Association of renal functional impairment and the severity of coronary artery disease/Renal fonksiyon bozuklugu ve koroner arter hastaliginin ciddiyeti arasindaki iliski.

ABSTRACT

Objective: Cardiovascular diseases are the most common cause of death in patients with renal failure. Glomerular filtration rate (GFR) is used for the assessment of the renal functional status. In this study we aimed to examine the association between severity of coronary stenosis and renal function by quantifying the coronary lesions, angiographically and calculating the renal function with the use of GFR.

Methods: Forty-three patients with decreased renal function (calculated GFR<80 ml/min) with a mean age of 67.8 [+ or -] 9.0 years and 49 patients without impaired renal function (calculated GFR=80 ml/min) with a mean age of 52.5 [+ or -] 10.3 years were studied consecutively from March 2005 to September 2005. Glomerular filtration rate was calculated according to a given formula. All patients underwent selective coronary artery angiography and Gensini scoring system was used for the detection of severity of coronary atherosclerosis.

Results: In linear regression analysis, a negative correlation was found between renal function and the severity of coronary atherosclerosis (r=0.326, p=0.002). All patients were classified into quartiles of Gensini score level. In multivariate analysis, the multiple-adjusted odds ratio (OR) of the risk of decreased renal function was 0.99 (95% CI 0.24-4.15) for quartile 2, 4.38 (95% CI 1.11-17.20, p=0.03) for quartile 3, and 7.01 (95% CI 1.72-28.61, p=0.007) for quartile 4 of Gensini score level compared with the quartile 1.

Conclusion: Coronary atherosclerosis quantified by Gensini score is significantly associated with the severity of decreased renal function and this association is independent of age and other cardiovascular risk factors. (Anadolu Kardiyol Derg 2007; 7: 44-8)

Key words: Coronary artery disease, renal insufficiency, coronary angiography 

OZET

Amac: Kardiyovaskuler hastaliklar bobrek yetmezligi bulunan hastalardaki olumun en sik nedenidir. Glomeruler filtrasyon hizi (GFH), renal fonksiyonun durumunu degerlendirmek icin kullanilir. Bu Calismada anjiyografik olarak koroner lezyonlarin ve GFH nin kullanilarak renal fonksiyonlarin tespiti ile koroner stenozun ciddiyeti ve renal fonksiyonlar arasindaki iliskiyi Calismayi amacladik.

Yontemler: Ortalama yasi 67.8 [+ or -] 9.0 olan azalmis renal fonksiyonlu (GFH<80 ml/dak) 43 hasta ile ortalama yasi 52.5 [+ or -] 10.3 olan renal fonksiyon bozuklugu bulunmayan (GFH=80 ml/dak) 49 hasta Mart-Eylul 2005 tarihleri arasinda ardisik olarak Calisildi. Glomeruler filtrasyon hizi verilen formule gore hesaplandi. Tum hastalara selektif koroner anjiyografi uygulandi ve koroner aterosklerozun ciddiyetinin tespiti icin Gensini skorlama sistemi kullanildi.

Bulgular: Lineer regresyon analizinde, renal fonksiyon ve koroner aterosklerozun ciddiyeti arasinda negatif korelasyon bulundu (r=0.326, p=0.002). Gensini skor duzeyine gore tum hastalar dortlu gruplara ayrildi. Coklu degisken analizinde, azalmis renal fonksiyon riskinin coklu degiskenlere gore ayarlanmis OR si, Gensini skoru icin grup 1 ile kiyaslandiginda, grup 2 icin 0.99 (%95 CI 0.24-4.15), grup 3 icin 4.38 (%95 CI 1.11-17.20, p=0.03) ve grup 4 icin 7.01 (%95 CI 1.72-28.61, p=0.007) idi.

Sonuc: Gensini skoru ile gosterilen koroner ateroskleroz azalmis renal fonksiyonun ciddiyeti ile anlamli olarak iliskilidir ve bu iliski yas ve diger kardiyovaskuler risk faktorlerinden bagimsizdir. (Anadolu Kardiyol Derg 2007; 7: 44-8)

Anahtar kelimeler: Koroner arter hastaligi, bobrek yetersizligi, koroner anjiyografi

Introduction

Survival of patients with renal functional impairment is low because of increased risk of death from cardiovascular causes. However, cardiovascular diseases are not the only cause of high mortality. There are other reasons (infection, malnutrition etc) for increased mortality in these patients. Cardiovascular disease (CVD) accounts for around 44% of overall mortality among patients on long term dialysis and the mortality rate from the cardiovascular causes in a young patient undergoing dialysis is about the same as that of a elderly patient from the general population (1). Angiographically significant coronary artery disease (CAD) has been found in 85% of patients with end-stage renal disease (ESRD) (2). The traditional risk factors for coronary artery disease including age, sex, hypertension, diabetes mellitus, dyslipidemia, smoking habit and family history have been well-established. Although the prevalence of traditional Framingham risk factors is found much more in patients with ESRD, non-traditional risk factors such as inflammation and oxidative stress have been studied recently (3, 4).

