Hyperviscosity in Renal Transplant Recipients E. Tutala, M. Erkmen Uyara,*, S. Uyanikb, Z. Bala, O. Guliyeva, S.K. Toprakc, O. Ilhanc, S. Sezera, and M. Haberald a
Department of Nephrology, Baskent University, Ankara, Turkey; bDepartment of Internal Medicine, Baskent University, Ankara, Turkey; Department of Hematology, Ankara University, Ankara, Turkey; and dDepartment of General Surgery, Baskent University, Ankara, Turkey c
ABSTRACT Objective. The resistance of blood to flow is called plasma viscosity. Increased blood viscosity has been described in patients with coronary and peripheral arterial disease. In this study, we evaluated the influence of clinical and laboratory findings on plasma viscosity in renal transplant recipients. Methods. Eighty-one kidney transplant recipients (37.8 11.3 years old, 50.38 16.8 months post-transplantation period, 27 female) with normal graft functions were enrolled. The biochemical and clinical parameters in the 1st year after transplantation were retrospectively recorded, and graft function was evaluated by means of the yearly decline in eGFR. Plasma viscosity was measured and searched for the association with crosssectionally analyzed cardiovascular parameters including body composition analyses, ambulatory blood pressure monitoring (ABPM) data, and pulse-wave velocity. Results. Patients were divided into 2 groups according to the median value of serum viscosity. Patients with high viscosity had higher serum low-density lipoprotein (P ¼ .042) and C-reactive protein (P ¼ .046) levels than lower viscosity group. In ABPM, daytime (P ¼ .047) and office systolic (P ¼ .046) blood pressure levels and left ventricular mass index (LVMI; P ¼ .012) were significantly higher in patients with hyperviscosity. Patients with high viscosity had higher hip circumference (P ¼ .038) and fat mass (P ¼ .048). Estimated glomerular filtration rate decline was significantly higher in high-viscosity patients than in patients with low viscosity levels (12.9% vs 17.2%; P ¼ .001) at 2 years’ follow-up. Conclusions. We suggest that the hyperviscous state of the renal transplant recipients may arise from the inflammatory state, hypertension, and increased fat mass and increased LVMI. Hyperviscosity is also closely related to renal allograft dysfunction.
T
HE RESISTANCE of blood to flow is called plasma viscosity. Blood is a complex body fluid, so not only body temperature but also components of blood, such as hematocrit and plasma, and rheologic characteristics, such as the deformability of erythrocytes, all affect plasma viscosity [1]. Blood viscosity and erythrocyte deformability play a key role in maintaining and regulating microcirculation. Plasma viscosity is influenced by diseases with altered plasma protein composition, as determined by various macromolecules, eg, fibrinogen, immunoglobulin, and lipoproteins [2,3]. An elevated viscosity significantly increases the risk of inflammatory diseases; the strong positive correlation between
plasma viscosity and fibrinogen has been reported in several studies [2,3]. Elevated plasma viscosity results in greater flow resistance and a high incidence of circulatory complications [4]. Increased blood and plasma viscosity has been described in patients with coronary and peripheral arterial disease. Increased viscosity may increase the risk of thrombosis or thromboembolic events [5]. Altered rheologic parameters *Address correspondence to Mehtap Erkmen Uyar, Meseli sokak, No: 15/19 06010, Etlik, Ankara, Turkey. E-mail: [email protected]
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.03.001
Transplantation Proceedings, 47, 1165e1169 (2015)
1165
1166
