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Endothelial dysfunction and increased carotid intima-media thickness in patients with autosomal dominant polycystic kidney disease
Endothelial Dysfunction and Increased Carotid Intima-Media Thickness in Patients With Autosomal Dominant Polycystic Kidney Disease Orhan Kocaman, MD, Huseyin Oflaz, MD, Ensar Yekeler, MD, Memduh Dursun, MD, Dogan Erdogan, MD, Seref Demirel, MD, Sabahat Alisir, MD, Faruk Turgut, MD, Fehmi Mercanoglu, MD, and Tevfik Ecder, MD ● Background: Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Endothelial dysfunction (ED) and intima-media thickness (IMT) are predictors for the development and progression of atherosclerosis. In the present study, ED and IMT were investigated in patients with ADPKD. Methods: Fifteen hypertensive and 16 normotensive patients with ADPKD with preserved renal function, 16 patients with essential hypertension, and 24 healthy subjects were included in the study. Endothelial function of the brachial artery was evaluated by means of high-resolution vascular ultrasound. Endothelial-dependent dilatation (EDD) was assessed by establishing reactive hyperemia, and endothelialindependent dilatation was determined by using sublingual isosorbide dinitrate. Carotid IMT was measured by means of high-resolution vascular ultrasound. Results: EDD was significantly worse in hypertensive patients with ADPKD compared with patients with essential hypertension (9.1% ⴞ 4.1% versus 12.4% ⴞ 4.6%; P < 0.05) and even in normotensive patients with ADPKD compared with healthy subjects (13.1% ⴞ 5.2% versus 18.1% ⴞ 8.1%; P < 0.01). Moreover, carotid IMT was significantly greater in both hypertensive (0.71 ⴞ 0.10 mm; P < 0.01) and normotensive (0.57 ⴞ 0.14 mm; P < 0.001) patients with ADPKD compared with healthy subjects (0.45 ⴞ 0.10 mm). Conclusion: Both hypertensive and normotensive patients with ADPKD show significant ED and increased IMT, which are predictors of atherosclerosis. Am J Kidney Dis 43:854-860. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Endothelial dysfunction (ED); endothelial-dependent dilatation (EDD); carotid intima-media thickness (IMT); autosomal dominant polycystic kidney disease (ADPKD).
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UTOSOMAL DOMINANT polycystic kidney disease (ADPKD) is the most common hereditary renal disease, occurring in 1 of 400 to 1,000 individuals.1 It is responsible for approximately 4% of end-stage renal disease (ESRD) in the United States and 8% to 10% in Europe.1 Hypertension, a common finding in patients with ADPKD, often occurs before the onset of renal insufficiency and is associated with faster progression to ESRD and increased cardiovascular mortality.2–4 Cardiovascular prob-
From the Departments of Internal Medicine, Cardiology, and Radiology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey. Received October 6, 2003; accepted in revised form January 6, 2004. Supported in part by grant no. 2004/3 from the Turkish Kidney Foundation. Presented in part at the World Congress of Nephrology, Berlin, Germany, June 8-12, 2003. Address reprint requests to Tevfik Ecder, MD, Istanbul School of Medicine, Department of Internal Medicine, Division of Nephrology, Capa, 34390, Istanbul, Turkey. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4305-0011$30.00/0 doi:10.1053/j.ajkd.2004.01.011 854
lems are a major cause of morbidity and mortality in patients with ADPKD.4 Activation of the renin-angiotensin-aldosterone system (RAAS) caused by cyst expansion and local renal ischemia has been proposed to have an important role in the development of hypertension in patients with ADPKD.5 Stimulation of the RAAS starts at an early stage of the disease and precedes hypertension and the major clinical manifestations of ADPKD.6,7 Increased intrarenal activity of the RAAS has been shown in both hypertensive and normotensive patients with ADPKD with normal renal function compared with age-matched healthy control subjects.6,7 The RAAS has a significant impact on the development of target-organ damage, such as atherosclerosis, left ventricular hypertrophy (LVH), and ESRD.8–10 Endothelial dysfunction (ED) is an early manifestation of vascular injury, mediated to some degree by angiotensin II.11 During the past decade, a noninvasive technique has evolved to evaluate flow-mediated dilatation, an endothelial-dependent function, in the brachial artery after occlusion.12–14 This stimulus provokes the endothelium to release nitric oxide (NO), with subsequent vasodilation that
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ENDOTHELIAL DYSFUNCTION IN ADPKD
can be imaged and quantitated as an index of vasomotor function.15 Ultrasound imaging of the brachial artery during reactive hyperemia is a widely used tool for quantifying endotheliumdependent vasomotion.16 Impaired endothelialdependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium and may be a marker of increased future cardiovascular risk.17 Carotid intima-media thickness (IMT), measured noninvasively by ultrasonography, is a well-established index of atherosclerosis and directly associated with an increased risk for cardiovascular disease.18–20 The aim of the present study is to investigate ED and carotid IMT in normotensive and hypertensive patients with ADPKD with well-preserved renal function. METHODS Thirty-one patients with ADPKD were included in the study. Fifteen patients had hypertension (blood pressure ⱖ 140/90 mm Hg in the sitting position or administered antihypertensive drugs) and 16 patients were normotensive. Sixteen patients with essential hypertension and 24 healthy subjects also were included in the study. Creatinine clearances were calculated using the Cockcroft-Gault formula.21 All patients had creatinine clearances greater than 60 mL/min/ 1.73 m2. Subjects affected by diabetes mellitus, established cardiovascular disease, other chronic diseases that could affect endothelial function, a family history of hyperlipidemia, and premature atherosclerosis were excluded. Biochemical markers of thyroid and liver function were within normal range in all subjects. During