Renal hemodynamic and tubular responses to salt in women using oral contraceptives

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1 Kidney Interntionl, Vol. 64 (2003), pp VASCULAR BIOLOGY HEMODYNAMICS HYPERTENSION Renl hemodynmic nd tubulr responses to slt in women using orl contrceptives ANTOINETTE PECHÈRE-BERTSCHI, MARC MAILLARD, HANS STALDER, PAUL BISCHOF, MARC FATHI, HANS R. BRUNNER, nd MICHEL BURNIER Policlinique of Medicine nd Division of Endocrinology, Reproduction nd Chemicl Lbortories University Hospitl, Genev, Switzerlnd; nd Division of Hypertension nd Vsculr Medicine, University Hospitl, Lusnne, Switzerlnd Renl hemodynmic nd tubulr responses to slt in women using orl contrceptives. Bckground. The use of orl contrceptives is ssocited with n incresed risk of developing hypertension but the mechnisms of this hypertensive effect re not completely defined. The purpose of the present study ws to ssess prospectively the systemic nd renl hemodynmic nd tubulr responses to slt in women tking orl contrceptives. Methods. Twenty seven young helthy normotensive women tking orl contrceptives contining monophsic combintion of 30 g ethynilestrdiol nd 150 g desogestrel for 6 months were enrolled. All women were ssigned t rndom to receive low (40 mmol/dy) or high (250 mmol/dy) sodium diet for 1 week on two consecutive menstrul cycles during the ctive orl contrceptive phse. At the end of ech diet period, 24-hour mbultory blood pressure, renl hemodynmics, sodium hndling, nd hormonl profile were mesured. Results. The blood pressure response to slt on orl contrceptives ws chrcterized by slt-resistnt pttern with norml circdin rhythm. Slt loding results in n increse in glomerulr filtrtion rte (GFR) (P 0.05 vs. low slt), with no chnge in the renl plsm flow, thus leding to n increse in the filtrtion frction (P 0.05). At the tubulr level, women on orl contrceptives responded to low slt intke with mrked incresed in proximl sodium conservtion (P 0.01 vs. high slt) nd with n lmost complete rebsorption of sodium reching the distl tubule. After sodium loding, both the proximl nd the distl rebsorption of sodium decresed significntly (P 0.01). Conclusion. The use of orl contrceptives is not ssocited with n incresed blood pressure response to slt in young normotensive women. However, orl contrceptives ffect the renl hemodynmic response to slt, high slt intke leding to n increse in GFR nd filtrtion frction. This effect is possibly medited by the estrogen-induced ctivtion of the renin-ngiotensin system. Orl contrceptives lso pper to increse the tubulr responsiveness to chnges in sodium intke. Tken together, these dt point out evidence tht synthetic sex ste- Key words: blood pressure, sodium, lithium, renl, hemodynmics, orl contrceptives. Received for publiction Jnury 4, 2003 nd in revised form Mrch 22, 2003 Accepted for publiction June 10, by the Interntionl Society of Nephrology roids hve significnt impct on renl function in women. The renl effects of orl contrceptives should be tken into ccount when mnging young women with renl diseses. The use of orl contrceptives is known to increse blood pressure in lrge proportion of women nd is ssocited with n incresed risk of developing hypertension [1, 2]. The mechnisms whereby orl contrceptives trigger blood pressure elevtion re not well understood. In erly studies, elevted plsm levels of renin nd ngiotensinogen were found in women receiving estrogens [3 5]. It ws concluded from these observtions tht the renin-ngiotensin system plys mjor role in mediting the chnges in blood pressure in orl contrceptive users. However, similr increses in ngiotensinogen were mesured in both normotensive nd hypertensive women tking orl contrceptives, suggesting tht the heptic stimultion of ngiotensinogen by estrogens is probbly not the only determinnt of the chnge in blood pressure [6, 7]. An impired negtive feedbck on renin secretion induced by orl contrceptives represents nother mechnism tht could led to the rise in blood pressure in hypertensive women receiving orl contrceptives [8]. Yet, more recent study filed to confirm tht the renin-ngiotensin system plys prominent role in mintining high blood pressure in women with orl contrceptive ssocited hypertension [9]. Sodium retention is yet nother potentil mechnism whereby orl contrceptives could led to n increse in blood pressure. In Dhl slt-sensitive rts, femle sex hormones pper to protect ginst the development of sodium-dependent nd -independent hypertension s ovriectomized Dhl slt-sensitive rts exhibit n exggerted development of hypertension [10, 11]. In humns, the incidence of hypertension clerly increses in postmenopusl femles, when femle sex hormones decrese [12] nd this my gin be relted to greter sodium retention. Indeed, we hve reported recently tht meno- 1374