are correlated with arterial hypertension severity and complications including left ventricular hypertrophy. In hypertensive patients, blood hyperviscosity contributes to coronary reserve limitation [6] as well as to thrombogenesis [7]. Chronic kidney disease (CKD) is also associated with alterations of coagulation that favor a hypercoagulable or prothrombotic state [8,9] and thus an increased thrombotic risk that may contribute to an increase in cardiovascular morbidity and mortality [10]. Cardiovascular disease is the most important cause of mortality in patients with CKD in native kidneys as well as in renal transplant recipients (RTRs). In renal disease, mechanisms including hypertension, hyperhomocysteinemia, dyslipidemia, elevation of hemostatic derived cardiovascular risk factors (fibrinogen and proconvertin) [10], and amplification of the inflammatory cascade at the endothelial cell (growth factors, cytokines, and adhesion molecules) [11] are activated [12]. The characteristic of blood flow is closely related to the blood flow circumstances with all of the factors above, as seen in atherosclerotic diseases [13]. In light of these data, we evaluated the influence of clinical and laboratory findings on plasma viscosity in renal transplant patients. PATIENTS AND METHODS Patients were selected according to the following exclusion criteria: 1) irregular drug usage or patient incompliance; 2) lack of regular followup data; 3) bone marrow transplant or other solid organs before or at the time of transplantation (including previous kidney transplantation); 4) malign disease, rheumatologic or chronic inflammatory disease of unknown origin, systemic vasculitis history; 5) acute rejection periods after the 1st year of transplantation; 6) graft failure (glomerular filtration [GFR] rate 130 g/m2 were defined as high left ventricular mass. Pulse-wave velocity (PWV) is defined as the velocity of the arterial pulse for moving along the vessel wall. PWV along the aorta was measured with the use of 2 ultrasound or pressure-sensitive transducers fixed transcutaneously over the course of a pair of arteries separated by a known distance: the femoral and right common carotid arteries. PWV was calculated from measurements of pulse transit time and the distance according to the following formula: PWV (m/s) ¼ distance (m)/ transit time (s). Measurement of PWV values was done after abstinence from caffeine or smoking and after an overnight fast without intake of antihypertensive drugs. PWV was determined by using the Sphygmocor CVMS V9 system, and values >7 m/s were defined as increased.
Statistical Analysis Statistical analyses were performed with the use of SPSS software (Statistical Package for the Social Sciences, version 11.0; SSPS, Chicago, Illinois). Normality of data was analyzed with the use of a KolmogorovSmirnov test. All numeric variables with normal distribution were expressed as mean SD, and variables with skew distribution were expressed as median (interquartile range [IQR]). Categoric variables were expressed as percentages and compared by means of chi-square test. Normally distributed numeric variables were analyzed by means of independent-samples t or 1-way analysis of variance (post hoc Tukey) tests according to distribution normality. Skew-distributed numeric variables were compared by means of the Mann-Whitney U and Kruskal-Wallis tests according to distribution normality. Spearman and Pearson correlation tests were used for correlation analyses. A P value of 16 g/dL; n ¼ 8) had significantly higher serum viscosity levels (2.32 1.66 vs 1.62 0.36 mPas; P ¼ .0001) than patients with lower Hb levels. In ambulatory blood pressure monitoring analysis; overall mean systolic (142.12 20.55 vs 132.84 16.88 mm Hg; P ¼ .048), daytime mean systolic (143.52 20.24 vs 134.11 16.34 mm Hg; P ¼ .047), and office systolic (134.75 16.52 vs 112 13.8 mm Hg; P ¼ .046) BP levels were significantly higher in patients with high viscosity than in patients with low viscosity. In echocardiographic evaluation, patients with high viscosity had significantly higher LVMI (242.53 80.43 vs 171.15 49.52 g/m2; P ¼ .012) than patients with low viscosity. According to anthrophometric measurements; patients with high viscosity had higher hip circumference (99.61 8.52 vs 96.44 6.46 cm; P ¼ .038) than patients with low viscosity. Body composition analyses revealed that patients with high viscosity had higher fat mass (15.96 6.83 vs 12.93 6.83 kg; P ¼ .048) than patients with low viscosity. Estimated GFR decline was significantly higher (81.39 to 67.31 mL/min/1.73 m2) in high-viscosity patients than in
patients with low viscosity levels (12.9% vs 17.2%; P ¼ .001) at 2 years’ follow-up. Multivariate analysis of all significant factors including serum CRP and LDL levels, fat mass, office systolic BP, LVMI, and eGFR decline revealed that eGFR decline (95% confidence interval [CI], 1.4e4.7; P ¼ .042) was an independent predictor of hyperviscosity. DISCUSSION