the testing period, all subjects were asked to keep their normal diet and physical activity level and not perform intense physical activity. Written informed consent was obtained from all subjects included in the study. Systolic and diastolic blood pressures were measured on the right arm of subjects in an upright sitting position after at least 5 minutes of rest using an Erka sphygmomanometer (PMS Instruments Ltd, Berkshire, UK) with appropriate cuff size. Two readings were recorded for each individual. The average of 2 readings was defined as the subject’s blood pressure. Venous blood samples for biochemical analyses were drawn after an overnight fast between 8:00 PM and 8:00 AM. Echocardiographic examination was performed using an echocardiographic system equipped with 2.5-MHz transducers (Vingmed System Five, Oslo, Norway). M-Mode and 2-dimensional measurements were performed in accordance with methods recommended by the American Society of Echocardiography.22,23 Cardiac mass was calculated by means of the formula derived by Devereux and Reichek.24
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Brachial Artery Measurements Endothelium-dependent dilatation (EDD) of the brachial artery after transient ischemia, a noninvasive method to assess endothelial function, was performed according to methods defined by Celermajer et al13 using a highresolution ultrasound machine (Vingmed System Five). All subjects abstained from smoking and consuming caffeinecontaining drinks for at least 12 hours before testing. Subjects were kept in a supine position for 10 minutes in a stable room temperature between 20°C and 25°C. To best visualize the brachial artery, the arm was immobilized comfortably in the extended position, and the brachial artery was scanned in the longitudinal section 3 to 5 cm above the antecubital fossa by using a 10-MHz high-resolution linear-array transducer. After optimal transducer positioning, the skin was marked for reference for later measurements, and the arm was kept in the same position throughout the study. All measurements of brachial artery internal diameter were assessed at end-diastole (timed by the QRS complex) and calculated as the average of measurements obtained during 3 consecutive cardiac cycles. After baseline measurements of the brachial artery were recorded, the cuff was inflated to 200 mm Hg (or 50 mm Hg higher than systolic blood pressure) for 5 minutes to create forearm ischemia. Subsequently, the cuff was deflated and arterial diameter was measured 60 seconds after deflation. In addition, endothelium-independent dilatation (EID), a surrogate marker for vascular smooth muscle function, was assessed by measuring changes in brachial artery diameter after sublingual nitrate administration in all subjects. Ten minutes after EDD measurement, 5 mg of isosorbide dinitrate was administered sublingually, and measurements were repeated 3 minutes later. All measurements were performed by a single investigator blinded to clinical and biochemical data of the study groups and were recorded on VHS videotape for subsequent off-line analysis. EDD and EID are expressed as percentage of change in brachial artery diameter from baseline to after reactive hyperemia and to after sublingual isosorbide dinitrate administration, respectively. Intraobserver variability for brachial artery measurements was 3%.
Carotid IMT Measurements Bilateral carotid ultrasound was performed on an ultrasound system with a high-resolution 10-MHz linear-array scan head (attached to a standard Vingmed System Five). The common carotid arteries were scanned longitudinally. Bulb dilation served as a landmark to indicate the border between the distal common carotid artery and carotid bulb. Images were obtained from the distal portion of the common carotid artery, 1 to 2 cm proximal to the carotid bulb. Images were saved and stored on S-VHS videotape. The 2 bright echogenic lines in the arterial wall were identified as the intima and media lines. Intimal plus medial thickness (IMT) was measured as the distance from the main edge of the first to the main edge of the second echogenic line. Each measurement was repeated 3 times, and the mean of the left and right common carotid arteries was obtained and used for further analysis. All scans were performed by the same observer, who was blinded to clinical and biochemical data. No
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KOCAMAN ET AL Table 1.
Age (y) Sex (M/F) Body mass index (kg/m2) Smokers (n) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Creatinine clearance (mL/min/ 1.73 m2) Total cholesterol (mg/dL) Triglycerides (mg/dL) LVMI (g/m2)
Patient Characteristics
Hypertensive Patients With ADPKD (n ⫽ 15)
Normotensive Patients With ADPKD (n ⫽ 16)
Patients With Essential Hypertension (n ⫽ 16)
Healthy Subjects (n ⫽ 24)
39.6 ⫾ 7.2 4/11 25.5 ⫾ 3.5 2 138 ⫾ 18* 85 ⫾ 11† 91 ⫾ 29
35.8 ⫾ 8.8 7/9 23.4 ⫾ 4.1 3 120 ⫾ 18 74 ⫾ 8 106 ⫾ 17
40.8 ⫾ 4.8 7/9 26.0 ⫾ 3.2 4 134 ⫾ 14* 77 ⫾ 13 112 ⫾ 14
38.1 ⫾ 8.8 8/16 24.7 ⫾ 3.5 3 119 ⫾ 14 75 ⫾ 9 105 ⫾ 12
195 ⫾ 23 121 ⫾ 37 132 ⫾ 23‡
181 ⫾ 30 99 ⫾ 39 108 ⫾ 24
179 ⫾ 29 115 ⫾ 35 111 ⫾ 16§
180 ⫾ 30 114 ⫾ 37 95 ⫾ 17
NOTE. To convert creatinine clearance in mL/min to mL/s, multiply by 0.01667; serum total cholesterol in mg/dL to mmol/L, multiply by 0.02586; serum triglycerides in mg/dL to mmol/L, multiply by 0.01129. *P ⬍ 0.01 versus normotensive patients with ADPKD and healthy subjects. †P ⬍ 0.005 versus normotensive patients with ADPKD and healthy subjects. ‡P ⫽ 0.02 versus normotensive patients with ADPKD, P ⬍ 0.02 versus patients with essential hypertension, P ⬍ 0.0001 versus healthy subjects. §P ⬍ 0.005 versus healthy subjects.
subject had atheromatous plaque, localized lesion of thickness greater than 2.0 mm, or stenosis in this region. The intraobserver coefficient of variation for carotid IMT was 2.6%.
Statistical Analyses Comparison of groups was performed using MannWhitney U and chi-square tests. Mann-Whitney U test was applied to the groups in pairs, for all possible combinations. P less than 0.05 is considered statistically significant. All values are expressed as mean ⫾ SD.
