Essential Hypertension, Progressive Renal Disease, and Uric Acid: A Pathogenetic Link?
Richard J. Johnson*,
Mark S. Segal*,
Titte Srinivas*,
Ahsan Ejaz*,
Wei Mu*,
Carlos Roncal*,
Laura G. Sánchez-Lozada,
Michael Gersch*,
Bernardo Rodriguez-Iturbe,
Duk-Hee Kang and
Jaime Herrera Acosta
* Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, Florida; Department of Nephrology, Instituto Nacional de Cardiología "Ignacio Chávez," México City, México; Renal Service Laboratory, Hospital Universitario and Instituto de Investigaciones Biomédicas, Maracaibo, Venezuela; Division of Nephrology, Ewha University College of Medicine, Seoul, Korea
Address correspondence to: Dr. Richard Johnson, University of Florida, Section of Nephrology, 1600 SW Archer Road, Gainesville, FL 32610. Phone: 352-392-4008; Fax: 352-392-5465; E-mail: johnsrj{at}medicine.ufl.edu
Hypertension and hypertension-associated ESRD are epidemic insociety. The mechanisms responsible for renal progression inmild to moderate hypertension and those groups most at riskneed to be identified. Historic, epidemiologic, clinical, andexperimental studies on the pathogenesis of hypertension andhypertension-associated renal disease are reviewed and an overview/hypothesisfor the mechanisms involved in renal progression is presented.There is increasing evidence that hypertension may exist inone of two forms/stages. The first stage, most commonly observedin early or borderline hypertension, is characterized by salt-resistance,normal or only slightly decreased GFR, relatively normal ormild renal arteriolosclerosis, and normal renal autoregulation.This group is at minimal risk for renal progression. The secondstage, characterized by salt-sensitivity, renal arteriolar disease,and blunted renal autoregulation, defines a group at highestrisk for the development of microalbuminuria, albuminuria, andprogressive renal disease. This second stage is more likelyto be observed in blacks, in subjects with gout or hyperuricemia,with low level lead intoxication, or with severe obesity/metabolicsyndrome. The two major mechanistic pathways for causing impairedautoregulation at mild to moderate elevations in BP appear tobe hyperuricemia and/or low nephron number. Understanding thepathogenetic pathways mediating renal progression in hypertensivesubjects should help identify those subjects at highest riskand may provide insights into new therapeutic maneuvers to slowor prevent progression.
Hypertension is epidemic in our society and is the most commoncardiovascular disease. In the United States, the prevalenceof hypertension has increased markedly in the past 100 yr, froma frequency of 6 to 11% in the population in the early 1900s(1) to >30% today (2). The increase in hypertension doesnot simply reflect an increase in the aging population, becausethe prevalence of hypertension among individuals between theages of 45 and 54 increased from 11% in the 1930s to 31% in2000 (2,3). Hypertension was also nearly absent outside Europeand America in the early 1900s but now affects 25 to 30% ofpeople throughout the world (4). This increase in hypertensiontracks with the epidemic increase in obesity, metabolic syndrome,type II diabetes, and ESRD, raising the likelihood that theseconditions are pathogenetically related and intricately linkedto environmental and especially dietary changes that have occurredin the world population over the past 100 yr.
Hypertension is important in nephrology. According to the UnitedStates Renal Data System Report, hypertension remains the secondmost common cause of ESRD, accounting for nearly 80,000 patientsin 2001 (5). The incidence of ESRD attributed to hypertensionhas increased nearly eight-fold since 1981, suggesting thathypertension should be considered as important as diabetes inthe current epidemic of renal disease (5). Understanding thepathogenesis of hypertension and how it may lead to progressiverenal disease is therefore critical.
