Original Article
Renal Hemodynamics and the Renin–Angiotensin–Aldosterone System in Normotensive Subjects with Hypertensive and Normotensive Parents
N Engl J Med 1991; 324:1305-1311May 9, 1991
- Abstract
- Abstract
Background and Methods.
The kidney is important in blood-pressure regulation, but its role in the development of essential hypertension is still subject to debate. We compared renal hemodynamics, measured in terms of the clearance of para-aminohippuric acid and inulin, and the characteristics of the renin–angiotensin–aldosterone system in three groups of normotensive subjects at different degrees of risk for hypertension: 41 subjects with two normotensive parents, 52 with one normotensive and one hypertensive parent, and 61 with two hypertensive parents. The subjects ranged in age from 7 to 32 years.
Results.
The mean renal blood flow was lower in the subjects with two hypertensive parents than in those with two normotensive parents (mean difference [±SE], 198±61 ml per minute per 1.73 m2 of body-surface area; P = 0.002). Moreover, both the filtration fraction and renal vascular resistance were higher in the subjects with two hypertensive parents (filtration fraction: mean difference, 3.0±1.1 percentage points; P = 0.006; renal vascular resistance: mean difference, 2.7±0.8 mm Hg per deciliter per minute per 1.73 m2; P = 0.006). The subjects with two hypertensive parents had lower plasma concentrations of renin (mean difference, 3.3±1.6 mU per liter; P = 0.03) and aldosterone (mean difference, 111±36 pmol per liter; P = 0.003) than those with two normotensive parents. The differences could not be explained by the small differences in blood pressure between the groups. The values in the subjects with one hypertensive and one normotensive parent fell between those for the other two groups.
Conclusions.
Renal vasoconstriction is increased and renin and aldosterone secretion is decreased in young persons at risk for hypertension. These findings support the hypothesis that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension. (N Engl J Med 1991; 324:1305–11.)
Media in This Article
Figure 1
Renal Blood Flow, as Measured by the Urinary Method, in Subjects with Two Normotensive Parents, One Normotensive and One Hypertensive Parent, or Two Hypertensive Parents, According to Age.Figure 2
Ratios of Plasma Renin Activity and of the Plasma Aldosterone Concentration to 24-Hour Urinary Sodium Excretion in Subjects with Two Normotensive Parents, One Normotensive and One Hypertensive Parent, or Two Hypertensive Parents.Article Activity
- Article
THE role of the kidney as a long-term regulator of blood volume and blood pressure is well established.1 Any increase in blood pressure is compensated for by an increase in the renal excretion of water and salt. During the development of hypertension, the relation between blood pressure and natriuresis is set at a higher level of arterial pressure, but the mechanism responsible for the change in the setting is unknown.2 On the basis of the results of renal-transplantation experiments in animals and humans, it appears that this mechanism may reside in the kidney itself.3 4 5 However, renal-function tests in subjects with established6 7 8 9 or borderline10 , 11 hypertension or in young subjects with hypertension12 13 14 have not had consistent results.
Before hypertension develops, the influence of the kidney can be studied by comparing renal function in subjects with a high risk and those with a low risk of future hypertension. The risk of hypertension may be estimated on the basis of the presence or absence of a family history of hypertension.15 Bianchi et al. reported a higher mean level of renal perfusion in young people with two hypertensive parents than in those with two normotensive parents.16 , 17 These findings, however, contrast with those of others, which suggest that renal vasoconstriction is increased in the prehypertensive state.18 19 20 21 22
We studied renal hemodynamics and the renin–angiotensin–aldosterone system in 154 normotensive young people (age range, 7 to 32 years) from 97 families in which both, one, or neither of the parents had hypertension. To avoid errors in classifying the parents as hypertensive or normotensive, and in order to include relatively young children, we recruited the parents from a group of 1642 couples who participated in a population-based study, conducted in Zoetermeer, the Netherlands. Selection was based on blood-pressure levels that remained hypertensive or normotensive over a 10-year follow-up period. In this way we were able to study renal hemodynamics and the renin–angiotensin–aldosterone system in a relatively large, relatively young group of normotensive children of three groups of parents who differed markedly in blood-pressure characteristics.
