Lise BANKIR Nadine BOUBY, Daniel BICHET, Pascale BARDOUX, Julie PERUCCA, Gilberto VELHO, Ronan ROUSSEL March 7 2017
INSERM Unit 1138 Cordeliers Research Center Paris, France
ØIntroduction about vasopressin Ø Because of recent results of epidemiologic studies Ø Because of direct evidence in animal models Ø Because vasopressin was shown to induce glomerular hyperfiltration (a known process leading to nephron damage) Ø Conclusion
Vasopressin = AVP or Antidiuretic hormone = ADH - Small peptidic hormone of 9 amino acids (MW = 1080) - Di-sulfur bond (ring structure) - Very ancient in evolution (similar hormones in worms and insects, present in all vertebrates) - Synthetized in the hypothalamus and stored in the neurohypophysis. - Secreted in response to rise in plasma osmolarity (Na), or reduction in blood volume, or stress - Strong reproducibility (plus heritability) of threshold and sensitivity - Measurement is time-consuming and not well standardized. - Higher concentration in urine than in plasma. But urinary excretion rate may not reflect the plasma levels.
Vasopressin and its receptors ü Very short biological half life ( 3 min) > Effects are very prompt, and promptly reversible (contrary to those of aldosterone) ü Very low plasma levels: usual range is 0 to 3 pg/ml 3 x 10-12 M ü Three receptors Ø V2R : 2 nd messenger = cyclic AMP Ø V1aR : 2 nd messenger = intracellular Ca ++. Ø V1bR : 2 nd messenger = intracellular Ca ++. Also called V3R ü Non peptidic ANTAgonists (orally active) V2R antagonist = Tolvaptan Mixed V1a and V2 antagonist = Conivaptan
V1b V1a Brain Target organs of AVP V1b Anterior pituitary Centrally released AVP V1a V2 Plasma AVP V1a V1b V1a V2 V1a AVP released in portal hypothalamic blood Platelets Endothelium Kidney V2: Effects on AQP2, ENaC, UT-A1 Pancreatic islets Liver Vascular smooth muscle Aggregation Coagulation V1a: Pgs production Secretion of pancreatic hormones Metabolism V1a : Vasoconstriction V2 : NO release NOTE : The sensitivity to AVP is most probably not the same in all target organs. The Kidney V2R is extremely sensitive. Sensitivity in other organs is poorly documented.
Ø Introduction about vasopressin ØRecent results of epidemiologic studies Ø Because of direct evidence in animal models Ø Because vasopressin was shown to induce glomerular hyperfiltration (a known process leading to nephron damage) Ø Conclusion
In the last 5 years, several epidemiologic studies in human cohorts have revealed significant relationships between the vasopressin/hydration system and adverse effects on kidney function Vasopressin is difficult to measure (small size, very low level, degradation). In these studies, the possible influence of vasopressin is evaluated indirectly by looking at : - water intake or urine volume, or urine osmolarity - plasma copeptin concentration (recent immuno assay) Pre-pro-hormone of vasopressin Vasopressin and copeptin realeased simultaneously in equimolar amouts. But copeptin levels are higher (longer half life?) And Copeptin is easier to measure
General population : egfr decline according to 24 h urine volume at baseline Change in egfr ml/min per 1.73 m 2-0 - 1-2 - 3-4 - 5-6 - 7-8 p < 0.02 < 1.0 1.0-1.9 2.0-2.9 > 3.0 Urine volume at baseline, L/24h Adapted after Clark et al, CJASN, 2011 0 1 2 3 4 5 6 7 8 n = 2148 (Canadian population) Baseline egfr > 60 ml/min.1.73 m 2 Follow-up = 5.7 years. GFR decline was far more rapid in those with a low urine volume. Adjusted for : - age, gender, - baseline estimated GFR, - dipstick protein, - medication for hypertension - diabetes - cardiovascular disease
CKD patients : Time to initiation of dialysis according to urine osmolarity at baseline Cumulative incidence probability for dialysis initiation 775 mosmol/l 510 mosmol/l 315 mosmol/l p < 0.001 Follow up (months) n = 273 patients with CKD stages 1 to 4 Follow-up = 7 years The cummulative probability for dialysis initation was 3-fold higher in patients with high baseline U osm than in those with low baseline U osm Adjusted for baseline GFR and several other risk factors Pflischke et al, PlosOne 2014