Nevertheless, controversy exists over whether the diagnosisof essential hypertension-associated ESRD is correct for thelarge number of cases reported (6,7). There is no doubt thatsevere (malignant) hypertension may cause progressive renalfailure and that lowering BP in this condition can slow or preventprogression (8). However, the issue is whether mild hypertensioncan cause progressive renal disease. Whereas epidemiologic studiesshow that the risk for ESRD increases step-wise as BP increasesfrom 120 or 130 mmHg systolic pressure (9–13), opponentspoint out that in many cases pre-existing renal disease wasnot excluded (6,7). It is well known that hypertension oftenaccompanies a decline in GFR regardless of cause (14). Becauserenal biopsy is not typically performed in essential hypertension,the possibility exists that cases diagnosed as hypertension-associatedESRD could represent misdiagnosed cases of atheroemboli, ischemicnephropathy secondary to atheromatous disease, or glomerulonephritis(15,16). Furthermore, although some studies have reported anincreased risk for renal progression in subjects with mild ormoderate hypertension, especially blacks (17), it is often questionedwhether the observations in this particular group can be carriedover to the general hypertensive population. Finally, it hasbeen difficult to show that antihypertensive treatment altersthe risk for renal progression in subjects with mild hypertension(18–20), and in some cases renal function has worsened(21,22). Nevertheless, there are reports that antihypertensivetreatment can slow renal progression in mild to moderate hypertensionin both whites (23) and blacks (24).
In this review, we present new insights generated from recentexperimental and clinical studies that should shed light onnot only the role of the kidney in causing hypertension butalso the role of hypertension in causing renal disease. Finally,we provide guidance for the identification of those hypertensivesubjects most at risk for progression.
Essential hypertension is classically defined as hypertensionthat occurs in the absence of a known secondary cause. However,there are important clinical, pathologic, and hemodynamic featuresthat characterize this entity. Clinically, hypertension frequentlydevelops in subjects who are obese, have the metabolic syndrome,are hyperuricemic, or who have features of a hyperactive sympatheticnervous system (including type A personalities, subjects witha high baseline pulse, or a positive cold-pressor test). Othercommon characteristics include a positive family history, blackrace, the presence of low-level lead intoxication, and a historyof low birth weight (25).
When hypertension first presents it is often termed "borderline,"in that the hypertension is either mild or intermittent. Earlyhypertension is also frequently salt-resistant, in that it isnot significantly altered by changes in dietary salt intake.In the older subject, hypertension is usually salt-sensitive.Pathologically, hypertension is highly associated with small-vesseldisease (arteriolosclerosis), particularly involving the preglomerularvessels in the kidney (26–28). The classic finding consistsof medial hypertrophy of the interlobular and arcuate arteriesthat may progress to medial fibrosis (fibroelastic thickening)associated with neointimal hyperplasia. Afferent arteriolesare also affected and may show thickening and/or hyalinosis,in which there is subendothelial deposition of homogenous eosinophilicmaterial (26–29). Although these changes are seen in themajority (>95%) of subjects with hypertension, some subjectswith mild or early hypertension may demonstrate minimal arteriolardisease (26–29), although evidence for arteriolar spasmis usually present (inferred from an abnormal concentric overlappingof vascular smooth muscle cells) (28). Hypertension that ismore severe or prolonged is usually associated with more severerenal arteriolosclerotic changes (29,30), and in subjects withmalignant hypertension the vascular lesions may result in severeconcentric hypertrophy (onion-skin vessels) and even fibrinoidnecrosis (31).
The prominent involvement of the preglomerular vasculature isaccompanied hemodynamically by evidence of increased resistanceof the afferent arteriole (32), with a marked decline in renalplasma flow and relative preservation of GFR (33). Corticalvasoconstriction is the result, with relative preservation ofblood flow in the deeper portions of the kidney (34,35). Inaddition to vascular involvement, biopsy and autopsy studiesdemonstrate that there is substantial tubular injury with featuresof ischemia, often accompanied by mild inflammatory cell infiltration(28). Glomeruli may show evidence for ischemia with collapseof the glomerular tuft and eventual obsolescence (36). However,a subset of subjects with essential hypertension may have enlargedglomeruli with segmental scars resembling focal glomerulosclerosis(36–38). This type of injury has been termed "decompensatedglomerulosclerosis" by Bohle and Ratschek (37).
