Mild Renal Dysfunction and Cardiovascular Risk in Hypertensive Patients
Giovanna Leoncini,
Francesca Viazzi,
Denise Parodi,
Elena Ratto,
Simone Vettoretti,
Valentina Vaccaro,
Maura Ravera,
Giacomo Deferrari and
Roberto Pontremoli
Department of Internal Medicine, Section of Nephrology, University of Genoa, Genoa, Italy
Correspondence to Dr. Roberto Pontremoli, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6-16132 Genoa, Italy. Phone: +39-010-353-8932; Fax: +39-02-700-509-259; E-mail: rpontrem{at}medicina.unige.it
ABSTRACT. Mild renal dysfunction, defined as GFR <60 to 70ml/min and/or the presence of increased urinary albumin excretion,is associated with higher cardiovascular morbidity and mortalityin primary hypertension. The aim of the present study was toinvestigate the relationship between renal dysfunction and targetorgan damage (TOD), namely left ventricular hypertrophy (LVH),retinal vascular changes, and carotid atherosclerosis, in alarge cohort of unselected middle-aged hypertensive patientswith normal serum creatinine. A group of 934 untreated patientswith primary hypertension (543 men, 391 women; mean age 50 ±11 yr) was studied. Renal function was estimated by the creatinineclearance using the Cockcroft-Gault formula and by the presenceof albuminuria, measured as the albumin to creatinine ratio(A/C) in first morning urine samples. LVH was determined accordingto electrocardiographic criteria, and retinal vascular changeswere evaluated by direct ophthalmoscopy in all patients. Ina subgroup of patients (n = 340; 208 men, 132 women; mean age47 ± 9), the presence and extent of cardiac and vascularorgan damage was also assessed by ultrasound techniques. Creatinineclearance was on the average 82 ± 20 ml/min. The overallprevalence of ECG-detected LVH and retinopathy was 12 and 49%,respectively. Creatinine clearance was inversely related toduration of disease, systolic BP, serum glucose, total cholesterol,LDL cholesterol, and early signs of TOD, namely retinal vascularchanges and LVH. Patients in the bottom quintile of creatinineclearance showed higher prevalence of both ECG-determined LVH(P = 0.04) and retinal vascular changes (P = 0.02). In the subgroupof patients who underwent ultrasound evaluation of cardiovascularstructures, the prevalence of mild renal dysfunction was 18%,whereas the prevalence of LVH and carotid plaque was 49 and26%, respectively. Patients with mild renal dysfunction showedhigher left ventricular mass and increased intima-media thickness(P < 0.0001), as well as higher prevalence of LVH and carotidplaque as compared with those with normal renal function. Controllingfor duration of hypertension and mean BP, the risk of TOD inour cohort increased by 20% for each 10 ml/min decrease in creatinineclearance and by 30% for each 0.2 mg/mmol increase in Log A/C.In conclusion, mild renal dysfunction is associated with preclinicalend-organ damage in patients with primary hypertension. Thesedata may help to explain the observed increase in cardiovascularmortality reported in these patients. The evaluation of creatinineclearance and urinary albumin excretion could be useful foridentifying patients who are at higher cardiovascular risk.
The cardiovascular system is profoundly influenced by abnormalitiesin renal function. In fact, cardiovascular morbidity and mortalityhave long been known to be significantly increased in patientswho are on renal replacement therapy as compared with age-matchedcontrol subjects with normal renal function (1). Recently, ithas been pointed out that cardiovascular risk progressivelyincreases as the GFR declines and is already significantly elevatedeven in the earliest stages of renal damage (2). These findingsare even more noteworthy when one considers that a mild reductionin renal function is relatively common in hypertensive patients.According to data from the Third National Health and NutritionExamination Survey, approximately 13% of all nondiabetic adultsin the United States have a creatinine clearance <60 ml/min(3). The presence of clinical proteinuria is also a powerful,independent risk factor for cardiovascular complications inthis subgroup of patients (4). More recently, the associationbetween urinary protein excretion and cardiovascular morbidityand mortality has been extended to low-grade albuminuria, suchas microalbuminuria, both in diabetic and nondiabetic populations(5). Optimal BP control, as indicated by international guidelines,is of the utmost importance both to slow the progression ofrenal damage and to prevent cardiovascular events (6). However,target BP levels are often very difficult to achieve, and mostrenal patients remain hypertensive despite treatment (7).