Hyperviscosity has effects leading to atherosclerosis, and its negative impact on atherosclerosis was found to be more intense than traditional risk factors [14,15]. Increased viscosity also has negative impact on vascular structure. Yarnell et al found that in a population of 4,860 men, death, acute myocardial infraction, and urgent cardiovascular surgery requirement were significantly higher in the hyperviscosity group than in patients with lower blood viscosity [16]. On the other hand, traditional cardiovascular risk factors, such as hypertension, obesity, smoking, high LDL-cholesterol levels, and diabetes, are also known to cause hyperviscosity [17e19]. Therefore, the interaction between blood viscosity and cardiovascular risk factors is complex but undeniable [20,21]. Renal transplant recipients are at w6 times increased risk for cardiovascular disease (CVD) compared with the general population [22]. It has been shown that both traditional risk factors and transplant-specific cardiovascular risk factors contribute to the high CVD burden after renal
1168
transplantation [23,24]. Hypertension is the most prevalent traditional cardiovascular risk factor in RTRs, affecting 75%e90% of them, and it is associated with poor patient and graft survivals [25,26]. In the present study, we found higher systolic BP values and high LVMI in renal transplant patients with high viscosity. Ciuffetti et al showed a strong correlation between hypertension and blood viscosity and left ventricular hypertrophy [27]. Increased plasma viscosity may in turn result from higher fibrinogen levels [28,29], which may arise from a chronic-phase protein reaction, possibly associated with the increased catecholamine release in hypertension [28]. Although the pathophysiology of hypertension is still unknown, emerging studies have shown that systemic inflammation contributes to its development and increases the risk of CVD [30,31]. The association between inflammation and CVD is especially evident in patients with renal disease. Despite the fact that classic markers of chronic inflammation decrease after transplantation [32], systemic inflammation remains increased in stable grafts months after transplantation [33], and pretransplantation inflammation has been associated with longterm graft outcomes in renal transplants [34]. Consistent with these data, we found higher LDL and CRP values in renal transplant patients with high viscosity. The inflammatory state plays an important role in causing oxidative stress, especially in end-stage renal disease and among RTRs [35,36]. In addition to adversely affecting the allograft function and structure, oxidative stress plays a major role in the pathogenesis of systemic inflammation, hypertension, cardiovascular disease, and metabolic syndrome among other complication in transplant recipients. In our study, the patients with high viscosity had features of metabolic syndrome such as higher fat mass and hip circumference. All of the above factors are not only risk factors for CVD but they are also associated with graft dysfunction in RTRs. In the present study, we evaluated yearly decline in eGFR values for 2 years’ follow-up, and patients with high viscosity had significantly higher ratios of eGFR decline. We suggest that the altered lipid profile, hypertension, and increased fat mass leading to microinflammation could influence viscosity in RTRs, and that hyperviscosity is closely related with renal allograft dysfunction. In conclusion, according to our findings we suggest that the higher viscosity levels in RTRs may arise mostly from the inflammatory situation, hypertension, metabolic syndrome features such as dyslipidemia, and high fat mass of body composition. Hyperviscosity seems to be closely related to graft dysfunction. Therapies targeting hyperviscosity and related comorbidities may reduce cardiovascular complications and graft dysfunction in RTRs. Further prospective studies with long term follow-up are needed to show the exact mechanisms of hyperviscosity in RTRs. REFERENCES [1] Yonem A, Cakir B, Azal O, et al. Blood viscosity and its relationship with plasma fibrinogen and cholesterol levels in young obese patients. Turk Med J 1999;6:295e8.
