Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Endothelial Dysfunction and the Kidney: Emerging Risk Factors for Renal Insufficiency and Cardiovascular Outcomes in Essential Hypertension
Carmine Zoccali
Consiglio Nazionale delle Ricerche-Istituto di Bio-Medicina, Clinical Epidemiology & Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy
Address correspondence to: Dr. Carmine Zoccali, CNR-IBIM Sezione di Epidemiologia Clinica e Fisiopatologia delle Malattie Renali e dell’Ipertensione Arteriosa, Ospedali Riuniti, Nefrologia (VI Piano), 89124 Reggio Calabria, Italy. Phone: +39-0965-397010; Fax: +39-0965-397000; E-mail: carmine.zoccali{at}tin.it
Renal insufficiency in essential hypertension represents theexpression of a medium- and small-size arteriolopathy characterizedby intimal hyperplasia, hyalinosis, and smooth muscle cell hypertrophy(nephroangiosclerosis). Because in animal models endothelialdysfunction plays a role in this alteration, nephroangiosclerosisand the attendant renal insufficiency may be the expressionof a systemic dysfunction of vascular endothelium. Endothelialfunction in the kidney vasculature of hypertensive individualshas been investigated little because studies on the hemodynamicresponse of the kidney to nitric oxide activation and blockadeare laborious to perform. There is no direct proof that endothelialdysfunction in the forearm or in the coronary circulation isparalleled by a similar hemodynamic dysfunction in the kidney.A recent study in a large population of patients with essentialhypertension showed that, independent of other risk factors,the GFR in these patients is strongly related to the forearmblood flow response to acetyl choline (an established test ofendothelial function). Furthermore, in this study, C-reactiveprotein was inversely related to the GFR and with the vasodilatoryresponse to acetyl choline, pointing to inflammation as a likelymechanism to explain the association between endothelial dysfunctionand impaired renal function in essential hypertension. A dysfunctionalendothelium may represent a critical link accounting for therisk for both renal impairment and cardiovascular complicationsin essential hypertension.
Nephroangiosclerosis: The Cinderella of Renal Diseases
According to major renal registries, nephroangiosclerosis isa disease that is responsible for at least one third of casesof ESRD. Comparatively, the contribution of glomerulonephritidesis just one fifth to one sixth that of nephroangiosclerosis.In general, the epidemiologic burden of this disease still isnot appreciated by internists and renal physicians. This isbecause only in a minority of patients (approximately 1:1000)does nephroangiosclerosis evolve to the end stage. Althoughrarely progressing to advanced renal failure, it is so prevalentin the general population that it eventually represents themost frequent cause of ESRD. That the epidemiologic burden ofnephroangiosclerosis still is overlooked is transparent alsofrom the scanty research efforts focused on this disease. Indeed,search of the major medical database PubMed shows that duringthe last 10 yr, the publication rate of papers that deal withglomerulonephritides has remained stably at approximately 1000papers per year, whereas the corresponding figure for nephroangiosclerosishas been a mere 50 papers per year. This is a sort of scientificparadox because research efforts seem to be diverted towardrelatively rare causes of ESRD and inexplicably overlook themost common cause of ESRD.
During the past 5 yr, substantial knowledge has been accruedon the high frequency of minor degrees of renal insufficiency.In the United States, approximately 8 million Americans, orapproximately 7% of the general population, display moderate(GFR 30 to 60 ml/min) chronic kidney disease (CKD). Such a highfrequency cannot be attributed to immunologic or genetic diseasesbecause these are rare, affecting less than 0.01% of the population.The most common causes of CKD are atherogenic diseases (hypertension,dyslipidemia, and type 2 diabetes [1]), diseases in which theunderlying histologic alteration is commonly represented bynephroangiosclerosis. It is just the extension of atherogenicdiseases to the kidney vasculature that establishes the perversecardiovascular–renal link that is responsible for thecurrent epidemic of CKD in Western countries and that propelsthe high rate of cardiovascular complications in this population(2). The importance of a moderate degree of renal insufficiencyin the high cardiovascular risk of hypertensive individualsis epitomized by observations made in the Progetto IpertensioneUmbria Monitoraggio Ambulatoriale (PIUMA) study cohort (3).Indeed, on the basis of the data reported in this study, wecalculated that, independent of other risk factors, includingleft ventricular hypertrophy, and 24-h average ambulatory BPmonitoring, the presence of a moderate degree of renal insufficiencyentails a 90% increase in the risk for incident cardiovascularcomplications. Therefore, nephroangiosclerosis and the attendantrenal function loss are important not only because they maybe conducive to ESRD but also because they trigger cardiovascularevents.
Nephroangiosclerosis, Intimal Hyperplasia, and Endothelial Dysfunction
The most typical finding in nephroangiosclerosis is representedby intimal hyperplasia of medium and small renal arteries. Suchan alteration is the expression of systemic endothelial damagebeing extended to the whole arterial system, from small vesselsto the aorta (4). Therefore endothelial damage seems to be thebasic anatomic alteration that eventually leads to disastrousvascular events in the heart, brain, and kidney (5). In linewith this interpretation, the inability of medium and smallvessels to respond appropriately to vasodilatory stimuli (6)that are mediated by the nitric oxide (NO) system, such as theparasympathetic neuromediator acetylcholine (ACh), is an establishedfunctional correlate of intimal hyperplasia.