2 Pechère-Bertschi et l: Renl response to slt on orl contrceptives 1375 pusl women not on hormonl replcement therpy re slt-sensitive, their blood pressure incresing significntly on high slt diet [bstrct; Pechère-Bertschi A et l, J Am Soc Nephrol 10:369, 1999]. This contrsts mrkedly with nonmenopusl women who re rther slt-resistnt whtever the phse of the menstrul cycle [13]. The reltive contribution of estrogens nd progesterone in mediting these vrious responses to slt in nonmenopusl nd menopusl women is still uncler becuse the direct effects of femle sex hormones on renl sodium hndling hve not been investigted in gret detils. Severl studies hve demonstrted tht progesterone is ntriuretic but the effects of endogenous s well s exogenous estrogens on sodium excretion re not clerly defined. Ribstein et l [9] hve recently suggested tht there is n ltered utoregultion of renl sodium hndling in hypertensive women tking orl contrceptives. However, women included in this study were not investigted under different slt diets. Thus, whether orl contrceptives ffect the blood pressure by influencing the renl response to slt is still unknown. The gols of the present study were therefore to investigte prospectively the blood pressure nd the renl hemodynmic nd tubulr responses to slt in young normotensive helthy women tking orl contrceptives using stndrd protocol tht hs been used previously in noncontrceptive users [13, 14]. METHODS Subjects The study popultion consisted of 27 young white normotensive femle volunteers recruited mostly mong the medicl students nd the hospitl stff of the University Hospitl of Genev. All women were helthy nd hd been on orl contrceptives contining 30 g ethynilestrdiol plus 150 g desogestrel for 6 months. They were nonsmokers nd were not tking ny mediction known to ffect blood pressure nd renl function. At the initil visit, full medicl history nd clinicl exmintion were undertken. The volunteers were rndomly ssigned to be studied t the beginning (dy 4 to dy 12) nd t the end (dy 21 to dy 28) of the tretment cycles. The study protocol hs been reviewed nd pproved by the Institutionl Ethics Committee (University Hospitl, Genev) nd ll subjects gve their written informed consent. Clinicl investigtion The volunteers were rndomly llocted to receive low (40 mmol sodium per dy) nd high (250 mmol sodium per dy, chieved by dding 6 g of slt in their usul diet) sodium diet for 7-dy period during two consecutive months. The diets were conducted t home nd ll women received detiled recommendtions on how to follow low slt diet. After ech 7-dy diet period, 24-hour urines were collected seprtely during the dy (from 8:00.m. to 10:00 p.m.) nd during the night (from 10:00 p.m. to 8:00.m.) in order to mesure sodium excretion. Concomitntly, 24-hour blood pressure ws recorded using mbultory blood pressure monitoring (Disys, Physicor, Genev, Switzerlnd). This device hs been vlidted by the British Hypertension Society nd ws rted B/A. Ambultory blood pressure ws mesured t 20-minute intervls during the dy (from 8:00.m. to 10:00 p.m.) nd every 60 minutes during the night (from 10:00 p.m. to 8:00.m.). On the next dy, the volunteers were dmitted to the hospitl t 8:30.m. fter n overnight fst to mesure their renl function. Renl hemodynmics ws mesured using sinistrin (n nlog of inulin) nd prminohippuric cid (PAH) clernces s described previously [15]. After lying quietly for 90-minute period of equilibrtion in supine position nd dministrtion of n orl wter lod of 5 ml/kg to ensure stble urine output, the glomerulr filtrtion rte (GFR), nd the effective renl plsm flow (ERPF) were mesured twice, in two 90-minute clernce intervls. Anlytic procedures Sodium excretion ws expressed s U N V in mmol/ dy or mol/min, where U N is the urinry sodium concentrtion nd V is the urinry volume expressed either in ml/24 hours or in ml/min. Proximl renl sodium hndling ws ssessed by the determintion of endogenous lithium in plsm nd urine using grphite furnce tomic bsorption spectrophotometry [16, 17] nd by the frctionl excretion of lithium nd sodium using the stndrd formul (FE X clernce of x divided by the GFR). In ddition, the frctionl distl rebsorption of sodium (i.e., the percentge of the distlly delivered sodium rebsorbed in the postproximl nephron segments) ws clculted s [(FE Li FE N )/FE Li ] 100. Plsm ctecholmines were determined by high-performnce liquid chromtogrphy [18] nd plsm renin ctivity (PRA) nd ldosterone by rdioimmunossy [19, 20]. Plsm progesterone levels were mesured using n enzyme immunossy (Kryptor, CIS Bio, Scly, Frnce). Sinistrin (Inutest ) ws purchsed from Levosn Gesellschft (Zürich, Switzerlnd) nd PAH from SERB, Lbortoires Phrmceutiques (Pris, Frnce). Sttistics All results re expressed s men stndrd error (SEM). Dt were then nlyzed using pired or unpired Student t test for independent smples when pproprite. A one-wy nlysis of vrince ws used for comprison between orl contrceptive users nd nonusers.