Diabetic patients : Renal events according to plasma copeptin at baseline 3101 participants with type 2 diabetes and albuminuria follow-up : 6 year (DIABHYCAR trial) Copeptin tertiles Low Intermediate 729 patients High p=0.005 All 3101 patients Only the 729 patients with macroalbuminuria at inclusion Velho et al, Diabetes Care 2013
Ø Introduction about vasopressin Ø Recent results of epidemiologic studies ØDirect evidence in animal models Ø Because vasopressin was shown to induce glomerular hyperfiltration (a known process leading to nephron damage) Ø Conclusion
An increase in water intake protects the kidney in rats with CKD (5/6th nephrectomy) The increase in water intake was induced by providing the food as a water-rich agar gel A 3-fold increase in water intake (lowering AVP secretion) ameliorated proteinuria, blood pressure, glomerulosclerosis, and mortality in rats with 5/6th nephrectomy Bouby & Bankir, Am.J.Physiol., 1990
ddavp infusion increases urinary albumin excretion in healthy subjects (n = 6) Urine osmolality Urinary excretion mosm/kg H2O ddavp µg / min mg / min Urine albumin excretion NO rise in UAE in NDI subjects with mutation of the V2 receptor Urine albumin excretion µg / min ddavp µg / min ddavp Bardoux et al, NDT 18:497, 2003
The lack of AVP protects the kidney in rats with streptozotocin-induced diabetes mellitus Study in homozygous Brattleboro rats with central diabetes insipidus (due to a mutation in the AVP gene) 40 30 20 10 Plasma glucose (mmol/l) Creatinine clear. (ml/min) *** *** 4 ** 3 2 1 0 Cont. DM Normal AVP Cont. DM No AVP 0 Cont. DM Normal AVP Cont. DM No AVP 4 3 2 1 Urinary albumin excr. (mmol/d) 2 Kidney weight (g/300 g) 4 *** 3 2 1 *** *** 0 Cont. DM Normal AVP Cont. DM No AVP 0 Cont. DM Normal AVP Cont. DM No AVP Bardoux et al, PNAS 1999
Ø Introduction about vasopressin Ø Recent results of epidemiologic studies Ø Direct evidence in animal models ØVasopressin induces glomerular hyperfiltration and the resulting risk Ø Conclusion
From 1990 to 2010, 15 original papers by Bankir, Bouby, Bardoux et al + a few by other groups (one by the group of G. Remuzzi) Adverse effects of chronic ddavp (V2 agonist) infusion - Hyperfiltration and kidney hypertrophy in normal rats >>> similar to that induced by a high protein intake - Worsening of CKD in 5/6 nephrectomized rats - Increase in urine albumin excretion in normal rats - Increase in ENaC abundance and in blood pressure in normal rats Beneficial effects of lowering (moderately) AVP secretion - Reduction in GFR in normal rats - Slowing CKD progression in the 5/6 nephrectomy model - Preventing the rise in urine albumin excretion in rats with diabetes mellitus
Mechanism of these adverse effects of vasopressin? - The adverse effects of high protein intake on the kidney are, at least in part, due to the need : - not only to EXCRETE more urea and other nitrogen endproducts (ammonia, uric acid, phosphates, etc...) - but also to CONCENTRATE urea and other wastes in the urine. - Infusion of ddavp to normal rats resultes in a rise in GFR and a hypertrophy of the kidney that shares a similar pattern to that induced by high protein intake
Concentration of main solutes in plasma and urine Data for healthy human subjects on a normal Western-type diet Note the ten-fold difference in the scales of the abcissa Micromolar range Bankir et al, Amer. J. Physiol. Renal Physiol. 2015 Uric acid
Hydration (Vasopressin) and GFR in humans N = 12 healthy subjects, acute study High Hydration = 4.0 ml/kg BW/30 min Low Hydration = 0.5 ml/kg BW/30 min Two weeks apart (random order) p < 0.001 During low Hydration Inulin clearance (ml/min) Inulin clearance (ml/min) High Low Hydration Anastasio et al, Kidney Int. 2001 Urine osmolality (mosm/kg H2O)
Mechanism of these (adverse) effects of vasopressin - ddavp is a selective V2 receptor agonist - There are no V2 receptors in the glomeruli - The adverse effects are secondary to the action of vasopressin on the renal tubule Note: These effects are different from those observed in ADPKD that are due to stimulating action of camp on cyst growth. (They are most probably additive).
