/ V 2 RA administration, pos- ACEI or an ARB alone. Th e authors sug- angiotensin II exerts non-hemodynamic sibly because of AVP-resistant downregu- gest that non-peptide arginine vasopressin effects on vascular smooth muscle, lation of aquaporin-2 and -3, as well as (AVP) receptor antagonists could be reno- endothelial and mesangial cells, podo- downregulation of aquaporin-1.11 protective in patients with proteinuric cytes, and tubular epithelial and intersti- Like angiotensin II, AVP has eff ects on chronic kidney disease (CKD). tial cells that contribute to CKD glomerular hemodynamics, arterial Th e identifi cation of a common path- progression. blood pressure, and non-hemodynamic way of progressive renal damage, regard- Although under-recognized, a large renal mechanisms. AVP acts on three G less of the initiating injury, achieved by body of evidence suggests that AVP con- protein-coupled receptors: V2 (cyclic research in animal models of nondiabetic tributes to nondiabetic and diabetic CKD adenosine monophosphate (cAMP ) sec- CKD (5/ 6 nephrectomy) and diabetic progression. Plasma AVP levels are ond messenger) and V1a and V1b (also CKD (streptozotocin-induced diabetes increased in animal models and patients called V 3 ) (calcium second messenger). mellitus) has been one of the major with nondiabetic CKD, in animal models In the kidney, V 2 receptors are found in achievements in nephrology. 2 Th is path- of streptozotocin-induced and genetic the medullary thick ascending limb of way includes reductions in aff erent and, diabetes mellitus, and in patients with Henle (TAL), macula densa, connecting to a lesser degree, eff erent arteriolar tone; type 1 and type 2 diabetes mellitus. 3,4 tubule, and cortical and medullary col- Plasma levels of copeptin, a surrogate lecting ducts, and to a lesser extent in 1 Mayo Clinic College of Medicine , Rochester , MN , marker derived from the C-terminal por- the cortical TAL and distal convoluted U S A tion of the AVP precursor, are inversely tubule (Figure 1). 12 Contrary to previ- Correspondence: Vicente E. Torres, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, correlated with glomerular fi ltration rate ous belief, a recent comparative study 5 Minnesota 55905, USA. (GFR). Suppression of AVP by increasing has shown similar patterns of V2 recep- E-mail: [email protected] water ingestion reduces blood pressure, tor expression in the rat, mouse, and

Kidney International (2009) 76 925 commentary

Filtered plus recycled urea CNT CNT CNT CCD C CCD C CCD Filtered C M DCT DCT urea M DCT aa aa aa ILA MD ILA MD ILA MD ea CTAL ea CTAL ea CTAL

AVR OS AVR OS AVR OS AA DVR AA DVR AA DVR

MTAL IS MTAL IS MTAL IS

UT-B

IM IM IM

MCD MCD MCD

UT-A2 Strong intensity Intermediate intensity UT-B UT-A1/A3 Low intensity Positive signal No signal Recycled Positive α-intercalated cells Positive α-intercalated cells urea Urea excretion