3 1376 Pechère-Bertschi et l: Renl response to slt on orl contrceptives Tble 1. Chrcteristics of orl contrception users (N 27) Age yers 26 (rnge, 20 40) Fmily history of hypertension 14/27 Weight kg Body mss index kg/m Premenstrul symptoms 20/27 Cycle study dy (rnge, 4 12, N 13) (rnge, 14 21, N 14) Orl contrceptives Ethinylestrdiol 30 g desogestrel 150 g Serum cretinine lmol/l 76 2 Thirteen women were studied during the first week of tking orl contrceptives nd 14 women were studied during the third week of the tretment. The results were exctly of the sme mgnitude, which is why the two groups were pooled. Tble 2. Ambultory blood pressure response to slt on orl contrceptives Dy Night Sodium diet Low High Low High Systolic blood pressure mm Hg Distolic blood pressure mm Hg Pulse pressure mm Hg Hert rte bets/min P 0.01 vs. dytime RESULTS The bseline chrcteristics of the women included in this study re presented in Tble 1. More thn hlf of the subjects suffered from mild premenstrul symptoms. There ws fmily history of hypertension in bout hlf of the volunteers. Blood pressure nd hert rte response to slt The chnges in 24-hour urinry sodium excretion induced by the two diets were significntly different. On low slt diet, U N V ws 26 3 mmol/24 hours, nd on high slt diet, the men sodium excretion ws mmol/24 hours (P 0.01). The slt-induced chnges in dytime nd nighttime mbultory blood pressure, hert rte, nd pulse pressure on orl contrceptives re presented in Tble 2. No significnt differences in dytime or nocturnl mbultory blood pressure or hert rte were observed on high compred with low sodium intke on orl contrceptives. A significnt nocturnl dip in both systolic nd distolic blood pressures ws found whtever the diet (P 0.01 nighttime compred with dytime). Figure 1 illustrtes the pressure-ntriuresis reltionship in subjects on orl contrceptives in comprison with women not receiving contrceptives nd evluted either during the folliculr or during the lutel phse of norml menstrul cycle. The grph demonstrtes tht blood pressure on orl contrceptives is essentilly slt-resistnt, s found in the two phses of the norml menstrul cycle without orl contrceptives [13]. Fig. 1. Reltionship between men mbultory blood pressure (mm Hg) nd sodium excretion ( mol/min) in normotensive women studied on orl contrceptive gents nd in orl contrceptive nonusers. All vlues re men SE. Tble 3. Renl hemodynmic nd hormonl responses to slt on orl contrceptives Low Sodium diet High GFR ml/min/1.73 m ERPF ml/min/1.73 m FF % PRA ng/ml/hour b Aldosterone nmol/l b Adrenline nmol/l Nordrenline nmol/l Progesterone ng/ml Abbrevitions re: GFR, glomerulr filtrtion rte; ERPF, effective renl plsm flow; FF, filtrtion frction; PRA, plsm renin ctivity. P 0.05; b P 0.01 vs. low slt diet Renl hemodynmic nd hormonl response to slt The effects of chnging the sodium intke on renl hemodynmics nd hormonl profile on orl contrceptives re presented in Tble 3. Slt loding induced significnt increse in GFR (P 0.05) nd no significnt chnge in ERPF compred with low slt intke, consequently filtrtion frction ws significntly incresed (P 0.05). The effects of chnging sodium intke on the vsoctive hormones profile in orl contrceptive users re lso presented in Tble 3. As expected, PRA nd ldosterone levels decresed significntly (P 0.01) fter sodium loding. Plsm nordrenline nd drenline levels were not significntly chnged by the different sodium diets. On orl contrceptives, plsm progesterone levels were low nd not ffected by the sodium content of the diet.

