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Aortic pulse wave velocity in renal transplant patients
Kidney International, Vol. 66 (2004), pp. 1486–1492
Aortic pulse wave velocity in renal transplant patients SOLA AOUN BAHOUS, ANTOINE STEPHAN, WADAD BARAKAT, JACQUES BLACHER, ROLAND ASMAR, and MICHEL E. SAFAR ˆ ˆ Nephrology and Transplantation Center, Rizk Hospital, Beirut Lebanon; Centre de Diagnostic, Hopital Hotel-Dieu, Paris, France; and L’Institut Cardio-Vasculaire, Clinique Mozart, Paris, France
Aortic pulse wave velocity in renal transplant patients. Background. In subjects with end-stage renal disease (ESRD) undergoing hemodialysis, aortic pulse wave velocity (PWV) is increased independently of blood pressure level and mostly is a strong predictor of cardiovascular risk. Few studies on this subject have been performed in renal transplant patients. Methods. Aortic PWV was determined noninvasively in 106 patients with kidney transplantation and treated using a standard immunosuppression protocol. Mean age was 43 ± 14 years. During the follow-up period (mean duration 54.3 ± 28.9 months), the following parameters were studied: characteristics of the renal graft, degree of renal insufficiency, number of acute rejections, cardiovascular risk factors, drug medications, and cardiovascular complications. Results. Aortic PWV was increased in subjects with renal transplants independently of age and mean blood pressure. Acute renal rejection and smoking habits were the principal factors modulating together: the increase of aortic PWV and the reduction of the glomerular filtration rate (GFR). The latter renal parameter was also influenced by the donor age. Two main parameters were predictors of cardiovascular events: a past history of cardiovascular disease and the pulse pressure × heart rate product, the major mechanical consequence of increased PWV. Conclusion. In renal transplant subjects, tobacco consumption and mostly acute renal rejection modulate both aortic stiffness and chronic renal failure independent of blood pressure level and donor characteristics. Pulsatile stress mediates cardiovascular complications and predicts cardiovascular risk, particularly in the presence of increased heart rate.
Increased aortic pulse wave velocity (PWV) is an independent predictor of cardiovascular risk in subjects with hypertension [1] and in subjects with advanced renal failure [2]. Increased aortic PWV contributes, at any given value of mean blood pressure (MBP) to increase systolic blood pressure (SBP) and to decrease diastolic blood pressure (DBP), leading to an increase in pulse
pressure (PP). The SBP enhancement favors increased oxygen myocardial consumption and cardiac hypertrophy, while the DBP reduction alters the coronary perfusion and even creates myocardial ischemia. In addition increased PP may distort the material of the arterial wall, particularly when the number of pulsations per unit time (PP multiplied by heart rate) is increased [3, 4]. In subjects with advanced renal failure undergoing hemodialysis, increased aortic PWV has been shown to be, independently of blood pressure and mechanical stress, the stronger predictor of cardiovascular complications. In milder forms of renal insufficiency, renal function, judged by the formula of Cockcroft-Gault (expressed in mL/min/1.73 m2 and adjusted for gender), and aortic PWV are inversely related, independently of MBP and other conventional cardiovascular risk factors [5]. Few studies on the mechanical properties of large arteries have been reported in subjects with renal insufficiency who underwent kidney transplantation. However, it seems that alterations of arterial vessel wall structure and function persist after renal transplantation and they may contribute to the high cardiovascular morbidity and mortality observed in these patients [6, 7]. This finding is of major interest since large artery alterations, which are related to the classical cardiovascular risk factors, might also be related to the immunologic alterations accompanying renal transplantation in these patients. The purpose of the present study was (1) to evaluate large artery stiffness in subjects submitted to renal transplantation using the easy and reproducible measurement of aortic PWV, (2) to evaluate whether this large artery change was related to immunologic factors like acute renal rejection, the major predictor of long-term renal dysfunction in these patients, and (3) to determine whether, in this population, aortic PWV predicts cardiovascular risk.
Key words: pulse wave velocity, arterial stiffness, renal transplantation. Received for publication September 17, 2003 and in revised form November 23, 2003, February 25, 2004, and April 14, 2004 Accepted for publication May 11, 2004 C
METHODS Patients Between August 1992 and December 2001, 202 dialysis patients were transplanted at Rizk hospital (Beirut,
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Lebanon). Twelve patients died several years after transplantation, four of them from cardiovascular events. Twenty-one patients returned to dialysis and 29 were referred to their nephrologists for follow-up. The remaining patients were contacted and 106 accepted participation in the study. All of them were still dialysis free. The mean age at inclusion was 43.09 ± 14.05 years. The mean duration of transplantation at inclusion was 54.1 ± 29.2 months with a minimum of 6 months and a maximum of 118 months. One hundred and four patients had been on hemodialysis and two had been on peritoneal dialysis prior to transplantation, with a mean dialysis duration of 25.05 ± 28.7 months. The etiology of the renal disease was unknown in 54 patients (51%), adult polycystic kidney disease in 13 patients (12.3%), chronic pyelonephritis in 11 patients (10.4%), chronic glomeruloneohritis in eight patients (7.5%), IgA nephropathy in seven patients (6.6%), diabetic nephropathy in six patients (5.7%), systemic lupus erythematosis in three patients (2.8%), nephroangiosclerosis in two patients (1.9%) and other etiologies in two patients (1.9%). Forty-six patients (43.4%) received kidneys from living-related donors, 50 (47.2%) received kidneys from living unrelated donors, and 10 (9.4%) received kidneys from cadaveric donors. The donors were carefully evaluated prior to transplantation and only “ideal donors” were accepted [8, 9]. Exclusion criteria related to the donor included old age (>60 years), any history of hypertension, diabetes mellitus, cardiovascular disease, renal disease, connective tissue disease or any systemic illness, and cancer. The immunosuppression protocol consisted of a quadruple sequential therapy [10, 11] with cyclosporin started at a dose of 7 mg/kg/24 hours around the 3 to 4 days posttransplantation after the serum creatinine has decreased below 2 mg/dL. Prednisone, azathioprine, and antithymocyte globulins (ATG) were started at the evening, 1 day prior to transplantation from 1992 until the end of 1996. Since 1997, mycophenolate mofetil was used instead of azathioprine at induction [11]. Since 2000, only hyperimmunized patients or patients receiving a second renal transplant (five patients) are induced with ATG, in addition to prednisone, mycophenolate mofetil [12] and cyclosporin, while the rest are receiving a humanized monoclonal antibody directed against the interleukin-2 receptor, ZenapaxR [13, 14], 1 mg/kg as a single dose on the evening of the transplantation, repeated 7 days later and in some patients at day 14 posttransplantation. Eighty-eight patients (83%) had immediate diuresis and 18 (17%) had delayed diuresis. There was no primary graft failure. Forty-two patients (39.6%) developed at least one acute rejection episode with a total of 71 rejection episodes and a mean of 1.69 rejection episode per patient. Acute rejection was defined as a persistent rise in
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serum creatinine of at least 0.3 mg/dL with either biopsyproven or presumed acute rejection after having ruled out other causes of acute renal dysfunction like obstructive, vascular, and infectious etiologies. Thirty-four rejection episodes (48%) were pathologically confirmed and 37 (52%) were only presumed. Rejection episodes, whether presumed or biopsy-proven, were treated with steroids (3 successive days of 500 mg intravenous methylprednisolone followed by progressive tapering). Biopsyproven episodes which failed to respond to glucocorticoids (six episodes) were treated with ATG. Patients with presumed acute rejection unresponsive to glucocorticoids (four episodes) underwent renal graft biopsy for confirmation of the diagnosis before ATG was given. The mean rise in serum creatinine during the acute rejection episode (highest creatinine reached − baseline creatinine) was 1.2 mg/dL in the biopsy-proven group and 1.3 mg/dL in the presumed group. All the rejection episodes were successfully treated with resumption of baseline serum creatinine in a period of 10 days in 61 cases (episodes which responded to steroids) and near baseline (creatinine stabilized at baseline plus a mean of 0.5 mg/dL) in 10 episodes (glucocorticoid-resistant ones). The immunosuppressive medications taken at inclusion included prednisone (106 patients), cyclosporin (88 patients), mycophenolate mofetil (55 patients), azathioprine (48 patients), rapamune (13 patients), and tacrolimus (1 patient). Twelve patients (11.3%) had diabetes mellitus defined as a fasting blood glucose level >7 mmol/L or on the presence of antidiabetic medication (sulfonylurea, biguanide, and/or insulin). Fifty-one patients (48.1%) had hypertension defined as a SBP > 140 mm Hg and/or a DBP > 90 mm Hg, measured by mercury sphygmomanometer, in the supine position, with a minimum of three casual measurements during the last month, or when the patient was known to have hypertension and was treated for this reason with antihypertensive medications. Fifteen patients (14.2%) were on angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (Ang IIA) for treatment of posttransplant erythrocytosis or for renal protection in cases of biopsy-proven cyclosporin toxicity. The antihypertensive drugs included ACE inhibitors (34 patients), Ang IIA (13 patients), calcium channel blockers (six patients), beta blockers (18 patients), diuretics (four patients), and alpha blockers (one patient) either alone (N = 40 patients) or in combination (N = 23 patients). Twenty-six patients (24.5%) were receiving a statin at inclusion for hyperlipidemia and/or for its immunomodulator effect [15]. A cardiovascular event was considered whenever a clinical event had occurred at the coronary, cerebral, aortic, or peripheral levels. Nine patients (8.5%) developed one or more cardiovascular events at least 6 months after the renal transplantation with a total of 10 events.
