Arterial Elasticity Measurement in Renal Transplant Patients Under Anticalcineurin Immunosuppression A. Martı´nez-Castelao, X. Sarrias, O. Bestard, S. Gil-Vernet, D. Serón, J.M. Cruzado, F. Moreso, A. Dı´ez-Noguera, and J.M. Grinyó ABSTRACT Introduction. Calcineurin inhibitors may be associated with decreased arterial elasticity and increased vascular risk. We measured pulse wave velocity (PWV) in large or small arteries as an index of elasticity. The aim of our study was to determine aortic and radial arterial elasticity in 30 stable kidney transplant patients treated with calcineurin inhibitor immunosuppression. Patients and methods. In stable kidney transplant patients we determined the usual biochemical parameters as well as lipid profiles, 24-hour blood pressure (BP) monitoring (CBPM) using a chronobiological program (Garapa), and PWV with a HDI-PWV CR-2000 monitor. Results. Sixteen patients received cyclosporine (CsA, G-1) and 14 tacrolimus (G-2) immunosuppression. There were no baseline differences regarding age (G-1: 56 ⫾ 12 years, G-2: 56 ⫾ 14 years), renal transplant follow-up (G-1: 7 ⫾ 3 years, G-2: 7.5 ⫾ 3 years), Systolic BP, pulse pressure or plasma creatinine (G-1: 163 ⫾ 35 umol/L, G-2: 173 ⫾ 26 umol/L). Patients in the G-1 showed higher diastolic BP (79 ⫾ 11 vs 74 ⫾ 8 mm Hg), greater proteinuria (1.26 ⫾ 0.4 vs 0.6 ⫾ 0.2 g/d, P ⬍ .05), total cholesterol (5.51 ⫾ 1.2 mmol/L) and low-density lipoprotein (3.08 ⫾ 0.3 vs 2.99 ⫾ 0.3 mmol/L, P ⫽ NS). Aortic arterial elasticity was decreased in G-1 patients (10.4 ⫾ 6 vs 14.3 ⫾ 2 mL/mm Hg ⫻10, P ⬍ .05) as well as that in the radial artery (G-1: 5.52 ⫾ 1 vs 5.57 ⫾ 1.2 mL/mm Hg ⫻100, P ⫽ NS). Almost 100% of the patients presented normal diurnal BP with high nocturnal BP in a nondipper pattern in both groups. Conclusion. Calcineurin immunosuppression may contribute to arterial stiffness in kidney transplant patients. No differences between CsA or tacrolimus were observed in our study. CBPM and PWV are useful tools to evaluate subclinical atherosclerosis in renal transplant patients.
H
IGH BLOOD PRESSURE (BP) contributes to induction of vascular modifications that produce compliance disturbances, distensibility, and elasticity modifications in large and small vessels. This arterial remodeling causes left ventricular hypertrophy through a post load increase.1,2 On the other hand, kidney transplant patients have an autonomous nervous system alteration that avoids supraquiasmatic nucleus connection. They lose the usual circadian rhythm, with a nondipper or a reverse dipper pattern under a 24-hour continuous BP monitoring (CBPM). This alteration of the circadian rhythm increases vascular risk.1 The determination of power wave velocity (PWV) constitutes a noninvasive method to measure vascular compliance and elasticity.3–5 The
QKD interval is the time from the onset of the QRS wave on the electrocardiogram and the detection of the last Korotkoff sound during measurement of BP.6 A nondipper pattern is accompanied by a drop of QKD values. A decrease in this value is usual in arteriosclerosis. (Gosse 3) From the Nephrology Department (A.M.-C., X.S., O.B., S.G.-V., D.S., J.M.C., F.M., J.M.G.) and Physiology Department (A.D.-N.), Pharmacy Faculty, UB, Hospital Universitari Bellvitge, IDIBELL, Hospitalet Llobregat, Barcelona, Spain. Address reprint requests to Alberto Martı´nez Castelao, Servei Nefrologia, C/Feixa Llarga s/n, 08907 Hospitalet L1. Barcelona, Spain. E-mail:
[email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.078
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 37, 3788 –3790 (2005)
ARTERIAL ELASTICITY MEASUREMENT
3789 Table 1. Patient Characteristics
G-I (n ⫽ 16) G-II (n ⫽ 14) P
Age (y)
Gender (M/F)
RT follow-up (m)
Creat (mol/L)
56 ⫾ 12 56 ⫾ 14 NS
6/10 7/7 NS
84 ⫾ 36 90 ⫾ 36 NS
163 ⫾ 35 173 ⫾ 26 NS
It has been described that anticalcineurin agents induce changes in compliance, increasing vascular risk.7 The aim of the study was to estimate whether cyclosporin (CsA) versus tacrolimus contributed to an increased vascular compliance by studying PWV in stable kidney transplant patients. PATIENTS AND METHODS Thirty kidney transplant patients, who were treated with CsA (group I, n ⫽ 16) or tacrolimus (G-II, n ⫽ 14) immunosuppression and showed stable renal function for the last 6 months, as evidenced by the plasma creatinine not increasing more than 25% from the baseline value were included in the study. After obtaining oral informed consent, we obtained biochemical, hematological, and lipid profile analyses. CBPM was done by the means of a Diasys Integra Monitor, with the Garapa chronobiological program. Vascular resistances were assessed, by means of the modified algorithm of Windkessel, which measures the compliance of large arteries (aorta, C1) and medium to small arteries (radial, C2). The C1 term is derived from an analysis of the diastolic slope decay of the arterial wave form obtained from the contour of the radial artery pressure curve calibrated against the BP obtained from the brachial artery using a Windkessel model (Blacher et al). The QKD interval was measured: Q for QRS; K for Korotkof; and D, for diastole as determined by the last audible sound (3 Rodbard). The mean of three C1 and C2 values were calculated. PWV was analyzed by means of a HDI/PWV CR-2000 Monitor Cardiovascular Profiling Instrument.
