Renal Perfusion in Blacks
Alterations Caused by Insuppressibility of Intrarenal Renin With Salt
We have reported that an increased intrarenal renin-angiotensin system activity may be responsible for the reduction in renal plasma flow (RPF) in apparently healthy blacks in comparison to healthy whites during high salt balance. To ascertain whether these differences only exist in the high salt state, we performed the following study, concentrating on the manipulation of the renin system during low salt intake. We measured in 19 healthy blacks and 22 healthy whites para-aminohippurate and inulin clearances as an indication of RPF and glomerular filtration rate, respectively, on both high (200 mmol/d) and low (10 mmol/d) salt balance in random order. A subset of 11 blacks and 12 whites additionally received an angiotensin II infusion while in low salt balance (3 ng/kg per minute for 45 minutes) and captopril to assess differences in RPF response to a converting enzyme inhibitor. The 19 whites had significantly higher RPF when compared with blacks (P=0.033) when studied on high salt. However, during low salt balance, the RPFs were comparable in the 2 groups. Plasma renin activity was similar in the 2 groups on both diets. In the subset that received angiotensin II and captopril while in low salt balance, the renal vascular response was not different in whites and blacks. These data provide additional support for the concept that the intrarenal tissue renin system is more active in blacks than whites on a typical (high salt) diet and that the difference reflects primarily incomplete tissue renin suppression with an increase in salt intake. The mechanism involved may contribute to the increased susceptibility to renal injury in blacks.
The striking increase in risk of nephropathy in blacks has focused attention on the determinants of renal perfusion and function in this population. We have recently reported that the control of renal perfusion in apparently healthy blacks differs from that in whites. Renal perfusion was lower in blacks compared with healthy whites in high salt balance.1 This difference was corrected with a small dose of captopril. Several observations suggested that this reduction in renal perfusion reflected an increase in intrarenal formation of angiotensin (Ang) II, including blunting of the renal vascular response to endogenous Ang II infusion, and enhanced renal vasodilator responses to captopril, which also enhanced the renal vascular response to Ang II. Because all of these findings were present despite an essentially identical level of plasma renin activity (PRA), the findings suggested activation of the intrarenal-angiotensin system. All of these studies were performed on a high salt diet, selected to suppress the endogenous renin-angiotensin system (RAS).
Because salt intake is a major determinant of not only the state of the RAS but also the contribution of renin activity to renal vascular tone and renal perfusion, in this study we undertook to assess systematically the renal vascular response to a change in salt intake in healthy blacks. We also investigated the renal hemodynamic response to exogenously administered Ang II and the ACE inhibitor captopril in the low salt state when endogenous Ang II levels are high. In other settings, activation of the intrarenal RAS is associated with blunting of the renal hemodynamic response to changes in salt intake.2,3⇓ Thus, a limited renal hemodynamic response to a change in salt intake would provide additional evidence favoring activation of the intrarenal RAS. The nature of the differential control in blacks and whites is also unclear. If the difference in renal perfusion is just as large on a low and high salt diet, the conclusion would be that a substantial shift in the entire relation exists. Conversely, if the renal hemodynamics are similar on a low salt diet but become different with an increase in salt intake, the difference in control mechanism would involve the processes responsible for suppression of the renin system on a high salt diet. In low salt balance, blunting of the renal response to Ang II and vasodilation to captopril is the normal state.4,5⇓ We sought to determine if the level of blunting with Ang II or the dilation with captopril would be comparable in the 2 groups, as it was not on a high salt intake. Our data suggest that the difference between blacks and whites involves the ability of a high salt intake to suppress the intrarenal RAS, which corrects with an ACE inhibitor. This anomaly is similar to what we described in the control of renal perfusion and function in patients with type 2 diabetes mellitus5,6⇓ and in some patients with essential hypertension.2,7⇓ These observations provide further insight into the increased risk of nephropathy in blacks.
We studied 19 healthy blacks (age, 31±3 years) and 22 healthy age-matched whites (28±2 years) in balance on both high salt (HS) and low salt (LS) diets. All were free of cardiovascular, renal, and endocrine disease. After an outpatient evaluation, which included a medical history, physical examination, and appropriate laboratory studies, eligible subjects were admitted to the protocol. All subjects were studied during admission to a metabolic ward, the General Clinical Research Center of Brigham and Women’s Hospital. Written informed consent was obtained from each subject. The protocol was approved by the Human Subjects Institutional Review Board Committee.