Figure 1 | Mechanisms of vasopressin effects on the kidney. ( a) Segmental distribution of AVP V 1a receptor. AVP, acting on V1a receptors in the macula densa, regulates renin secretion; acting on V 1a receptors in the vasa recta, it reduces blood flow to the inner medulla and minimizes solute escape from the medullary interstitium; and acting on V1a receptors on the luminal side of collecting-duct principal cells, it stimulates synthesis of prostaglandins that attenuate V2 -mediated antidiuretic action and inhibit sodium transport. (Adapted from refs. 13, 14, and 31.) (b ) Segmental distribution of AVP V 2 receptor. AVP, acting on V2 receptors, contributes to urinary concentration by inserting aquaporin-2 (AQP-2) into the apical cell membrane of collecting-duct principal cells within minutes and upregulating AQP-2 gene expression in the longer term; activating UT-A1 and UT-A3 in the terminal part of the inner medullary collecting duct; stimulating epithelial sodium channel (ENaC) sodium transport in cortical and outer medullary collecting ducts; and increasing NaK2Cl cotransporter expression and sodium reabsorption in the thick ascending limb of the loop of Henle. (Adapted from ref. 12.) ( c) Vascular and tubular routes of urea recycling within the kidney. Only a long loop of Henle is depicted, for simplicity. Urea delivery to the inner medulla and transit in ascending vasa recta are shown in green. The pathways allowing urea to return to the inner medulla are indicated by red arrows for the vascular route and by blue arrows for the tubular route. (Adapted from ref. 38 ) AA, arcuate artery; aa, afferent arteriole; AVR, ascending vasa recta; C, cortex; CCD, cortical collecting duct; CNT, connecting tubule; CTAL, cortical thick ascending limb of Henle; DCT, distal convoluted tubule; DVR, descending vasa recta; ea, efferent arteriole; ILA, interlobular artery; IM, inner medulla; IS, inner stripe of the outer medulla; M, mesangium; MCD, medullary collecting duct; MD, macula densa; MTAL, medullary thick ascending limb of Henle; OS, outer stripe of the outer medulla; UT-A1/ A3, vasopressin-regulated urea transporters A1/ A3; UT-A2, urea transporter A2; UT-B, urea transporter B. human TAL and collecting duct, and of receptor agonist 1-deamino-8 -D- arginine probably due to suppression of tubu- AVP-dependent NaK2Cl cotransporter AVP (DDAVP), but not AVP, worsens loglomerular feedback, possibly caused phosphorylation in TAL cells from rats proteinuria and renal insuffi ciency in 5 / 6 by enhanced urea recycling and / or 12 and rabbits. V1a receptors are found in nephrectomized Brattleboro rats even sodium chloride reabsorption in the TAL, the renal vasculature from the interlob- raised the possibility that V 1a eff ects of lowering the sodium concentration at the ular arteries to the eff erent arterioles AVP could afford a relative protection macula densa. Th ese eff ects, which are and vasa recta, mesangial cells, macula against deleterious V2 eff ects. Th erefore, more marked in juxtamedullary neph- densa, and collecting-duct principal and the relative contributions of V 2 and V 1a rons, may be responsible for functional ␣-intercalated cells.13,14 Th e localization receptors to, and potential usefulness of and structural diff erences between super- 18 and function of V1b receptors in the kid- V2 and V 1a receptor antagonists for the fi cial and deep nephrons. Urine-con- ney, possibly in the inner medullary col- treatment of CKD remain ill-defi ned. centrating activity and GFR (or renal lecting duct, are not well characterized. Strong experimental evidence supports blood fl ow) are also correlated in healthy Although RWJ-676070, the compound the hypothesis that the V 2 -mediated human volunteers during low and high 1 19 used by Perico et al. , is a dual V1a / V2 RA, urine-concentrating activity is mainly hydration. AVP administration to it has higher affi nity for rat V2 than for V 1a responsible for the renal hemodynamic water-loaded healthy volunteers induces 16,17 receptors ( K i 16 and 86 nM, respec- eff ects of AVP (Figure 1). A positive parallel increases in creatinine clearance tively).15 Previous studies had shown that correlation between urine osmolality and and urine osmolality. 20 Conversely, V 2RA or V 1aRA or both in combination GFR was observed (only when urine administration of V2 RA aft er dehydration have a renoprotective eff ect, suggesting osmolality was equal to or above that of induces a fall in creatinine clearance. that both receptors contribute to CKD plasma) in conscious rats when urine- Compelling arguments have been made progression (Table 1). Nevertheless, the concentrating activity was increased by a linking increased levels of AVP and urine- specificity of these antagonists is not constant infusion of DDAVP or reduced concentrating activity to the increased absolute. One study showing that the V2 by increasing water intake. This is risk for CKD progression associated with

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Table 1 Studies ascertaining eff ects of V2 and/ or V 1a agonism or antagonism on chronic kidney disease progression

Study a Drug Class Animal model Treatment duration Outcome

Okada et al. , 1994 OPC-21268 or V 1a RA, V 2 RA DOCA-salt- and 2 – 6 wk All reduced BP rise, OPC-31260 or both adriamycin-treated rats V 1a RA / V 2RA ameliorated histology

Okada et al. , 1995 OPC-21268 or V1a RA, V 2RA Uninephrectomized 6 – 10 wk (starting at V 2 RA or V 1aRA / V 2 RA OPC-31260 or both DOCA-salt hypertensive rats surgery or 4 wk later) reduced BP rise

Okada et al. , 1995 OPC-21268 or V 1a RA, V 2RA 5 / 6 nephrectomized 10 wk (starting at V 1a RA or V 1aRA / V 2 RA OPC-31260 or both spontaneously surgery) reduced BP rise, proteinuria, hypertensive rats and arteriolosclerosis

Okada et al. , 1996 OPC-21268 or V1a RA, V 2 RA Adriamycin-treated rats 5 – 7 wk All reduced proteinuria and OPC-31260 or both histological alterations