Natural history studies before effective antihypertensive therapydocumented that 35 to 65% of subjects with essential hypertensiondeveloped proteinuria, with one third developing renal insufficiencyand 6 to 10% dying from uremia (39–41). The greatest riskwas for subjects with sustained systolic BP >200 mmHg (39).The risk for mortality and for renal insufficiency (measuredby inulin clearance) correlated with the severity of renal arterioscleroticlesions (42). The mortality risk also correlated with the severityof microvascular changes in the retina, with the survival forgrade 3 (cotton wool exudates/hemorrhages) and grade 4 (papilledema)disease being only 0 to 20% at 5 yr (43–45). It is thusapparent from the historical literature that many untreatedhypertensive subjects developed renal insufficiency; however,it is likely that many of these subjects had severe, accelerated,or malignant hypertension.
Experimental Insights into the Cause of Hypertension
Recent studies by our group and others have provided new insightsinto the pathogenesis of essential hypertension. Specifically,we have demonstrated in animals that hypertension often involvestwo stages.
The first stage of hypertension is primarily initiated by extrarenalstimuli, which may by themselves raise BP but which all havein common the induction of renal vasoconstriction. Examplesinclude hyperuricemia (46–48), angiotensin II (49,50),catecholamines (51), endothelial dysfunction with impaired releaseof nitric oxide (52), or various agents such as cyclosporine(53). During the initial phase, the renal arteriolar structureis normal or only minimally abnormal; however, the arteriolesare functionally constricted, resulting in a decline in renalplasma flow and renal ischemia with tubular injury and interstitialinflammation (46–53). Similar changes can be shown byexposing animals to systemic hypoxia (54).
The initial BP response depends in part on the type of externalstimuli, and whether renal vasoconstriction is intermittentor constant. Intermittent activation of the sympathetic nervoussystem may result in intermittent elevations in BP (51); endothelialdysfunction caused by systemic depletion of nitric oxide resultsin constant elevations in pressure (52); and cyclosporine administrationin rats may result in only mildly elevated BP initially (53).
The second stage is characterized by renal cortical vasoconstrictionthat persists despite removal of the original stimulus (55).This is associated with the development of structural changesin the kidney, characterized primarily by arterioloscleroticchanges (disease of the afferent arteriole) and interstitialinflammation, similar to the changes observed in most subjectswith essential hypertension. Studies in animal models have suggestedthat both the arteriolar and interstitial changes have a keyrole in the hemodynamic response. Thus, the interstitial inflammatorychanges (characterized by monocyte/macrophages and T cells)may have a role in mediating the renal vasoconstriction by producingoxidants and angiotensin II that inactivate local nitric oxide.In contrast, the structural changes in the arteriole may havea key role in helping to maintain the renal ischemia that drivesthe interstitial inflammatory reaction (55).
Hemodynamically, the renal vasoconstriction is associated witha decline in cortical plasma flow, a decline in single-nephronGFR, and a decrease in the ultrafiltration coefficient, Kf (48,50).Nevertheless, overall GFR is normal or only minimally decreased(47,48,50). This suggests that there is a compensatory increasein juxtamedullary nephron GFR (48,50). In this regard, it isknown that juxtamedullary nephrons, which account for 25 to30% of all nephrons, are unlike cortical glomeruli in that theyare capable of increasing their GFR up to three-fold under physiologicconditions (56).