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Table 1. Demographic data and standard laboratory analyses of the renal transplant patients
Age years
Entire population (N = 106)
Subjects with positive end point (N = 13)
Subjects with negative end point (N = 93)
43.09 ± 14.05
47.2 ± 17.7
42.5 ± 13.5
Gender Male 73 (68.9%) 9 (69.2%) Female 33 (31.1%) 4 (30.8%) Body mass index 26.07 ± 4.27 24.4 ± 4.7 kg/m2 Waist/hip ratio 0.96 ± 9.28 0.99 ± 10 arbitrary units Tobacco consumption 14.98 ± 29.3 17.1 ± 19.9 pack-years Fasting blood glucose 98.08 ± 20.87 95.8 ± 20.5 mg/dL Total cholesterol 218.04 ± 47.3 217.8 ± 33 mg/dL Total cholesterol/high- 4.14 ± 1.38 4.18 ± 1.2 density lipoprotein arbitrary units Triglycerides mg/dL 156.3 ± 94.8 147.3 ± 52.8 Glomerular filtration 73.1 ± 19.4 49.8 ± 21.6a rate Cockroft-Gault mL/min/1.73 m2
64 (68.8%) 29 (31.2%) 26.3 ± 4.2 0.96 ± 9.2 14.7 ± 30.5 98.2 ± 20.9 217.9 ± 48.4 4.13 ± 1.4 157.8 ± 98 75.2 ± 18.3
Values are expressed as means ± SD except for gender which is represented by the number and the percentage of patients. a < P 0.0001 vs. group with negative end point.
Seventeen patients (16%) had a past history of cardiovascular events (before transplantation) with a total of 22 events. Six patients of these developed a new event at least 6 months after renal transplantation. The serum creatinine concentration at discharge from the hospital immediately after renal transplantation was used for estimation of baseline renal function. Four patients had a serum creatinine at inclusion at least two times greater than that at baseline. In this study, the primary end point was the composite of at least a doubling of the baseline serum creatinine concentration and/or the occurrence of a new cardiovascular event at least 6 months after renal transplantation [16]. A total of 13 patients (12.3%) reached the primary end point during follow-up. Tables 1 to 3 indicate the baseline characteristics of the total renal transplant population as well as those of the two subgroups (with a positive and a negative end point). Each subject provided informed consent for the study. A questionnaire was filled for each patient and contained information related to the recipient and to his or her family in terms of family (first-degree relatives) history of premature cardiovascular events (<55 years in men and <60 years in women). The protocol was approved by the regular local ethical committee. Protocol The hemodynamic measurements were performed in the afternoon, each patient being in the supine position. Brachial blood pressure was measured with a mercury
Table 2. Hemodynamic and transplantation-related parameters of the renal transplant patients Entire population (N = 106) SBP brachial mm Hg DBP brachial mm Hg MBP brachial mm Hg PP brachial mm Hg Heart rate bpm PP × heart rate product mm Hg/beat/min Aortic PWV m/sec Transplant age months Warm ischemia time minutes Donor age years Dialysis duration months Creatinine at discharge mg/dL Acute rejection nb (%) T2 ng/mL Nephrectomy (native kidneys)
Subjects with Subjects with positive end negative end point (N = 13) point (N = 93)
121.3 ± 19.8 70 ± 12.5 87.1 ± 13.3 51.3 ± 16.3 78.7 ± 13.3 4054 ± 1513
129 ± 22.9 70.8 ± 17.4 90.3 ± 16.6 58.2 ± 16.6 87 ± 16.4a 5092 ± 2056b
120.2 ± 19.2 69.9 ± 11.8 86.7 ± 12.8 50.3 ± 15.4 77.5 ± 12.5 3909 ± 1374
11.13 ± 2.82 54.1 ± 29.2 21.4 ± 4.1
12.8 ± 4.3a 42.5 ± 18.2 22.7 ± 6.7
10.9 ± 2.5 38 ± 13.5 21.1 ± 3.6
38.8 ± 10.6 25.05 ± 28.7
38.6 ± 11.1 22.3 ± 16.5
38.8 ± 10.7 25.4 ± 30.1
1.18 ± 0.29
1.1 ± 0.25
1.2 ± 0.3
42 (39.6%)
8 (61.5%)
34 (36.6%)
445.7 ± 210.7 432.7 ± 191.4 27 (25.5%) 4 (30.8%)
447 ± 213.8 24 (25.8%)
Abbreviations are: SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure; bpm, beats per minute; PWV, pulse wave velocity; T2, serum cyclosporin level 2 hours after the morning dose. Values are expressed as mean ± SD except for acute rejection and nephrectomy of native kidneys which are expressed as the numbers and the percentages of patients. a < P 0.05 vs. group with negative end point. b < P 0.01 vs. group with negative end point.