4 Pechère-Bertschi et l: Renl response to slt on orl contrceptives 1377 Tble 4. Segmentl tubulr renl sodium response to slt on orl contrceptives (N 27) Low Sodium diet High Body weight kg Urinry volume L Dy Night b b U N Vlmol/min Dy c Night b,c FE N % Dy c Night c Cl Li ml/min Dy c Night c FE Li % Dy c Night c FDR N % Dy c Night c FE K % Dy c Night c Abbrevitions re: U, urinry; FE N, frctionl excretion of sodium; Cl, clernce; FE Li, frctionl excretion of lithium; FDR N, frctionl distl rebsorption of sodium; K, potssium. P 0.05; b P 0.01 dytime vs. nighttime; c P 0.01 vs. low slt diet Segmentl renl sodium hndling on orl contrceptives nd the effect of slt On orl contrceptives, dministrtion of high sodium diet cused significnt increse in body weight ( kg). Tble 4 shows the diet-induced chnges in sodium excretion nd proximl nd distl renl sodium hndling. The urinry volume did not chnge significntly from low to high slt diet. As expected from the diets, the dytime nd nighttime urinry sodium excretion incresed significntly from low to high sodium intke (P 0.01), indicting tht complince to the regimen ws excellent. On high slt diet, sodium excretion decresed significntly during the night (P 0.01, dy vs. night). The frctionl excretion of endogenous lithium (FE Li ), mrker of proximl excretion, incresed significntly on high sodium diet (P 0.01), nd the frctionl distl rebsorption of sodium (FDR N ) decresed significntly, indicting tht sodium blnce is mintined by both decrese in proximl nd distl sodium rebsorption in women on orl contrceptives. DISCUSSION The min objective of the present study ws to evlute the effect of orl contrceptives on the blood pressure nd the renl response to slt. Our results show tht the blood pressure response to slt in young normotensive women on orl contrceptives is chrcterized by sltresistnt pttern, with norml circdin rhythm. In the kidney, chronic slt loding results in significnt increse in GFR with no chnge in ERPF, thus leding to n increse in filtrtion frction. At the tubulr level, women on orl contrceptives respond to low slt intke with incresed proximl sodium conservtion nd with n lmost complete rebsorption of the sodium reching the distl level of the tubule. After sodium loding, both the proximl nd the distl rebsorption of sodium decreses significntly. The dministrtion of orl contrceptives hs been ssocited with rise in blood pressure nd some women my even develop significnt but reversible hypertension [1, 2]. Activtion of the renin-ngiotensin system is generlly considered s the min fctor leding to the increse in blood pressure since estrdiol dministrtion stimultes the heptic synthesis of ngiotensinogen [21, 22]. The exogenous femle sex hormones cn lso cuse decrese in sodium excretion ccompnied by wter retention, two fctors tht my further contribute to increse blood pressure [23]. In this study, we show for the first time tht the pressure-ntriuresis reltionship of women tking orl contrceptives is of the slt-resistnt pttern, s it is in orl contrceptive nonusers in both phses of the menstrul cycle [13] (Fig. 1). Interestingly, the slt-resistnt pttern is observed despite the reltive stimultion of the renin-ngiotensin system. As expected, PRA in our orl contrceptive users is higher thn the ctivity mesured in orl contrceptive nonusers studied t comprble levels of slt intke [13] nd the chnges in PRA induced by the chnges in sodium intke is significntly greter in orl contrceptive users thn in nonusers s shown in Tble 5. Yet, in orl contrceptive users, PRA cn still be prtilly suppressed on high slt intke. The slt-resistnt pttern in fce of n ctivted renin-ngiotensin system is therefore in ccordnce with the findings of Hll et l [23] who hve shown in dogs tht slt sensitivity develops primrily when the ctivity of the renin-ngiotensin cscde cnnot be modulted. The results of the present study suggest tht exogenous femle sex hormones influence mrkedly the renl hemodynmic response to slt without ffecting systemic blood pressure. Indeed, slt loding in orl contrceptive users induced significnt increse in GFR with no chnge in ERPF, hence filtrtion frction incresed. The slt-induced chnges in GFR nd ERPF re shown in Tble 5 for orl contrceptive users nd nonusers. A comprble but nonsignificnt trend ws observed in orl contrceptive nonusers studied during the folliculr phse [14]. In contrst, during the lutel phse of the norml menstrul cycle, we found tht slt loding induces renl vsodilttion with no chnge in GFR. There re few dt on the renl hemodynmic effects of orl contrceptives. An erly study by Hollenberg et