Prevalence and Prognostic Value of Mild Renal Dysfunction
Mild renal dysfunction, defined as a GFR <60 ml/min and/orthe presence of increased urinary albumin excretion, variesfrom 10 to 40% in patients with long-standing primary hypertension(8). Among patients who participated in the Microalbuminuria:A Genoa Investigation on Complications Study (n = 787; meanage 51 ± 10 yr; mean arterial BP 122 ± 8), approximately14% had an estimated creatinine clearance below 60 ml/min (9).Several prospective studies have shown that a mild degree ofrenal insufficiency identifies subgroups of hypertensive patientsat higher risk for developing cardiovascular events. In theHypertension Detection and Follow-up Study carried out on 10,940patients, a linear correlation between serum creatinine andcardiovascular mortality was observed over a 5-yr follow-up,with a two-times higher risk in patients with serum creatinine>1.7 mg/dl (10). More recently, the Hypertension OptimalTreatment Study evaluated 18,790 hypertensive subjects over4 yr. Patients with baseline serum creatinine >1.5 mg/dlhave a twofold increased adjusted risk for major cardiovascularcomplications and for all-cause mortality (11). It is interestingthat in the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale(PIUMA) study, serum creatinine in the upper-normal range wasan independent predictor of cardiovascular morbidity regardlessof several confounders, such as age, gender, diabetes, smokinghabits, lipid profile, or BP load (12).
Mild Renal Dysfunction as a Marker of Target Organ Damage
The high cardiovascular risk reported in patients with mildrenal dysfunction cannot be completely attributed to traditionalcardiovascular risk factors; therefore, it is likely to be amultifactorial process, in part still unexplained (2). A reductionin GFR per se is associated with several metabolic changes thatenhance the atherogenic process at the systemic level. In fact,oxidative stress, inflammation, insulin resistance, endothelialdysfunction, and hyperhomocysteinemia have already been describedin the initial stages of renal disease (13–15). However,the impairment of renal function may, in turn, be the manifestationat the level of the kidney of generalized, subclinical atherothromboticdisease. To investigate this issue further, we evaluated therelationship between early renal dysfunction and subclinicaltarget organ damage (TOD), namely LVH, retinal vascular changes,and carotid atherosclerosis, in a large cohort (n = 934; meanage 50 ± 11) of unselected middle-aged hypertensive patientswith normal serum creatinine. Creatinine clearance (estimatedby means of the Cockcroft-Gault formula) was inversely relatedto history of hypertension (P < 0.0001), systolic BP (P =0.001), serum glucose (P = 0.007), lipid profile (P < 0.0001),and prevalence of ECG-determined LVH (P = 0.04) as well as ofretinal vascular changes (P = 0.02) observed at fundoscopy.Moreover, in a subgroup of patients (n = 340; mean age 47 ±9) who also underwent ultrasound evaluation of cardiovascularstructures, those with mild renal dysfunction (18%) had a worseglobal cardiovascular risk profile as compared with those withnormal renal function. In fact, they were older, had higherlevels of BP and uric acid, had longer history of hypertension,and were more likely to be smokers. Furthermore, they showedhigher left ventricular mass and increased intima-media thickness(P < 0.0001), as well as higher prevalence of LVH and carotidplaque as compared with subjects with normal renal function(Figure 1). It is interesting that these differences remainedsignificant (P = 0.02 and P = 0.004, respectively) after adjustingfor age, systolic BP, reported duration of disease, and serumuric acid. Controlling for duration of hypertension and meanBP, the risk of ultrasound-determined TOD in our cohort increasedby 20% for each 10-ml/min decrease in creatinine clearance andby 30% for each 0.2-mg/mmol increase in Log A/C.
Figure 1. Mild renal dysfunction and target organ damage in patients with essential hypertension. Left ventricular mass index (LVMI) and carotid intima-media thickness (IMT) were analyzed on the basis of the presence/absence of mild renal dysfunction.
Mild renal dysfunction, regardless of its cause, is a powerfulpredictor of cardiovascular events in high-risk patients, aswell as in the general population (16–18). In hypertensivepatients with normal serum creatinine, the presence of microalbuminuriaand/or creatinine clearance <60 ml/min is associated withsubclinical cardiovascular organ involvement regardless of BPload and other traditional risk factors. These findings mayaccount for the worse cardiovascular prognosis reported in thesepatients. In fact, hypertensive TOD is known to precede andpredict major cardiovascular events (19). Our results strengthenthe usefulness of routinely determining creatinine clearanceand urinary albumin excretion in clinical practice, not onlyto evaluate renal function but also to stratify cardiovascularrisk in hypertensive patients. A similar diagnostic approachmay also have therapeutic implications. In fact, on the basisof current recommendations, lower BP levels and specific drugclasses (i.e., renin-angiotensin system inhibitors) should beused in this subgroup of patients at risk (20,21).
