Renin-Aldosterone Relationships in Pregnancy-Induced Hypertension Mark A. Brown, Vivienne

C. Zammit,

Dina A. Mitar, and Judith A.

C

oncentrations of all the components of the renin-angiotensin system are increased during normal pregnancy. " Conversely, plasma renin concentration (PRC) or activity (PRA), plasma aldosterone concentration (PAC), and angioten­ sin II levels (All) in women with pregnancy-induced hypertension (PIH) are usually, " but not invari­ ably, ' reduced in comparison to normal pregnancy. 1

6

7

14

4 15

(277 to 598) ν normal pregnancy 195 (158 to 337), Ρ < .001], with a rise in the slope (sensitivity) of the logPRC-logPAC relationship in women with PIH (P < .001). Thus there is proportionately greater aldosterone release in the third trimester of normal pregnancy than in nonpregnant women. This preferential in­ crease in aldosterone may be due to altered adrenal sensitivity to angiotensin II or may reflect en­ hanced nonangiotensin stimulation of aldosterone during pregnancy. Women with PIH have reduced PRC and PAC but relatively greater stimulation of aldosterone than normal pregnant women, possibly due to enhanced sensitivity of the adrenal glands to angiotensin II. Am J Hypertens 1992;5:366-371 KEY WORDS: Renin, aldosterone, angiotensin II, pregnancy, adrenal glands, pregnancy-induced hy­ pertension.

The mechanism(s) of these changes are unclear. It is generally accepted that in normal pregnancy these are secondary responses to vasodilation or an offset of the sodium losing tendency of increased filtered sodium, progesterone, and other factors. ' This latter concept is supported by the observation that plasma renin and aldosterone respond appropriately to high- and low-salt intakes, " diuretic therapy, saline infusion, ' and upright posture and ambulation ' in normal pregnant women, despite basal plasma concentrations well above those of age-matched nonpregnant women. Attention has focused recently upon a possible disso­ ciation of the gradual changes in renin and aldosterone throughout pregnancy, as plasma and urinary aldoster­ one appear to rise proportionately more than renin by the third trimester. This could mean that factors other than renin (and hence angiotensin II) influence 1 16

5,17

21

15

6

11 25,26

Received August 28, 1991. Accepted February 4, 1992. From the Department of Renal Medicine and School of Medicine, St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia. This work was supported by the St. George Hospital Obstetric Re­ search Fund. Address correspondence and reprint requests to Dr. M.A. Brown, Dept. of Renal Medicine, St. George Hospital, Kogarah, NSW 2217, Australia.

13,27

22-24

Downloaded from http://ajh.oxfordjournals.org/ at University of Manitoba on September 11, 2015

The relationship between plasma renin (PRC) and aldosterone (PAC) concentrations was determined in 83 normal third trimester pregnant women (P), 50 women with pregnancy-induced hypertension (PIH), and 80 age-matched nonpregnant women not taking oral contraceptives (NP). Normal pregnant women had a slightly higher 24-h urine so­ dium : creatinine ratio than the other groups (P < .001) (NP: 10 ± 4 ν Ρ: 15 ± 8 ν PIH: 12 ± 7; mean ± SD). Both PRC and PAC were higher in normal pregnant women as was the ratio P A C : PRC [nor­ mal pregnant 195 (158 to 337) ν nonpregnant 130 (101 to 209), median (interquartile range); Ρ < .001]. This was accompanied by a slightly reduced slope (sensitivity) of the logPRC-logPAC relationship in normal pregnant women (P < .05). Women with PIH had reduced PRC and PAC compared with normal pregnant women but a two­ fold greater increase in P A C : P R C ratio [PIH 411

Whitworth

aldosterone release more during pregnancy than in the nonpregnant state. Alternatively, adrenal sensitivity to All may be enhanced by late pregnancy. There is in­ creased pressor sensitivity to All in women with PIH, but it is not known whether adrenal sensitivity is also enhanced. This study was undertaken to determine the relationships between PRC and PAC in nonpregnant women, normal third trimester pregnant women, and women with PIH. Adrenal sensitivity to All was as­ sessed indirectly by the slope of the plasma renin-aldos­ terone relationship. 28