Relevance of Stages of Hypertension with the Development of Salt Sensitivity
Sodium retention results and BP increases whenever there ispersistent renal vasoconstriction, because of glomerular (decreasedKf and/or GFR) and tubular (increased Na re-absorption) mechanisms(55, 57). However, differences in salt sensitivity are reflectedin part by the stage of the hypertension. Thus, when the renalvasoconstriction is mediated primarily by humoral mechanisms,and when arteriolar disease is mild, the constriction is relativelyuniform and hence an increase in renal arterial pressure willrelieve ischemia uniformly throughout the kidney. Sodium handlingthen returns to normal but at an expense of a higher BP anda parallel shift in the pressure natriuresis curve, resultingin a salt-resistant form of hypertension (58). In contrast,as arteriolar disease develops, the variability in the lesionswill result in heterogeneous perfusion, with some regions ofthe kidney remaining ischemic and others overperfused. Glomerularand peritubular capillary hypertension is then likely to develop,with focal loss of capillaries and the development of renalischemia. As a consequence, the hypertension will be more ofa salt-sensitive type because ischemia will continue to drivesodium re-absorption (55,57). In addition, a heterogeneous responseof renin is likely to occur, which would also play a role inthe hypertensive response as proposed by Sealey et al. (59).
A key issue then relates to the mechanisms involved in the inductionof arteriolar disease. In this regard, arteriolar changes areparticularly severe if induced by angiotensin II, hyperuricemia,or blockade of the nitric oxide system (46–50,52,60),whereas the arteriolar changes are relatively minimal with catecholaminesor hypokalemia (51,61). The arteriolosclerotic changes are alsofocal (particularly occurring at branch points) in some geneticstrains, such as in the Dahl salt-sensitive rat, whereas thecongenital narrowing of the arterioles are more uniform in therelatively salt-resistant spontaneously hypertensive rat. Interestingly,in most of these models the arteriolopathy can be shown to bemediated by angiotensin II (60,62,63). The mechanism likelyinvolves activation of NADPH oxidases and the generation ofoxidants that causes local vascular smooth muscle cell proliferationand activation (64,65).
Relevance of Stages of Hypertension with the Progression of Renal Disease
The stage of hypertension and the type of arteriolar injurywould likely have a major impact on the risk for renal progression.Thus, in the first stage the renal arteriolar structure remainslargely intact. As a consequence, the arteriolar vasoconstrictionwill function adequately from the autoregulatory standpointto prevent excessive transmission of systemic pressures intothe glomerular and peritubular capillaries. Glomerular pressurewill remain normal, and the risk for renal injury in this settingwould be relatively minimal.
An appropriate analogy for this stage is the spontaneously hypertensiverat. In this hypertensive strain, there is a congenital reductionin afferent arteriolar diameter that results in renal ischemia.An increase in BP ensues, but the autoregulatory response ofthe preglomerular vasculature is functional and vasoconstrictsappropriately to prevent the development of glomerular and peritubularcapillary hypertension (66,67). In addition, renal ischemiais minimal because the increase in systemic and renal perfusionpressure will act to relieve it (55).
In contrast, the risk for renal injury is greater in the secondstage of hypertension, particularly depending on the natureand type of the arteriolar injury. Thus, if the structural changesin the renal microvasculature are nonuniform, then the ischemia-inducedincrease in BP would result in heterogeneous perfusion of therenal parenchyma. In this scenario, some glomeruli would beoverperfused and others underperfused for the same renal arterialperfusion pressure. The overperfused glomeruli may develop intraglomerularhypertension, whereas the underperfused glomeruli may becomeischemic, resulting in persistent stimulation of juxtaglomerularrenin release (59).
There is also increasing evidence that preglomerular arteriolardisease may also impair the autoregulatory response (47,48,68).Thus, in experimental hyperuricemia, the development of thepreglomerular arteriolar lesions has been shown to result inreduced renal blood flow and glomerular hypertension, and boththe arteriolar lesions and hemodynamic changes do not occurif hyperuricemia is prevented with allopurinol (47,48). Similarfindings have been demonstrated in the remnant kidney model(68). We have postulated that the deposition of extracellularmatrix into the arteriolar walls affects its ability to constrictappropriately for the degree of systemic BP elevation (48).The development of glomerular hypertension would then resultin glomerular hypertrophy and the "decompensated glomerulosclerosis"lesion, and this is observed in chronically hyperuricemic rats(69) and in rats with remnant kidneys (68). Interestingly, renalautoregulation is relatively maintained in rats with preglomerulararteriolar disease induced by transient exposure to angiotensinII, and in these animals glomerular hypertension did not developafter salt-loading (50). Whether this is because the vasculardisease is more uniform and whether autoregulation would continueto remain intact as the vascular disease worsens are unclear.