RESULTS
There was no significant difference between groups regarding age, sex, body mass index, smoking status, renal function, and lipid levels (Table 1). Hypertensive patients with ADPKD and patients with essential hypertension had significantly greater systolic blood pressures compared with normotensive patients with ADPKD and healthy subjects. Hypertensive patients with ADPKD also had significantly greater diastolic blood pressures compared with normotensive patients with ADPKD and healthy subjects. Hypertensive patients with ADPKD had a significantly greater left ventricular mass index (LVMI) compared with all other groups. Patients with essential hypertension also had a significantly elevated LVMI compared with healthy subjects. Normotensive patients with ADPKD had a greater
LVMI compared with healthy subjects. Although this was not statistically significant, P was 0.06. No patient in the groups had been administered statins. Five patients were administered angiotensin-converting enzyme (ACE) inhibitors; 4 patients, calcium channel blockers (CCBs); 3 patients, angiotensin-receptor blockers (ARBs); and 3 patients, a combination of ACE inhibitors and CCBs in the hypertensive ADPKD group. Six patients were administered ACE inhibitors; 3 patients, CCBs; 4 patients, ARBs; 3 patients, a combination of ACE inhibitors and CCBs; and 1 patient, a -blocker in the essential hypertensive group. No statistically significant difference in antihypertensive use was present between the hypertensive ADPKD group and essential hypertensive group. Basal diameter of the brachial artery was 3.4 ⫾ 0.6 mm in hypertensive patients with ADPKD, 3.1 ⫾ 0.5 mm in normotensive patients with ADPKD, 3.6 ⫾ 0.4 mm in patients with essential hypertension, and 3.5 ⫾ 0.6 mm in healthy subjects. It was significantly less in normotensive patients with ADPKD compared with patients with essential hypertension (3.1 ⫾ 0.5 versus 3.6 ⫾ 0.4 mm; P ⬍ 0.05). EDD was significantly worse in hypertensive patients with ADPKD compared with patients with essential hypertension (9.1% ⫾ 4.1% versus 12.4% ⫾
ENDOTHELIAL DYSFUNCTION IN ADPKD
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Fig 1. Results of brachial artery measurements: (A) EDD and (B) EID. *P < 0.05 versus normotensive patients with ADPKD and patients with essential hypertension; P < 0.01 versus healthy subjects. **P < 0.01 versus healthy subjects.
4.6%; P ⬍ 0.05), normotensive patients with ADPKD (9.1% ⫾ 4.1% versus 13.1% ⫾ 5.2%; P ⬍ 0.05), and healthy subjects (9.1% ⫾ 4.1% versus 18.1% ⫾ 8.1%; P ⬍ 0.01). EDD was significantly worse even in normotensive patients with ADPKD compared with healthy subjects (13.1% ⫾ 5.2% versus 18.1% ⫾ 8.1%; P ⬍ 0.01). EID was significantly less in patients with ADPKD (both hypertensive and normotensive) and patients with essential hypertension compared with healthy subjects (Fig 1). Carotid IMT was significantly greater in hypertensive patients with ADPKD (0.71 ⫾ 0.10 mm; P ⬍ 0.01) and patients with essential hypertension (0.71 ⫾ 0.10 mm; P ⬍ 0.01) compared with normotensive patients with ADPKD (0.57 ⫾ 0.14 mm) and healthy subjects (0.45 ⫾ 0.10 mm; Fig 2). Carotid IMT also was significantly greater in normotensive patients with ADPKD compared with healthy subjects (0.57 ⫾ 0.14 versus 0.45 ⫾ 0.10 mm; P ⬍ 0.001).
DISCUSSION
The RAAS has a detrimental role in the pathogenesis of target-organ damage, such as atherosclerosis, LVH, heart failure, and ESRD.8–11 The RAAS is stimulated at an early stage of ADPKD, even before the onset of hypertension and clinical findings.6,7 Thus, increased activity of the RAAS may contribute to the increased incidence of cardiovascular complications in patients with ADPKD. ED is considered to have an important role in the pathogenesis of vascular disease.11 An imbalance characterized by reduced NO production or increased reactive oxygen species production may promote ED.25,26 It has been shown that angiotensin II contributes to ED by stimulating the production of reactive oxygen species, such as superoxide, through the activation of membrane-bound reduced nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide phosphate oxidase.27
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Fig 2. Measurements of carotid IMT. *P < 0.01 versus normotensive patients with ADPKD and healthy subjects. **P < 0.001 versus healthy subjects.
Wang et al28 reported that both normotensive and hypertensive patients with ADPKD have impaired endothelial-dependent relaxation of small resistance vessels. In that study, acetylcholine-induced relaxation rate was decreased in resistance vessels obtained by biopsy of subcutaneous fat from the gluteal region. In our study, a noninvasive method of high-resolution vascular ultrasound was used to determine ED and carotid IMT in patients with ADPKD during the early stages of their disease. Evaluation of endotheliumdependent flow-mediated vasodilatation of the brachial artery is a method widely used for the determination of early atherosclerosis and cardiovascular risks.13–15 Likewise, carotid IMT is a well-established index of atherosclerosis and the only noninvasive imaging test currently recommended by the American Heart Association for inclusion in the evaluation of risk.18,29 This is the first study showing ED and increased carotid IMT by using these noninvasive methods in patients with ADPKD. In the present study, patients with essential hypertension and hypertensive patients with ADPKD had significantly less EDD compared with normotensive patients with ADPKD and healthy subjects. This is an expected finding because it has been shown that endothelial function becomes progressively impaired as blood pressure increases, and degree of dysfunction is related to severity of hypertension.30,31 Importantly, hypertensive patients with ADPKD had significantly less EDD compared with patients with essential hypertension with similar blood pressures. This may occur because the RAAS is stimulated significantly more in hypertensive patients with
ADPKD than in similar patients with essential hypertension.5 Another factor that could have contributed to the difference in EDD may be that hypertensive patients with ADPKD likely could have elevated blood pressures for a longer period than patients with essential hypertension. In the present study, hypertensive patients with ADPKD had a significantly greater LVMI compared with subjects in all other groups. The high incidence of LVH has been reported in patients with ADPKD.32 Findings of both ED and LVH are consistent with the high rate of cardiovascular morbidity and mortality in patients with ADPKD. All hypertensive patients were receiving antihypertensive therapy. Thus, the direct effect of these drugs on vascular function cannot be excluded in the present study. Furthermore, blood pressure was lower in patients with essential hypertension than in hypertensive patients with ADPKD (134/77 versus 138/85 mm Hg, respectively), although not significant. Therefore, the lower blood pressure of patients with essential hypertension may have masked the full extent of ED in this group. An important finding in the present study is the observation of significant ED, even in normotensive patients with ADPKD. Although not statistically significant, LVMI also was greater in these patients compared with healthy subjects (P ⫽ 0.06). Previous studies showed signs of target-organ damage, such as microalbuminuria and LVH, in normotensive patients with ADPKD with normal renal function.33,34 It also was reported that the nocturnal decrease in blood pressure is attenuated in normotensive patients with
ENDOTHELIAL DYSFUNCTION IN ADPKD