METHODS

Clinical Studies Following a 24-h urine collection for measurement of sodium (UNa), potassium (UK), and creatinine (Ucreat) excretion, subjects attended our clin­ ical research room between 9 AM and 11 AM. After the subject had sat for 5 to 10 min, the BP was recorded on the right arm using a standard mercury sphygmoma­ nometer. Diastolic BP was recorded as the fourth Korotkoff sound in pregnant women and the fifth sound in nonpregnant women. All women then lay in left lateral recumbency for 30 to 60 min and blood was drawn for measurement of PRC, PAC, and plasma Na, K, uric acid, and creatinine. Laboratory Measurements PRC was measured at physiological pH (7.4) as the generation of angiotensin I (Al) in the presence of excess renin substrate (nephrec­ tomized sheep plasma), as described previously. The intra- and interassay coefficients of variation (CV) for this assay are 7.1 and 10.6%, respectively. PAC was measured by direct radioimmunoassay (SB-ALDO-2, Australian Nuclear Science and Technology Organiza­ 10

Statistics Data for PRC and PAC were not normally distributed and are expressed as median and interquar­ tile range (IQR). All other data are expressed as mean and standard deviation (SD). Differences amongst groups were tested by analysis of variance after logtransformation of PRC and PAC. Differences between medians were then tested by the Mann-Whitney test and between means by Student's t test. Correlations were tested after log-transformation of PRC and PAC values and regression by the least squares method after this transformation. Differences between slopes were tested by analysis of co variance. RESULTS Subjects (Table 1) Normal pregnant women (n = 83) were heavier than nonpregnant women (n = 80) (P < .001) and had significantly lower plasma sodium, potas­ sium, and creatinine concentrations (P < .001). Blood pressure, plasma uric acid, and urine sodium and potas­ sium excretion were similar in these two groups but the urinary creatinine excretion was lower and the so­ dium : creatinine ratio higher in normal pregnant than in nonpregnant women (P < .001). Women with PIH (n = 50) were slightly older (P < .001) and heavier (P < .01) than normal pregnant women and had significantly higher blood pressure, plasma uric acid, and potassium and creatinine concen­ trations (P < .001). Urinary sodium, potassium, and cre­ atinine excretions were similar to those in normal preg­ nancy. Both groups were studied at similar gestations. Birth weight was lower in babies of women with PIH than normal pregnant women (P < .001). Women with features of severe PIH had similar mean blood pressures to those with mild PIH, but had higher plasma urate (severe 0.39 ± 0.06 ν mild 0.33 ± 0.05 mmol/L; Ρ < .001) and creatinine concentration (severe 70 ± 10 ν mild 62 ± 11 //mol/L; Ρ < .05). Urinary sodium, potas­ sium, and creatinine excretion were similar. Birth weight was lower in babies of women with severe rather than mild PIH (severe: 2500 ± 724 ν mild 3147 ± 432 g; Ρ < .001). Plasma Renin and Aldosterone Concentrations PRC and PAC were increased in normal pregnant women compared with nonpregnant women (Table 2), as was the ratio of P A C : PRC (Figure 1). PRC was reduced to the values for nonpregnant women in those with PIH, particularly if the disorder was severe (Table 2). PAC

Downloaded from http://ajh.oxfordjournals.org/ at University of Manitoba on September 11, 2015

Subjects Women with PIH were all inpatients at the time of study. PIH was defined as the development of diastolic blood pressure (DBP) > 9 0 mm Hg after 20 weeks gestation in a nullipara with normal BP prior to 16 weeks and no prior history of hypertension or renal disease, with blood pressure (BP) returning to normal within three months postpartum. PIH was considered severe if any of the following were present: systolic BP (SBP) > 170 mm Hg or DBP > 110 mm Hg, protein­ uria ( > 2 + dipstick testing or > 500 mg/day), thrombo­ cytopenia, abnormal liver function and/or epigastric pain, neurological disturbances, or renal impairment. None of the women were taking medications other than iron or vitamins at the time of these studies. Normal pregnant women were recruited from private practices and the antenatal clinic of our hospital and nonpregnant women from midwives and medical and laboratory staff. None of the women were taking oral contracep­ tives or other medications and all women were eating a free diet at the time of study. The study was approved by the Ethics Committee of the Southern Sydney Area Health Service.

tion, Sydney, Australia). Plasma from pregnant women was diluted 1 : 1 with phosphate buffered saline con­ taining 5 % bovine serum albumin prior to assay for PAC. The intra- and interassay CV's for this assay are 8.9 and 10.3%, respectively. Urine Na and Κ were measured with a flame photo­ meter and urine creatinine and plasma Na, K, uric acid, and creatinine with a autoanalyzer.

