Original Article
The Renin–Angiotensin–Aldosterone System and Autosomal Dominant Polycystic Kidney Disease
N Engl J Med 1990; 323:1091-1096October 18, 1990
- Abstract
- Abstract
Background.
A high incidence of hypertension (50 to 75 percent) occurs early in the course of autosomal dominant polycystic kidney disease. Cyst enlargement, causing bilateral renal ischemia and subsequent release of renin, is proposed as the cause of this form of hypertension.
Methods.
To investigate this hypothesis, we measured plasma renin activity and aldosterone concentrations during short-term and long-term converting-enzyme inhibition in 14 patients with hypertension due to polycystic kidney disease, 9 patients with essential hypertension, 11 normotensive patients with polycystic kidney disease, and 13 normal subjects. The groups were comparable with respect to age, sex, body-surface area, degree of hypertension, sodium excretion, and renal function.
Results.
During the short-term study, the mean (±SE) plasma renin activity was significantly higher in the hypertensive patients with polycystic kidney disease than in the patients with essential hypertension, in the supine (0.36±0.06 vs. 0.22±0.06 ng per liter · second, P = 0.05) and upright positions (1.03±0.14 vs. 0.61±0.08 ng per liter · second, P<0.03) and after converting-enzyme inhibition (1.97±0.28 vs. 0.67±0.17 ng per liter · second, P<0.0006). The mean arterial pressures measured in the supine and upright positions and the plasma aldosterone concentrations measured in the upright position were significantly higher in the normotensive patients with polycystic kidney disease than in the normal subjects. After six weeks of converting-enzyme inhibition, renal plasma flow increased (P<0.005), and both renal vascular resistance (P<0.007) and the filtration fraction (P<0.02) decreased significantly in the hypertensive patients with polycystic kidney disease but not in the patients with essential hypertension.
Conclusions.
The renin–angiotensin–aldosterone system is stimulated significantly more in hypertensive patients with polycystic kidney disease than in comparable patients with essential hypertension. The increased renin release, perhaps due to renal ischemia caused by cyst expansion, probably contributes to the early development of hypertension in polycystic kidney disease. (N Engl J Med 1990; 323:1091–6.)
Media in This Article
Figure 1
Mean (±SE) Plasma Renin Activity and Plasma Aldosterone Concentrations in 14 Patients with Hypertension and Polycystic Kidney Disease (Hatched Bars) and 9 Patients with Essential Hypertension (Crosshatched Bars).Figure 2
Mean (±SE) Values for Renal Vascular Resistance and Filtration Fraction before (Open Bars) and after (Hatched Bars) Six Weeks of Oral Therapy with the Angiotensin-Converting—Enzyme Inhibitor Enalapril.Article Activity
- Article
HYPERTENSION occurs in 50 to 75 percent of patients with autosomal dominant polycystic kidney disease before there is serious loss of renal function.1 2 3 4 5 6 7 8 9 10 11 Although many investigators have searched for potential pathogenetic mechanisms causing early hypertension in this disease, the cause is unclear. Renal cyst formation with secondary arteriolar attenuation has been observed on renal angiography in patients with polycystic kidney disease,12 , 13 and immunohistochemical studies have demonstrated increased numbers of renin-secreting granules in renal tissue from such patients.14 These findings suggest that renal ischemia and activation of the renin–angiotensin–aldosterone system may occur in polycystic kidney disease.
The results of studies of the renin–angiotensin–aldosterone system in hypertensive patients with polycystic kidney disease are conflicting, however.5 6 7 8 9 Small numbers of patients,6 , 8 wide variability in dietary sodium intake7 and glomerular filtration rates,5 and the use of saralasin,15 an angiotensin antagonist with partial agonistic properties,16 are potential reasons for these inconsistent results. Moreover, and perhaps most important, the bilateral nature of the renal cystic involvement is similar to that of bilateral renal-artery stenosis, in which initial plasma volume expansion and suppression of an activated renin—angiotensin system occur, making incrimination of the renin–angiotensin–aldosterone system more complex than in the case of unilateral renal ischemia. Specifically, the sodium—renin profiles differ in unilateral and bilateral renal ischemia, because in the former, pressure natriuresis in the uninvolved kidney can compensate for the sodium retention caused by activation of the renin–angiotensin–aldosterone system. This is not the case with bilateral renal ischemia. Nevertheless, Bell et al.9 recently found that inhibition of the angiotensin-converting enzyme with captopril stimulated the renin–angiotensin–aldosterone system more in hypertensive than in normotensive patients with polycystic kidney disease, all of whom had normal renal function.