Table 3. Multivariate analysis showing the variables independently associated with an increase in aortic PWV and those independently associated with a decrease in the glomerular filtration rate (GFR) (estimated by the formula of Cockcroft-Gault, expressed in mL/min/1.73 m2 and adjusted for gender) in the renal transplant patients Standard error of b
P value
Part of variance explained
9.37 7.46 1.15 0.02
1.72 1.6 0.44 8.3
<0.0001 <0.0001 0.01 0.025
26.7% 12.2% 4% 2.2%
−15.87 −0.63 −0.12
3.73 0.18 6.13
<0.0001 0.0005 0.058
13% 8.5% 3%
b Aortic PWV Age MBP Acute rejection Tobacco consumption GFR Acute rejection Donor age Tobacco consumption
Abbreviations are: b, regression coefficient; MBP, mean blood pressure; tobacco consumption expressed in pack-years.
sphygmomanometer after 15 minutes of rest. Phases I and V of the Korotkoff sounds were considered as SBP and DBP, respectively. The MBP was calculated from the following formula: DBP + (SBP − DBP)/3. PP was calculated as SBP-DBP. In each subject, the number of pulsations per unit time was calculated as PP multiplied by heart rate (PP × heart rate product). Five measurements 2 minutes apart were averaged.
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Statistical analysis Statistical analysis was performed on NCSS 6.0.21 software [21]. Descriptive statistics were used to evaluate the characteristics of the renal transplant patients. Hypertension, diabetes mellitus, as well as some other parameters, were used as dummy variables (e.g., 1, hypertensive patient; 0, normotensive patient). Simple regression was performed to evaluate linear associations between the hemodynamic parameters as PWV, the renal function parameters as the value of Cockcroft-Gault in mL/min/1.73 m2 (adjusted for gender), and the other biologic, morphologic, and therapeutic variables. All the parameters showing significant correlation with the PWV and/or the value of CockcroftGault (mL/min/1.73 m2 ), and those which are theoretically or historically related to theses two parameters were integrated in a stepwise regression analysis with backward elimination to determine the ones independently associated with a significant modification of the above parameters. The primary end point was the composite of at least a doubling of the baseline serum creatinine concentration and/or the occurrence of a new cardiovascular event at least 6 months after renal transplantation. To determine the parameters associated with the occurrence of the primary endpoint during the follow-up period, we used the proportional hazards regression analysis with the time variable being the follow-up time. All the parameters which were significantly correlated with the primary end point in the simple regression analysis, together with
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14 12 Aortic PWV, m/s
After blood pressure determination the aortic PWV was measured in a controlled environment at 22◦ C using an automatic device, the “Complior” (Colson, Paris, France). This method allows an online pulse wave recording and automatic calculation of the PWV. The validation of this method and its reproducibility has been previously reported, with an intraobserver and an interobserver repeatability coefficients of 0.935 and 0.890, respectively [17]. In our normotensive population, the mean value of carotid-femoral PWV in men (aged 14 to 77 years) was 8.7 ± 1.6 m/sec, and in women (aged 23 to 66 years) was 8.21 ± 1.26 m/sec [18]. Venous blood samples were obtained after an overnight fast. Laboratory tests included measurement of a complete lipid profile, blood urea nitrogen (BUN), creatinine, fasting blood sugar, and hemoglobin A 1c (HbA 1c ) (in diabetic subjects), and 24-hour urine collection for creatinine and protein. The formula of Cockroft-Gault was used for the estimation of the glomerular filtration rate (GFR) and was adjusted for gender (0.85 for females). The values were expressed in mL/min/1.73 m2 . Validation of the method has been published in detail elsewhere [19, 20].
10 8 6 4 2 0
Men with kidney graft
Normal Women Normal men with women controls kidney graft controls
73 renal transplant men, mean age = 44.44 ± 13.6 years 33 renal transplant women, mean age = 40.12 ± 14.8 years
74 normal men controls, mean age = 45.6 ± 14.3 years 60 normal women controls, mean age = 41.48 ± 10.94 years
Fig. 1. Aortic pulse wave velocity (PWV) in men and women with kidney graft compared to normal men and women controls of the same age (means ± SD). ∗∗∗ P < 0.0001.
those which are theoretically associated with the occurrence of the primary end point, were integrated in the proportional hazards regression analysis. Student t test was used for comparison of normally distributed variables between the two subgroups (patients who did not reach the primary end point and those who reached the primary end-point during the follow-up period). Dummy variables were compared between the two subgroups using the chi-square test. A value of P ≤ 0.05 was considered significant. RESULTS Tables 1 and 2 indicate successively in the studied population the demographic data and standard laboratory analyses (Table 1), and the hemodynamic and the transplantation-related parameters (Table 2), including the findings related to warm ischemia, donor age, acute rejection, and nephrectomy of native kidneys. The only parameters which differed significantly between the two groups (those who reached the primary end point and those who did not) were heart rate, PWV, and the PP × heart rate product (Table 2), pretransplant cardiovascular events (46.2% vs. 11.8% in the positive end point group vs. the negative end point group, respectively) (P < 0.01, data not shown), altered GFR (Table 1) and finally, drug treatment with aspirin (results not shown). Figure 1 shows that, compared to normotensive men and women of the same age, renal transplant patients had significantly higher carotid-femoral PWV (P < 0.0001 for both genders), despite the fact that men with kidney graft had slightly but significantly lower MBP compared to normal controls (87.8 ± 13.5 mm Hg vs. 94.5 ± 6.7 mm
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Table 4. Proportional hazards regression showing the parameters associated with the occurrence of a cardiovascular event at least 6 months after renal transplantation and/or doubling of serum creatinine
Model 1 Heart rate Aortic PWV Model 2 Heart rate × PP(b) Pretransplant cardiovascular events
b
Standard error of b
P value
Part of variance explained
7.16 0.25
0.02 9.16
0.001 0.006
16.6% 12.9%
3.7 1.16
1.6 0.6
0.02 0.04
9.3% 7.5%
Abbreviations are: b, regression coefficient; PWV, pulse wave velocity; PP(b), pulse pressure at the brachial level.