Methods
Subjects
From 1975 to 1978, all the residents of two districts of the town of Zoetermeer, the Netherlands, were invited to participate in a study of blood pressure and other cardiovascular risk factors.23 Blood pressure was measured in 10,532 of the 13,462 eligible residents (78 percent). This group included 1642 couples with children. A stringent selection procedure, described previously,24 was applied to these couples to select groups whose children would have a maximal contrast in familial predisposition to hypertension. Individual parents with both systolic and diastolic blood pressure in the upper (hypertensive) or lower (normotensive) quartile of the age- and sex- specific blood-pressure distribution were selected, as part of the Dutch Hypertension and Offspring Study, a collaborative study supervised by a steering committee drawn from four Dutch universities and clinical research centers. Those who were receiving antihypertensive medication were included in the hypertensive group. Three groups of couples with children were invited for remeasurement of blood pressure for this study after a period of more than ten years: couples of which both members were normotensive, those with one normotensive and one hypertensive member, and those of which both members had hypertension. At the time of remeasurement, the same criteria for hypertension and normotension were applied as at the initial screening. Of 250 couples that were restudied (80 percent of those invited), 121 were still in the blood-pressure category to which they had originally been assigned: 35 couples of which both members were normotensive, 35 with one normotensive and one hypertensive member, and 51 of which both members were hypertensive. These 121 couples had 291 healthy biologic children, all of whom were invited to take part in this study. Of these children, who ranged from 7 to 32 years of age, 154 participated: 41 with two normotensive parents, 52 with one normotensive and one hypertensive parent, and 61 with two hypertensive parents. The blood-pressure values and other characteristics of the parents and their children (subjects) at the time of enrollment are shown in Table 1Table 1
Blood Pressure and Related Characteristics of Subjects and Their Parents, According to Study Group.*. The study protocol was approved by the ethics committee of the University Hospital Dijkzigt, and informed consent was obtained from the subjects and their parents.Protocol
All the subjects collected a 24-hour urine sample during the day before the study. Their usual diet was not altered, but they were asked to refrain from smoking and from drinking coffee. At the examination center, the blood pressure in the left arm was measured with a random-zero sphygmomanometer by a trained paramedical assistant. Two readings were made with the subject seated, and the mean of these readings was used in the analysis. The blood pressure of the parents had been measured in the same way at base line (from 1975 to 1978) and during the selection process for the current study (1986). Weight and height were measured with the subject wearing indoor clothes but no shoes. Before the beginning of the renal-function tests, an intravenous cannula was inserted; the subject then remained supine in a quiet room for 30 minutes, after which fasting venous blood samples were collected: 6 ml in a chilled tube containing disodium EDTA (final concentration, 5 mmol per liter) and o-phenanthroline (1.25 mmol per liter) for measurement of immunoreactive angiotensin II and 16 ml in a tube containing disodium EDTA (5 mmol per liter) for measurement of plasma renin activity and renin, prorenin, and aldosterone concentrations. For the renal-function tests, a second intravenous cannula was inserted in the opposite arm. The effective renal plasma flow and glomerular filtration rate were calculated on the basis of measurements of the clearance of paraaminohippuric acid and inulin (Inutest, Boehringer–Mannheim, Mannheim, Germany) with use of a constant-infusion technique and timed collections of urine.25 After a bolus injection, a continuous infusion was given for 2 1/2 hours to achieve levels of 200 mg of inulin per liter and 20 mg of paraaminohippuric acid per liter in extracellular fluid and plasma. During this period the subjects were not allowed to eat, but they were asked to drink at least 10 ml of fluid per kilogram of body weight per hour. To determine the starting dose of inulin and paraaminohippuric acid, the volume of extracellular fluid was estimated to be 20 percent of body weight. The doses for the subsequent infusion of inulin were calculated from the clearance of inulin according to the formula of Cockcroft and Gault, which estimates the creatinine clearance on the basis of age, weight, sex, and serum creatinine level.26 To determine the doses of para-aminohippuric acid to be infused, the clearance of paraaminohippuric acid was assumed to be five times the calculated creatinine clearance. The amount of inulin and para-aminohippuric acid excreted by the kidneys was intended to be in equilibrium with the amount infused after 1 1/2 hours. Urine samples were collected by active voiding before and 1 1/2 and 2 1/2 hours after the beginning of the infusion. Blood samples were collected just after voiding. Clearance rates were calculated from both the rate of intravenous infusion and the rate of urinary excretion for the 1-hour period between 1 1/2 and 2 1/2 hours after the beginning of the infusion.