Subjects were studied twice, under both HS and LS balance, in random order. When the HS protocol was done first, subjects were placed on an HS diet (200 mmol of sodium, 100 mmol potassium, 2500 mL fluid intake per day) 3 days before admission. Each subject was admitted 24 to 48 hours before the study day and was maintained on the diet. Daily 24-hour urine collections were obtained for measurement of sodium, potassium, protein, and creatinine excretion. Subjects were studied when 24-hour urine sodium was >150 mmol/L. When the LS protocol was done first, subjects started an outpatient diet consisting of 10 mmol/L sodium, 100 mmol/L potassium, and at least 2500 mL fluid intake 3 to 4 days before admission. Each subject was admitted 3 to 4 days before the study day and maintained on the diet. Once the 24-hour urine sodium was <20 mmol/L, the study was initiated. While in LS balance, 11 blacks (age, 32±5 years) and 12 whites (age, 32±5 years) received 3 ng/kg per minute of Ang II for 45 minutes. Ang II was then discontinued. Captopril (25 mg) was administered orally; measurements for para-aminohippurate (PAH) and inulin were continued for an additional 135 minutes.
Subjects fasted overnight and remained recumbent throughout the study. Studies began at ≈7 am. One intravenous catheter was placed in each arm at least 2 hours before the study, one for infusions and the other for blood drawing. PAH and inulin were infused, and clearances reflected renal plasma flow (RPF) a glomerular filtration rate (GFR), respectively, as described previously.8 Blood samples for baseline PAH and inulin and PRA measurements were drawn 60 minutes later. Blood pressure was recorded by an automatic recording device (Dinamap, Critikon) at 15-minute intervals. During the Ang II infusion, blood pressure monitoring was recorded every 2 minutes.
Blood samples were collected on ice and spun immediately, and the plasma was stored at −80°C until the time of assay. Serum and urinary sodium and potassium levels were measured using the ion-selective electrode. Serum creatinine, PAH, and inulin were measured by an autoanalyzer technique. PRA was measured by radioimmunoassay.9
All data are expressed as mean±SEM. Statistical differences in 2-sample data were assessed by t test and the nonparametric Mann-Whitney test. Analysis of data within each group was done by paired t tests. The null hypothesis was rejected when the probability value was <0.05.
The 19 blacks and 22 whites in this study were all well matched for age, serum creatinine, sodium, and potassium concentration (Table 1). Sodium balance as reflected in 24-hour sodium excretion was comparable between the races on both diets (Table 2). Blacks tended to be heavier than whites on both diets (Table 2). Weight increased in both groups when changing from an LS to an HS diet, although the change did not reach statistical significance.
PRA was not statistically different between blacks and whites on either diet (Table 2). RPF was lower in healthy blacks compared with age-matched whites while in balance on an HS diet (575±24 versus 636±20 mL/min per 1.73 m2; P=0.033, Table 3). During the LS diet, RPF between the races was comparable. RPF increased significantly in whites when changing from LS to HS diets (+52±14 mL/min per 1.73 m2; P=0.05). Despite similar PRA, blacks did not show the same RPF response to a change to HS diet (586±21 to 575±21 mL/min per 1.73 m2; Δ−10.7±17.5 mL/min per 1.73 m2; Figure).
There were no differences in GFR between the 2 groups on either diet (Table 3). The GFR increased when changing from an LS state to the HS state but did not reach significance in either group. There were also no significant differences in filtration fraction (FF) between the 2 groups for both diets, although it trended higher in blacks on the HS diet.
The subset of 11 blacks (age, 29±4.4 years) and 12 whites (age, 32±4.5 years) continued on the LS diet to receive Ang II infusions and captopril. At baseline, both groups had comparable RPF (564±29 versus 570±22 mL/min per 1.73 m2; blacks versus whites). After receiving 3 ng/kg per minute of Ang II for 45 minutes, both groups had a similarly significant decrease in renal perfusion (−104±12 versus −82±8 mL/min per m2; blacks (P=0.01) versus whites [P=0.009]). Likewise, captopril gave a similarly significant vasodilator response (564±29 to 643±30 mL/min per 1.73 m2 in blacks; P=0.002 versus 570±22 to 657±37 mL/min per 1.73 m2 in whites; P=0.003).
The Ang II infusion caused a significant elevation in both systolic and diastolic blood pressure in the 2 groups from baseline (11.4±2.7/6.9±1.4 in whites, P=0.002 versus 15.5±3.4/7.9±1.6 in blacks, P=0.003); however, the changes were not different in comparing the 2 groups of subjects. Likewise, captopril caused a significant decrease in both systolic (−5.9±1.4, P=0.003) and diastolic (−7.7±1.2, P<0.0001) pressure in blacks and caused a marginal decrement in systolic (−3±1.6, P=0.09) and significant decrement in diastolic (−6.1±1.5, P=0.003) pressure in whites. The blood pressure change between the 2 groups was not different.
This study was designed on the basis of our previous finding that RPF was lower in healthy blacks compared with healthy whites and that this difference may reflect activation of the RAS in the blacks that was not present in the whites.1 In view of striking evidence that RAS activation dominates renal vascular responses to shifts in salt intake in healthy whites, we undertook a systematic comparison of these responses in healthy blacks and healthy whites. Healthy whites responded to a reduction in salt intake with a rise in PRA and fall in RPF. Despite an essentially identical rise in PRA, healthy blacks did not change RPF with a fall in sodium intake. In carefully age-matched subjects, RPF was essentially identical in blacks and whites on an LS diet but increased only in whites with a shift to HS intake.