Hg, respectively) (P < 0.0001) and women with kidney graft had a tendency toward a lower MBP compared to their controls (85.7 ± 12.8 mm Hg vs. 89.4 ± 7 mm Hg, respectively) (P = 0.068). Stepwise regression analysis with backward elimination in renal transplant patients showed that in addition to age and MBP, PWV was influenced by only two factors: presence of acute rejection and increased tobacco consumption (Table 3). The same factors influenced the decrease in GFR (Table 3) observed after transplantation. The decrease in GFR was also independently influenced by the age of the donor. Transplantation-related parameters, other than acute renal rejection, were not associated with a significant modification of the aortic PWV in the renal transplant patients. Specifically, the graft age, the warm ischemia time, the type of diuresis (immediate vs. delayed), the pretransplant dialysis duration, the serum creatinine at discharge and at the enrollment, and the immunosuppressive drugs, mainly calcineurin inhibitors (represented as the dose at inclusion in mg/kg/24 hours and as the total cumulative dose), did not show any significant association with the PWV either in univariate or in multivariate analysis. In addition, an increase in serum creatinine, whether secondary to acute rejection, chronic allograft nephropathy, recurrence of the basic renal disease, or to any other etiology, was not associated with a significant modification in the aortic PWV. Finally, the occurrence of renal and/or cardiovascular events following transplantation was influenced by two factors: heart rate (P < 0.001) and PWV (P < 0.006) (Table 4). When PP was multiplied by heart rate, this product was a significant (P < 0.02) and independent factor influencing cardiovascular events in transplanted patients, in addition to a past history of cardiovascular events (P < 0.04). DISCUSSION The salient finding in this study of renal transplant patients in their middle age was that aortic PWV was increased, compared to normal controls of the same age,
despite a lower MBP in the renal transplant group. Furthermore, independent of age and blood pressure level, increased PWV was influenced by increased tobacco consumption and acute renal rejection, two factors also implicated in the mechanism of GFR reduction. The latter was also influenced by another independent factor, the donor age. Finally, increased PWV, mainly through its consequences on PP and mostly the PP × heart rate product, might influence cardiovascular events during the follow-up. In the present study, we used PWV as a marker of aortic stiffness, since it is related to the square root of the elasticity modulus and to the thickness/radius ratio [4]. The PWV, determined from foot-to-foot transit time in the aorta, offers a simple, reproducible, and noninvasive evaluation of regional aortic stiffness. Since the principal factors modulating the level of PWV are age and blood pressure, studies using PWV should adjust the values obtained to these two parameters, as we did [18, 22, 23]. Our results showed that in addition to recipient age and MBP, PWV in renal transplant patients was mainly influenced by tobacco consumption and acute renal rejection. Other parameters like donor age, the presence in the recipient of diabetes mellitus and/or hyperlipidemia, and the kind of antihypertensive medications were not associated with a significant modification of the aortic PWV. Chronic allograft nephropathy, the major predictor of long-term allograft dysfunction, may be secondary to antigen-dependent and/or to antigen-independent mechanisms [24, 25]. In the present study, both factors were involved, including age of donor, smoking, and acute renal rejection. The major finding of this investigation was that the two latter factors were the same factors that influenced PWV. Increased tobacco consumption is a classical cardiovascular risk factor, the role of which is well established for cancer and atherosclerosis, mainly of the lower limbs and of the coronary arteries. To our knowledge, this study is the first involving tobacco consumption and acute rejection in both the prognosis of renal function and increased PWV in renal transplant patients. Regarding acute renal rejection (biopsy-proven in 48% and not documented by biopsy in 52% of the cases), it is the first time, to our knowledge, that this immunologic alteration has been found to be associated with increased PWV, independent of serum creatinine. Acute rejection might be responsible for both renal insufficiency and changes of large artery stiffness. This association is not unexpected since the immunologic changes induced by the presence of the graft might be observed at the site of large vessels, as previously reported in cardiac transplants [26]. In renal transplant patients, although increased PWV and renal insufficiency are associated factors, it does not seem likely that MBP or associated cardiovascular risk factors (diabetes, hypercholesterolemia, increased tobacco consumption) or even the presence of native kidneys may
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be a common denominator. Such an association has been already observed in subjects with advanced renal failure and even in patients with mild renal insufficiency (i.e., in the total absence of renal graft [5]). Taken together, all these findings indicate that, in chronic kidney diseases of various origins, renal dysfunction may be associated not only with arteriolar but also with large artery changes, independently of mechanical stress and the presence of atherosclerosis [5]. In this report, we found that old donor age was associated with lower long-term graft survival. The decrease of renal graft survival as function of donor age is usually explained by reduced functional reserve in transplanted kidneys, making them more vulnerable during procurement, rejection, and even calcineurin inhibitor exposure [27–29]. Another hypothesis could be that the cardiovascular risk factors which characterize the donor influence independently kidney reserve and thus contribute to the developpement of chronic renal insufficiency. However, this hypothesis has never been tested clinically. In subjects with advanced renal failure, it has been shown that the major predictors of cardiovascular complications were a past history of cardiovascular diseases and mostly an increase of aortic PWV [2]. In subjects with renal transplants, the cardiovascular complications are less severe than in patients with end-stage renal disease (ESRD) [30, 31]. In this study, we showed that increased PWV was a major cardiovascular predictor, as it was previously shown for reduced carotid arterial distensibility [6]. Transplantation-related parameters, specifically dialysis duration, the age of the graft, and the immunosuppressive medications were not associated with a modification of the hemodynamic parameters and were not predictors of cardiovascular events in our study. Increased heart rate, a classical index of cardiovascular risk [32], seemed to be of better predictive value. Indeed tachycardia is frequent in renal transplants, particularly in the presence of the native kidneys and of drug treatment by cyclosporin or tacrolimus [33, 34]. However, in the present study, the most interesting parameter to consider for cardiovascular risk was the PP × heart rate product, which represents in each individual the magnitude of pulsatile stress on the arterial wall per unit time. On the basis of animal and human studies [3, 35, 36], pulsatile stress, more than steady stress, is susceptable to distort the arterial wall and to promote arteriosclerosis, thus favoring cardiovascular complications. In this context, increased heart rate is important to consider per se in the mechanism of increased pulsatility [4]. Enhanced activity of the autonomic nervous system is a characteristic feature in numerous subjects with renal transplants [33]. CONCLUSION The present study has shown that increased PWV was a distinct feature in subjects submitted to renal transplan-
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tation. Independent of age and MBP, increased PWV is influenced by increased tobacco consumption and mostly by acute renal rejection, the principal predictive factor of renal insufficiency during long-term follow-up. Cardiovascular risk is directly related to increased PWV and to increased pulsatility on the arterial wall whether through an increase in the heart rate or in the PP × heart rate product. Long-term studies in larger populations are needed to evaluate whether cardiovascular risk results from immunologic or non immunologic alterations or, more probably, from their combination. In addition, whether immunomodulation or sympathetic nervous system blockade could affect the cardiovascular outcome in renal transplant patients remains to be addressed. ACKNOWLEDGMENT This study was performed with the help of “CEDRE” (Cooperation ´ pour l’Evaluation et le Developpement ´ de la Recherche): The FrancoLebanese scientific collaboration. In addition, we thank Mrs. Veronique ´ Labro and Miss Farida Younan for their excellent assistance. Reprint requests to Profressor Michel E. Safar, Centre de Diagnostic, ˆ ˆ Hopital Hotel-Dieu, 1, place du Parvis Notre Dame, 75181 Paris Cedex 04, France. E-mail: [email protected]
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with daclizumab prophylaxis for prevention of acute rejection after renal transplantation. Transplantation 72:839–845, 2001 KWAK B, MULHAUPT F, MYIT S, MACH F: Statins as a newly recognized type of immunomodulator. Nat Med 6:1399–1402, 2000 CARVALHO MF, SOARES V: Hyperlipidemia as a risk factor of renal allograft function impairment. Clin Transplant 15:48–52, 2001 ASMAR R, BENETOS A, TOPOUCHIAN J, et al: Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies. Hypertension 26:485–490, 1995 ASMAR R, BENETOS A, LONDON G, et al: Aortic distensibility in normotensive, untreated and treated hypertensive patients. Blood Press 4:48–54, 1995 LEVEY AS, BOSCH JP, LEWIS JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461–470, 1999 AOUN S, BLACHER J, SAFAR ME, MOURAD JJ: Diabetes mellitus and renal failure: Effects on large artery stiffness. J Hum Hypertens 15: 693–700, 2001 HINTZE JL: Number Cruncher Statistical System 1995, User Manual, Statistical Solutions Limited, Ireland, November 1995 BENETOS A, ASMAR R, GAUTIER S, et al: Heterogeneity of the arterial tree in essential hypertension: A noninvasive study of the terminal aorta and the common carotid artery. J Hum Hypertens 8:501–507, 1994 AVOLIO AP, DENG FQ, LI WQ, et al: Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: Comparison between urban and rural communities in China. Circulation 71:202–210, 1985 ¨ ¨ K, KOSKINEN P, HAYRY LEMSTROM P: Molecular mechanisms of chronic renal allograft rejection. Kidney Int 48(Suppl 52):S2–S10, 1995 ¨ ¨ K, et al: Molecular biology of chronic HAYRY P, YILMAZ S, LEMSTROM rejection and predictive value of biopsies, in Solid Organ Transplant Rejection: Mechanisms, Pathology, and Diagnosis, edited by Solez
26. 27. 28. 29. 30. 31. 32. 33.