TUTAL, ERKMEN UYAR, UYANIK ET AL [2] Jung F, Pindur G, Kiesewetter H. Plasma viscosity dependence on proteins and lipoproteins: results of the Aachen Study. Clin Hemorheol 1992;12:557e71. [3] Koenig W, Sund M, Filipiak B, et al. Plasma viscosity and the risk of coronary heart disease: results from the MONICA-Augsburg Cohort Study, 1984 to 1992. Arterioscler Thromb Vasc Biol 1998;18:768e72. [4] McMillan DE. Physical factors in the development of atherosclerosis in diabetes. Diabetic Care 1981;30(2):97e104. [5] Ho CH. White blood cell and platelet counts could affect whole blood viscosity. J Chin Med Assoc 2004;67(8):394e7. [6] Zannad F, Stoltz J. Interest and methods of study of hemorheology in vascular pathology and pharmacology. Arch Mal Coeur Vaiss 1990;83:33e6. [7] Lee A. The role of rheological and haemostatic factors in hypertension. J Hum Hypertens 1997;11:767e76. [8] Molino D, de Lucia D, Gaspare de Santo N. Coagulation disorders in uremia. Semin Nephrol 2006;26:46e51. [9] Ambuhl PM, Wuthrich RP, Korte W, Schmid L, Krapf R. Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation. Nephrol Dial Transplant 1997;12: 2355e64. [10] Gris J-C, Branger B, Vecina F, et al. Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Kidney Int 1994;46: 807e13. [11] Ferrara N, Bunting S. Vascular endothelial growth factor, a specific regulator of angiogenesis. Curr Opin Nephrol Hypertens 1995;5:35e44. [12] Aguilera A, Bajo MA, Díez JJ, et al. Effects of human recombinant erythropoietin on inflammatory status in peritoneal dialysis patients. Adv Perit Dial 2002;18:200e5. [13] Lowe GDO. Blood viscosity and cardiovascular disease. Thromb Haemost 1992;67:494e8. [14] Kensey KR. The mechanistic relationships between hemorheological characteristics and cardiovascular disease. Curr Med Res Opin 2003;19:587e96. [15] Lee AJ, Mowbray PI, Lowe GD, et al. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation 1998;97:1467e73. [16] Yarnell JW, Baker IA, Sweetnam PM, et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies. Circulation 1991;83:836e44. [17] Bogar L. Hemorheology and hypertension: not “chicken or egg” but two chickens from similar eggs. Clin Hemorheol Microcirc 2002;26:81e3. [18] Rampling MW. Haemorheological disturbances in hypertension: the influence of diabetes and smoking. Clin Hemorheol Microcirc 1999;21:183e7. [19] de Simone G, Devereux RB, Chien S, et al. Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 1990;81:107e17. [20] Dikmenoglu N. An important risk factor as smoking and hypercholesterolemia for cardiovascular disease: blood viscosity. Hacettepe Med J 2006;37:93e7. [21] Erkmen Uyar M, Toprak SK, Saglam H, et al. rHuEPO hyporesponsiveness and related high dosages are associated with hyperviscosity in maintenance hemodialysis patients. Scientific WorldJournal 2013;2013:792698. [22] Oterdoom LH, de Vries AP, van Ree RM, et al. N-Terminal proeB-type natriuretic peptide and mortality in renal transplant recipients versus the general population. Transplantation 2009;87: 1562e70. [23] Ibernon M, Moreso F, Sarrias X, et al. Reverse dipper pattern of blood pressure at 3 months is associated with inflammation and outcome after renal transplantation. Nephrol Dial Transplant 2012;27:2089e95.
HYPERVISCOSITY IN RENAL TRANSPLANT RECIPIENTS [24] Mattos AM, Prather J, Olyaei AJ, et al. Cardiovascular events following renal transplantation: role of traditional and transplant-specific risk factors. Kidney Int 2006;70:757e64. [25] First MR, Neylan JF, Rocher LL, et al. Hypertension after renal transplantation. J Am Soc Nephrol 1994;4:s30e6. [26] Opelz G, Dohler D. Collaborative Transplant Study. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant 2005;5: 2725e31. [27] Ciuffetti G, Pasqualini L, Pirro M, et al. Blood rheology in men with essential hypertension and capillary rarefaction. J Hum Hypertens 2002;16:533e7. [28] Lowe GDO. Blood rheology in general medicine and surgery. Baillieres Clin Haematol 1987;1:827e61. [29] Chien S. Blood rheology in hypertension and cardiovascular disease. Cardiovasc Med 1977;2:356e60. [30] Montecucco F, Pende A, Quercioli A, et al. Inflammation in the pathophysiology of essential hypertension. J Nephrol 2011;24: 23e34.