RESULTS
The patient characteristics are shown in Table 1. There were no differences regarding age, gender, chronic renal failure etiology, follow-up time, BP, or plasma creatinine between groups. Patients in group II showed greater proteinuria (1.26 ⫾ 0.4 vs 0.6 ⫾ 0.2 gr/d), total cholesterol (5.51 ⫾ 1.2 mmol/L), or low-density lipoprotein cholesterol (3.08 ⫾ 0.3 vs 2.99 ⫾ 0.3 mmol/L), but the differences were not significant, except for proteinuria (P ⬍ .05). CsA mean trough levels were 167 ⫾ 25 ng/mL and those for tacrolimus, 7.6 ⫾ 1.2 ng/mL. Table 2 shows the systolic, diastolic, and pulse pressure at
Prota (g/d)
1.26 ⫾ 0.4 0.6 ⫾ 0.2 ⬍.05
Tot-cholest (mmol/L)
LDL-c (mmol/L)
5.5 ⫾ 1.2 5.3 ⫾ 1.1 NS
3.08 ⫾ 0.3 2.99 ⫾ 0.3 NS
day and night, as well as C1 and C2 parameters. The number of antihypertensive drugs was similar in both groups (2.1 ⫾ 1.2 vs 2.3 ⫾ 1.2, P ⫽ NS). A high number of patients, 11 in G-I and 10 in G-II, showed a nondipper or reverse-dipper pattern: that is, normal diurnal BP with high BP with no normalization at night. C1 values were normal when compared to similar-age normal individuals, but C2 values were decreased when compared with normal individuals of similar age. QKD values were decreased in both groups, with nonsignificant differences between groups. When we compare QKD values with those of the two control groups (asymptomatic individuals: n ⫽ 20, QKD ⫽ 216 ms and essential hypertension patients: n ⫽ 30, QKD ⫽ 202 ms, and QKD ⫽ 209 ms after treatment with doxazosine), the values were decreased in both CsA and tacrolimus group (P ⬍ .05). DISCUSSION
Our patients showed almost normal large-vessel compliance although they displayed decreased elasticity of medium-size vessels when compared with normal individuals of the same age. That signifies an increased degree of endothelial dysfunction and atherosclerosis. Kidney transplant patients are especially at risk to develop atherosclerosis and vascular complications, which enhance morbidity and mortality. Cardiovascular complications are the first cause of mortality among long-term transplant patients.8 Atherosclerosis begins in the arterial wall with endothelial dysfunction accompanied by functional and structural changes that influence arterial stiffness. Reduced distensibility of large arteries plays an important role in cardiovascular disease. The technique of using pulse contour recording combined with computer analysis offers a means to screen vascular disease before it becomes clinically apparent or to identify earlier disease to prevent further damage.2 Pulse control analysis provides an assessment of compliance or elasticity of the large conduit arteries (C1) and small microcirculatory arteries (C2). Lower values of C1 are thought to reflect a reduced
Table 2. CBPM and PWV
G-I (n ⫽ 16) G-II (n ⫽ 14) P
BP d
BP n
PP d
HBP
QKD
C1
124/81.8 140/89 SBP*
126/84 139/89 DBP*
44.5 51 NS
HBP night (n ⫽ 11) HBP night (n ⫽ 10) NS
194 198 NS
10.2 12.6 NS
C1 Normal estrat. by age
9.85
C2
C2 Normal estrat. by age
5.1 5.1 NS
5.5 6.2 NS
SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse P; QKD,; HBP, high blood pressure, C1, aorta elasticity in mL/mm Hg ⫻ 10; C2, radial elasticity in mL/mm Hg ⫻ 100.