TABLE 1. SUBJECT CHARACTERISTICS IN NONPREGNANT AND NORMAL PREGNANT WOMEN AND WOMEN WITH PREGNANCY-INDUCED HYPERTENSION (PIH) Normal Pregnant (n = 83)

PIH (n = 50)

26(3) 60.0(9.1)

25(5) 71.9(11.2)* 35(2) 109(10) 67(9) 0.26(0.05) 138(2)* 3.6(0.2)* 56(10)* 114(43) 58(22) 8.8(2.8)* 15(8)* 7(3) 3394(503)

28(6)t 78.6(11.6)t 36(2) 131(10)t 90(6)t 0.36(0.06)1 137(2) 3.9(0.3)f 66(1 l)t 102(49) 51(25) 9.9(4.2) 12(7) 6(3» 2863(658)t

109(11) 68(9) 0.27(0.06) 141(2) 3.8(0.3) 72(11) 106(45) 62(25) 10.7(2.0) 10(4) 6(3)

Mean (SD). * Ρ < .002, normal pregnant ν nonpregnant, t Ρ < .01, f Ρ < -001, normal pregnant ν PIH.

was also reduced significantly in women with PIH com­ pared with normal pregnant women (Table 2), but the P A C : PRC ratio was two-fold greater in women with PIH (Figure 1). There was no significant difference in PAC or the P A C : PRC ratio between those with mild and severe PIH (Table 2, Figure 1). PRC was low (within the lowest quartile of normal pregnancy) in 7 8 % of women with PIH, whilst PAC was low in 4 8 % of these women. PRC and PAC were significantly correlated in non­ pregnant women (r = 0.47, Ρ < .001), in normal preg­ nant women (r = 0.40, Ρ < .001), and in women with PIH (r = 0.76, Ρ < .001). The slope of the logPRClogPAC relationship was reduced slightly, but signifi­ cantly, in normal pregnant women (0.43 ± 0.18; mean ± SD) compared with nonpregnant women (0.47 ± 0 . 1 0 , P < . 0 5 ) (Figure 2). This slope was in­

creased markedly in women with PIH (0.78 ± 0.10) compared with nonpregnant or normal pregnant women (P < .001) (Figure 2). This was true for both mild and severe PIH. LogPRC did not correlate significantly with urinary sodium excretion in normal pregnant women (r = - 0 . 2 2 ) or women with PIH (r = - 0 . 1 8 ) , but correlated in nonpregnant women (r = —0.32, Ρ < .05). There was a significant correlation between logPRC and birth weight (r = 0.29, Ρ < .05) and be­ tween logPAC and birth weight (r = 0.37, Ρ < .01) in women with PIH, but not in normal pregnant women. DISCUSSION This study demonstrates that although both plasma renin and aldosterone concentrations are increased in third trimester normal pregnant women, there is a pro­ portionately higher PAC than PRC compared with non-

TABLE 2. PLASMA RENIN (PRC) AND ALDOSTERONE (PAC) CONCENTRATIONS IN NONPREGNANT AND NORMAL PREGNANT WOMEN AND IN WOMEN WITH PREGNANCY-INDUCED HYPERTENSION (PIH)

PRC (pmol AI/mL/h) PAC (fmol/mL)

Nonpregnant (n = 80)

Normal Pregnant (n = 83)

2.9 (1.8-4.4) 417 (256-599)

7.3* (4.9-10) 1690* (1095-2488)

Data are median (interquartile range). * Ρ < .001, nonpregnant ν normal pregnant. Χ Ρ < .01, J Ρ < .001, normal pregnant ν P7H. ** Ρ < .01 mild ν severe PIH.

PIH (n = 50)

PIH—Mild (n = 28)

2.8f (1.7-4.2)

3.5 (2.4-5.5) 1455 (851-2206)

\\\7%

(745-1996)

PIH—Severe (n = 22) 19** (1.4-3.1) 906 (593-1497)

Downloaded from http://ajh.oxfordjournals.org/ at University of Manitoba on September 11, 2015

Age (years) Weight (kg) Gestation (weeks) Systolic BP (mm Hg) Diastolic BP (mm Hg) Plasma uric acid (mmol/L) Plasma sodium (mmol/L) Plasma potassium (mmol/L) Plasma creatinine (//mol/L) Urinary sodium (mmol/day) Urinary potassium (mmol/day) Urinary creatinine (mmol/day) Urinary sodium: creatinine Urinary potassium: creatinine Birth weight (g)

Nonpregnant (n = 80)