34. 35. 36.
K, Racusen LC, Billingham ME, New York, Marcel Dekker Inc., 1996, pp 77–106 FUJITA M, RUSSELL ME, MASEK MA, et al: Graft vascular disease in the great vessels and vasa vasorum. Hum Pathol 24:1067–1072, 1993 RAMOS E, AOUN S, HARMON WE: Expanding the donor pool: Effect on graft outcome. J Am Soc Nephrol 13:2590–2599, 2002 USLU A, TOKAT Y, OK E, et al: Impact of extreme donor age on the outcome of living-related donor kidney transplantation. Transplant Proc 30:734–737, 1998 ABDI R, SLAKEY D, KITTUR D, et al: Baseline glomerular size as a predictor of function in human renal transplantation. Transplantation 66:329–333, 1998 KASISKE BL, GUIJARRO C, MASSY ZA, et al: Cardiovascular disease after renal transplantation. J Am Soc Nephrol 7:158–165, 1996 LEVEY AS: Controlling the epidemic of cardiovascular disease in chronic renal disease: Where do we start? Am J Kidney Dis 32 (5 Suppl 3):S5–S13, 1998 KANNEL W, KANNEL C, PAFFENBARGER R, CUPPLES LA: Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 113:1489–1494, 1987 KOSCH M, BARENBROCK M, KISTERS K, et al: Relationship between muscle sympathetic nerve activity and large artery mechanical vessel wall properties in renal transplant patients. J Hypertens 20:501– 508, 2002 LUCINI D, MILANI RV, VENTURA HO, et al: Study of arterial and autonomic effects of cyclosporin in humans. Hypertension 35:1258– 1263, 2000 DARNE´ B, GIRERD X, SAFAR ME, et al: Pulsatile versus steady component of blood pressure: A cross-sectional and a prospective analysis on cardiovascular mortality. Hypertension 13:392–400, 1989 KU DN, GIDDENS DP, ZARINS CK, GLAGOV S: Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis 5:293–302, 1985
Aortic pulse wave velocity in renal transplant patients SOLA AOUN BAHOUS, ANTOINE STEPHAN, WADAD BARAKAT, JACQUES BLACHER, ROLAND ASMAR, and MICHEL E. SAFAR ˆ ˆ Nephrology and Transplantation Center, Rizk Hospital, Beirut Lebanon; Centre de Diagnostic, Hopital Hotel-Dieu, Paris, France; and L’Institut Cardio-Vasculaire, Clinique Mozart, Paris, France
Aortic pulse wave velocity in renal transplant patients. Background. In subjects with end-stage renal disease (ESRD) undergoing hemodialysis, aortic pulse wave velocity (PWV) is increased independently of blood pressure level and mostly is a strong predictor of cardiovascular risk. Few studies on this subject have been performed in renal transplant patients. Methods. Aortic PWV was determined noninvasively in 106 patients with kidney transplantation and treated using a standard immunosuppression protocol. Mean age was 43 ± 14 years. During the follow-up period (mean duration 54.3 ± 28.9 months), the following parameters were studied: characteristics of the renal graft, degree of renal insufficiency, number of acute rejections, cardiovascular risk factors, drug medications, and cardiovascular complications. Results. Aortic PWV was increased in subjects with renal transplants independently of age and mean blood pressure. Acute renal rejection and smoking habits were the principal factors modulating together: the increase of aortic PWV and the reduction of the glomerular filtration rate (GFR). The latter renal parameter was also influenced by the donor age. Two main parameters were predictors of cardiovascular events: a past history of cardiovascular disease and the pulse pressure × heart rate product, the major mechanical consequence of increased PWV. Conclusion. In renal transplant subjects, tobacco consumption and mostly acute renal rejection modulate both aortic stiffness and chronic renal failure independent of blood pressure level and donor characteristics. Pulsatile stress mediates cardiovascular complications and predicts cardiovascular risk, particularly in the presence of increased heart rate.
Increased aortic pulse wave velocity (PWV) is an independent predictor of cardiovascular risk in subjects with hypertension [1] and in subjects with advanced renal failure [2]. Increased aortic PWV contributes, at any given value of mean blood pressure (MBP) to increase systolic blood pressure (SBP) and to decrease diastolic blood pressure (DBP), leading to an increase in pulse
pressure (PP). The SBP enhancement favors increased oxygen myocardial consumption and cardiac hypertrophy, while the DBP reduction alters the coronary perfusion and even creates myocardial ischemia. In addition increased PP may distort the material of the arterial wall, particularly when the number of pulsations per unit time (PP multiplied by heart rate) is increased [3, 4]. In subjects with advanced renal failure undergoing hemodialysis, increased aortic PWV has been shown to be, independently of blood pressure and mechanical stress, the stronger predictor of cardiovascular complications. In milder forms of renal insufficiency, renal function, judged by the formula of Cockcroft-Gault (expressed in mL/min/1.73 m2 and adjusted for gender), and aortic PWV are inversely related, independently of MBP and other conventional cardiovascular risk factors [5]. Few studies on the mechanical properties of large arteries have been reported in subjects with renal insufficiency who underwent kidney transplantation. However, it seems that alterations of arterial vessel wall structure and function persist after renal transplantation and they may contribute to the high cardiovascular morbidity and mortality observed in these patients [6, 7]. This finding is of major interest since large artery alterations, which are related to the classical cardiovascular risk factors, might also be related to the immunologic alterations accompanying renal transplantation in these patients. The purpose of the present study was (1) to evaluate large artery stiffness in subjects submitted to renal transplantation using the easy and reproducible measurement of aortic PWV, (2) to evaluate whether this large artery change was related to immunologic factors like acute renal rejection, the major predictor of long-term renal dysfunction in these patients, and (3) to determine whether, in this population, aortic PWV predicts cardiovascular risk.
