These data demonstrate that hypertensive African-American subjects had disproportionate elevation in renal medullary volume and blood flows as compared to Caucasians, even after allowing for differences in age and body size. Elevated medullary volume was characterized by higher levels of deoxyhemoglobin (as reflected by R2*) under basal conditions, consistent with more extensive oxygen consumption in deep medullary segments that reversed after administration of furosemide. We interpret this response to furosemide primarily to reflect oxygen consumption related to tubular solute transport under these conditions, consistent with reabsorption of a high filtered sodium load 16
. Unlike Caucasians, higher blood flows to the kidney in African-Americans were related to urinary excretion of PGF2α
, suggesting that high oxygen consumption in turn increased generation of stable products of oxidative stress.
Previous studies suggest that hypertension in African-Americans is associated with earlier onset and more severe target manifestations 1,17
. Measurements of renal hemodynamics and function have produced widely varied results, often depending upon conditions of sodium intake and/or medications. Our results extend those of Parmer and colleagues, who identified no differences in untreated subjects during low sodium intake, but identified increased GFR during “high” (ad libitum, measured output 155 mmol/d) sodium intake similar to the levels in our protocol 18
. Our studies were performed during continued antihypertensive therapy with agents that block the renin-angiotensin system. We employed this strategy because angiotensin II is known to modulate renal hemodynamics and may affect efficiency of sodium transport and associated oxygen consumption 19;20
and BOLD MR signaling 21
. To minimize this variable for these studies, we elected to continue treatment in all subjects. Because experimental diabetes also is known to affect tissue oxygenation in the kidney, our studies excluded individuals with identified diabetes mellitus. As expected, the African-American subjects were younger than Caucasians although reported duration of hypertension (not shown) was similar. As a group, the AA subjects were more obese than the Caucasians studied. We cannot exclude an additional confounding role for obesity in AA that may increase both blood flows and GFR 22;23
. However, no independent effect of body mass index (BMI) was apparent in multivariate analysis, and treated blood pressure levels, sodium intake and output, and metabolic parameters were otherwise similar between the two groups.
Our data using BOLD MR confirm and extend observations that a sizable gradient develops between cortical levels of deoxyhemoglobin (with low R2* levels) and deep medullary segments (higher R2* levels). These levels are consistent with measurements in normal subjects and essential hypertensive subjects as previously reported from our center and others using 3-Tesla magnetic fields 11;24;25
. Pruijm and colleagues demonstrated a rise in medullary R2* values in normal subjects undergoing in increase from low to high sodium intake 25
. Experimental studies using oxygen-sensitive probes confirm substantial and progressive decrements in tissue oxygenation and rise in deoxyhemoglobin within the ranges observed here as a result of changes in blood flow and solute transport 12;20;26
A major new observation in this study is that while cortical oxygenation did not differ between Caucasian and African American hypertensive subjects, R2* levels in medullary segments were higher in AAs, suggesting that these kidneys were functioning at more extreme levels of deoxygenation, despite high levels of blood flow. These data are consistent with higher filtered sodium loads in AAs with higher solute reabsorption required to maintain sodium balance. Our results indicating that R2* levels fell to similar levels with Caucasians after furosemide indicate that these changes represent a functional level of oxygen consumption primarily related to solute transport 27;28
We interpret these results to suggest that medullary segments in AA subjects were in fact consuming more oxygen, thereby leaving medullary segments relatively more “hypoxic” as compared to Caucasian subjects. These results provide an additional physiologic mechanism generally consistent with the theoretical model proposed by Aviv and colleagues related to a proposed “sodium glomerulopathy” 8
in African Americans. Our results provide an additional metabolic framework for considering the hazards of “hyperfiltration” beyond those associated with alterations in glomerular filtration pressures. It is known that the normal kidney generates regional oxygen gradients based on solute reabsorption that are closely regulated 29
. Even sustained reductions in main renal artery blood flow sufficient to reduce glomerular filtration, lead to functional adaptation for metabolic work capable of preserving regional tissue oxygenation 13
. Our results indicate that one consequence of glomerular “hyperfiltration” is delivery of high filtered loads of sodium to energy-requiring tubular reabsorptive sites. The energy requirements to reabsorb these high solute loads were associated with more severe tissue deoxygenation, measured here as high medullary R2* values ().
The implications of large medullary volumes and extreme tissue deoxygenation in stable human subjects are not known. Our results suggest that the level of blood flows to the kidney in AA—both in cortex and medulla—were correlated with urinary PGF2α
level. This marker of oxidative stress reflects excessive generation of reactive oxygen species capable of accelerating tissue injury in many experimental models 30,31;32
. No such relationship was evident in Caucasian subjects under the same protocol conditions. Previous studies indicate that hypertensive African-Americans with varied kidney disorders are demonstrably more “salt-sensitive” 7
and have higher circulating markers of tissue injury and repair, such as TGFβ 33
. We consider it plausible that increased oxidative stress in deep medullary segments eventually may contribute to small vessel injury and tissue fibrosis, as observed elsewhere 15;30;34;35
. Kidney function was preserved in our patients and urinary total protein levels were normal, although many of these subjects were obese and had modestly elevated microalbumin excretion. Whether obesity, ethnicity or other factors were paramount in defining the relationship between oxidative markers and blood flow cannot be resolved with the present data.
Previous studies suggest that a predilection to renal injury is present in AA subjects as a consequence of low birth weight and reduced nephron number 17;36
. We have no direct measure of nephron number or accurate birth weight in our subjects and cannot exclude this possibility. Inasmuch as renal cortical volume may be an index of nephron number 37
, it was not decreased in our patients.
Is it possible that these data reflect a “phenotype” of pre-existing renal structural abnormalities related to a genetic abnormality highly prevalent in the African-American population, as recently proposed 38;39
? Subtle renal abnormalities also have been postulated to account for “salt-sensitive” hypertension 40
. Our subjects were hypertensive at a young age, but had no other overt stigmata of kidney disease. Although total urinary protein excretion was within normal limits, urinary microalbumin levels were above normal in both white and AA cohorts. These levels suggest early renal abnormalities and elevated cardiovascular risk for some of these participants.. Data from the National Health and Nutrition Examination Survey (NHANES) indicate that differences in health behaviors alone between whites and AA’s do not explain the disparities in hypertension prevalence and control 41
. We believe it possible that genetic segregation of renal traits may include structural differences in medullary size and hemodynamics that predispose to glomerular injury and focal glomerular sclerosis 38;39
. Whether medullary volumes and sodium reabsorption might have been “pre-conditioned” by higher dietary sodium or other solutes constituents cannot be established by the present data. We believe it to be possible that previous exposures to sustained high sodium intakes may favor medullary expansion. The potential for sodium restriction to reduce medullary deoxygenation in this cohort merits further study.
These studies were necessarily limited to individuals without evident kidney injury who agreed to participate. AA subjects were not specifically matched by age or body weight although precautions were taken to exclude diabetes. No verifiable information regarding prior nutrient intake was available, although dietary intake during protocol evaluation was carefully monitored. Care was taken to adjust for differences in mean age and body size in data analysis and presentation.
Taken together, our studies extend observations regarding tissue oxygenation using BOLD MR to examine within the gradients developed in kidney tissue. They argue that the robust ability to recover and transport sodium and chloride is associated with enhanced energy consumption that ultimately may be associated with generation of reactive oxygen species in African American subjects. Whether this provides an avenue to identify patients at risk for progressive kidney injury and a potential site for intervention warrants further study.