This study was undertaken to explore further the potential role of the renin–angiotensin–aldosterone system in the hypertension associated with polycystic kidney disease. Since renal perfusion is a known determinant of renal release of renin, we compared hypertensive patients who had polycystic kidney disease with patients with essential hypertension who were similar in age, sex, body-surface area, sodium excretion, renal function, and mean arterial pressures. We also compared normotensive patients who had polycystic kidney disease with normal subjects to determine whether activation of the renin–angiotensin–aldosterone system occurs before the development of hypertension in polycystic kidney disease.
Methods
We studied 14 hypertensive patients and 11 normotensive patients with polycystic kidney disease, 9 patients with essential hypertension, and 13 normal subjects, all between the ages of 19 and 48 years. This study was approved by the human subjects committee of the University of Colorado Health Sciences Center. Written informed consent was obtained before each procedure. Subjects were considered eligible for the study if their weight was less than 140 percent of their ideal body weight, as determined by standard life-insuranceance tables. Given the young age at the onset of hypertension among patients with polycystic kidney disease, only normal subjects and patients with essential hypertension under 45 years old were recruited. All 47 subjects had creatinine clearance values above 1.17 ml per second per 1.73 m2 of body-surface area (70 ml per minute per 1.73 m2).
Polycystic kidney disease was defined by the presence of five or more cysts distributed bilaterally, as determined on ultrasonography. In both the essential hypertension group and the polycystic kidney disease group, hypertension was defined as blood pressure above 140/90 mm Hg measured in the sitting position on three separate occasions, or a previous diagnosis of hypertension (blood pressure above 140/90 mm Hg) and treatment with one or more antihypertensive medications. Patients were considered to have essential hypertension if their serum electrolyte concentrations and microscopical urine analyses were normal and they had no history of diabetes mellitus, renal disease, or renal stones.
Patients who had been taking antihypertensive medications discontinued them for at least two weeks before entering the study. Any patient whose blood pressure increased to more than 150/110 mm Hg after the discontinuation of antihypertensive medications was not studied further. The patients' dietary intake of protein and sodium was estimated on the basis of a dietary history before the study. No vegetarians were included in the study. All patients were instructed to maintain their usual diet and sodium intake during withdrawal from their medications. All subjects were instructed not to take nonsteroidal antiinflammatory agents or products containing aspirin for 48 hours before the start of the study. All subjects were instructed to collect a 24-hour urine specimen on the day before the initial study for the determination of levels of sodium and potassium excretion.
Study Protocol
After an overnight fast (except that the drinking of water was allowed), the subjects began the study in the General Clinical Research Center at the University of Colorado Health Sciences Center at 8 a.m. After their height, weight, blood pressure, and pulse rate had been measured, the subjects were placed in the supine position for two hours. The blood pressure was then measured three times in the right arm with a Dinamap machine (Critikon, Tampa, Fla.), and the mean arterial pressure was calculated according to the following formula:
diastolic blood pressure + [(systolic − diastolic blood pressure) ÷ 3].
Blood was obtained for the measurement of plasma renin activity and aldosterone concentrations, serum levels of creatinine, sodium, potassium, chloride, and total carbon dioxide, blood urea nitrogen, hematocrit, and in the women, qualitative determinations of human chorionic gonadotropin beta subunit. The subjects walked comfortably in the ward for two hours, after which their blood pressure was measured three times and blood was collected for determinations of plasma renin activity and aldosterone concentration. The patients with hypertension and polycystic kidney disease and those with essential hypertension then underwent simultaneous measurements of creatinine, inulin, and p-aminohippurate clearance with use of an initial oral water load of 10 ml per kilogram of body weight and oral hydration at a rate of 300 ml per hour to maintain urinary flow rates above 100 ml per hour. Three 30-minute clearances were obtained. Blood pressure was measured every hour during the clearance study, and blood samples were taken at the midpoint of each clearance period for determinations of serum levels of creatinine, inulin, and p-aminohippurate.