ADPKD.35 Stimulation of the RAAS very early in the course of ADPKD may contribute to these findings.6,7 Wang et al28 found an inverse relationship between degree of EDD and mean arterial pressure and suggested that impaired endothelial function may contribute to hypertension in these patients. Similarly, in our study, the finding of significant ED in normotensive patients with ADPKD compared with healthy subjects and more severe ED in hypertensive patients suggests that ED may predispose to hypertension in patients with ADPKD. Nitroglycerin is used to determine the maximum obtainable vasodilator response and serve as a measure of EID reflecting vascular smooth muscle function.36 Thus, decreased vasodilatory response to exogenous administration of NO donor suggests smooth muscle dysfunction in the arterial wall. Wang et al28 reported that endothelium-independent relaxation response to an NOdonor (SIN-1) was similar in hypertensive and normotensive patients with ADPKD, patients with essential hypertension, and control subjects. However, in the present study, vasodilator response to isosorbide dinitrate was impaired in patients with essential hypertension and hypertensive and normotensive patients with ADPKD compared with healthy subjects. This finding suggests smooth muscle dysfunction in these patients. Impaired EID has been reported even in asymptomatic subjects with reduced EDD who are at risk for atherosclerosis.37 Although increased activity of the RAAS might have an effect on this finding, additional studies are needed to understand the pathogenesis. Multiple studies have shown that carotid artery IMT, measured noninvasively by ultrasonography, is associated directly with increased risk for cardiovascular disease, and it has been shown to be an independent predictor of cardiovascular disease after adjustment for traditional risk factors.18 The presence of a significant increase in carotid IMT in normotensive patients with ADPKD compared with healthy subjects reflects the increased cardiovascular risk, even in the early stages of the disease. In conclusion, findings of significant ED and increased carotid IMT in both hypertensive and normotensive patients with ADPKD with wellpreserved renal function suggest that atheroscle-
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rosis starts at a very early stage of the disease. Because cardiovascular problems are a major cause of morbidity and mortality in patients with ADPKD, risk factors for atherosclerosis should be treated aggressively. Prospective randomized studies are needed to determine the benefits of this approach in these patients. Interventional trials using drugs that block the RAAS or statins could be of particular importance owing to their beneficial effects on endothelial function. REFERENCES 1. Fick-Brosnahan GM, Ecder T, Schrier R: Polycystic kidney disease, in Schrier RW (ed): Diseases of the Kidney and Urinary Tract. (ed 7). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 547-588 2. Ecder T, Schrier RW: Hypertension in autosomaldominant polycystic kidney disease: Early occurrence and unique aspects. J Am Soc Nephrol 12:194-200, 2001 3. Schrier RW, McFann KK, Johnson AM: Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease. Kidney Int 63:678-685, 2003 4. Fick GM, Johnson AM, Hammond WS, Gabow PA: Causes of death in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 5:2048-2056, 1995 5. Chapman AB, Johnson A, Gabow PA, Schrier RW: The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med 323:10911096, 1990 6. Harrap SB, Davies DL, Macnicol AM, et al: Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease. Kidney Int 40:501-508, 1991 7. Barrett BJ, Foley R, Morgan J, Hefferton D, Parfrey P: Differences in hormonal and renal vascular responses between normotensive patients with autosomal dominant polycystic kidney disease and unaffected family members. Kidney Int 46:118-1123, 1994 8. Brunner HR: Experimental and clinical evidence that angiotensin II is an independent risk factor for cardiovascular disease. Am J Cardiol 87:3C-9C, 2001 9. Hirsch AT, Pinto YM, Schunkert H, Dzau VJ: Potential role of the tissue renin-angiotensin system in the pathophysiology of congestive heart failure. Am J Cardiol 66:22D-30D, 1990 10. Wolf G: Angiotensin II: A pivotal factor in the progression of renal diseases. Nephrol Dial Transplant 14:S42-S44, 1999 (suppl 1) 11. Lu¨ scher TF: Endothelial dysfunction: The role and impact of the renin-angiotensin system. Heart 84:Si20-Si22, 2000 (suppl 1) 12. Anderson EA, Mark AL: Flow-mediated and reflex changes in large peripheral artery tone in humans. Circulation 79:93-100, 1989 13. Celermajer DS, Sorensen KE, Gooch VM, et al: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:11111115, 1992 14. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al:
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Non-invasive measurement of human endothelium dependent arterial responses: Accuracy and reproducibility. Br Heart J 74:247-253, 1995 15. Corretti MC, Anderson TJ, Benjamin EJ, et al: Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 39:257-265, 2002 16. Barth JD: Which tools are in your cardiac workshop? Carotid ultrasound, endothelial function, and magnetic resonance imaging. Am J Cardiol 87:8A-14A, 2001 17. Celermajer DS: Endothelial dysfunction: Does it matter? Is it reversible? J Am Coll Cardiol 30:325-333, 1997 18. O’Leary DH, Polak JF: Intima-media thickness: A tool for atherosclerosis imaging and event prediction. Am J Cardiol 90:18L-21L, 2002 19. Crouse JR III, Craven TE, Hagaman AP, Bond MG: Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery. Circulation 92:1141-1147, 1995 20. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340:14-22, 1999 21. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 22. Henry WL, DeMaria A, Gramiak R, et al: Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two Dimensional Echocardiography. Circulation 62:212-217, 1980 23. Sahn DJ, DeMaria A, Kisslo J, Weyman A: Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 58:1072-1083, 1978 24. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 55:613-618, 1977 25. Drexler H, Hornig B: Endothelial dysfunction in human disease. J Mol Cell Cardiol 31:51-60, 1999 26. Dijkhorst-Oei LT, Stroes ES, Koomans HA, Rabelink TJ: Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo. J Cardiovasc Pharmacol 33:420-424, 1999 27. Rajagopalan S, Kurz S, Munzel T, et al: Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase
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activation. Contribution to alterations of vasomotor tone. J Clin Invest 97:1916-1923, 1996 28. Wang D, Iversen J, Wilcox CS, Strandgaard S: Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease. Kidney Int 64:1381-1388, 2003 29. Greenland P, Smith SC, Grundy SM: Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 104:1863-1867, 2001 30. Dohi Y, Thiel MA, Buhler FR, Luscher TF: Activation of endothelial L-arginine pathway in resistance arteries: Effect of age and hypertension. Hypertension 16:170-179, 1990 31. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA: Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 87:1468-1474, 1993 32. Chapman AB, Johnson AM, Rainguet S, Hossack K, Gabow P, Schrier RW: Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 8:1292-1297, 1997 33. Bardaji A, Martinez-Vea A, Gutierrez C, Ridao C, Richart C, Oliver JA: Left ventricular mass and diastolic function in normotensive young adults with autosomal dominant polycystic kidney disease. Am J Kidney Dis 32:970975, 1998 34. Martinez-Vea A, Gutierrez C, Bardaji A, et al: Microalbuminuria in normotensive patients with autosomal dominant polycystic kidney disease. Scand J Urol Nephrol 32:356-359, 1998 35. Valero FA, Martinez-Vea A, Bardaji A, et al: Ambulatory blood pressure and left ventricular mass in normotensive patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 10:1020-1026, 1999 36. Ducharme A, Dupuis J, McNicoll S, Harel F, Tardif JC: Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects. Am J Cardiol 84:952-954, 1999 37. Adams MR, Robinson J, McCredie R, et al: Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis. J Am Coll Cardiol 32:123-127, 1998