700 η

31

600

ο

500

g "c φ

-

400

φ

cz

2

+++

φ to

300

11 i i 111

CO CO

Ε

3,4 32

cl

200

100

Nonpregnant

Normal pregnant

PIH

PIH

severe

1. Ratio of plasma aldosterone: plasma renin concen­ tration in nonpregnant and normal pregnant women and in women with pregnancy-induced hypertension (PIH). Data are me­ dians and interquartile ranges. + + + Ρ < .002, normal pregnant ν nonpregnant women. *** Ρ < .002, normal pregnant women ν women with PIH. FIGURE

pregnant women. This occurs despite a slight reduction in the sensitivity (slope) of the renin-aldosterone rela­ tionship. Conversely, women with PIH, either mild or severe, have significantly reduced PRC and PAC, but a markedly increased P A C : PRC ratio with an increased sensitivity (slope) of the PRC-PAC relationship com­ pared with normal pregnant women. In addition, this study confirms earlier observations ' that plasma renin and birth weight are correlated in women with PIH. Although numerous reports have documented in­ creased plasma renin activity (PRA) or concentration, PAC, urinary aldosterone excretion, and aldosterone secretion rate in normal pregnant w o m e n , the rela­ tionships between PRC and PAC have not been ex­ plored in detail. We have shown previously that PRA and PAC re­ spond appropriately to high- and low-salt diets, and are correlated significantly over a wide range of salt intakes in normal pregnant women. We also observed that the slope of that relationship was reduced in preg­ nant women compared with nonpregnant women, but, as PRA is both substrate- and enzyme-dependent, we could not be confident that this reflected changes in 13 29

1-6

1

30

33

Normal pregnant and nonpregnant women had simi­ lar urinary sodium excretion and, although sodium in­ take was not controlled, it is unlikely that a differing sodium balance could explain the increased P A C : PRC in normal pregnancy. Other factors which may alter PAC independently or in concert with All include in­ creased plasma K, corticotropin, dopamine, atrial natriuretic peptide (ANP), or perhaps prostacyclin concentrations. Plasma Κ concentration was reduced in normal pregnant women compared with nonpreg­ nant women in this study and therefore could not ex­ plain these findings. Our observation of a proportion­ ately greater increase in aldosterone compared with renin concentration during normal pregnancy, as com­ pared to nonpregnant women, has not been reported previously. Examination of mean data from another group, using a calculated PRC, supports this observa­ tion. Similarly, P A C : P R A was probably higher in normal pregnant than in nonpregnant women in the study of Karlberg et al though not in that of Fievet et al. The relationship between PRC and PAC is quite dif34

35

37

38

27

7

12

36

Downloaded from http://ajh.oxfordjournals.org/ at University of Manitoba on September 11, 2015

£

the relationship between renin and aldosterone. More­ over, those studies were made during sodium intakes ranging from 10 to 400 mmol/day, which may substan­ tially modify adrenal sensitivity to angiotensin II. In this study we measured renin concentration and PAC during ad lib salt intakes and significant correla­ tions between PRC and PAC were obtained in each group. Moreover, it is clear that PAC is increased propor­ tionately more than PRC by the third trimester of nor­ mal pregnancy in comparison with the nonpregnant state. This at first implies enhanced adrenal sensitivity to angiotensin II, based upon the assumption that PRC reflects plasma All production. A number of studies have shown a significant positive correlation between plasma renin activity or concentration and plasma an­ giotensin II in normal or hypertensive pregnancies. ' Thus, alterations in the slope of PRC-PAC relationships provide a good, albeit indirect, assessment of adrenal sensitivity to AIL On this basis the increased P A C : PRC ratio in normal pregnant women may not be due to enhanced adrenal sensitivity, as the slope of the PRCPAC relationship in these women was less than that of nonpregnant women. This interpretation is supported by our previous observation of a normal aldosterone response to infused angiotensin II in first trimester preg­ nant women. This proportionately greater increase in plasma aldosterone compared to renin in late pregnancy may reflect an increase in nonangiotensin stimulation of aldosterone release. Alternatively, it is possible that al­ dosterone release is augmented at high plasma concen­ trations of renin and All or that there is altered degrada­ tion of angiotensin I during pregnancy with a shift in the balance between All, angiotensin III, and inactive pep­ tide fragments.

3.5

* **

Ί

Relationship between log plasma renin concentration (PRC) and log plasma aldosterone concentration (PAC) in nonpregnant and normal pregnant women and women with pregnancy-induced hy­ pertension (PIH). The equations are: Nonpregnant: logPAC = 2.39 + 0.468 logPRC (r = 0.47; Ρ < .002); Normal pregnant: logPAC = 2.83 + 0.434 logPRC (r = 0.40; Ρ < .002); PIH: logPAC = 2.71 + 0.783 logPRC (r = 0.76; Ρ < .001). ***?

Renin-aldosterone relationships in pregnancy-induced hypertension.

The relationship between plasma renin (PRC) and aldosterone (PAC) concentrations was determined in 83 normal third trimester pregnant women (P), 50 wo...
1MB Sizes 0 Downloads 0 Views