After the clearance determinations, the subjects were seated for 30 minutes with their legs hanging down. They were then given an oral dose of 50 mg of captopril dissolved in water, and their blood pressure was measured every 5 minutes for 60 minutes. The plasma renin activity and aldosterone level and serum sodium and potassium concentrations were determined 60 minutes after the ingestion of captopril.17
The subjects were discharged from the General Clinical Research Center after these studies and instructed to continue their normal dietary and sodium intake. The patients with hypertension and polycystic kidney disease and those with essential hypertension were given enalapril (5 mg per day) at discharge. They were also given Marshall-85 blood-pressure cuffs and, after calibration, careful instruction, and evidence of competent self-measurement, were asked to measure their blood pressure in the seated position before their morning dose of enalapril and early in the evening (before 8 p.m.). The patients' blood-pressure logbooks were reviewed every seven days, at which times the enalapril dose was increased by 5-mg increments until their blood pressures reached a level of 110/70 mm Hg, the mean arterial pressure decreased by 30 mm Hg, or a drug dosage of 20 mg per day was reached. The blood-pressure recordings from the initial study day were compared with the mean weekly recordings from the patients' logbooks and with the recordings made at the time of the return visit within each group.
After six weeks of enalapril therapy, the patients collected a 24-hour urine specimen and returned to the General Clinical Research Center for restudy. After an overnight fast in which only the ingestion of water and enalapril was allowed, the subjects were studied according to a protocol identical to that of the initial study day, except that no captopril was given.
Assays and Calculations
Plasma renin activity18 and plasma aldosterone concentrations19 were determined by radioimmunoassay. Serum levels of sodium, potassium, chloride, and total carbon dioxide, blood urea concentrations, and hematocrit were determined by standard laboratory techniques in the General Clinical Research Center laboratory. Serum and urinary creatinine concentrations were determined by the modified Jaffé picrate reaction with a Beckman 2 AutoAnalyzer, and inulin and p-aminohippurate concentrations were determined by standard colorimetric techniques.20 All clearance values were corrected to correspond to those of a subject with 1.73 m2 of body-surface area. Renal vascular resistance was calculated with the following formula:
[mean arterial pressure × (1 − hematocrit/100) × 79,920]/p-aminohippurate clearance.
Statistical Analysis
Comparisons were made by rank-sum analysis between the patients with hypertension and polycystic kidney disease and those with essential hypertension and between the normotensive patients with polycystic kidney disease and the normal subjects. Changes within groups were compared by signed-rank analysis. Changes in blood pressure after short-term and long-term converting-enzyme inhibition were compared by multivariate repeated-measures analysis. Statistical significance was defined as being indicated by a P value <0.05; significant P values are provided below. All values are reported as means ±SE.
Results
Short-Term Studies in the Two Groups of Hypertensive Patients
The sex distribution, age, body-surface area, 24-hour sodium excretion, and inulin, p-aminohippurate, and creatinine clearances were similar in the two groups of patients with hypertension (Table 1Table 1
Characteristics of the Two Groups of Hypertensive Subjects at the Beginning of the Study.*). The blood pressures in the supine and upright positions and the maximal change in mean arterial pressure after the ingestion of 50 mg of captopril were also similar in both groups (Table 1).As measured in both the supine and the upright positions and after the ingestion of captopril, the mean plasma renin activity was higher in the group with hypertension and polycystic kidney disease than in the group with essential hypertension (Fig. 1Figure 1
Mean (±SE) Plasma Renin Activity and Plasma Aldosterone Concentrations in 14 Patients with Hypertension and Polycystic Kidney Disease (Hatched Bars) and 9 Patients with Essential Hypertension (Crosshatched Bars).). The mean values measured in the supine position were 0.36±0.06 and 0.22±0.06 ng per liter · second, respectively (P = 0.05); in the upright position, 1.03±0.14 and 0.61±0.08 ng per liter · second (P<0.03); and after the ingestion of captopril, 1.97±0.28 and 0.67±0.17 ng per liter · second (P<0.0006). The increment in plasma renin activity after captopril ingestion was also significantly greater in the group with hypertension and polycystic kidney disease than in the group with essential hypertension (P<0.005).The mean plasma aldosterone concentration was significantly higher in the group with hypertension and polycystic kidney disease than in the group with essential hypertension, as measured in the supine position and after captopril ingestion. The plasma aldosterone concentrations also tended to be higher when measured in the upright position in the group with hypertension and polycystic kidney disease (P = 0.055) (Fig. 1). The initial serum sodium and potassium concentrations in both groups were normal and did not change after the ingestion of captopril (data not shown).