A
UTOSOMAL DOMINANT polycystic kidney disease (ADPKD) is the most common hereditary renal disease, occurring in 1 of 400 to 1,000 individuals.1 It is responsible for approximately 4% of end-stage renal disease (ESRD) in the United States and 8% to 10% in Europe.1 Hypertension, a common finding in patients with ADPKD, often occurs before the onset of renal insufficiency and is associated with faster progression to ESRD and increased cardiovascular mortality.2–4 Cardiovascular prob-
From the Departments of Internal Medicine, Cardiology, and Radiology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey. Received October 6, 2003; accepted in revised form January 6, 2004. Supported in part by grant no. 2004/3 from the Turkish Kidney Foundation. Presented in part at the World Congress of Nephrology, Berlin, Germany, June 8-12, 2003. Address reprint requests to Tevfik Ecder, MD, Istanbul School of Medicine, Department of Internal Medicine, Division of Nephrology, Capa, 34390, Istanbul, Turkey. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4305-0011$30.00/0 doi:10.1053/j.ajkd.2004.01.011 854
lems are a major cause of morbidity and mortality in patients with ADPKD.4 Activation of the renin-angiotensin-aldosterone system (RAAS) caused by cyst expansion and local renal ischemia has been proposed to have an important role in the development of hypertension in patients with ADPKD.5 Stimulation of the RAAS starts at an early stage of the disease and precedes hypertension and the major clinical manifestations of ADPKD.6,7 Increased intrarenal activity of the RAAS has been shown in both hypertensive and normotensive patients with ADPKD with normal renal function compared with age-matched healthy control subjects.6,7 The RAAS has a significant impact on the development of target-organ damage, such as atherosclerosis, left ventricular hypertrophy (LVH), and ESRD.8–10 Endothelial dysfunction (ED) is an early manifestation of vascular injury, mediated to some degree by angiotensin II.11 During the past decade, a noninvasive technique has evolved to evaluate flow-mediated dilatation, an endothelial-dependent function, in the brachial artery after occlusion.12–14 This stimulus provokes the endothelium to release nitric oxide (NO), with subsequent vasodilation that
American Journal of Kidney Diseases, Vol 43, No 5 (May), 2004: pp 854-860
ENDOTHELIAL DYSFUNCTION IN ADPKD
can be imaged and quantitated as an index of vasomotor function.15 Ultrasound imaging of the brachial artery during reactive hyperemia is a widely used tool for quantifying endotheliumdependent vasomotion.16 Impaired endothelialdependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium and may be a marker of increased future cardiovascular risk.17 Carotid intima-media thickness (IMT), measured noninvasively by ultrasonography, is a well-established index of atherosclerosis and directly associated with an increased risk for cardiovascular disease.18–20 The aim of the present study is to investigate ED and carotid IMT in normotensive and hypertensive patients with ADPKD with well-preserved renal function. METHODS Thirty-one patients with ADPKD were included in the study. Fifteen patients had hypertension (blood pressure ⱖ 140/90 mm Hg in the sitting position or administered antihypertensive drugs) and 16 patients were normotensive. Sixteen patients with essential hypertension and 24 healthy subjects also were included in the study. Creatinine clearances were calculated using the Cockcroft-Gault formula.21 All patients had creatinine clearances greater than 60 mL/min/ 1.73 m2. Subjects affected by diabetes mellitus, established cardiovascular disease, other chronic diseases that could affect endothelial function, a family history of hyperlipidemia, and premature atherosclerosis were excluded. Biochemical markers of thyroid and liver function were within normal range in all subjects. During the testing period, all subjects were asked to keep their normal diet and physical activity level and not perform intense physical activity. Written informed consent was obtained from all subjects included in the study. Systolic and diastolic blood pressures were measured on the right arm of subjects in an upright sitting position after at least 5 minutes of rest using an Erka sphygmomanometer (PMS Instruments Ltd, Berkshire, UK) with appropriate cuff size. Two readings were recorded for each individual. The average of 2 readings was defined as the subject’s blood pressure. Venous blood samples for biochemical analyses were drawn after an overnight fast between 8:00 PM and 8:00 AM. Echocardiographic examination was performed using an echocardiographic system equipped with 2.5-MHz transducers (Vingmed System Five, Oslo, Norway). M-Mode and 2-dimensional measurements were performed in accordance with methods recommended by the American Society of Echocardiography.22,23 Cardiac mass was calculated by means of the formula derived by Devereux and Reichek.24
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Brachial Artery Measurements Endothelium-dependent dilatation (EDD) of the brachial artery after transient ischemia, a noninvasive method to assess endothelial function, was performed according to methods defined by Celermajer et al13 using a highresolution ultrasound machine (Vingmed System Five). All subjects abstained from smoking and consuming caffeinecontaining drinks for at least 12 hours before testing. Subjects were kept in a supine position for 10 minutes in a stable room temperature between 20°C and 25°C. To best visualize the brachial artery, the arm was immobilized comfortably in the extended position, and the brachial artery was scanned in the longitudinal section 3 to 5 cm above the antecubital fossa by using a 10-MHz high-resolution linear-array transducer. After optimal transducer positioning, the skin was marked for reference for later measurements, and the arm was kept in the same position throughout the study. All measurements of brachial artery internal diameter were assessed at end-diastole (timed by the QRS complex) and calculated as the average of measurements obtained during 3 consecutive cardiac cycles. After baseline measurements of the brachial artery were recorded, the cuff was inflated to 200 mm Hg (or 50 mm Hg higher than systolic blood pressure) for 5 minutes to create forearm ischemia. Subsequently, the cuff was deflated and arterial diameter was measured 60 seconds after deflation. In addition, endothelium-independent dilatation (EID), a surrogate marker for vascular smooth muscle function, was assessed by measuring changes in brachial artery diameter after sublingual nitrate administration in all subjects. Ten minutes after EDD measurement, 5 mg of isosorbide dinitrate was administered sublingually, and measurements were repeated 3 minutes later. All measurements were performed by a single investigator blinded to clinical and biochemical data of the study groups and were recorded on VHS videotape for subsequent off-line analysis. EDD and EID are expressed as percentage of change in brachial artery diameter from baseline to after reactive hyperemia and to after sublingual isosorbide dinitrate administration, respectively. Intraobserver variability for brachial artery measurements was 3%.