Clinical evidence provides support for these pathways. Thus,early borderline hypertension is often salt-resistant (70) withminimally decreased renal plasma flow and normal GFR (71), andthis corresponds with the renal hemodynamic changes associatedwith minimal renal arteriolar lesions (42). Younger subjectswith short-duration (mean, 3 yr) hypertension also do not showany increase in peritubular capillary hydrostatic pressure withsalt-loading, consistent with a normal autoregulatory response(72). In contrast, older hypertensive subjects tend to be salt-sensitive(70), have lower renal blood flow (73), have more prominentrenal arteriolar changes (30), and worse renal function (30);some studies suggest that the age-dependent decline in GFR inour population may largely relate to the presence of hypertension(74). Subjects with salt-sensitive hypertension are also morelikely to demonstrate renal progression compared with salt-resistantsubjects and to have microalbuminuria (75). This latter conditionis also associated with vascular changes in their retina (76),reduced renal function (76,77) and severe hypertension (78).Finally, subjects with salt-sensitivity and microalbuminuriademonstrate an increase in calculated glomerular hydrostaticpressure with salt loading in contrast to salt-resistant subjects,suggesting an impaired autoregulatory response (75).
Clearance studies also provide insight into the mechanisms ofrenal progression in subjects with essential hypertension. Renalplasma flows (RPF) (measured by p-aminohippurate clearance)decrease stepwise from 616 to 660 ml/min in normal subjectsto 532 ml/min in borderline hypertensive subjects, to 475 to505 ml/min in subjects with essential hypertension, to 317 ml/minin malignant hypertension (71,79). The level of GFR correlateswith the changes in renal plasma flow (80) but does not showdetectable decrease until the RPF falls to <450 to 475 ml/min(79). Interestingly, studies by Talbot et al. in the 1940s showedthat the changes in renal plasma flow and GFR also correlatewith the severity of the renal arteriolar lesions (by biopsy)(42). Thus, as arteriolar scores increased from 0 to 4, renalplasma flow decreased stepwise from 625, 552, 470, 440, to 283,with a decrease in GFR from 94, 104, 91, 89, to 64 ml/min (42).Interestingly, GFR did not decline until RPF decreased to <400(late-stage hypertensive disease). One might posit that as thevascular disease worsens, the renal autoregulatory responsealso worsens, with some glomeruli displaying hypertension, whereasothers remain ischemic. Eventually, however, renal perfusionpressures will not be able to sustain adequate glomerular pressures(even with maximal efferent vasoconstriction), and at this pointglomerular obsolescence and collapse would occur. This is observedwith severe, untreated, malignant hypertension (31).
Why Does Hypertension Progress in Some Subjects but in Others It Does Not?
These studies provide the necessary insight into better understandingwhy essential hypertension progresses in some subjects but inothers it does not. Renal progression would be expected to occurif the renal autoregulatory response is impaired, resultingin increased glomerular hypertension. This concept is not noveland has been suggested by others (81–83). This could theoreticallyoccur by several mechanisms. First, if the degree of hypertensionwas so severe that it exceeded the normal threshold for autoregulation.Studies of autoregulation have generally shown that glomerularpressure remains normal with systemic systolic pressure as highas 160 mmHg (84), although few studies have examined if autoregulationis maintained at higher pressures. However, one can observerenal injury developing in hypertensive kidneys in two-kidneyone-clip hypertension when the systolic BP is >160 mmHg,suggesting that the threshold may be overcome (85). It is likelythat this may represent one of the mechanisms by which malignanthypertension damages the kidney (86).