The simplest interpretation of this series of observations is that in blacks, the intrarenal RAS is not suppressed as effectively as in whites in response to an HS intake, but blacks show the same level of activation on an LS intake. Blacks in balance on an LS diet show a renal vascular response to renin and ACE inhibition identically to whites.10 An essentially identical construct has been presented for whites with a number of diseases, including essential hypertension in a syndrome called “nonmodulation” and in patients with type 1 and type 2 diabetes mellitus.5–7,8,11⇓⇓⇓⇓ In each case, evidence suggesting activation of the intrarenal RAS has gradually accumulated along with evidence that the activation contributes to disease pathogenesis.
Multiple observations have suggested that blacks differ from whites in a number of relevant ways including a blunting of sodium excretion in response to sodium loads.12,13⇓ Other than the 24-hour sodium excretion on the initial study day, the index we have of the influence of the change in salt intake on salt balance is reflected in body weight. Although there was insufficient power for a statistical difference, the increase in body weight in the blacks exceeded that in the whites by 0.5 kg.
In a previous study comparing, renal hemodynamics and salt sensitivity in hypertensive subjects, substantial racial differences were noted.14 The salt-sensitive (SS) subjects were largely black and the salt-resistant (SR) subjects were all white. When studied during LS balance, the SS and SR patients had similar mean arterial pressure, GFR, effective renal plasma flow (ERPF), and FF. However, during studies while in HS balance, several differences were observed: ERPF increased in the SR subjects (455±25 to 524±28 mL/min, P<0.01) yet decreased in the SS subjects (538±20 to 426±16 mL/min, P<0.01); GFR did not change in either group, therefore causing the FF to decrease in the SR subjects and increase in the SS subjects.14 The authors concluded that the renal hemodynamic abnormality that was displayed while on HS balance might partially be responsible for the high rate of kidney failure in hypertensive blacks. As the renal hemodynamic pattern that Campese et al14 noted is similar in our nonhypertensive, healthy blacks, these abnormalities cannot be related to hypertension per se or to salt sensitivity because our healthy subjects were SS yet normotensive. Perhaps the differences are related to underlying physiological differences in the kidneys of these 2 racial groups.
Why should ethnicity influence a fundamental mechanism in such a powerful way? We speculate on a role for specific genetic polymorphisms. Hopkins et al15 showed in healthy whites that threonine in place of methionine at Angiotensinogen Codon-235 influences the renal vascular response to Ang II. The frequency of this polymorphism of the AGT gene is much greater in blacks than whites.16
What influences other than genetics may play a role in the lower RPF that we find in blacks? A lower potassium intake has been described in blacks.17 We found that although serum potassium was comparable in the 2 groups, 24-hour urinary potassium excretion was significantly lower in blacks.1 This trend is seen in the current study, but only on HS intake. The 24-hour urine potassium levels were similar in the 2 populations on an LS diet. Once blacks were in HS balance, the urine potassium was decreased compared not only with the LS study day but also compared with urinary potassium excretion of the whites in HS balance. Potassium intake was controlled at the same high level in both groups at each level of sodium intake. We initially believed the time period of 2 days was not long enough to replete a total body potassium deficiency, which was perhaps reflected in the lower urinary potassium excretions of the blacks. However, this difference is now seen only on the HS diet, in which the renal perfusion differences are also noted. Since the HS and LS studies were only 1 to 2 weeks apart, a decrease in dietary potassium in the blacks is unlikely to account for the difference.
We have shown the inability to increase the renal plasma flow with a high sodium intake in healthy blacks—in the presence of a PRA level that is identical to whites—suggesting incomplete suppression of the renin system in the kidneys of blacks. The differences in RPF was corrected with a small dose of captopril to equal the RPF in whites, inferring that the RAS may be playing a role. This activation of the RAS, leading to a more vasoconstricted kidney, could make it more susceptible to injury. Although medication used to block the RAS has not traditionally been found to be beneficial in regard to blood pressure treatment in blacks,18,19⇓ there may be a role for its use in the treatment of vasoconstriction in an otherwise healthy kidney.
This work was supported in part by the National Institutes of Health (grants T32 HL-07609, NCRR GCRC M01RR026376, P01AC00059916, 1P50 ML 53000-01, 1 R01 DK54668-01, 1K23DK0281601). We are grateful for the assistance of Caroline Coletti, BS, MS, and Janelle Krupinski, BS, in the recruitment of patients for the study, and for the nursing support of Charlene Malarick, RN.
Presented in part at the 31st annual meeting of the American Society of Nephrology, Philadelphia, Pa, October 25–28, 1998.
- Received February 18, 2002.
- Revision received March 12, 2002.
- Accepted May 21, 2002.
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