Glomerular filtration rate (GFR) is a widely accepted, useful, easily calculated, and reproducible parameter used for the assessment of the renal functional status. Gradual decrease in this parameter demonstrates more decrease in renal function. Unfortunately, ESRD develops at the end of this progress. As mentioned above, decreased renal function is associated with higher incidence of atherosclerotic process and mortality from the cardiovascular disorders. Joki N, et al. have postulated in their studies that the severity of coronary atherosclerosis should be determined using numbers of effected vessels, numbers of stenotic lesions, and the degree of narrowing in patients with renal impairment (5, 6).

In the present study, we aimed to examine the association between severity of coronary stenosis and renal function by quantifying the coronary lesions, angiographically and calculating the renal function with the use of GFR. In addition, presence of any correlation between these two conditions was studied. It is a widely known fact that kidney failure, especially ESRD requiring hemodialysis, is associated with higher incidence of coronary events. However, in our study, GFR was calculated by using an indirect and easy method and we studied whether the obtained result might predict the severity of coronary artery disease. Because increased renal functional impairment is associated with more severe coronary heart disease.

Methods

Study population

Forty-three consecutive patients with the decreased renal function, GFR <80 ml/min, undergoing cardiac catheterization for proven or clinically suspected coronary artery disease were enrolled at the study between March 2005 and September 2005 (range 34-78 years). In addition, 49 patients with normal renal functional status, GFR =80 ml/min, undergoing cardiac catheterization for the same reason were recruited as control group (range 40-85 years). Exclusion criteria included the following: left ventricular dysfunction (left ventricular ejection fraction <50%); unstable ischemic conditions (unstable angina pectoris and myocardial infarction); valvular heart disease; hepatic dysfunction (aspartate aminotransferase and alanine aminotransferase >2 times upper limit of normal, respectively); and all forms of diabetes mellitus.

Assessment of renal function

Glomerular filtration rate was used for the detection of renal functional status. This parameter might be calculated by different methods. Although collected 24-hour urine sample is widely used for the calculation, in the present study we chose a more simple method, which does not contain 24-hour urine sampling:

GFR (ml/min) = (140-age [years]) X body weight (kg)/ plasma creatinine X 72. For female patients, obtained value was multiplied by 0.85.

Cardiac catheterization and determination of the severity of coronary atherosclerosis

All patients in the study underwent selective coronary artery angiography after appropriate patient preparation. Femoral artery cannulation was used for arterial access site and Judkins system was applied for cannulation the left and right coronary arteries. All angiograms were evaluated by two experienced physicians blinded to the study. Angiograms with stenotic lesion in all major epicardial coronary arteries including left main, left anterior descending (LAD), left circumflex (LCx), and right coronary (RCA) arteries were assessed and the severity of coronary artery disease was assessed by using the Gensini scoring system (7) which grades narrowing of the lumens of the coronary arteries as: 1 for 1-25% narrowing, 2 - 26-50% narrowing, 4 - 51-75% narrowing, 8 - 76-90% narrowing, 16 - 91- 99% narrowing, and 32 for total occlusion. This score was then multiplied by a factor that takes into account the importance of the lesion's position in the coronary arterial tree, for example, 5 for the left main coronary artery, 2.5 for the proximal LAD or proximal LCx, 1.5 for the mid-region of the LAD, and 1 for the distal LAD or mid-distal region of the LCx.

Laboratory data

Fasting peripheral venous blood samples were obtained from all patients in the study for the measurement of fasting plasma glucose, total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, and triglyceride levels. Blood samples were centrifuged and plasma was obtained. Fasting blood glucose, total cholesterol, HDL-cholesterol, and triglyceride levels were measured by different laboratory techniques. Measurement of LDL-cholesterol level was done through application of a formula as described by Friedewald et al (8). In addition, renal functional parameters (urea and creatinine) and fibrinogen levels were measured.

Anthropometric measurement

Height and weight of patients were measured and body mass index (BMI) was calculated through dividing weight in kilograms by height in meters squared and described as kg/m2.