5 1378 Pechère-Bertschi et l: Renl response to slt on orl contrceptives Tble 5. Renl response to slt: Comprison between orl contrceptive users nd nonusers Orl contrceptive Folliculr Lutel (N 27) (N 17) (N 18) Sodium diet High-low High-low High-low ANOVA GFR ml/min/1.73 m b P ERPF ml/min/1.73 m c P NS PRA ng/ml/hour b b P FE N % P 0.06 FE Li % d P 0.06 Abbrevitions re: GFR, glomerulr filtrtion rte; ERPF, effective renl plsm flow; PRA, plsm renin ctivity. All vlues hve been obtined by subtrcting the result of the low slt diet from tht of the high slt diet. b P 0.01 vs. orl contrceptive (unpired t test); c P 0.05; d P 0.01 vs. folliculr (pired t test) l [24] showed tht orl contrceptives in helthy young women reduced the ERPF nd reported negtive correltion between plsm ngiotensin II levels nd ERPF with significnt ctivtion of the renin-ngiotensin system. The dministrtion of orl contrceptives hs been found to increse cretinine clernce in young women studied on free sodium intke [25]. Kng et l [26] found significnt increses in systolic blood pressure, renl vsculr resistnce, nd filtrtion frction in orl contrceptive users compred to nonusers, nd showed tht these differences were t lest prtilly bolished by ngiotensin II blockde. At the glomerulr level, n increse in GFR nd filtrtion frction cn result either from vsodilttion of fferent rterioles ssocited or not with n increse in the tonus of the efferent rteriole or to vsoconstriction of the efferent rteriole with no chnge in the fferent tone. A direct effect on the glomerulus my lso produce n increse in filtrtion frction. To explin the slt-induced renl vsodilttion nd fll in filtrtion frction in women studied during the lutel phse, we hd proposed the hypothesis tht estrogens modulte the renl hemodynmics indirectly vi the nitric oxide pthwy nd perhps prostglndin formtion [13, 14], thereby inhibiting the effects of ngiotensin II on glomerulr hemodynmics. Through this mechnism, estrogens could cuse renl vsodilttion nd decrese in filtrtion frction. The sme mechnism my ctully be operting to explin the sltinduced increse in GFR in orl contrceptive users but with one importnt difference (i.e., the bseline ctivity of the renin-ngiotensin system). Thus, we hypothesize tht the vsodiltory effect of estrogens in orl contrceptive users my be more prominent t the level of fferent rteriole, thereby leding to n increse in GFR nd filtrtion frction. Of course, we relize tht this hypothesis is very specultive nd deserves further investigtions with more direct mesurements. Of note, high plsm estrogen levels hve been reported to ugment endothelil nitric oxide synthesis [27, 28]. The pprent difference between endogenous nd exogenous femle sex hormones s reflected by the more pronounced effect of slt loding on renl hemodynmic in orl contrceptive users thn in nonusers could be ttributed to differences in potency between endogenous nd exogenous femle sex hormones. Indeed, combined orl contrceptive gents deliver phrmcologic levels of estrogens tht exhibit 6 to 10 times the estrogenic ctivity provided by endogenous estrogens [29]. Finlly, the observtion of slt-induced increse in GFR nd filtrtion frction in orl contrceptive users my hve long-term clinicl impct nd implictions for use in ptients with renl disese. Indeed, in recent study, significnt increse in 24-hour urinry lbumin excretion ws found in normotensive s well s in hypertensive women using