Carotid IMT Measurements Bilateral carotid ultrasound was performed on an ultrasound system with a high-resolution 10-MHz linear-array scan head (attached to a standard Vingmed System Five). The common carotid arteries were scanned longitudinally. Bulb dilation served as a landmark to indicate the border between the distal common carotid artery and carotid bulb. Images were obtained from the distal portion of the common carotid artery, 1 to 2 cm proximal to the carotid bulb. Images were saved and stored on S-VHS videotape. The 2 bright echogenic lines in the arterial wall were identified as the intima and media lines. Intimal plus medial thickness (IMT) was measured as the distance from the main edge of the first to the main edge of the second echogenic line. Each measurement was repeated 3 times, and the mean of the left and right common carotid arteries was obtained and used for further analysis. All scans were performed by the same observer, who was blinded to clinical and biochemical data. No
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KOCAMAN ET AL Table 1.
Age (y) Sex (M/F) Body mass index (kg/m2) Smokers (n) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Creatinine clearance (mL/min/ 1.73 m2) Total cholesterol (mg/dL) Triglycerides (mg/dL) LVMI (g/m2)
Patient Characteristics
Hypertensive Patients With ADPKD (n ⫽ 15)
Normotensive Patients With ADPKD (n ⫽ 16)
Patients With Essential Hypertension (n ⫽ 16)
Healthy Subjects (n ⫽ 24)
39.6 ⫾ 7.2 4/11 25.5 ⫾ 3.5 2 138 ⫾ 18* 85 ⫾ 11† 91 ⫾ 29
35.8 ⫾ 8.8 7/9 23.4 ⫾ 4.1 3 120 ⫾ 18 74 ⫾ 8 106 ⫾ 17
40.8 ⫾ 4.8 7/9 26.0 ⫾ 3.2 4 134 ⫾ 14* 77 ⫾ 13 112 ⫾ 14
38.1 ⫾ 8.8 8/16 24.7 ⫾ 3.5 3 119 ⫾ 14 75 ⫾ 9 105 ⫾ 12
195 ⫾ 23 121 ⫾ 37 132 ⫾ 23‡
181 ⫾ 30 99 ⫾ 39 108 ⫾ 24
179 ⫾ 29 115 ⫾ 35 111 ⫾ 16§
180 ⫾ 30 114 ⫾ 37 95 ⫾ 17
NOTE. To convert creatinine clearance in mL/min to mL/s, multiply by 0.01667; serum total cholesterol in mg/dL to mmol/L, multiply by 0.02586; serum triglycerides in mg/dL to mmol/L, multiply by 0.01129. *P ⬍ 0.01 versus normotensive patients with ADPKD and healthy subjects. †P ⬍ 0.005 versus normotensive patients with ADPKD and healthy subjects. ‡P ⫽ 0.02 versus normotensive patients with ADPKD, P ⬍ 0.02 versus patients with essential hypertension, P ⬍ 0.0001 versus healthy subjects. §P ⬍ 0.005 versus healthy subjects.
subject had atheromatous plaque, localized lesion of thickness greater than 2.0 mm, or stenosis in this region. The intraobserver coefficient of variation for carotid IMT was 2.6%.
Statistical Analyses Comparison of groups was performed using MannWhitney U and chi-square tests. Mann-Whitney U test was applied to the groups in pairs, for all possible combinations. P less than 0.05 is considered statistically significant. All values are expressed as mean ⫾ SD.
RESULTS
There was no significant difference between groups regarding age, sex, body mass index, smoking status, renal function, and lipid levels (Table 1). Hypertensive patients with ADPKD and patients with essential hypertension had significantly greater systolic blood pressures compared with normotensive patients with ADPKD and healthy subjects. Hypertensive patients with ADPKD also had significantly greater diastolic blood pressures compared with normotensive patients with ADPKD and healthy subjects. Hypertensive patients with ADPKD had a significantly greater left ventricular mass index (LVMI) compared with all other groups. Patients with essential hypertension also had a significantly elevated LVMI compared with healthy subjects. Normotensive patients with ADPKD had a greater
LVMI compared with healthy subjects. Although this was not statistically significant, P was 0.06. No patient in the groups had been administered statins. Five patients were administered angiotensin-converting enzyme (ACE) inhibitors; 4 patients, calcium channel blockers (CCBs); 3 patients, angiotensin-receptor blockers (ARBs); and 3 patients, a combination of ACE inhibitors and CCBs in the hypertensive ADPKD group. Six patients were administered ACE inhibitors; 3 patients, CCBs; 4 patients, ARBs; 3 patients, a combination of ACE inhibitors and CCBs; and 1 patient, a -blocker in the essential hypertensive group. No statistically significant difference in antihypertensive use was present between the hypertensive ADPKD group and essential hypertensive group. Basal diameter of the brachial artery was 3.4 ⫾ 0.6 mm in hypertensive patients with ADPKD, 3.1 ⫾ 0.5 mm in normotensive patients with ADPKD, 3.6 ⫾ 0.4 mm in patients with essential hypertension, and 3.5 ⫾ 0.6 mm in healthy subjects. It was significantly less in normotensive patients with ADPKD compared with patients with essential hypertension (3.1 ⫾ 0.5 versus 3.6 ⫾ 0.4 mm; P ⬍ 0.05). EDD was significantly worse in hypertensive patients with ADPKD compared with patients with essential hypertension (9.1% ⫾ 4.1% versus 12.4% ⫾
ENDOTHELIAL DYSFUNCTION IN ADPKD
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Fig 1. Results of brachial artery measurements: (A) EDD and (B) EID. *P < 0.05 versus normotensive patients with ADPKD and patients with essential hypertension; P < 0.01 versus healthy subjects. **P < 0.01 versus healthy subjects.