The cause of nephroangiosclerosis in hypertension still is incompletelyunderstood. In the rat, renal alterations that are similar tothose of nephroangiosclerosis can be induced by the NO inhibitorNG-nitro-l-arginine methyl ester (7), suggesting that endothelialdamage is a critical element in the pathogenesis of this disease.There is consistent evidence that the endothelial response toACh in the forearm vasculature of individuals with essentialhypertension is compromised (8). Such an alteration largelyis independent of arterial pressure, overweight, smoking, andhypercholesterolemia, all factors that may be conducive perse to endothelial dysfunction (9). Of note, endothelium-dependentvasodilation in the forearm is closely related to that in coronaryarteries (10), again pointing to a systemic rather than to alocal disorder (5). Endothelial function in the kidney vasculaturein hypertensive patients has been investigated little becausestudies of the hemodynamic response of the kidney to NO activationand blockade are laborious to perform. There is no direct proofthat endothelial dysfunction in the forearm or in the coronarycirculation is paralleled by a similar hemodynamic dysfunctionin the kidney. As alluded to before, animal models suggest thatnephroangiosclerosis and the attendant renal insufficiency areexpected consequences of endothelial dysfunction in the renalcirculation (7). Therefore, testing the association betweenindicators of renal function and the forearm blood flow responseto ACh may provide circumstantial evidence in support of thehypothesis that nephroangiosclerosis is the expression of endothelialdysfunction in the kidney. We recently investigated this relationshipand renal function in 500 patients with uncomplicated, nevertreated, essential hypertension and serum creatinine <1.5mg/dl (11). Such a population seemed ideally suited to testthe hypothesis because drug treatment and background cardiovascularcomplications are notorious confounders in the interpretationof studies of endothelial function. Remarkably, we found a stronglink between the vasodilatory response to ACh and the GFR (Figure 1).Such a link was independent of arterial pressure and other riskfactors, suggesting that systemic endothelial dysfunction isan important mechanism that contributes to mild renal dysfunctionin essential hypertension.
Figure 1. Relationship between the vasodilatory response to acetylcholine (expressed in tertiles) and the GFR (Modification of Diet in Renal Disease [MDRD] formula). FBF, forearm blood flow.
Endothelial Dysfunction, Inflammation, and Renal Dysfunction in Essential Hypertension
It is well established that the endothelium synthesizes a varietyof inflammatory molecules, such as intercellular adhesion moleculeand vascular cellular adhesion molecule, and that, in turn,it is the target of inflammatory processes. Subtle elevationsin plasma concentration of C-reactive protein (CRP), a reliablemarker of inflammation, were associated with similarly subtlereductions in creatinine clearance in the Prevention of Renaland Vascular Endstage Disease (PREVEND) study (12). In linewith these observations in the general population, we foundthat CRP was inversely related both with the response to AChand with the GFR (Figure 2). These associations suggest thatendothelial dysfunction may be an intermediate mechanism mediatingthe effect of inflammation on renal function.
Figure 2. Relationship between C-reactive protein (CRP; expressed in tertiles) and the GFR (MDRD formula).
Collectively, these studies document that an impaired vasodilatoryresponse to ACh is a risk marker for renal function loss inpatients with essential hypertension and suggest that inflammationmay be the mechanism triggering both endothelial dysfunctionand renal insufficiency in essential hypertension. In this perspective,it seems to be of particular interest that high levels of asymmetricdimethylarginine (ADMA) may represent a possible mechanism thatis conducive to endothelial dysfunction in essential hypertension.The synthesis of this substance is increased in inflammatorystates (13), and acute inflammation may trigger a fully reversibleendothelial dysfunction in healthy young humans (14). Such ahypothesis is specifically supported by our findings showingthat ADMA is increased in patients with uncomplicated hypertensionand by the parallel observations that in these patients, theresponse to ACh is inversely related to plasma ADMA concentration(r = 0.58, P < 0.01) (15). The role of ADMA as a criticalplayer in endothelial dysfunction in essential hypertensionis also suggested by the fact that l-arginine infusion fullyrestores endothelium-dependent vasodilation in these patients(15).
As alluded to before, consistent evidence now has been accruedthat in individuals with essential hypertension, even minordegrees of renal insufficiency entail a high risk (3). Likewise,endothelial dysfunction now has emerged fully as a feature ofmajor clinical relevance in hypertensive patients (5,8) becauseindependent of arterial pressure levels and other risk factors,it is associated with left ventricular hypertrophy (16) andpredicts cardiovascular events (17).
A dysfunctional endothelium seems to be a key factor in therisk for renal insufficiency in individuals with essential hypertension.The inverse links between CRP and the GFR and the vasodilatoryresponse to ACh coherently suggest that inflammation is a likelymechanism explaining this association. The endothelium seemsto be at the crossroads of the risk for renal impairment andcardiovascular complications in individuals with essential hypertension.
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Nephroangiosclerosis: The...