Key words: pulse wave velocity, arterial stiffness, renal transplantation. Received for publication September 17, 2003 and in revised form November 23, 2003, February 25, 2004, and April 14, 2004 Accepted for publication May 11, 2004 C
METHODS Patients Between August 1992 and December 2001, 202 dialysis patients were transplanted at Rizk hospital (Beirut,
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Lebanon). Twelve patients died several years after transplantation, four of them from cardiovascular events. Twenty-one patients returned to dialysis and 29 were referred to their nephrologists for follow-up. The remaining patients were contacted and 106 accepted participation in the study. All of them were still dialysis free. The mean age at inclusion was 43.09 ± 14.05 years. The mean duration of transplantation at inclusion was 54.1 ± 29.2 months with a minimum of 6 months and a maximum of 118 months. One hundred and four patients had been on hemodialysis and two had been on peritoneal dialysis prior to transplantation, with a mean dialysis duration of 25.05 ± 28.7 months. The etiology of the renal disease was unknown in 54 patients (51%), adult polycystic kidney disease in 13 patients (12.3%), chronic pyelonephritis in 11 patients (10.4%), chronic glomeruloneohritis in eight patients (7.5%), IgA nephropathy in seven patients (6.6%), diabetic nephropathy in six patients (5.7%), systemic lupus erythematosis in three patients (2.8%), nephroangiosclerosis in two patients (1.9%) and other etiologies in two patients (1.9%). Forty-six patients (43.4%) received kidneys from living-related donors, 50 (47.2%) received kidneys from living unrelated donors, and 10 (9.4%) received kidneys from cadaveric donors. The donors were carefully evaluated prior to transplantation and only “ideal donors” were accepted [8, 9]. Exclusion criteria related to the donor included old age (>60 years), any history of hypertension, diabetes mellitus, cardiovascular disease, renal disease, connective tissue disease or any systemic illness, and cancer. The immunosuppression protocol consisted of a quadruple sequential therapy [10, 11] with cyclosporin started at a dose of 7 mg/kg/24 hours around the 3 to 4 days posttransplantation after the serum creatinine has decreased below 2 mg/dL. Prednisone, azathioprine, and antithymocyte globulins (ATG) were started at the evening, 1 day prior to transplantation from 1992 until the end of 1996. Since 1997, mycophenolate mofetil was used instead of azathioprine at induction [11]. Since 2000, only hyperimmunized patients or patients receiving a second renal transplant (five patients) are induced with ATG, in addition to prednisone, mycophenolate mofetil [12] and cyclosporin, while the rest are receiving a humanized monoclonal antibody directed against the interleukin-2 receptor, ZenapaxR [13, 14], 1 mg/kg as a single dose on the evening of the transplantation, repeated 7 days later and in some patients at day 14 posttransplantation. Eighty-eight patients (83%) had immediate diuresis and 18 (17%) had delayed diuresis. There was no primary graft failure. Forty-two patients (39.6%) developed at least one acute rejection episode with a total of 71 rejection episodes and a mean of 1.69 rejection episode per patient. Acute rejection was defined as a persistent rise in
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serum creatinine of at least 0.3 mg/dL with either biopsyproven or presumed acute rejection after having ruled out other causes of acute renal dysfunction like obstructive, vascular, and infectious etiologies. Thirty-four rejection episodes (48%) were pathologically confirmed and 37 (52%) were only presumed. Rejection episodes, whether presumed or biopsy-proven, were treated with steroids (3 successive days of 500 mg intravenous methylprednisolone followed by progressive tapering). Biopsyproven episodes which failed to respond to glucocorticoids (six episodes) were treated with ATG. Patients with presumed acute rejection unresponsive to glucocorticoids (four episodes) underwent renal graft biopsy for confirmation of the diagnosis before ATG was given. The mean rise in serum creatinine during the acute rejection episode (highest creatinine reached − baseline creatinine) was 1.2 mg/dL in the biopsy-proven group and 1.3 mg/dL in the presumed group. All the rejection episodes were successfully treated with resumption of baseline serum creatinine in a period of 10 days in 61 cases (episodes which responded to steroids) and near baseline (creatinine stabilized at baseline plus a mean of 0.5 mg/dL) in 10 episodes (glucocorticoid-resistant ones). The immunosuppressive medications taken at inclusion included prednisone (106 patients), cyclosporin (88 patients), mycophenolate mofetil (55 patients), azathioprine (48 patients), rapamune (13 patients), and tacrolimus (1 patient). Twelve patients (11.3%) had diabetes mellitus defined as a fasting blood glucose level >7 mmol/L or on the presence of antidiabetic medication (sulfonylurea, biguanide, and/or insulin). Fifty-one patients (48.1%) had hypertension defined as a SBP > 140 mm Hg and/or a DBP > 90 mm Hg, measured by mercury sphygmomanometer, in the supine position, with a minimum of three casual measurements during the last month, or when the patient was known to have hypertension and was treated for this reason with antihypertensive medications. Fifteen patients (14.2%) were on angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (Ang IIA) for treatment of posttransplant erythrocytosis or for renal protection in cases of biopsy-proven cyclosporin toxicity. The antihypertensive drugs included ACE inhibitors (34 patients), Ang IIA (13 patients), calcium channel blockers (six patients), beta blockers (18 patients), diuretics (four patients), and alpha blockers (one patient) either alone (N = 40 patients) or in combination (N = 23 patients). Twenty-six patients (24.5%) were receiving a statin at inclusion for hyperlipidemia and/or for its immunomodulator effect [15]. A cardiovascular event was considered whenever a clinical event had occurred at the coronary, cerebral, aortic, or peripheral levels. Nine patients (8.5%) developed one or more cardiovascular events at least 6 months after the renal transplantation with a total of 10 events.
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Table 1. Demographic data and standard laboratory analyses of the renal transplant patients
Age years
Entire population (N = 106)
Subjects with positive end point (N = 13)
Subjects with negative end point (N = 93)
43.09 ± 14.05
47.2 ± 17.7
42.5 ± 13.5
Gender Male 73 (68.9%) 9 (69.2%) Female 33 (31.1%) 4 (30.8%) Body mass index 26.07 ± 4.27 24.4 ± 4.7 kg/m2 Waist/hip ratio 0.96 ± 9.28 0.99 ± 10 arbitrary units Tobacco consumption 14.98 ± 29.3 17.1 ± 19.9 pack-years Fasting blood glucose 98.08 ± 20.87 95.8 ± 20.5 mg/dL Total cholesterol 218.04 ± 47.3 217.8 ± 33 mg/dL Total cholesterol/high- 4.14 ± 1.38 4.18 ± 1.2 density lipoprotein arbitrary units Triglycerides mg/dL 156.3 ± 94.8 147.3 ± 52.8 Glomerular filtration 73.1 ± 19.4 49.8 ± 21.6a rate Cockroft-Gault mL/min/1.73 m2
64 (68.8%) 29 (31.2%) 26.3 ± 4.2 0.96 ± 9.2 14.7 ± 30.5 98.2 ± 20.9 217.9 ± 48.4 4.13 ± 1.4 157.8 ± 98 75.2 ± 18.3
Values are expressed as means ± SD except for gender which is represented by the number and the percentage of patients. a < P 0.0001 vs. group with negative end point.
Seventeen patients (16%) had a past history of cardiovascular events (before transplantation) with a total of 22 events. Six patients of these developed a new event at least 6 months after renal transplantation. The serum creatinine concentration at discharge from the hospital immediately after renal transplantation was used for estimation of baseline renal function. Four patients had a serum creatinine at inclusion at least two times greater than that at baseline. In this study, the primary end point was the composite of at least a doubling of the baseline serum creatinine concentration and/or the occurrence of a new cardiovascular event at least 6 months after renal transplantation [16]. A total of 13 patients (12.3%) reached the primary end point during follow-up. Tables 1 to 3 indicate the baseline characteristics of the total renal transplant population as well as those of the two subgroups (with a positive and a negative end point). Each subject provided informed consent for the study. A questionnaire was filled for each patient and contained information related to the recipient and to his or her family in terms of family (first-degree relatives) history of premature cardiovascular events (<55 years in men and <60 years in women). The protocol was approved by the regular local ethical committee. Protocol The hemodynamic measurements were performed in the afternoon, each patient being in the supine position. Brachial blood pressure was measured with a mercury
Table 2. Hemodynamic and transplantation-related parameters of the renal transplant patients Entire population (N = 106) SBP brachial mm Hg DBP brachial mm Hg MBP brachial mm Hg PP brachial mm Hg Heart rate bpm PP × heart rate product mm Hg/beat/min Aortic PWV m/sec Transplant age months Warm ischemia time minutes Donor age years Dialysis duration months Creatinine at discharge mg/dL Acute rejection nb (%) T2 ng/mL Nephrectomy (native kidneys)
Subjects with Subjects with positive end negative end point (N = 13) point (N = 93)
121.3 ± 19.8 70 ± 12.5 87.1 ± 13.3 51.3 ± 16.3 78.7 ± 13.3 4054 ± 1513
129 ± 22.9 70.8 ± 17.4 90.3 ± 16.6 58.2 ± 16.6 87 ± 16.4a 5092 ± 2056b
120.2 ± 19.2 69.9 ± 11.8 86.7 ± 12.8 50.3 ± 15.4 77.5 ± 12.5 3909 ± 1374
11.13 ± 2.82 54.1 ± 29.2 21.4 ± 4.1
12.8 ± 4.3a 42.5 ± 18.2 22.7 ± 6.7
10.9 ± 2.5 38 ± 13.5 21.1 ± 3.6
38.8 ± 10.6 25.05 ± 28.7
38.6 ± 11.1 22.3 ± 16.5
38.8 ± 10.7 25.4 ± 30.1
1.18 ± 0.29
1.1 ± 0.25
1.2 ± 0.3
42 (39.6%)
8 (61.5%)
34 (36.6%)
445.7 ± 210.7 432.7 ± 191.4 27 (25.5%) 4 (30.8%)
447 ± 213.8 24 (25.8%)
Abbreviations are: SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure; bpm, beats per minute; PWV, pulse wave velocity; T2, serum cyclosporin level 2 hours after the morning dose. Values are expressed as mean ± SD except for acute rejection and nephrectomy of native kidneys which are expressed as the numbers and the percentages of patients. a < P 0.05 vs. group with negative end point. b < P 0.01 vs. group with negative end point.