Short-Term Studies in the Two Groups of Normotensive Subjects
The sex distribution, age, body-surface area, 24-hour sodium excretion, and creatinine clearance were similar in the normotensive patients with polycystic kidney disease and the normal subjects (Table 2Table 2
Characteristics of the Two Groups of Normotensive Subjects at the Beginning of the Study.*). The mean arterial pressure, however, was significantly higher in the normotensive group with polycystic kidney disease than in the normal group when measured in both the supine (P<0.02) and the upright (P<0.002) positions (Table 2). The mean arterial pressure increased significantly from the supine to the upright position in both groups.Despite the higher mean arterial pressure and the correspondingly higher renal perfusion pressure in the group with polycystic kidney disease as compared with the normal group, the mean plasma renin activity was similar in the two groups when measured in the supine and the upright positions (Table 2). However, the mean plasma aldosterone concentration measured in the upright position was significantly higher in the normotensive patients with polycystic kidney disease than in the normal subjects (P<0.02).
Long-Term Converting-Enzyme Inhibition in the Two Groups of Hypertensive Patients
During the six weeks of enalapril therapy, one man with hypertension and polycystic kidney disease was lost to follow-up; all the patients with essential hypertension completed the study. Side effects occurred at a similar rate and with similar severity in the two groups, the most common side effects being fatigue (in 12.9 percent), headache (in 12.1 percent), and cough (in 9.7 percent). The mean daily dose of enalapril in the two hypertensive groups was similar at the end of the six-week period (group with hypertension and polycystic kidney disease, 15.8±1.9 mg per day; group with essential hypertension 19.4±0.6 mg per day; P not significant). The decreases in mean arterial pressure from the initial to the final visit were similar, and the decreases were significant in both groups (group with hypertension and polycystic kidney disease, P<0.0005; group with essential hypertension, P<0.004).
Body-surface area, 24-hour sodium excretion, and creatinine and inulin clearance did not change in either group after six weeks of enalapril administration (Table 3Table 3
Characteristics of the Two Groups of Hypertensive Subjects before and after Six Weeks of Enalapril Therapy.*). However, 11 of the 13 patients with polycystic kidney disease who completed the study had increases in p-aminohippurate clearance, a measure of effective renal plasma flow, whereas in 2 patients this measure did not change. Among the nine patients with essential hypertension, p-aminohippurate clearance increased in five, decreased in two, and did not change in two. Therefore, renal plasma flow increased significantly (P<0.005) and the filtration fraction decreased significantly (P<0.02) in the hypertensive patients with polycystic kidney disease, but not in the patients with essential hypertension. Renal vascular resistance decreased significantly only in the group with polycystic kidney disease (Fig. 2Figure 2Mean (±SE) Values for Renal Vascular Resistance and Filtration Fraction before (Open Bars) and after (Hatched Bars) Six Weeks of Oral Therapy with the Angiotensin-Converting—Enzyme Inhibitor Enalapril.).Discussion
The 50 to 75 percent incidence of hypertension that occurs before the loss of renal function in patients with autosomal dominant polycystic kidney disease is an important feature of this hereditary disorder, and it may be a factor in the progression of renal disease.21 22 23 Moreover, since cardiovascular events are the chief cause of mortality in patients with polycystic kidney disease,1 , 24 hypertension may be a factor in these complications. Thus, the factors initiating hypertension associated with polycystic kidney disease are worthy of investigation.