In subjects with mild or moderate hypertension, one would positthat alteration in the renal autoregulatory response would benecessary if one were to observe an increased risk for renalprogression. One mechanism by which this may occur is in thesetting of a reduced nephron number, such as in the remnantkidney model, in which even high-normal systemic pressures canbe transmitted to glomeruli, resulting in glomerular damage(87). Another condition is experimental hyperuricemia, in whichglomerular hypertension occurs even under conditions of mildsystolic hypertension (47,48). As discussed, recent studieshave correlated both of these conditions with the developmentof structural lesions of the renal arteriole (47,48,68).
Genetic mechanisms could also be operative. For example, thefawn-hooded rat has a genetic defect in renal autoregulationthat results in early onset glomerular hypertension, followedby the accelerated development of renal disease (88). Numerousfactors are known to govern renal autoregulation (84), including20-hydroxyeicosatetraenoic acid (20-HETE) (89,90), and hencegenetic alterations in any of these mediators could also leadto an abnormal autoregulatory response and increase the riskfor progression in the subject with essential hypertension.
One can thus predict that the risk for renal progression ismost likely to occur in the setting in which hypertension issevere or prolonged, when renal arteriolosclerosis is severe,when nephron number is reduced, or in the setting of a geneticabnormality in the renal autoregulatory response. In this regard,a critical observation is that renal arteriolar injury may notsimply reflect hypertension-related damage but also can occurindependent of BP as a consequence of hyperuricemia (60). Themechanism appears to be mediated by direct entry of uric acidinto both endothelial and vascular smooth muscle cells, resultingin local inhibition of endothelial nitric oxide levels, stimulationof vascular smooth muscle cell proliferation, and stimulationof vasoactive and inflammatory mediators (91).
Specific Characteristics that Favor an Increased Risk for Renal Progression in Essential Hypertension
There are certain characteristics that favor an increased riskfor renal progression in the subject with essential hypertension(Table 1). An important risk factor is black race (92). Interestingly,several factors could account for this. First, blacks have beenreported to have lower birth weights, which translates intofewer nephrons at birth (93). Second, they are known to havea significantly higher frequency of gout (94); in the AfricanAmerican Study of Kidney Disease Trial, mean uric acid was 8.3mg/dl (95). Third, they also have higher serum TGF- levels,which might theoretically result in more severe renal scarring(96,97). Other characteristics also may predispose them to hypertension,including diets low in potassium and high in salt (98), endothelialdysfunction (99), and increased vascular reactivity (100,101).Thus, it is interesting that clinical studies suggest that blackshave a defect in renal autoregulation with increased glomerularpressure (102), and that by renal biopsy they have more severevascular and interstitial changes associated with glomerularhypertrophy and segmental sclerosis (103,104). The preglomerularvascular changes occur earlier and are more severe in blacks(105). It is perhaps not surprising that hypertension in blacksis primarily characterized by a high frequency of salt-sensitivity(106) and microalbuminuria (107).
Table 1. Risk factors that favor an increased risk for renal progression in the subject with essential hypertension
A second major risk factor for renal progression in hypertensivesubjects is the presence of hyperuricemia and/or gout. In thedays before treatment of gout was available, as many as 25%of subjects died from renal failure (108,109). In addition,the majority (50 to 70%) had hypertension, 25% had albuminuria,50 to 65% had decreased inulin clearances, 70 to 80% had decreasedrenal plasma flow, and 95% had histologic evidence of chronicrenal injury (108–110). The primary histologic lesionin gout noted by early investigators was the presence of preglomerularvascular disease. The French academician, Henri Huchard (whocoined the word hypertension), reported that gout was the mostcommon cause of arteriolosclerosis based on a large autopsyseries (111). Other changes include focal glomerulosclerosisand tubulointerstitial fibrosis (108,112). Medullary urate crystalsare also common but appear nonspecific (113).