Vasopressin does not act only on water permeability (AQP2). It also regulates ENaC and Urea Transporters V Na Urea Urine osmolality increases at the expense of a reduced efficiency in Na and Urea excretion Bouby et al, JASN 1996
Vicious circle due to glomerular hyperfiltration Diabetes High protein diet Reduced functionning nephron number Primary renal disease AVP Glomerular hyperfiltration Limits the rise in plasma Urea/NH 4 concentrations Glomerular sclerosis Water economy Increased glomerular pressures and flows Increased energy demand for reabsorption of extra solutes filtered Increased oxydative stress and interstitial inflammation Modified after Brenner, AJP 1985
Ø Introduction about vasopressin Ø Recent results of epidemiologic studies Ø Direct evidence in animal models Ø Vasopressin induces glomerular hyperfiltration ØConclusion
Water conservation under the influence of Vasopressin has a price to pay : - Hyperfiltration - Increased albuminuria - Rise in blood pressure Enhanced Vasopressin secretion occurs with : - High protein intake - Diabetes mellitus - Salt sensitive hypertension - Strenuous work in hot climate (Mesoamerican Nephropathy)
Importance of water conservation in Evolution Lack of water, Dehydration Life threatening in the Short-term (days) Good adaptation to water conservation Decline in kidney function, Hypertension,Metabolic disorders. Long-term consequences (yrs) Good water conservation was priviledged by evolution because poor Na/urea excretion does not exert any pressure on natural selection
Vasopressin : Past and Future For a long time, the possible influence of vasopressin was neglected in human studies. Thus, not much data available - No interest in urine volume or concentration - U osm rarely measured - AVP difficult to measure - In clinical investigations : water load + high hydration to facilitate urine collection --- >>> abolish possible vasopressin influence - No good antagonists available for altering vasopressin's effects Recently, new interest because of Copeptin assay, and Vaptans Need for new clinical trials and clinical investigations for evaluating the influence of hydration on GFR - for evaluating the influence of hydration on the progression of CKD, albuminuria, salt-sensitive hypertension, diabetic nephropathy
Two possible strategies to reduce vasopressin's actions Voluntary increase in water intake Treatment with a V2R antagonist Behaviour Increase in water intake Take a drug Cost Nil High Observance Difficult to drink when not thirsty Easy. Good observance Plasma Osmolarity Reduced Increased AVP secretion and Plasma AVP Reduced Increased Effects mediated by other Low or absent Increased receptors (V1aR & V1bR) (1) Possible side effects High diuresis High diuresis Increase in heptatic enzymes (1) Note: The effects mediated by V1a receptors may not be detrimental
Water intake trial (WIT) = "Impact of chronic water intake in CKD" ClinicalTrials.gov Identifier: NCT01766687 Purpose: Randomized controlled trial to test whether increased water intake slows renal decline in patients with Stage-III Chronic Kidney Disease Main investigator : William F. Clark, Lawson, Health Science Center, London, Ontario, Canada Intervention Participants randomized to the hydrationintervention group will be asked to drink 1.0 to 1.5 L of water per day (depending on sex and weight), in addition to usual consumed beverages, for 12 months. Inclusion criteria (700 subjects) : - GFR 30 to 60 ml/minx1.73m 2 - Proteinuria trace or greater by Albustix Or Alb/Creat ratio > 2.8 (male) or 2.0 (female) on any spot urine sample Primary Outcome : Renal decline [ Time Frame: Baseline and 12 months ] Change in estimated glomerular filtration rate between baseline and 12 months Secondary Outcome : - Change in albumin to creatinine ratio between baseline and 12 months - Rapid renal decline: Proportion with egfr decline > 5% between baseline and 12 months Results expected in March 2017 https://clinicaltrials.gov/ct2/show/nct01766687
Thank you for your attention Protein- and diabetes-induced hyperfiltration: Role of glucagon, vasopressin and urea