Measurements
Inulin and para-aminohippuric acid were measured in the infused solution and in the plasma and urine samples drawn before and 1 1/2 and 2 1/2 hours after the beginning of the infusion. Inulin was measured indirectly. After deproteinization with 0.6 N hydrochloric tetroxide, endogenous fructose and glucose were measured (designated A1). After a subsequent incubation period of 15 minutes at 70°C, inulin was converted into fructose, and the fructose was measured (A2). The difference between the values A2 and A1 was the amount of fructose originating from the acid hydrolysis of inulin (coefficient of variation for the assay: in plasma, 2.2 percent; in urine, 2.1 percent). Fructose was measured by an enzymatic method (716260, Boehringer–Mannheim) adapted to an automatic analyzer (Cobas Bio, Hoffmann—LaRoche, Basel, Switzerland) in which the conversion of NADP to NADPH is measured. Paraaminohippuric acid was measured by the method of Bratton and Marshall as modified by Smith et al.,27 after hydrolysis of conjugated para-aminohippuric acid by heating with 4 N hydrochloric acid for one hour in a boiling-water bath (coefficient of variation: in plasma, 4.7 percent; in urine, 1.7 percent). In this way the rate of intravenous infusion could also be used to calculate the effective renal plasma flow from the total para-aminohippuric acid clearance.25
The glomerular filtration rate and the effective renal plasma flow were calculated from the rates of clearance of inulin and paraaminohippuric acid; these rates were derived, in turn, from the rate of intravenous infusion if the plasma levels in individual blood samples were within 5 percent of the mean inulin or para-aminohippuric acid levels (plasma method) and from the rate of urinary excretion if urine samples could be obtained at the three sampling times (urinary method). The renal-function tests were completed for 135 of the 154 subjects: 32 with two normotensive parents, 44 with one normotensive and one hypertensive parent, and 59 with two hypertensive parents. Results were unavailable for the remaining 19 subjects because they declined to participate in the infusion studies (n = 13), because the test was not completed (n = 3), or because blood or urine samples were missing (n = 3) so that neither the rate of urinary excretion nor the rate of intravenous infusion could be estimated. Of the results from the 135 completed renal-function tests, the rates of clearance of inulin or para-aminohippuric acid calculated by the urinary method could be used for 131 subjects (30 with two normotensive parents, 42 with one normotensive and one hypertensive parent, and 59 with two hypertensive parents); complete urine samples were not available for the other 4 subjects. The plasma method could be used to calculate the glomerular filtration rate for 118 subjects (n = 27, 39, and 52, respectively). Calculations could not be made because of instability of the plasma inulin level in 17 subjects. The effective renal plasma flow could be calculated by the plasma method for 109 subjects with stable plasma levels of para-aminohippuric acid (n = 24, 38, and 47. respectively).
Renal blood flow was estimated by dividing the effective renal plasma flow by 1 minus the hematocrit. There was no reason to suspect differences in para-aminohippuric acid extraction among the groups, and no correction was made for incomplete extraction.8 The filtration fraction was calculated by dividing the glomerular filtration rate by the effective renal plasma flow. All calculations were standardized for body-surface area.28 Renal vascular resistance was estimated by dividing the calculated mean arterial pressure by the renal blood flow.
Immunoreactive angiotensin II and aldosterone were measured in plasma as described previously by Lijnen et al.29 and Malvano et al.30 plasma renin was measured in two ways — as plasma renin activity and as the plasma renin concentration. Plasma renin activity was determined by a radioimmunoassay for angiotensin I generated from endogenous renin substrate and expressed in femtomoles per liter per second (coefficient of variation, 10 percent). Plasma renin concentrations were determined by measuring the capacity of renin to generate angiotensin from saturating amounts of purified sheep renin substrate; the angiotensin formed was measured by radioimmunoassay (coefficient of variation, 11 percent).31 The conversion of prorenin to renin in plasma was activated by adding Sepharose-bound trypsin (coefficient of variation, 11 percent).31 Renin and prorenin levels were expressed in terms of milliunits per liter of the Medical Research Council human kidney renin standard (MRC 68/356, WHO International Laboratory for Biological Standards, Holly Hill, Hampstead, London). One milliunit of this standard equals about 1.4 mg of renin.32
Statistical Analysis
Descriptive data for the three groups are presented as means and standard deviations. For comparisons between groups, means and standard errors of the means are given, with the two-sided P value for the difference. Adjustments for differences in age, height, weight, and proportion of males among the three groups were made with use of a multiple linear regression model. Associations between variables were adjusted for differences in group characteristics (with use of indicator variables for group) and for age, height, weight, and sex (by multiple regression analysis).