Studies in the 1970s also demonstrated a strong associationof hypertension and renal disease with gout (114–116).For example, in one study approximately one third of subjectswith gout had significant renal dysfunction in association withhypertension (114). Because most forms of mild hypertensionare not associated with significant renal dysfunction, thisassociation is particularly striking (117). Recent epidemiologicstudies have further demonstrated that uric acid is a majorand independent risk factor for the development of renal diseasein the general population and in patients with glomerulonephritisand normal renal function (118–121). Experimental studieshave reported that hyperuricemia induces systemic hypertensionand renal injury via a crystal-independent mechanism, involvingrenal vasoconstriction mediated by endothelial dysfunction andactivation of the renin-angiotensin system (46–48). Overtime, the animals developed afferent arteriolar lesions, saltsensitivity, glomerular hypertension, glomerular hypertrophy,albuminuria, and eventually glomerulosclerosis (46–48,122).Thus, both experimental and human data clearly show that subjectswith hyperuricemia and/or gout are at marked risk for hypertensionwith renal insufficiency.
A third major risk factor is low-level chronic lead intoxication.Studies in the 1800s linked chronic lead intoxication with thedevelopment of hypertension and renal disease (111,123), a findingthat has been confirmed repeatedly in recent years (124–132).Subjects typically present with hypertension, slowly progressiverenal insufficiency, and often have hyperuricemia and/or gout(124–132). Histologically, the renal lesion also appearslike chronic hypertension, as characterized by prominent arteriolosclerosisand tubulointerstitial fibrosis (133), leading Huchard to declarethat lead intoxication was the second most common cause of arteriolosclerosis(111). The relation of renal disease with lead levels can bedemonstrated at levels well within the normal range (132), andsubtle lead intoxication is now recognized in some parts ofthe world as a common cause of ESRD (134–136). In contrast,high blood levels of lead are not associated with hypertensionbut rather with proximal tubular injury with a Fanconi pattern,i.e., intratubular nuclear inclusions (137,138).
A fourth major risk factor is obesity and the metabolic syndrome.It has become increasingly appreciated that obesity is associatednot only with hypertension but also with an increased frequencyof renal disease (139–144). Similar to the other conditions,obesity-associated renal disease is associated with vascularlesions, interstitial inflammation, glomerular hypertrophy andglomerulosclerosis, and with evidence for glomerular hypertension,as noted by elevated filtration fraction (141). The mechanismfor the increased susceptibility for renal injury may relateto activation of the sympathetic and renin-angiotensin systemsand/or the deposition of lipids in the renal parenchyma, resultingin increased interstitial pressure (139). Of additional interestis the finding that obesity-associated metabolic syndrome isalmost always associated with hyperuricemia (145). Finally,this hypertension also tends to be salt-sensitive (146).
Although controversial, a fifth major risk factor appears tobe diuretic use. Clinical and population-based studies havereported that diuretic usage does not slow but rather oftenaccelerates renal progression in hypertensive subjects (21,22,147–155).The usage of diuretics in the EWPHE (22,153), Syst-Eur (149),SHEP (150), INSIGHT (151), and ALLHAT (152) studies were allstatistically associated with a greater decline in renal functioncompared with the other treatment groups. Diuretics also exacerbaterenal disease in a model of experimental hypertension (156).The mechanism is likely multifactorial (155), but it is of interestthat even low-dose diuretic therapy is associated with an increasein serum uric acid (157,158).
It may appear surprising that diuretic usage is associated withworsening renal disease in hypertensive subjects given the knownprotective effects of diuretic on hypertension-related heartfailure and stroke. However, the degree of protection for coronaryevents with diuretics is also less than expected for the decreasein BP observed (159–161), and this increase in cardiovascularevents and mortality can be attributed in part to the effectof diuretics to raise uric acid levels (162,163). There is alsoa post hoc analysis in the LIFE trial that the added benefitof losartan to prevent cardiovascular events compared with -blockerscould be explained in part by its effect to lower uric acid(in addition to its well-known effect to block the angiotensintype 1 receptor) (164). Finally, it is interesting that diureticsprevent hypertension in experimental hyperuricemia but, unlikeangiotensin-converting enzyme inhibitors, do not block the developmentof the renal arteriolopathy (60). Similarly, a study in humansfound that angiotensin-converting enzyme inhibitors are ableto cause regression of retinal microvascular disease in hypertensivepatients but diuretic therapy was without benefit (165). Again,these studies in composite suggest that diuretics, likely byraising uric acid levels and stimulating the renin angiotensinsystem, may accelerate the development of renal microvasculardisease and thereby predispose the patient to renal progression.Nevertheless, this does not negate the fact that diuretics areoften a necessary part of the antihypertensive regimen in difficult-to-controlhypertension.