Statistical analysis

Data were analyzed with the SPSS software version 10.0 for Windows (SPSS Inc., Chicago, Illinois). Continuous variables were presented as mean [+ or -] SD and categorical variables as frequency and percentage. The Kolmogorov-Smirnov test was applied to assess the distribution of continuous variables. Student's t-test was used to compare normally distributed continuous variables and the Mann-Whitney U test for variables without normal distribution. A two-tailed p-value of <0.05 was considered to be statistically significant. Multiple logistic regression analysis was used to evaluate the independent associates of decreased renal function group. Parameters with a p-value <0.1 in univariate analysis were included in the model. The odds ratios (OR) and 95% confidence intervals (CI) were calculated.

Results

Baseline characteristics

Baseline demographic, laboratory, and hemodynamic characteristics of patients in both groups are outlined in Table 1. Patients with renal functional impairment were older than those without impairment (p<0.001). The prevalence of hypertension was significantly higher in decreased renal function group compared to control group (p=0.02). There were no significant differences between two groups concerning sex and BMI. Urea and creatinine, and fibrinogen levels were significantly higher in decreased renal function group compared to control group. No statistical significance was present between both groups for the measurement of fasting plasma glucose, total-, HDL-, LDL-cholesterols, and triglyceride levels. Hemodynamic parameters including systolic and diastolic blood pressures were not different between two groups (Table 1). More patients in decreased renal function group had history of hypertension yet the blood pressure measurements were same in both groups. This may be the result of medical treatment. Same can be true for the lipid values. Presumably, untreated patients with renal functional impairment for the traditional risk factors will have more severe atherosclerotic lesions. Nine patients (21%) in decreased renal function group were undergoing regular hemodialysis. Glomerular filtration rate values in decreased renal function group were significantly lower compared to control group. Similarly, Gensini scores were significantly higher in decreased renal function group compared to control group. This significant difference between groups might be essentially caused by the patients who were on dialysis.

Severity of the stenotic lesion

According to severity of the stenotic lesion, (Fig. 1) patients with = 50% of narrowing of any epicardial coronary arterial segment had more decreased GFR compared to those with < 50% of narrowing.

[FIGURE 1 OMITTED]

Linear regression analysis of relationship between renal function and the severity of coronary atherosclerosis

The significant linear relationship between Gensini score and glomerular filtration rate is reported in Figure 2 (r=0.326, p=0.002). With the decrease of GFR and so renal function, Gensini score increases demonstrating more severe coronary atherosclerosis.

[FIGURE 2 OMITTED]

Logistic regression analysis of the severity of renal functional impairment

All patients were classified into quartiles of Gensini score level to evaluate whether Gensini score was associated with the severity of decreased renal function in the study. We found that Gensini score was positively and significantly associated with the severity of renal functional impairment (Table 2). Twenty-seven percent of patients in the lowest quartile, 26% in the second quartile, 58% in the third quartile, and 74% in the highest quartile were found to have decreased renal function. The crude OR of the risk of decreased renal functional status was 0.94 (95% CI 0.25-3.53) for quartile 2, 3.73 (95% CI 1.08-12.91) for quartile 3, and 7.56 (95% CI 2.02-28.33) for quartile 4 of Gensini score level compared to quartile 1. The multiple-adjusted OR of the risk of decreased renal function was 0.99 (95% CI 0.24-4.15) for the second quartile, 4.38 (95% CI 1.11-17.20) for the third quartile, and 7.01 (95% CI 1.72-28.61) for the fourth quartile of Gensini score level compared with the lowest quartile after adjustment for age, the presence of hypertension, serum levels of fibrinogen, urea, and creatinine.

Discussion

In our study, we found that patients with decreased renal function had significantly increased severity of coronary atherosclerosis compared to control subjects. In addition, this significant and positive correlation was independent of risk factors for coronary artery disease although smoking and diabetes mellitus were not included in the study.

Patients with renal functional impairment (renovascular or renal parenchymal) have increased risk of cardiovascular diseases and increased mortality. This association is stronger in ESRD patients. Actually, the risk for CVD in a 30-year-old ESRD patient is similar to the calculated risk of a 70 to 80-year-old subject from the nonrenal population (9). Though the prevalence of traditional Framingham risk factors is very high in patients with renal impairment, non-traditional risk factors such as inflammation and oxidative stress, which are observed largely in renal failure causing atherosclerosis, have also been investigated (3, 4). Subjects with high risk have an active inflammatory process causing atherosclerosis. In addition, calcification in vascular wall is another important underlying inflammatory mechanism in the pathogenesis of atherosclerosis (10). Coronary artery calcification correlates with the extent of coronary artery atherosclerosis occurring more frequent in uremic patients than in the general population. Goodman et al. (11) used electron-beam computed tomography to demonstrate that coronary artery calcification is common and progressive, even in young adults undergoing dialysis. The highly possible etiology of uremic vasculopathy is derangement of the calcium-phosphate-parathyroid hormone axis resulted in secondary hyperparathyroidism. Recently, strong relationships among increased serum phosphate, calcium-phosphate product, parathyroid hormone, and mortality from cardiovascular causes have been demonstrated (12). Oh et al. (13) showed that coronary artery calcification in young adults was associated not only with a calcium-phosphate overload and hyperparathyroidism, but also with inflammation. Activated monocytes and macrophages infiltrate the vascular wall and enhance vascular calcification via cell-cell interaction and production of inflammatory mediators, such as tumor necrosis factor-a (14). Therefore, patients with decreased renal function have increased risk of coronary artery calcification resulted in enhanced coronary atherosclerosis.