Results
General Characteristics
Table 1 shows the general characteristics of the three groups of subjects. The systolic and diastolic blood pressure was higher in the subjects with two hypertensive parents than in the other two groups. These differences persisted after adjustments for differences in age, height, weight, and proportion of males among the groups. The serum levels and 24-hour urinary excretion of sodium and potassium were similar in the three groups, as was the hematocrit (data not shown).
Renal Hemodynamics
Renal-function characteristics calculated by the urinary method are shown in Table 2Table 2
Renal-Function Characteristics in the Subjects, According to Study Group.*. All values have been standardized for body-surface area and adjusted for differences in age and proportion of males among the groups. Compared with the value in the group of subjects with two normotensive parents, renal blood flow was significantly lower in the group with two hypertensive parents (mean difference [±SE], 198±61 ml per minute per 1.73 m2 of body-surface area; P = 0.002), but the glomerular filtration rate was not significantly different. The filtration fraction and renal vascular resistance were higher in the subjects with two hypertensive parents (filtration fraction: mean difference, 3.0±1.1 percentage points; P = 0.006; renal vascular resistance: mean difference, 2.7±0.8 mm Hg per deciliter per minute per 1.73 m2; P = 0.006). The pattern of differences was similar when the renal-function characteristics were calculated by the plasma method (Table 2). To assess whether the difference in renal blood flow was confounded by the difference in blood pressure between the groups, the results were adjusted for systolic blood pressure. After adjustment, the mean renal blood flow as estimated by the urinary method was 1167 ml per minute per 1.73 m2 in the subjects with two normotensive parents, 928 ml per minute per 1.73 m2 in those with one normotensive and one hypertensive parent (mean difference, 239±65 ml per minute per 1.73 m2; P<0.001), and 921 ml per minute per 1.73 m2 in those with two hypertensive parents (mean difference, 246±62 ml per minute per 1.73 m2; P<0.001).To determine whether the difference in renal blood flow among the three groups was already apparent at a young age, when the blood-pressure differences between the groups were smaller and of shorter duration,33 the three groups were divided into thirds according to age. For each age stratum, the differences in renal blood flow among the three groups of subjects were similar (Fig. 1Figure 1
Renal Blood Flow, as Measured by the Urinary Method, in Subjects with Two Normotensive Parents, One Normotensive and One Hypertensive Parent, or Two Hypertensive Parents, According to Age.). For the youngest third of subjects (mean age, 11 years), the mean (±SE) differences between the subjects with two normotensive parents and the other two groups were as follows: subjects with one normotensive and one hypertensive parent, 55±94 ml per minute per 1.73 m2 of body-surface area (P = 0.50); and subjects with two hypertensive parents, 346±102 ml per minute per 1.73 m2 (P = 0.004). For the middle third (mean age, 19 years), the differences were as follows: subjects with one normotensive and one hypertensive parent, 300±124 ml per minute per 1.73 m2 (P = 0.02); and subjects with two hypertensive parents, 245±119 ml per minute per 1.73 m2 (P = 0.04). For the oldest third (mean age, 27 years), the differences were as follows: subjects with one normotensive and one hypertensive parent, 175±90 ml per minute per 1.73 m2 (P = 0.05); and subjects with two hypertensive parents, 181±82 ml per minute per 1.73 m2 (P = 0.03). No relation was found between the renal blood flow or the glomerular filtration rate and 24-hour sodium excretion. Moreover, we found no significant association between the renal blood flow, renal vascular resistance, or the glomerular filtration rate on the one hand, and plasma renin activity or the plasma renin, angiotensin II, or aldosterone concentration on the other, either among or within groups.Hormones
The results of the measurements of plasma renin activity and of the plasma renin, angiotensin, and aldosterone concentrations are shown in Table 3Table 3
Characteristics of the Renin–Angiotensin–Aldosterone System in the Subjects, According to Study Group.*. All values were adjusted for differences in age, height, weight, and proportion of males among the groups. The level of renin, measured as either plasma renin activity or the plasma renin concentration, was significantly lower in the subjects with two hypertensive parents (mean difference in the plasma renin concentration, 3.3±1.6 mU per liter; P = 0.03). The values for prorenin were similar among the three groups. The plasma aldosterone level was lower in the groups of subjects with one or two hypertensive parents than in the group with two normotensive parents (mean difference, 111±36 pmol per liter; P = 0.003). The difference in renin values was not reflected in the angiotensin II level, which did not differ significantly among the three groups. The ratio of the plasma angiotensin II level to plasma renin activity was higher among the subjects with two hypertensive parents than among the offspring of two normotensive parents (35.0 vs. 26.1, P = 0.02). The ratio of the plasma aldosterone level to the plasma angiotensin level was lower among subjects with two hypertensive parents than among those with two normotensive parents (36.1 vs. 50.7, P = 0.001).Figure 2Figure 2