1169 [31] Roselló-Lletí E, Rivera M, Martínez-Dolz LL, et al. Inflammation activation and left ventricular mass in essential hypertension. Am J Hypertens 2009;22:444e50. [32] Ibernon M, Moreso F, Moreno JM, et al. Low serum mannose-binding lectin as a risk factor for new onset diabetes mellitus after renal transplantation. Transplantation 2009;88:272e8. [33] Cueto-Manzano AM, Morales-Buenrostro LE, GonzalezEspinosa L, et al. Markers of inflammation before and after renal transplantation. Transplantation 2005;80:47e51. [34] Dahle DO, Mjøen G, Oqvist B, et al. Inflammation-associated graft loss in renal transplant recipients. Nephrol Dial Transplant 2011;26:3756e61. [35] Cottone S, Palermo A, Vaccaro F, et al. In renal transplanted patients inflammation and oxidative stress are interrelated. Transplant Proc 2006;38:1026e30. [36] Juskowa J, Paczek L, Laskowska-Klita T, Rancewicz Z, Gajewska J, Jedynak-Oldakowska U. Selected parameters of antioxidant capacity in renal allograft recipients. Pol Arch Med Wewn 2001;105:19e27.
Department of Nephrology, Baskent University, Ankara, Turkey; bDepartment of Internal Medicine, Baskent University, Ankara, Turkey; Department of Hematology, Ankara University, Ankara, Turkey; and dDepartment of General Surgery, Baskent University, Ankara, Turkey c
ABSTRACT Objective. The resistance of blood to flow is called plasma viscosity. Increased blood viscosity has been described in patients with coronary and peripheral arterial disease. In this study, we evaluated the influence of clinical and laboratory findings on plasma viscosity in renal transplant recipients. Methods. Eighty-one kidney transplant recipients (37.8 11.3 years old, 50.38 16.8 months post-transplantation period, 27 female) with normal graft functions were enrolled. The biochemical and clinical parameters in the 1st year after transplantation were retrospectively recorded, and graft function was evaluated by means of the yearly decline in eGFR. Plasma viscosity was measured and searched for the association with crosssectionally analyzed cardiovascular parameters including body composition analyses, ambulatory blood pressure monitoring (ABPM) data, and pulse-wave velocity. Results. Patients were divided into 2 groups according to the median value of serum viscosity. Patients with high viscosity had higher serum low-density lipoprotein (P ¼ .042) and C-reactive protein (P ¼ .046) levels than lower viscosity group. In ABPM, daytime (P ¼ .047) and office systolic (P ¼ .046) blood pressure levels and left ventricular mass index (LVMI; P ¼ .012) were significantly higher in patients with hyperviscosity. Patients with high viscosity had higher hip circumference (P ¼ .038) and fat mass (P ¼ .048). Estimated glomerular filtration rate decline was significantly higher in high-viscosity patients than in patients with low viscosity levels (12.9% vs 17.2%; P ¼ .001) at 2 years’ follow-up. Conclusions. We suggest that the hyperviscous state of the renal transplant recipients may arise from the inflammatory state, hypertension, and increased fat mass and increased LVMI. Hyperviscosity is also closely related to renal allograft dysfunction.