Gradaus et al. (15) have demonstrated that a more rapid progression of coronary stenosis in patients with ESRD is present compared to patients with normal renal function. Increased prevalence of traditional cardiovascular risk factors including hypertension, diabetes mellitus and associated nephropathy, and dyslipidemia in these patients might be some mechanisms associated with the rapid progression (16). In addition, inflammatory substances like C-reactive protein have also been found in high concentrations. Prothrombotic factors (increased fibrinogen, decreased plasminogen activator inhibitor, and tissue plasminogen activator), increased oxidant stress, and hyperhomocysteinemia are the other causes and the mechanisms of why coronary lesions are more complex and severe in patients with impaired renal function (17, 18).

Study limitations

Although the relatively large number of study population was used in our study, we believe that it is still limited in number to generalize the results because of invasive nature of the study. The patients in the study group are heterogenous. That is; 9 patients having end-stage renal disease and undergoing maintenance hemodialysis while the rest have impaired renal function defined by a GFR of <80 ml/min. Patients having ESRD are very different from those who have a mild renal functional impairment. The mean age of the patients with impaired renal function is older than that of the control group. This is a major factor affecting the severity of coronary artery lesions. Lastly, the prerenal azotemia could not be ruled out in our study.

Conclusion

We have demonstrated that Gensini score, indicator of the risk of severity for coronary artery disease, in patients with decreased renal functional status was significantly and independently elevated compared to control subjects.

References

(1.) Sarnak M. Cardiovascular complications in chronic kidney disease. Am J Kidney Dis 2003;41:11-7.

(2.) Lippert J, Ritz E, Schwarzbeck A, Schneider P. The rising tide of endstage renal failure from diabetic nephropathy type II-an epidemiological analysis. Nephrol Dial Transplant 1995;10:462-7.

(3.) Stenvinkel P, Alvestrand P. Inflammation in end-stage renal disease: Sources, consequences and therapy. Seminar Dial 2002;15:330-8.

(4.) Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant of uremia: oxidative stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002;62:1524-38.

(5.) Joki N, Hase H, Takahashi Y, Ishikawa H, Nakamura R, Imamura Y, et al. Angiographical severity of coronary atherosclerosis predicts death in the first year of hemodialysis. Int Urol Nephrol 2003;35:289-97.

(6.) Joki N, Hase H, Saijyo T, Tanaka Y, Takahashi Y, Ishikawa H, et al. Combined assessment of cardiac systolic dysfunction and coronary atherosclerosis used to predict future cardiac deaths after starting hemodialysis. Am J Nephrol 2003;23:458-65.

(7.) Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606.

(8.) Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.

(9.) Stenvinkel P, Pecoits-Filho R, Lindholm B. Coronary artery disease in end-stage renal disease: no longer a simple plumbing problem. J Am Soc Nephrol 2003;14:1927-39.

(10.) Demer LL. Vascular calcification and osteoporosis: inflammatory responses to oxidized lipids. Int J Epidemiol 2002;31:737-41.

(11.) Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342:1478-83.

(12.) Ganesh SK, Stack AG, Levin N, Hulbert-Shearon T, Port FK. Association of elevated serum PO4, Ca-PO4 product and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-8.

(13.) Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, et al. Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 2002;106:100-5.

(14.) Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL. Monocyte/ macrophage regulation of vascular calcification in vitro. Circulation 2002;105:650-5.

(15.) Gradaus F, Ivens K, Peters AJ, Heering P, Schoebel FC, Grabensee B, et al. Angiographic progression of coronary artery disease in patients with end-stage renal disease. Nephrol Dial Transplant 2001;16:1198-202.

(16.) Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, et al. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol 2002;13:1918-27.