Ratios of Plasma Renin Activity and of the Plasma Aldosterone Concentration to 24-Hour Urinary Sodium Excretion in Subjects with Two Normotensive Parents, One Normotensive and One Hypertensive Parent, or Two Hypertensive Parents. shows the ratios of plasma renin activity and the plasma aldosterone concentration to urinary sodium excretion during a 24-hour period for each of the three study groups. Both ratios were lower in the subjects with two hypertensive parents. The differences in the ratios (±SE) between the subjects with one normotensive and one hypertensive parent and those with two normotensive parents were as follows: plasma renin activity, 0.64±0.64 fmol per liter per second per millimole of sodium per day (P = 0.3); and plasma aldosterone concentration, 1.08±0.52 pmol per liter per millimole of sodium per day (P = 0.04). The differences in the ratios (±SE) between the subjects with two hypertensive parents and those with two normotensive parents were as follows: plasma renin activity, 1.28±0.64 fmol per liter per second per millimole of sodium per day (P = 0.04); and plasma aldosterone concentration, 1.11±0.50 pmol per liter per millimole of sodium per day (P = 0.03).As shown in Table 1, the blood pressure was higher in the subjects with two hypertensive parents. To determine whether this factor might have influenced the difference in renin levels among the groups — for example, through renal autoregulation — we compared plasma renin activity and plasma renin concentrations among the groups after adjusting for systolic blood pressure. The differences between the subjects with two normotensive parents and those with two hypertensive parents remained; the plasma renin concentration was lower by 3.3±1.6 mU per liter (P = 0.05) and plasma renin activity was lower by 117.1±53.1 fmol per liter per second (P = 0.04) in the subjects with two hypertensive parents. After we corrected the plasma renin concentration and renin activity for the differences between the groups in renal vascular resistance, a measure more directly related to the physiology of renin regulation, however, the differences were smaller and no longer statistically significant; the adjusted difference between the subjects with two normotensive parents and those with two hypertensive parents was 2.9±1.7 mU per liter for the plasma renin concentration (P = 0.10) and 97.7±49.4 fmol per liter per second for plasma renin activity (P = 0.06).
Discussion
The findings of this study indicate that renal blood flow is lower and plasma renin and aldosterone concentrations are suppressed in the children of hypertensive parents, as compared with the children of normotensive parents. The reduction in renal blood flow was greater when renal hemodynamics were measured by the urinary method than when measured by the plasma method. The difference in the results obtained with the two methods may have resulted from the smaller number of test results that could be calculated by the plasma method. The absolute mean levels of renal blood flow were lower when calculated by the plasma method than when calculated by the urinary method. The opposite — i.e., a higher renal blood flow when calculated by the plasma method as compared with the urinary method — has been reported to occur as a result of extrarenal clearance of conjugates of para-aminohippuric acid.25 In our study, however, this problem was eliminated by hydrolysis of the conjugated para-aminohippuric acid in the plasma samples. In addition, the temporary accumulation of para-aminohippuric acid and inulin in the kidney at the end of the equilibrium period and the beginning of the clearance period, which results from relatively limited diuresis during the equilibrium period, may further raise the estimates obtained by the urinary method. The direction of the differences among the three groups calculated by the two methods was similar, however. Interestingly, the mean renal blood flow was already lower at a mean age of 11 years in the subjects with one or two hypertensive parents.
We included a group of subjects with one normotensive and one hypertensive parent in our study because of the possibility of expanding the study with genetic analyses. In the comparisons, this group was not consistently similar to either of the other two groups, although their mean values in general fell between those for the other two groups.