4.6%; P ⬍ 0.05), normotensive patients with ADPKD (9.1% ⫾ 4.1% versus 13.1% ⫾ 5.2%; P ⬍ 0.05), and healthy subjects (9.1% ⫾ 4.1% versus 18.1% ⫾ 8.1%; P ⬍ 0.01). EDD was significantly worse even in normotensive patients with ADPKD compared with healthy subjects (13.1% ⫾ 5.2% versus 18.1% ⫾ 8.1%; P ⬍ 0.01). EID was significantly less in patients with ADPKD (both hypertensive and normotensive) and patients with essential hypertension compared with healthy subjects (Fig 1). Carotid IMT was significantly greater in hypertensive patients with ADPKD (0.71 ⫾ 0.10 mm; P ⬍ 0.01) and patients with essential hypertension (0.71 ⫾ 0.10 mm; P ⬍ 0.01) compared with normotensive patients with ADPKD (0.57 ⫾ 0.14 mm) and healthy subjects (0.45 ⫾ 0.10 mm; Fig 2). Carotid IMT also was significantly greater in normotensive patients with ADPKD compared with healthy subjects (0.57 ⫾ 0.14 versus 0.45 ⫾ 0.10 mm; P ⬍ 0.001).
DISCUSSION
The RAAS has a detrimental role in the pathogenesis of target-organ damage, such as atherosclerosis, LVH, heart failure, and ESRD.8–11 The RAAS is stimulated at an early stage of ADPKD, even before the onset of hypertension and clinical findings.6,7 Thus, increased activity of the RAAS may contribute to the increased incidence of cardiovascular complications in patients with ADPKD. ED is considered to have an important role in the pathogenesis of vascular disease.11 An imbalance characterized by reduced NO production or increased reactive oxygen species production may promote ED.25,26 It has been shown that angiotensin II contributes to ED by stimulating the production of reactive oxygen species, such as superoxide, through the activation of membrane-bound reduced nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide phosphate oxidase.27
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Fig 2. Measurements of carotid IMT. *P < 0.01 versus normotensive patients with ADPKD and healthy subjects. **P < 0.001 versus healthy subjects.
Wang et al28 reported that both normotensive and hypertensive patients with ADPKD have impaired endothelial-dependent relaxation of small resistance vessels. In that study, acetylcholine-induced relaxation rate was decreased in resistance vessels obtained by biopsy of subcutaneous fat from the gluteal region. In our study, a noninvasive method of high-resolution vascular ultrasound was used to determine ED and carotid IMT in patients with ADPKD during the early stages of their disease. Evaluation of endotheliumdependent flow-mediated vasodilatation of the brachial artery is a method widely used for the determination of early atherosclerosis and cardiovascular risks.13–15 Likewise, carotid IMT is a well-established index of atherosclerosis and the only noninvasive imaging test currently recommended by the American Heart Association for inclusion in the evaluation of risk.18,29 This is the first study showing ED and increased carotid IMT by using these noninvasive methods in patients with ADPKD. In the present study, patients with essential hypertension and hypertensive patients with ADPKD had significantly less EDD compared with normotensive patients with ADPKD and healthy subjects. This is an expected finding because it has been shown that endothelial function becomes progressively impaired as blood pressure increases, and degree of dysfunction is related to severity of hypertension.30,31 Importantly, hypertensive patients with ADPKD had significantly less EDD compared with patients with essential hypertension with similar blood pressures. This may occur because the RAAS is stimulated significantly more in hypertensive patients with
ADPKD than in similar patients with essential hypertension.5 Another factor that could have contributed to the difference in EDD may be that hypertensive patients with ADPKD likely could have elevated blood pressures for a longer period than patients with essential hypertension. In the present study, hypertensive patients with ADPKD had a significantly greater LVMI compared with subjects in all other groups. The high incidence of LVH has been reported in patients with ADPKD.32 Findings of both ED and LVH are consistent with the high rate of cardiovascular morbidity and mortality in patients with ADPKD. All hypertensive patients were receiving antihypertensive therapy. Thus, the direct effect of these drugs on vascular function cannot be excluded in the present study. Furthermore, blood pressure was lower in patients with essential hypertension than in hypertensive patients with ADPKD (134/77 versus 138/85 mm Hg, respectively), although not significant. Therefore, the lower blood pressure of patients with essential hypertension may have masked the full extent of ED in this group. An important finding in the present study is the observation of significant ED, even in normotensive patients with ADPKD. Although not statistically significant, LVMI also was greater in these patients compared with healthy subjects (P ⫽ 0.06). Previous studies showed signs of target-organ damage, such as microalbuminuria and LVH, in normotensive patients with ADPKD with normal renal function.33,34 It also was reported that the nocturnal decrease in blood pressure is attenuated in normotensive patients with
ENDOTHELIAL DYSFUNCTION IN ADPKD
ADPKD.35 Stimulation of the RAAS very early in the course of ADPKD may contribute to these findings.6,7 Wang et al28 found an inverse relationship between degree of EDD and mean arterial pressure and suggested that impaired endothelial function may contribute to hypertension in these patients. Similarly, in our study, the finding of significant ED in normotensive patients with ADPKD compared with healthy subjects and more severe ED in hypertensive patients suggests that ED may predispose to hypertension in patients with ADPKD. Nitroglycerin is used to determine the maximum obtainable vasodilator response and serve as a measure of EID reflecting vascular smooth muscle function.36 Thus, decreased vasodilatory response to exogenous administration of NO donor suggests smooth muscle dysfunction in the arterial wall. Wang et al28 reported that endothelium-independent relaxation response to an NOdonor (SIN-1) was similar in hypertensive and normotensive patients with ADPKD, patients with essential hypertension, and control subjects. However, in the present study, vasodilator response to isosorbide dinitrate was impaired in patients with essential hypertension and hypertensive and normotensive patients with ADPKD compared with healthy subjects. This finding suggests smooth muscle dysfunction in these patients. Impaired EID has been reported even in asymptomatic subjects with reduced EDD who are at risk for atherosclerosis.37 Although increased activity of the RAAS might have an effect on this finding, additional studies are needed to understand the pathogenesis. Multiple studies have shown that carotid artery IMT, measured noninvasively by ultrasonography, is associated directly with increased risk for cardiovascular disease, and it has been shown to be an independent predictor of cardiovascular disease after adjustment for traditional risk factors.18 The presence of a significant increase in carotid IMT in normotensive patients with ADPKD compared with healthy subjects reflects the increased cardiovascular risk, even in the early stages of the disease. In conclusion, findings of significant ED and increased carotid IMT in both hypertensive and normotensive patients with ADPKD with wellpreserved renal function suggest that atheroscle-