Table 3. Multivariate analysis showing the variables independently associated with an increase in aortic PWV and those independently associated with a decrease in the glomerular filtration rate (GFR) (estimated by the formula of Cockcroft-Gault, expressed in mL/min/1.73 m2 and adjusted for gender) in the renal transplant patients Standard error of b
P value
Part of variance explained
9.37 7.46 1.15 0.02
1.72 1.6 0.44 8.3
<0.0001 <0.0001 0.01 0.025
26.7% 12.2% 4% 2.2%
−15.87 −0.63 −0.12
3.73 0.18 6.13
<0.0001 0.0005 0.058
13% 8.5% 3%
b Aortic PWV Age MBP Acute rejection Tobacco consumption GFR Acute rejection Donor age Tobacco consumption
Abbreviations are: b, regression coefficient; MBP, mean blood pressure; tobacco consumption expressed in pack-years.
sphygmomanometer after 15 minutes of rest. Phases I and V of the Korotkoff sounds were considered as SBP and DBP, respectively. The MBP was calculated from the following formula: DBP + (SBP − DBP)/3. PP was calculated as SBP-DBP. In each subject, the number of pulsations per unit time was calculated as PP multiplied by heart rate (PP × heart rate product). Five measurements 2 minutes apart were averaged.
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Statistical analysis Statistical analysis was performed on NCSS 6.0.21 software [21]. Descriptive statistics were used to evaluate the characteristics of the renal transplant patients. Hypertension, diabetes mellitus, as well as some other parameters, were used as dummy variables (e.g., 1, hypertensive patient; 0, normotensive patient). Simple regression was performed to evaluate linear associations between the hemodynamic parameters as PWV, the renal function parameters as the value of Cockcroft-Gault in mL/min/1.73 m2 (adjusted for gender), and the other biologic, morphologic, and therapeutic variables. All the parameters showing significant correlation with the PWV and/or the value of CockcroftGault (mL/min/1.73 m2 ), and those which are theoretically or historically related to theses two parameters were integrated in a stepwise regression analysis with backward elimination to determine the ones independently associated with a significant modification of the above parameters. The primary end point was the composite of at least a doubling of the baseline serum creatinine concentration and/or the occurrence of a new cardiovascular event at least 6 months after renal transplantation. To determine the parameters associated with the occurrence of the primary endpoint during the follow-up period, we used the proportional hazards regression analysis with the time variable being the follow-up time. All the parameters which were significantly correlated with the primary end point in the simple regression analysis, together with
16
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14 12 Aortic PWV, m/s
After blood pressure determination the aortic PWV was measured in a controlled environment at 22◦ C using an automatic device, the “Complior” (Colson, Paris, France). This method allows an online pulse wave recording and automatic calculation of the PWV. The validation of this method and its reproducibility has been previously reported, with an intraobserver and an interobserver repeatability coefficients of 0.935 and 0.890, respectively [17]. In our normotensive population, the mean value of carotid-femoral PWV in men (aged 14 to 77 years) was 8.7 ± 1.6 m/sec, and in women (aged 23 to 66 years) was 8.21 ± 1.26 m/sec [18]. Venous blood samples were obtained after an overnight fast. Laboratory tests included measurement of a complete lipid profile, blood urea nitrogen (BUN), creatinine, fasting blood sugar, and hemoglobin A 1c (HbA 1c ) (in diabetic subjects), and 24-hour urine collection for creatinine and protein. The formula of Cockroft-Gault was used for the estimation of the glomerular filtration rate (GFR) and was adjusted for gender (0.85 for females). The values were expressed in mL/min/1.73 m2 . Validation of the method has been published in detail elsewhere [19, 20].
10 8 6 4 2 0
Men with kidney graft
Normal Women Normal men with women controls kidney graft controls
73 renal transplant men, mean age = 44.44 ± 13.6 years 33 renal transplant women, mean age = 40.12 ± 14.8 years
74 normal men controls, mean age = 45.6 ± 14.3 years 60 normal women controls, mean age = 41.48 ± 10.94 years
Fig. 1. Aortic pulse wave velocity (PWV) in men and women with kidney graft compared to normal men and women controls of the same age (means ± SD). ∗∗∗ P < 0.0001.
those which are theoretically associated with the occurrence of the primary end point, were integrated in the proportional hazards regression analysis. Student t test was used for comparison of normally distributed variables between the two subgroups (patients who did not reach the primary end point and those who reached the primary end-point during the follow-up period). Dummy variables were compared between the two subgroups using the chi-square test. A value of P ≤ 0.05 was considered significant. RESULTS Tables 1 and 2 indicate successively in the studied population the demographic data and standard laboratory analyses (Table 1), and the hemodynamic and the transplantation-related parameters (Table 2), including the findings related to warm ischemia, donor age, acute rejection, and nephrectomy of native kidneys. The only parameters which differed significantly between the two groups (those who reached the primary end point and those who did not) were heart rate, PWV, and the PP × heart rate product (Table 2), pretransplant cardiovascular events (46.2% vs. 11.8% in the positive end point group vs. the negative end point group, respectively) (P < 0.01, data not shown), altered GFR (Table 1) and finally, drug treatment with aspirin (results not shown). Figure 1 shows that, compared to normotensive men and women of the same age, renal transplant patients had significantly higher carotid-femoral PWV (P < 0.0001 for both genders), despite the fact that men with kidney graft had slightly but significantly lower MBP compared to normal controls (87.8 ± 13.5 mm Hg vs. 94.5 ± 6.7 mm
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Table 4. Proportional hazards regression showing the parameters associated with the occurrence of a cardiovascular event at least 6 months after renal transplantation and/or doubling of serum creatinine
Model 1 Heart rate Aortic PWV Model 2 Heart rate × PP(b) Pretransplant cardiovascular events
b
Standard error of b
P value
Part of variance explained
7.16 0.25
0.02 9.16
0.001 0.006
16.6% 12.9%
3.7 1.16
1.6 0.6
0.02 0.04
9.3% 7.5%
Abbreviations are: b, regression coefficient; PWV, pulse wave velocity; PP(b), pulse pressure at the brachial level.