T
HE RESISTANCE of blood to flow is called plasma viscosity. Blood is a complex body fluid, so not only body temperature but also components of blood, such as hematocrit and plasma, and rheologic characteristics, such as the deformability of erythrocytes, all affect plasma viscosity [1]. Blood viscosity and erythrocyte deformability play a key role in maintaining and regulating microcirculation. Plasma viscosity is influenced by diseases with altered plasma protein composition, as determined by various macromolecules, eg, fibrinogen, immunoglobulin, and lipoproteins [2,3]. An elevated viscosity significantly increases the risk of inflammatory diseases; the strong positive correlation between
plasma viscosity and fibrinogen has been reported in several studies [2,3]. Elevated plasma viscosity results in greater flow resistance and a high incidence of circulatory complications [4]. Increased blood and plasma viscosity has been described in patients with coronary and peripheral arterial disease. Increased viscosity may increase the risk of thrombosis or thromboembolic events [5]. Altered rheologic parameters *Address correspondence to Mehtap Erkmen Uyar, Meseli sokak, No: 15/19 06010, Etlik, Ankara, Turkey. E-mail: [email protected]
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.03.001
Transplantation Proceedings, 47, 1165e1169 (2015)
1165
1166
are correlated with arterial hypertension severity and complications including left ventricular hypertrophy. In hypertensive patients, blood hyperviscosity contributes to coronary reserve limitation [6] as well as to thrombogenesis [7]. Chronic kidney disease (CKD) is also associated with alterations of coagulation that favor a hypercoagulable or prothrombotic state [8,9] and thus an increased thrombotic risk that may contribute to an increase in cardiovascular morbidity and mortality [10]. Cardiovascular disease is the most important cause of mortality in patients with CKD in native kidneys as well as in renal transplant recipients (RTRs). In renal disease, mechanisms including hypertension, hyperhomocysteinemia, dyslipidemia, elevation of hemostatic derived cardiovascular risk factors (fibrinogen and proconvertin) [10], and amplification of the inflammatory cascade at the endothelial cell (growth factors, cytokines, and adhesion molecules) [11] are activated [12]. The characteristic of blood flow is closely related to the blood flow circumstances with all of the factors above, as seen in atherosclerotic diseases [13]. In light of these data, we evaluated the influence of clinical and laboratory findings on plasma viscosity in renal transplant patients. PATIENTS AND METHODS Patients were selected according to the following exclusion criteria: 1) irregular drug usage or patient incompliance; 2) lack of regular followup data; 3) bone marrow transplant or other solid organs before or at the time of transplantation (including previous kidney transplantation); 4) malign disease, rheumatologic or chronic inflammatory disease of unknown origin, systemic vasculitis history; 5) acute rejection periods after the 1st year of transplantation; 6) graft failure (glomerular filtration [GFR] rate 130 g/m2 were defined as high left ventricular mass. Pulse-wave velocity (PWV) is defined as the velocity of the arterial pulse for moving along the vessel wall. PWV along the aorta was measured with the use of 2 ultrasound or pressure-sensitive transducers fixed transcutaneously over the course of a pair of arteries separated by a known distance: the femoral and right common carotid arteries. PWV was calculated from measurements of pulse transit time and the distance according to the following formula: PWV (m/s) ¼ distance (m)/ transit time (s). Measurement of PWV values was done after abstinence from caffeine or smoking and after an overnight fast without intake of antihypertensive drugs. PWV was determined by using the Sphygmocor CVMS V9 system, and values >7 m/s were defined as increased.
Statistical Analysis Statistical analyses were performed with the use of SPSS software (Statistical Package for the Social Sciences, version 11.0; SSPS, Chicago, Illinois). Normality of data was analyzed with the use of a KolmogorovSmirnov test. All numeric variables with normal distribution were expressed as mean SD, and variables with skew distribution were expressed as median (interquartile range [IQR]). Categoric variables were expressed as percentages and compared by means of chi-square test. Normally distributed numeric variables were analyzed by means of independent-samples t or 1-way analysis of variance (post hoc Tukey) tests according to distribution normality. Skew-distributed numeric variables were compared by means of the Mann-Whitney U and Kruskal-Wallis tests according to distribution normality. Spearman and Pearson correlation tests were used for correlation analyses. A P value of 16 g/dL; n ¼ 8) had significantly higher serum viscosity levels (2.32 1.66 vs 1.62 0.36 mPas; P ¼ .0001) than patients with lower Hb levels. In ambulatory blood pressure monitoring analysis; overall mean systolic (142.12 20.55 vs 132.84 16.88 mm Hg; P ¼ .048), daytime mean systolic (143.52 20.24 vs 134.11 16.34 mm Hg; P ¼ .047), and office systolic (134.75 16.52 vs 112 13.8 mm Hg; P ¼ .046) BP levels were significantly higher in patients with high viscosity than in patients with low viscosity. In echocardiographic evaluation, patients with high viscosity had significantly higher LVMI (242.53 80.43 vs 171.15 49.52 g/m2; P ¼ .012) than patients with low viscosity. According to anthrophometric measurements; patients with high viscosity had higher hip circumference (99.61 8.52 vs 96.44 6.46 cm; P ¼ .038) than patients with low viscosity. Body composition analyses revealed that patients with high viscosity had higher fat mass (15.96 6.83 vs 12.93 6.83 kg; P ¼ .048) than patients with low viscosity. Estimated GFR decline was significantly higher (81.39 to 67.31 mL/min/1.73 m2) in high-viscosity patients than in