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capacity of large vessels to accommodate each cardiac cycle.9 McVeigh et al10 found that the principal physiological determinants of C1 are the structural components of the large elastic artery walls, collagen and elastin, level of systolic BP, and age. On the other hand, small-artery elasticity contributes to the oscillations or reflected waves that distort the arterial pulse wave.11 The utility of vascular compliance to determine cardiovascular risk among patients with kidney diseases has been recently shown in dialysis patients. Studying 241 chronic hemodialysis patients Blacher et al observed that age and PWV were significant independent predictors of all causes of cardiovascular mortality.12 Research using arterial compliance measures such as reported in our work is limited. Barenbrock et al13 have shown that the reduction in common carotid distensibility is an independent predictor of cardiovascular diseases among a cohort of renal transplant recipients. In one study of 250 stable renal transplant recipients an increased aortic augmentation index was associated with CsA as compared with tacrolimus use.14 Khanna et al15 have shown that patients treated with CsA showed greater expression of fibrogenic genes, tumor growth factor-beta, collagen, fibronectin, and osteopontin, compared with patients treated with tacrolimus. In another study of 82 hemodialysis patients, Haydar et al16 have found that PWV is strongly related to the degree of coronary artery calcifications detected by electron-beam computerized tomography. The mean PWV of 9.13 m/s was strongly correlated with the total coronary calcification score (mean score 2551). Coronary calcifications were significantly different when compared according to PWV tertiles (P ⫽ .0001). Our cross-sectional study in a small number of patients was not designed to evaluate selective end points. Our results are consistent with a reduction in arterial elasticity in medium arteries among patients treated with anticalcineurin agents. These changes did not differ significantly in CsA- or tacrolimus-treated patients. Arterial elasticity changes may be related not only to the effect of these agents, but also to a confluence of many factors, including BP control, dyslipidemia, or hyperhomocysteinemia, which is frequently found in stable transplant patients. The combination of C1 and C2 measurements with determinations of the QKD interval is a noninvasive method that provides valuable information on arterial elasticity to prevent or restore abnormal endothelial function that can lead to atherosclerosis and cardiovascular events in renal transplant patients. Detection of early vascular disease requires a more sensitive and specific marker for the risk of cardiovascular morbid events than the associated risk factors that currently serve as guides for preventive measures.17
MARTÍNEZ-CASTELAO, SARRIAS, BESTARD ET AL
Thus, evaluation of CBPM, PWV, and QKD interval is a good tool to assess the vascular status of patients, which may be applied in early stages to stratify cardiovascular risk18 and accurately control antihypertensive and antiatherosclerotic treatment for these patients. REFERENCES 1. Palma JL: Métodos no invasivos para la evaluación de las propiedades físicas de las grandes arterias en la hipertensión arterial. Nefrologı´a 22:16, 2002 2. Gosse P, Jullien V, Jarnier P, et al: Reduction in arterial distensibility in hypertensive patients as evaluated by Ambulatory measurement of the QKD interval is correlated with concentric remodelling of the left ventricle. AJH 12:252, 1999 3. Cohn JN, Finkelstein S, McVeigh G, et al: Non-invasive pulse wave analysis for the early detection of vascular disease. Hypertension 26:503, 1995 4. Gosse Ph, Guillo P, Gilles A, et al: Assessment of arterial distensibility by monitoring the timing of Korotkoff sounds. Am J Hypertens 7:228, 1994 5. Agmar R, Darne B, el Assaad M, et al: Assessment of outcomes other than systolic and diastolic blood: pulse pressure, arterial stiffness and heart rate. Blood Pressure Monitoring 6:329, 2001 6. Rodbard S, Rubinstein HM, Rosenblum S: Arrival time and calibrated contour of the pulse wave determinated indirectly from recordings of arterial compression sounds. Am Heart J 53:205, 1957 7. Cohen DL, Warurton KM, Warren G, et al: Pulse wave velocity analysis to assess vascular changes in stable renal transplant recipients. AJH 17:209, 2004 8. Kasiske BL: Epidemiology of cardiovascular disease after renal transplantation. Transplantation 72(suppl 6):s5, 2001 9. Resnick LM, Miltianu D, Cunnings AJ, et al: Pulse waveform analysis of arterial compliance: relation to other techniques, age and metabolic variables. Am J Hypertens 13:1243, 2000 10. McVeigh GE, Bratteli CW, Morgan DJ, et al: Age-related abnormalities in arterial compliance identified by pressure pulse contour analysis: aging and arterial compliance. Hypertension 33:1392, 1999 11. Finkelstein SM, Cohn JN: First- and third-order models for determining arterial compliance. J Hypertens 10(Suppl 6):s11, 1992 12. Blacher J, Pannier B, Guerin AP, et al: Carotid arterial stiffness as a predictor of cardiovascular and all cause mortality in end-stage renal disease. Hypertension 32:570, 1998 13. Barenbrock M, Kosch M, Joster E, et al: Reduced arterial distensibility is a predictor of cardiovascular disease in patients after renal transplantation. J Hypertens 20:79, 2002 14. Ferro CJ, Savage T, Pinder SJ, et al: Central aortic pressure augmentation in stable renal transplant recipients. Kidney Int 62:166, 2002 15. Kahnna A, Plummer M, Bromberek C, et al: Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity. Kidney Int 62:2257, 2002 16. Haydar AA, Covic A, Colhoun H, et al: Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients. Kidney Int 65:1790, 2004 17. Lloyd-Jones DM, Kannel WB: Coronary risk factors: an overview. In Willerson JT, Cohn JN (eds): Cardiovascular medicine. New York: Churchill Livingstone; 2000; p 2193 18. Cohn JN: Arterial compliance to stratify cardiovascular risk; more precision in therapeutic decision making. Am J Med 14:2585, 2001