Kurihara et al. , 1996 OPC-21268 V1a RA Uninephrectomized 9 wk V1a RA reduced BP and spontaneously glomerular sclerosis and hypercholesterolemic rats improved renal function

Bouby et al. , 1999 DDAVP V2 R agonist 5 / 6 nephrectomized 13 wk DDAVP increased Brattleboro rats proteinuria and worsened renal function

Naito et al. , 2001 DDAVP and VP-343 V2 R agonist, V2 RA Sprague-Dawley rats 15 days (VP-343 given DDAVP induced and VP-343 only on days 5 – 15) prevented hypertrophy, tubular dilatation, and interstitial infi ltration

Fernandes et al. , DDAVP or SR-121463 V 2 R agonist, V2 RA Uninephrectomized 8 wk DDAVP worsened 2002 DOCA-salt hypertensive rats hypertension, albuminuria, and histology

Bardoux et al. , 2003 SR-121463 V2 RA Streptozotocin-induced 9 wk V 2 RA prevented rise in diabetes mellitus albuminuria

Windt et al. , 2006 YM-218 V1a RA 5 / 6 nephrectomized rats 8 wk (starting 2 wk after V 1 RA reduced proteinuria surgery) and glomerular sclerosis

Windt et al. , 2006 YM-218 V1a RA 5 / 6 nephrectomized rats 4 wk (starting 6 wk after No eff ect surgery)

Okada et al. , 2009 Tolvaptan V2 RA Puromycin aminonucleoside 10 days V 2 RA reduced proteinuria nephrosis and kidney weight and improved renal function

P e r i c o et al. , 2009 RWJ-676070 V1a / V2 RA 5 / 6 nephrectomized rats 39 days (starting 3 wk V 1a / V2 RA reduced BP rise, after surgery) proteinuria, and glomerular sclerosis BP, blood pressure; DDAVP, 1-deamino-8-d-arginine AVP; DOCA, deoxycorticosterone acetate; RA, receptor antagonist. a References available on request. high protein intake, male gender, and of diabetes insipidus in dogs is associated accompanied by an increase in plasma black race.21 – 23 with eff erent arteriolar dilation. 27 Admin- renin activity in humans and are prevented 30 Under physiological conditions, the istration of a V 1 antagonist to euvolemic by ACEIs in rats. V1a receptors are coex- renal vasculature and total renal blood anesthetized rats lowers GFR and fi ltra- pressed with neuronal nitric oxide syn- fl ow are relatively insensitive to the action tion fraction with no change in renal thase and/ or cyclic oxygenase-2 in the of AVP on V1a receptors, possibly because blood fl ow, presumably by blocking the macula densa and distal tubules and may of shear stress–mediated release of nitric eff ect of the anesthesia-induced AVP ele- control renin secretion by stimulation of oxide.24 A renal vasoconstrictor response vation on the eff erent arterioles. 28 Admin- production of nitric oxide and /or prostag- 31 to AVP is observed only with very high istration of a V 1a receptor antagonist to landin E2 . Stimulation of renin secretion, local concentrations or in pathological patients with non-insulin-dependent dia- along with suppression of tubuloglomeru- conditions such as congestive heart failure betes mellitus is also associated with a lar feedback, may lead to glomerular with simultaneous activation of the renin – decrease in GFR and fi ltration fraction. 29 hyperfi ltration, albuminuria, renal hyper- angiotensin and sympathetic nervous sys- Th e renal hemodynamic eff ects of AVP trophy, and tubulointerstitial disease. tems. Under physiological conditions, may also be due to its eff ects on the renin– Th e eff ects of AVP on blood pressure are however, AVP has a signifi cant eff ect on angiotensin system. AVP could potentially complex. V1a eff ects on vascular smooth the medullary circulation. 25 At physiolog- stimulate renin secretion directly via acti- muscle and medullary renal blood fl ow 32 − 1 2 − 1 1 ␤ ␥ ical concentrations (10 to 10 M ) , vation of V2 receptors or indirectly through and V2 eff ects enhancing - and -epithelial AVP contracts eff erent arterioles isolated reduction in sodium concentration at the sodium channel (ENaC) expression and from rabbit kidneys, whereas it has no macula densa. 12 Indeed, DDAVP-induced ENaC function in the cortical collecting eff ect on aff erent arterioles. 26 D e v e l o p m e n t increases in urine albumin excretion are duct33 increase blood pressure. On the other

Kidney International (2009) 76 927 commentary

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