A final risk factor is aging. It is well known that aging isassociated with a high frequency of preglomerular vascular lesions(including hyalinosis and arteriolar thickening), with impairedrenal function, and with salt-sensitive hypertension (70). Thereis even morphometric evidence that the arteriolar lesions maypredispose to impaired autoregulation (166). The mechanismsresponsible for the development of the renal lesions are undergoingstudy but can be largely prevented by long-term treatment withagents that block the renin angiotensin system (167).
Summary and Hypothesis
Hypertension is epidemic in our society and is currently consideredthe second most common cause of ESRD. In this review, we havepresented evidence that hypertension may exist in two stages(or forms). In the setting in which arteriolar disease is minimal,the arteriole may continue to appropriately autoregulate toprevent transmission of systemic pressures to the glomeruli.In this setting, which likely affects a substantial portionof the population, renal disease progresses slowly over time,and GFR remains relatively preserved. However, under conditionsin which significant renal arteriolar disease develops, suchas in the setting of severe hypertension, marked reduction innephron number, or hyperuricemia, then the autoregulatory responsebecomes impaired and renal progression occurs much more rapidly.It is intriguing that most of the major groups associated withan increased risk for progression, namely, black race (94,95),subjects with gout or hyperuricemia, subjects with chronic leadingestion (125,128), severe obesity/metabolic syndrome (145),and chronic diuretic use (155,158), all have relatively highuric acid levels. We suggest that uric acid may have a key rolein initiating renal arteriolar lesions in these patients andthus in increasing their risk for early progression. There isalso evidence that an elevated uric acid may potentiate theeffects of angiotensin II to induce renal vasoconstriction (168),which could possibly be mediated by its effect to upregulateangiotensin type 1 receptors on vascular smooth muscle cells(169).
Thus, we propose trials to determine if reducing uric acid mayhave a role in slowing renal progression in subjects with hypertension.Although there is mixed literature on the role of reducing uricacid on slowing renal progression in gout, with both positiveand negative results reported (170,171), most studies were limitedby poor controls, short duration of therapy, or inadequate reductionof uric acid (117). Furthermore, it is important to recognizethat when the microvascular disease develops, it is the vasculardisease that will drive renal progression, much like the renalmicrovascular disease drives the salt-sensitive hypertension(25,55). Hence, studies to examine the role of uric acid inrenal disease are best if they focus on the initiation of theprocess more than on its maintenance.
Acknowledgments
Supported by National Institutes of Health grants DK-52121,HL-68607, and a George O’Brien Center grant (DK-64233).
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
Dr. Richard Johnson has a consultantship with TAP Pharmaceuticals.
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Top
Abstract
Introduction
levels, which might theoretically result in more severe renal scarring (96,97). Other characteristics also may predispose them to hypertension, including diets low in potassium and high in salt (98), endothelial dysfunction (99), and increased vascular reactivity (100,101). Thus, it is interesting that clinical studies suggest that blacks have a defect in renal autoregulation with increased glomerular pressure (102), and that by renal biopsy they have more severe vascular and interstitial changes associated with glomerular hypertrophy and segmental sclerosis (103,104). The preglomerular vascular changes occur earlier and are more severe in blacks (105). It is perhaps not surprising that hypertension in blacks is primarily characterized by a high frequency of salt-sensitivity (106) and microalbuminuria (107). 