patients with low viscosity levels (12.9% vs 17.2%; P ¼ .001) at 2 years’ follow-up. Multivariate analysis of all significant factors including serum CRP and LDL levels, fat mass, office systolic BP, LVMI, and eGFR decline revealed that eGFR decline (95% confidence interval [CI], 1.4e4.7; P ¼ .042) was an independent predictor of hyperviscosity. DISCUSSION
Hyperviscosity has effects leading to atherosclerosis, and its negative impact on atherosclerosis was found to be more intense than traditional risk factors [14,15]. Increased viscosity also has negative impact on vascular structure. Yarnell et al found that in a population of 4,860 men, death, acute myocardial infraction, and urgent cardiovascular surgery requirement were significantly higher in the hyperviscosity group than in patients with lower blood viscosity [16]. On the other hand, traditional cardiovascular risk factors, such as hypertension, obesity, smoking, high LDL-cholesterol levels, and diabetes, are also known to cause hyperviscosity [17e19]. Therefore, the interaction between blood viscosity and cardiovascular risk factors is complex but undeniable [20,21]. Renal transplant recipients are at w6 times increased risk for cardiovascular disease (CVD) compared with the general population [22]. It has been shown that both traditional risk factors and transplant-specific cardiovascular risk factors contribute to the high CVD burden after renal
1168
transplantation [23,24]. Hypertension is the most prevalent traditional cardiovascular risk factor in RTRs, affecting 75%e90% of them, and it is associated with poor patient and graft survivals [25,26]. In the present study, we found higher systolic BP values and high LVMI in renal transplant patients with high viscosity. Ciuffetti et al showed a strong correlation between hypertension and blood viscosity and left ventricular hypertrophy [27]. Increased plasma viscosity may in turn result from higher fibrinogen levels [28,29], which may arise from a chronic-phase protein reaction, possibly associated with the increased catecholamine release in hypertension [28]. Although the pathophysiology of hypertension is still unknown, emerging studies have shown that systemic inflammation contributes to its development and increases the risk of CVD [30,31]. The association between inflammation and CVD is especially evident in patients with renal disease. Despite the fact that classic markers of chronic inflammation decrease after transplantation [32], systemic inflammation remains increased in stable grafts months after transplantation [33], and pretransplantation inflammation has been associated with longterm graft outcomes in renal transplants [34]. Consistent with these data, we found higher LDL and CRP values in renal transplant patients with high viscosity. The inflammatory state plays an important role in causing oxidative stress, especially in end-stage renal disease and among RTRs [35,36]. In addition to adversely affecting the allograft function and structure, oxidative stress plays a major role in the pathogenesis of systemic inflammation, hypertension, cardiovascular disease, and metabolic syndrome among other complication in transplant recipients. In our study, the patients with high viscosity had features of metabolic syndrome such as higher fat mass and hip circumference. All of the above factors are not only risk factors for CVD but they are also associated with graft dysfunction in RTRs. In the present study, we evaluated yearly decline in eGFR values for 2 years’ follow-up, and patients with high viscosity had significantly higher ratios of eGFR decline. We suggest that the altered lipid profile, hypertension, and increased fat mass leading to microinflammation could influence viscosity in RTRs, and that hyperviscosity is closely related with renal allograft dysfunction. In conclusion, according to our findings we suggest that the higher viscosity levels in RTRs may arise mostly from the inflammatory situation, hypertension, metabolic syndrome features such as dyslipidemia, and high fat mass of body composition. Hyperviscosity seems to be closely related to graft dysfunction. Therapies targeting hyperviscosity and related comorbidities may reduce cardiovascular complications and graft dysfunction in RTRs. Further prospective studies with long term follow-up are needed to show the exact mechanisms of hyperviscosity in RTRs. REFERENCES [1] Yonem A, Cakir B, Azal O, et al. Blood viscosity and its relationship with plasma fibrinogen and cholesterol levels in young obese patients. Turk Med J 1999;6:295e8.