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rosis starts at a very early stage of the disease. Because cardiovascular problems are a major cause of morbidity and mortality in patients with ADPKD, risk factors for atherosclerosis should be treated aggressively. Prospective randomized studies are needed to determine the benefits of this approach in these patients. Interventional trials using drugs that block the RAAS or statins could be of particular importance owing to their beneficial effects on endothelial function. REFERENCES 1. Fick-Brosnahan GM, Ecder T, Schrier R: Polycystic kidney disease, in Schrier RW (ed): Diseases of the Kidney and Urinary Tract. (ed 7). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 547-588 2. Ecder T, Schrier RW: Hypertension in autosomaldominant polycystic kidney disease: Early occurrence and unique aspects. J Am Soc Nephrol 12:194-200, 2001 3. Schrier RW, McFann KK, Johnson AM: Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease. Kidney Int 63:678-685, 2003 4. Fick GM, Johnson AM, Hammond WS, Gabow PA: Causes of death in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 5:2048-2056, 1995 5. Chapman AB, Johnson A, Gabow PA, Schrier RW: The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med 323:10911096, 1990 6. Harrap SB, Davies DL, Macnicol AM, et al: Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease. Kidney Int 40:501-508, 1991 7. Barrett BJ, Foley R, Morgan J, Hefferton D, Parfrey P: Differences in hormonal and renal vascular responses between normotensive patients with autosomal dominant polycystic kidney disease and unaffected family members. Kidney Int 46:118-1123, 1994 8. Brunner HR: Experimental and clinical evidence that angiotensin II is an independent risk factor for cardiovascular disease. Am J Cardiol 87:3C-9C, 2001 9. Hirsch AT, Pinto YM, Schunkert H, Dzau VJ: Potential role of the tissue renin-angiotensin system in the pathophysiology of congestive heart failure. Am J Cardiol 66:22D-30D, 1990 10. Wolf G: Angiotensin II: A pivotal factor in the progression of renal diseases. Nephrol Dial Transplant 14:S42-S44, 1999 (suppl 1) 11. Lu¨ scher TF: Endothelial dysfunction: The role and impact of the renin-angiotensin system. Heart 84:Si20-Si22, 2000 (suppl 1) 12. Anderson EA, Mark AL: Flow-mediated and reflex changes in large peripheral artery tone in humans. Circulation 79:93-100, 1989 13. Celermajer DS, Sorensen KE, Gooch VM, et al: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:11111115, 1992 14. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al:
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Non-invasive measurement of human endothelium dependent arterial responses: Accuracy and reproducibility. Br Heart J 74:247-253, 1995 15. Corretti MC, Anderson TJ, Benjamin EJ, et al: Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 39:257-265, 2002 16. Barth JD: Which tools are in your cardiac workshop? Carotid ultrasound, endothelial function, and magnetic resonance imaging. Am J Cardiol 87:8A-14A, 2001 17. Celermajer DS: Endothelial dysfunction: Does it matter? Is it reversible? J Am Coll Cardiol 30:325-333, 1997 18. O’Leary DH, Polak JF: Intima-media thickness: A tool for atherosclerosis imaging and event prediction. Am J Cardiol 90:18L-21L, 2002 19. Crouse JR III, Craven TE, Hagaman AP, Bond MG: Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery. Circulation 92:1141-1147, 1995 20. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340:14-22, 1999 21. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 22. Henry WL, DeMaria A, Gramiak R, et al: Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two Dimensional Echocardiography. Circulation 62:212-217, 1980 23. Sahn DJ, DeMaria A, Kisslo J, Weyman A: Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 58:1072-1083, 1978 24. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 55:613-618, 1977 25. Drexler H, Hornig B: Endothelial dysfunction in human disease. J Mol Cell Cardiol 31:51-60, 1999 26. Dijkhorst-Oei LT, Stroes ES, Koomans HA, Rabelink TJ: Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo. J Cardiovasc Pharmacol 33:420-424, 1999 27. Rajagopalan S, Kurz S, Munzel T, et al: Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase
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activation. Contribution to alterations of vasomotor tone. J Clin Invest 97:1916-1923, 1996 28. Wang D, Iversen J, Wilcox CS, Strandgaard S: Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease. Kidney Int 64:1381-1388, 2003 29. Greenland P, Smith SC, Grundy SM: Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 104:1863-1867, 2001 30. Dohi Y, Thiel MA, Buhler FR, Luscher TF: Activation of endothelial L-arginine pathway in resistance arteries: Effect of age and hypertension. Hypertension 16:170-179, 1990 31. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA: Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 87:1468-1474, 1993 32. Chapman AB, Johnson AM, Rainguet S, Hossack K, Gabow P, Schrier RW: Left ventricular hypertrophy in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 8:1292-1297, 1997 33. Bardaji A, Martinez-Vea A, Gutierrez C, Ridao C, Richart C, Oliver JA: Left ventricular mass and diastolic function in normotensive young adults with autosomal dominant polycystic kidney disease. Am J Kidney Dis 32:970975, 1998 34. Martinez-Vea A, Gutierrez C, Bardaji A, et al: Microalbuminuria in normotensive patients with autosomal dominant polycystic kidney disease. Scand J Urol Nephrol 32:356-359, 1998 35. Valero FA, Martinez-Vea A, Bardaji A, et al: Ambulatory blood pressure and left ventricular mass in normotensive patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 10:1020-1026, 1999 36. Ducharme A, Dupuis J, McNicoll S, Harel F, Tardif JC: Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects. Am J Cardiol 84:952-954, 1999 37. Adams MR, Robinson J, McCredie R, et al: Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis. J Am Coll Cardiol 32:123-127, 1998