(17.) Mezzano D, Tagle R, Panes O, Perez M, Downey P, Munoz B, et al. Hemostatic disorder of uremia: the platelet defect, main determinant of the prolonged bleeding time, is correlated with indices of activation of coagulation and fibrinolysis. Thromb Haemost 1996;76:312-21.

(18.) London GM, Parfrey PS. Cardiac disease in chronic uremia: pathogenesis. Adv Ren Replace Ther 1997;4:194-211.

Serkan Cay, Fatma Metin, Sule Korkmaz Department of Cardiology, Yuksek Ihtisas Heart-Education and Research Hospital, Ankara, Turkey

Address for Correspondence: Dr. Serkan Cay, Oba Sokak 11/6 Hurriyet Apt., Cebeci 06480, Ankara, Turkey Tel: [phone] Fax: [phone] E-mail: [e-mail]

Table 1. Baseline demographic, laboratory, and hemodynamic
characteristics

                                     Normal renal
                                    function group
Variables                              (n = 49)

Age, years                        52.5 [+ or -] 10.3
Male sex, n (%)                        43 (88)
Hypertension, n (%)                     4 (8)
Body mass index, kg/m2            27.3 [+ or -] 5.2
Fasting plasma glucose, mg/dl       92 [+ or -] 14
Cholesterol, mg/dl
  Total                            172 [+ or -] 25
  LDL                              104 [+ or -] 20
  HDL                               41 [+ or -] 10
Triglycerides, mg/dl               134 [+ or -] 65
Fibrinogen, mg/dl                 3.49 [+ or -] 1.45
Urea, mg/dl                         36 [+ or -] 10
Creatinine, mg/dl                 0.87 [+ or -] 0.17
Systemic pressures, mmHg
  Systolic                         118 [+ or -] 13
  Diastolic                         73 [+ or -] 9
GFR, ml/min                        108 [+ or -] 24
Gensini score                       13 [+ or -] 16

                                   Decreased renal
                                    function group
Variables                              (n = 43)

Age, years                        67.8 [+ or -] 9.0
Male sex, n (%)                        35 (81)
Hypertension, n (%)                    11 (26)
Body mass index, kg/m2            25.3 [+ or -] 4.5
Fasting plasma glucose, mg/dl       97 [+ or -] 14
Cholesterol, mg/dl
  Total                            164 [+ or -] 28
  LDL                               99 [+ or -] 23
  HDL                               42 [+ or -] 10
Triglycerides, mg/dl               118 [+ or -] 50
Fibrinogen, mg/dl                 4.30 [+ or -] 1.74
Urea, mg/dl                         61 [+ or -] 35
Creatinine, mg/dl                 1.47 [+ or -] 0.91
Systemic pressures, mmHg
  Systolic                         123 [+ or -] 15
  Diastolic                         75 [+ or -] 9
GFR, ml/min                         55 [+ or -] 17
Gensini score                       35 [+ or -] 33

Variables                                 P

Age, years                              <0.001
Male sex, n (%)                           NS
Hypertension, n (%)                      0.02
Body mass index, kg/m2                    NS
Fasting plasma glucose, mg/dl             NS
Cholesterol, mg/dl
  Total                                   NS
  LDL                                     NS
  HDL                                     NS
Triglycerides, mg/dl                      NS
Fibrinogen, mg/dl                        0.02
Urea, mg/dl                             <0.001
Creatinine, mg/dl                       <0.001
Systemic pressures, mmHg
  Systolic                                NS
  Diastolic                               NS
GFR, ml/min                             <0.001
Gensini score                           <0.001

Values are mean [+ or -] SD or number and percentages of patients

GFR- glomerular filtration rate, HDL- high-density lipoprotein,
LDL- low-density lipoprotein, NS- not significant

Table 2. Logistic regression analysis odds ratios of decreased renal
function according to Gensini score

                   n                    OR (95% CI)

                          Decreased        Crude          Multiple-
                            renal                         adjusted *
                          function.
                            n (%)
Gensini score

  Quartile 1       22      6 (27)           1.00             1.00
  (1.0-3.5)

  Quartile 2       23      6 (26)           0.94             0.99
  (4.0-11.0)                            (0.25-3.53)      (0.24-4.15)
                                          p = 0.93         p = 0.99

  Quartile 3       24      14 (58)         3.73              4.38
  (11.5-29.0)                           (1.08-12.91)     (1.11-17.20)
                                          p = 0.04         p = 0.03

  Quartile 4       23      17 (74)          7.56             7.01
  (29.5-115.0)                          (2.02-28.33)     (1.72-28.61)
                                         p = 0.003        p = 0.007

* Adjusted for age, the presence of hypertension, serum levels of
fibrinogen, urea, and creatinine

CI- confidence interval, OR- odds ratio