TUTAL, ERKMEN UYAR, UYANIK ET AL [2] Jung F, Pindur G, Kiesewetter H. Plasma viscosity dependence on proteins and lipoproteins: results of the Aachen Study. Clin Hemorheol 1992;12:557e71. [3] Koenig W, Sund M, Filipiak B, et al. Plasma viscosity and the risk of coronary heart disease: results from the MONICA-Augsburg Cohort Study, 1984 to 1992. Arterioscler Thromb Vasc Biol 1998;18:768e72. [4] McMillan DE. Physical factors in the development of atherosclerosis in diabetes. Diabetic Care 1981;30(2):97e104. [5] Ho CH. White blood cell and platelet counts could affect whole blood viscosity. J Chin Med Assoc 2004;67(8):394e7. [6] Zannad F, Stoltz J. Interest and methods of study of hemorheology in vascular pathology and pharmacology. Arch Mal Coeur Vaiss 1990;83:33e6. [7] Lee A. The role of rheological and haemostatic factors in hypertension. J Hum Hypertens 1997;11:767e76. [8] Molino D, de Lucia D, Gaspare de Santo N. Coagulation disorders in uremia. Semin Nephrol 2006;26:46e51. [9] Ambuhl PM, Wuthrich RP, Korte W, Schmid L, Krapf R. Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation. Nephrol Dial Transplant 1997;12: 2355e64. [10] Gris J-C, Branger B, Vecina F, et al. Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Kidney Int 1994;46: 807e13. [11] Ferrara N, Bunting S. Vascular endothelial growth factor, a specific regulator of angiogenesis. Curr Opin Nephrol Hypertens 1995;5:35e44. [12] Aguilera A, Bajo MA, Díez JJ, et al. Effects of human recombinant erythropoietin on inflammatory status in peritoneal dialysis patients. Adv Perit Dial 2002;18:200e5. [13] Lowe GDO. Blood viscosity and cardiovascular disease. Thromb Haemost 1992;67:494e8. [14] Kensey KR. The mechanistic relationships between hemorheological characteristics and cardiovascular disease. Curr Med Res Opin 2003;19:587e96. [15] Lee AJ, Mowbray PI, Lowe GD, et al. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation 1998;97:1467e73. [16] Yarnell JW, Baker IA, Sweetnam PM, et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies. Circulation 1991;83:836e44. [17] Bogar L. Hemorheology and hypertension: not “chicken or egg” but two chickens from similar eggs. Clin Hemorheol Microcirc 2002;26:81e3. [18] Rampling MW. Haemorheological disturbances in hypertension: the influence of diabetes and smoking. Clin Hemorheol Microcirc 1999;21:183e7. [19] de Simone G, Devereux RB, Chien S, et al. Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 1990;81:107e17. [20] Dikmenoglu N. An important risk factor as smoking and hypercholesterolemia for cardiovascular disease: blood viscosity. Hacettepe Med J 2006;37:93e7. [21] Erkmen Uyar M, Toprak SK, Saglam H, et al. rHuEPO hyporesponsiveness and related high dosages are associated with hyperviscosity in maintenance hemodialysis patients. Scientific WorldJournal 2013;2013:792698. [22] Oterdoom LH, de Vries AP, van Ree RM, et al. N-Terminal proeB-type natriuretic peptide and mortality in renal transplant recipients versus the general population. Transplantation 2009;87: 1562e70. [23] Ibernon M, Moreso F, Sarrias X, et al. Reverse dipper pattern of blood pressure at 3 months is associated with inflammation and outcome after renal transplantation. Nephrol Dial Transplant 2012;27:2089e95.
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