We examined the hypothesis that the initiation of hypertension in patients with polycystic kidney disease involves cyst-induced bilateral renal ischemia with activation of the renin–angiotensin–aldosterone system. A study of normotensive and hypertensive patients with polycystic kidney disease and normal renal function at our institution had demonstrated that hypertensive patients had significantly larger renal volumes.11 This finding was compatible with bilateral cystic involvement, renal vascular compression, and activation of the renin–angiotensin–aldosterone system as factors initiating hypertension in this disorder.9
Plasma renin activity, however, has not been found to be higher in hypertensive than in normotensive patients with polycystic kidney disease.5 6 7 8 Despite this finding, the renin–angiotensin–aldosterone system may still have an important role in hypertension in polycystic kidney disease, as is the case in the one-kidney Goldblatt model of hypertension or in bilateral renal-artery stenosis.25 , 26 In unilateral renal-artery stenosis, tubular sodium reabsorption is increased in the affected kidney, but a pressure natriuresis occurs in the contralateral kidney so that an elevated plasma renin activity persists.26 However, bilateral renal-artery stenosis, or bilateral renal ischemia, as may occur in polycystic kidney disease, may cause increased tubular sodium reabsorption in both kidneys, with the result that plasma renin activity may not exceed values in the normal range.27 Another confounding factor is the ability of an increase in renal perfusion pressure to suppress renal release of renin. A comparison of the activity of the renin–angiotensin–aldosterone system in hypertensive patients with polycystic kidney disease and patients with essential hypertension at comparable blood-pressure levels is therefore appropriate.
It is reasonable to propose that cyst-induced renal ischemia causes stimulation of the renin–angiotensin–aldosterone system, since the degree of renal cystic involvement correlates with the presence of early hypertension in polycystic kidney disease.11 Further support for this possibility is provided by renal angiographic studies, which demonstrate the attenuation of peripheral renal vessels in patients with polycystic kidney disease,12 , 13 and by the observation that cyst decompression is associated with a decrease in mean arterial pressure.27 , 28
The short-term inhibition of angiotensin-converting—enzyme activity resulted in a greater increase in plasma renin activity in the hypertensive patients with polycystic kidney disease than in the patients with essential hypertension. Likewise, long-term inhibition had markedly different effects on renal hemodynamics in the two groups. Specifically, effective renal plasma flow increased and the filtration fraction and renal vascular resistance decreased after six weeks of converting-enzyme inhibition in patients with hypertension and polycystic kidney disease, but not in patients with essential hypertension. The glomerular filtration rate did not change in either group. Although angiotensin II predominantly stimulates the contraction of efferent arterioles,29 it also stimulates the contraction of afferent arterioles.30 In this context, the constancy of the glomerular filtration rate in hypertensive patients with polycystic kidney disease during the inhibition of angiotensin-converting enzyme may have been due to vasodilation of both afferent and efferent arterioles.
We also sought evidence to support the theory of activation of the renin–angiotensin–aldosterone system before the emergence of hypertension in patients with polycystic kidney disease. The mean arterial pressures in the supine and upright positions and plasma aldosterone concentrations in the upright position were significantly higher in the normotensive patients with polycystic kidney disease than in the normal subjects, whereas the plasma renin activity was similar in the two groups. The results with respect to plasma renin activity must, however, be interpreted in the light of the higher mean arterial, and consequently renal perfusion, pressures in the patients with polycystic kidney disease — an effect that suppresses plasma renin activity in normal subjects. Taken together, these results suggest that the normotensive patients with polycystic kidney disease may be progressing toward a hypertensive state.
We conclude that the renin–angiotensin–aldosterone system is stimulated in patients with hypertension and polycystic kidney disease, as compared with patients with essential hypertension who are comparable with respect to mean arterial pressure and several other determinants of blood pressure. This finding therefore supports the hypothesis that cyst-induced bilateral renal ischemia, with subsequent activation of the renin–angiotensin–aldosterone system, is an important factor in the initiation of hypertension in polycystic kidney disease.
Supported by a grant (DK34039) from the National Institute of Diabetes and Digestive and Kidney Diseases and a grant (MORR-00051) from the General Clinical Research Center of the National Institutes of Health.
Presented in abstract form at the 22nd annual meeting of the American Society of Nephrology, Washington, D.C., December 3–6, 1989.
Source Information
From the Department of Medicine, Box C283, University of Colorado School of Medicine, 4200 E. 9th Ave., Denver, CO 80262, where reprint requests should be addressed to Dr. Chapman.
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