Luke RG: Chronic renal failure—A vasculopathic state. N Engl J Med 339: 841–843, 1998[Free Full Text]
Culleton BF, Larson MG, Wilson PW, Evans JC, Parfrey PS, Levy D: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 56: 2214–2219, 1999[CrossRef][Medline]
Clase CM, Garg AX, Kiberd BA: Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 13: 1338–1349, 2002[Abstract/Free Full Text]
Keane WF: Proteinuria: Its clinical importance and role in progressive renal disease. Am J Kidney Dis 35 [4 Suppl 1]: S97–S105, 2000[Medline]
Donnelly R, Yeung JM, Manning G: Microalbuminuria: A common, independent cardiovascular risk factor, especially but not exclusively in type 2 diabetes. J Hypertens Suppl 21 [Suppl 1]: S7–S12, 2003[Medline]
Yu HT: Progression of chronic renal failure. Arch Intern Med 163: 1417–1429, 2003[Abstract/Free Full Text]
Coresh J, Wei GL, McQuillan G, Brancati FL, Levey AS, Jones C, Klag MJ: Prevalence of high blood pressure and elevated serum creatinine level in the United States: Findings from the third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med 161: 1207–1216, 2001[Abstract/Free Full Text]
Ruilope LM: The kidney as a sensor of cardiovascular risk in essential hypertension. J Am Soc Nephrol 13 [Suppl 3]: S165–S168, 2002[Abstract/Free Full Text]
Pontremoli R, Sofia A, Ravera M, Nicolella C, Viazzi F, Tirotta A, Ruello N, Tomolillo C, Castello C, Grillo G, Sacchi G, Deferrari G: Prevalence and clinical correlates of microalbuminuria in essential hypertension: The MAGIC Study. Microalbuminuria: A Genoa Investigation on Complications. Hypertension 30: 1135–1143, 1997[Abstract/Free Full Text]
Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension 13 [5 Suppl]: I80–I93, 1989
Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I, Wedel H, Zanchetti A: Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 12: 218–225, 2001[Abstract/Free Full Text]
Schillaci G, Reboldi G, Verdecchia P: High-normal serum creatinine concentration is a predictor of cardiovascular risk in essential hypertension. Arch Intern Med 161: 886–891, 2001[Abstract/Free Full Text]
Fliser D, Pacini G, Engelleiter R, Kautzky-Willer A, Prager R, Franek E, Ritz E: Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int 53: 1343–1347, 1998[CrossRef][Medline]
Stam F, van Guldener C, Schalkwijk CG, ter Wee PM, Donker AJ, Stehouwer CD: Impaired renal function is associated with markers of endothelial dysfunction and increased inflammatory activity. Nephrol Dial Transplant 18: 892–898, 2003[Abstract/Free Full Text]
Parsons DS, Reaveley DA, Pavitt DV, Brown EA: Relationship of renal function to homocysteine and lipoprotein(a) levels: The frequency of the combination of both risk factors in chronic renal impairment. Am J Kidney Dis 40: 916–923, 2002[CrossRef][Medline]
Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Ann Intern Med 134: 629–636, 2001[Abstract/Free Full Text]
Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB: Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 137: 555–562, 2002[Abstract/Free Full Text]
Henry RM, Kostense PJ, Bos G, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD: Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int 62: 1402–1407, 2002[CrossRef][Medline]
Devereux RB, Alderman MH: Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation 88: 1444–1455, 1993[Abstract/Free Full Text]
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 289: 2560–2572, 2003[Abstract/Free Full Text]
Guidelines Committee: 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 21: 1011–1053, 2003[CrossRef][Medline]
This article has been cited by other articles:
F. A. Benedetto, G. Tripepi, F. Mallamaci, and C. Zoccali Rate of Atherosclerotic Plaque Formation Predicts Cardiovascular Events in ESRD
J. Am. Soc. Nephrol.,
April 1, 2008;
19(4):
757 - 763.
[Abstract][Full Text][PDF]
Top
Abstract
Introduction