orl contrceptives when compred with nonusers with similr blood pressure [9]. In this clinicl sitution, low sodium intke my lower intrglomerulr pressure nd hence reduce urinry protein excretion. The effects of exogenous femle sex hormones on renl tubulr function re not known. Endogenous progesterone is known to be ntriuretic, but synthetic derivtives of progesterone my not hve similr ntriuretic properties. Indeed, erly studies hve demonstrted tht synthetic progestins hd decresed ffinity for renl minerlocorticoid receptors, explining lck of ntriuretic ctivity of these compounds [30]. Whether estrogen ffects tubulr sodium hndling is not known. In our orl contrceptive users, the tubulr response to chnges in sodium intke ws reltively comprble to tht obtined in normotensive men [31] nd in women studied during the folliculr phse of the menstrul cycle (Tble 5) [14]. Indeed, the proximl rebsorption of sodium incresed mrkedly on low sodium diet, s reflected by decrese in FE Li, nd decresed significntly on high sodium diet. As shown in Figure 2, the FE Li /FE N reltionship is prllel but shifted to lower levels of FE Li in women receiving orl contrceptives when compred to women studied in the folliculr phse. This shift my gin be ttributed to the ctivtion of the renin-ngiotensin system leding to n incresed proximl rebsorption of sodium. A high rebsorption of sodium ws lso found to occur in the distl tubule s reflected by the

6 Pechère-Bertschi et l: Renl response to slt on orl contrceptives 1379 ACKNOWLEDGMENTS This work ws supported by the Fonds Ntionl Suisse de l Recherche Scientifique (grnt nos nd to M. B.). A.P.-B. ws supported by Mrie-Heim Vögtlin grnt (no ). Reprint requests to Antoinette Pechère-Bertschi, M.D., Medicl Policlinic nd Division of Endocrinology, HUG, 1214 Genev 4, Switzerlnd. E-mil: Antoinette.Pechere@hcuge.ch REFERENCES Fig. 2. Slt-induced vritions in dytime frctionl excretion of sodium (FE N ) nd endogenous lithium (FE Li ) in normotensive women studied on orl contrceptives. For comprison, the sme prmeters studied in the folliculr nd lutel phses of the norml menstrul cycle published previously re presented [14]. Low slt, 40 mmol/dy; high slt, 250 mmol/dy. very high FDR N. Thus, combined orl contrceptives do not pper to ffect the blnce between the proximl nd the distl nephron segments. However, becuse of the ctivtion of the renin-ngiotensin system, women on orl contrceptives my hve greter tubulr responsiveness. Interestingly, in our study, chronic orl contrceptive dministrtion resulted in positive sodium blnce when diet chnges from low to high slt diet, reflected in men weight gin of 1.5 kg. CONCLUSION This study shows tht the use of hormonl contrceptives is not ssocited with n incresed blood pressure response to slt, nd women on orl contrceptives hve slt-resistnt pttern like orl contrceptive nonusers. However, orl contrceptives do ffect the renl hemodynmic response to slt, n effect tht ppers to be medited by the combined effects of estrogens on the renin-ngiotensin system nd on vsodiltory fctors such s nitric oxide nd prostglndins. The increse in filtrtion frction observed with the dministrtion of contrceptives in women receiving high slt diet my be of clinicl concern since high filtrtion frction hs been ssocited with n incresed incidence of microlbuminuri nd proteinuri s well s with n incresed risk of glomerulr sclerosis. At lst, exogenous femle sex hormones pper to increse the tubulr responsiveness to chnges in sodium intke leding to n incresed rebsorption of sodium. Tken together, these dt point out evidence tht synthetic sex steroids differ in their effects on kidney from endogenous steroids. In generl point of view, it implictes tht in women on orl contrceptives suffering from ny kidney problem, sodium restriction should be encourged. 1. Chsn-Tber L, Willett WC, Mnson JAE, et l: Prospective study of orl contrceptives nd hypertension mong women in the United Sttes. 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