The mechanisms responsible for the decrease in renal blood flow, the increase in renal vascular resistance and the filtration fraction, and the decrease in the plasma renin and aldosterone levels in the early phase of essential hypertension are not known. Increased renal vasoconstriction may reduce renal blood flow if the blood pressure and cardiac output remain normal. The combination of reduced renal blood flow with an increased filtration fraction and a reduced plasma renin concentration might point to an increase in resistance in renal efferent arterioles.34 Such abnormalities, in a more pronounced form, have been found in adults with established hypertension.35 Recently, Dluhy and coworkers proposed the presence of "nonmodulators" in subjects with a family history of hypertension,36 who are characterized by an inability to modulate normally the responsiveness of the renal vasculature and adrenal gland to angiotensin II at different levels of sodium intake. Such nonmodulation could reflect increased renal vasoconstriction. In our study several characteristics of the normotensive subjects with hypertensive parents were compatible with nonmodulation. In particular, the reduced renal blood flow in subjects with hypertensive parents resembled the reduced renal blood flow measured in nonmodulators with a high salt intake,37 , 38 and the reduced ratio of plasma aldosterone to plasma angiotensin II is analogous to the diminished responsiveness of aldosterone to infused angiotensin II.37 However, we found differences between the groups of subjects in our study without the infusion of vasoactive substances, perhaps because of the large contrast in familial predisposition to hypertension among the groups, which resulted from the strict selection criteria.
In apparent contrast with our findings are those of Bianchi and coworkers,16 , 17 who reported that young people with a family history of hypertension had increased renal blood flow, normal cardiac output, and slightly increased glomerular filtration rates. The age range and blood-pressure level of these subjects were similar to those in our study group. Only measurements obtained by the plasma method were reported, however, and the conjugation of para-aminohippuric acid was not taken into account. If the extrarenal clearance of para-aminohippuric acid had been more pronounced in subjects with hypertensive parents, this difference could have artificially created the differences in renal blood flow observed between the groups.25 Another problem with the calculation of renal blood flow and glomerular filtration rates by the plasma method may be the selective withdrawal of those with unstable plasma levels of para-aminohippuric acid and inulin.25
Differences in sodium balance might explain the different results of studies comparing renin profiles in various groups. We found that plasma renin activity and renin levels were lower in subjects with hypertensive parents, both with and without adjustment for sodium intake. Bianchi et al. reported both similar and decreased levels of renin in the children of hypertensive parents, as compared with those of normotensive parents.16 , 17 In both these studies, the sodium balance was the same in both groups, but the mean intake was higher than in our study.
In conclusion, we found that renal blood flow, plasma renin activity, and plasma renin and aldosterone concentrations were lower and renal vascular resistance was higher in subjects with hypertensive parents than in those with normotensive parents. Our results support the hypothesis that changes in renal hemodynamics take place at an early stage in the development of familial hypertension. These changes may set the stage for a more rapid and pronounced increase in blood pressure with age in the children of hypertensive parents.2 The mechanisms responsible for the differences in renal hemodynamics remain to be established.
Supported by a grant (35.004) from the Netherlands Heart Foundation.
We are indebted to Professor H.A. Valkenburg for his general support and organization of the population study in Zoetermeer; to Professor P. van Brummelen, Professor K.H. Rahn, and Dr. Th. Thien for their support and contributions; to all the study subjects and their parents; to H. Kornman for assistance throughout the study; and to J. van't Hof, J. Ambagtsheer, P. Tchang, R. de Bos, and R. de Bruin for their laboratory work.
Source Information
From the Department of Epidemiology and Biostatistics, Erasmus University Medical School (I.M.S.v.H., D.E.G., A.H.), the Department of Internal Medicine I, University Hospital Dijkzigt (l.M.S.v.H., F.H.M.D., M.A.D.H.S.), and the Department of Internal Medicine, Zuiderziekenhuis (P.W. de L.), all in Rotterdam, the Netherlands. Address reprint requests to Dr. Grobbee at the Department of Epidemiology and Biostatistics, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands.
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M. Ritt, R. Janka, M. P. Schneider, P. Martirosian, J. Hornegger, W. Bautz, M. Uder, R. E. Schmieder. (2010) Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome. Nephrology Dialysis Transplantation 25:4, 1126-1133
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