Hg, respectively) (P < 0.0001) and women with kidney graft had a tendency toward a lower MBP compared to their controls (85.7 ± 12.8 mm Hg vs. 89.4 ± 7 mm Hg, respectively) (P = 0.068). Stepwise regression analysis with backward elimination in renal transplant patients showed that in addition to age and MBP, PWV was influenced by only two factors: presence of acute rejection and increased tobacco consumption (Table 3). The same factors influenced the decrease in GFR (Table 3) observed after transplantation. The decrease in GFR was also independently influenced by the age of the donor. Transplantation-related parameters, other than acute renal rejection, were not associated with a significant modification of the aortic PWV in the renal transplant patients. Specifically, the graft age, the warm ischemia time, the type of diuresis (immediate vs. delayed), the pretransplant dialysis duration, the serum creatinine at discharge and at the enrollment, and the immunosuppressive drugs, mainly calcineurin inhibitors (represented as the dose at inclusion in mg/kg/24 hours and as the total cumulative dose), did not show any significant association with the PWV either in univariate or in multivariate analysis. In addition, an increase in serum creatinine, whether secondary to acute rejection, chronic allograft nephropathy, recurrence of the basic renal disease, or to any other etiology, was not associated with a significant modification in the aortic PWV. Finally, the occurrence of renal and/or cardiovascular events following transplantation was influenced by two factors: heart rate (P < 0.001) and PWV (P < 0.006) (Table 4). When PP was multiplied by heart rate, this product was a significant (P < 0.02) and independent factor influencing cardiovascular events in transplanted patients, in addition to a past history of cardiovascular events (P < 0.04). DISCUSSION The salient finding in this study of renal transplant patients in their middle age was that aortic PWV was increased, compared to normal controls of the same age,
despite a lower MBP in the renal transplant group. Furthermore, independent of age and blood pressure level, increased PWV was influenced by increased tobacco consumption and acute renal rejection, two factors also implicated in the mechanism of GFR reduction. The latter was also influenced by another independent factor, the donor age. Finally, increased PWV, mainly through its consequences on PP and mostly the PP × heart rate product, might influence cardiovascular events during the follow-up. In the present study, we used PWV as a marker of aortic stiffness, since it is related to the square root of the elasticity modulus and to the thickness/radius ratio [4]. The PWV, determined from foot-to-foot transit time in the aorta, offers a simple, reproducible, and noninvasive evaluation of regional aortic stiffness. Since the principal factors modulating the level of PWV are age and blood pressure, studies using PWV should adjust the values obtained to these two parameters, as we did [18, 22, 23]. Our results showed that in addition to recipient age and MBP, PWV in renal transplant patients was mainly influenced by tobacco consumption and acute renal rejection. Other parameters like donor age, the presence in the recipient of diabetes mellitus and/or hyperlipidemia, and the kind of antihypertensive medications were not associated with a significant modification of the aortic PWV. Chronic allograft nephropathy, the major predictor of long-term allograft dysfunction, may be secondary to antigen-dependent and/or to antigen-independent mechanisms [24, 25]. In the present study, both factors were involved, including age of donor, smoking, and acute renal rejection. The major finding of this investigation was that the two latter factors were the same factors that influenced PWV. Increased tobacco consumption is a classical cardiovascular risk factor, the role of which is well established for cancer and atherosclerosis, mainly of the lower limbs and of the coronary arteries. To our knowledge, this study is the first involving tobacco consumption and acute rejection in both the prognosis of renal function and increased PWV in renal transplant patients. Regarding acute renal rejection (biopsy-proven in 48% and not documented by biopsy in 52% of the cases), it is the first time, to our knowledge, that this immunologic alteration has been found to be associated with increased PWV, independent of serum creatinine. Acute rejection might be responsible for both renal insufficiency and changes of large artery stiffness. This association is not unexpected since the immunologic changes induced by the presence of the graft might be observed at the site of large vessels, as previously reported in cardiac transplants [26]. In renal transplant patients, although increased PWV and renal insufficiency are associated factors, it does not seem likely that MBP or associated cardiovascular risk factors (diabetes, hypercholesterolemia, increased tobacco consumption) or even the presence of native kidneys may
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be a common denominator. Such an association has been already observed in subjects with advanced renal failure and even in patients with mild renal insufficiency (i.e., in the total absence of renal graft [5]). Taken together, all these findings indicate that, in chronic kidney diseases of various origins, renal dysfunction may be associated not only with arteriolar but also with large artery changes, independently of mechanical stress and the presence of atherosclerosis [5]. In this report, we found that old donor age was associated with lower long-term graft survival. The decrease of renal graft survival as function of donor age is usually explained by reduced functional reserve in transplanted kidneys, making them more vulnerable during procurement, rejection, and even calcineurin inhibitor exposure [27–29]. Another hypothesis could be that the cardiovascular risk factors which characterize the donor influence independently kidney reserve and thus contribute to the developpement of chronic renal insufficiency. However, this hypothesis has never been tested clinically. In subjects with advanced renal failure, it has been shown that the major predictors of cardiovascular complications were a past history of cardiovascular diseases and mostly an increase of aortic PWV [2]. In subjects with renal transplants, the cardiovascular complications are less severe than in patients with end-stage renal disease (ESRD) [30, 31]. In this study, we showed that increased PWV was a major cardiovascular predictor, as it was previously shown for reduced carotid arterial distensibility [6]. Transplantation-related parameters, specifically dialysis duration, the age of the graft, and the immunosuppressive medications were not associated with a modification of the hemodynamic parameters and were not predictors of cardiovascular events in our study. Increased heart rate, a classical index of cardiovascular risk [32], seemed to be of better predictive value. Indeed tachycardia is frequent in renal transplants, particularly in the presence of the native kidneys and of drug treatment by cyclosporin or tacrolimus [33, 34]. However, in the present study, the most interesting parameter to consider for cardiovascular risk was the PP × heart rate product, which represents in each individual the magnitude of pulsatile stress on the arterial wall per unit time. On the basis of animal and human studies [3, 35, 36], pulsatile stress, more than steady stress, is susceptable to distort the arterial wall and to promote arteriosclerosis, thus favoring cardiovascular complications. In this context, increased heart rate is important to consider per se in the mechanism of increased pulsatility [4]. Enhanced activity of the autonomic nervous system is a characteristic feature in numerous subjects with renal transplants [33]. CONCLUSION The present study has shown that increased PWV was a distinct feature in subjects submitted to renal transplan-
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tation. Independent of age and MBP, increased PWV is influenced by increased tobacco consumption and mostly by acute renal rejection, the principal predictive factor of renal insufficiency during long-term follow-up. Cardiovascular risk is directly related to increased PWV and to increased pulsatility on the arterial wall whether through an increase in the heart rate or in the PP × heart rate product. Long-term studies in larger populations are needed to evaluate whether cardiovascular risk results from immunologic or non immunologic alterations or, more probably, from their combination. In addition, whether immunomodulation or sympathetic nervous system blockade could affect the cardiovascular outcome in renal transplant patients remains to be addressed. ACKNOWLEDGMENT This study was performed with the help of “CEDRE” (Cooperation ´ pour l’Evaluation et le Developpement ´ de la Recherche): The FrancoLebanese scientific collaboration. In addition, we thank Mrs. Veronique ´ Labro and Miss Farida Younan for their excellent assistance. Reprint requests to Profressor Michel E. Safar, Centre de Diagnostic, ˆ ˆ Hopital Hotel-Dieu, 1, place du Parvis Notre Dame, 75181 Paris Cedex 04, France. E-mail: [email protected]
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