Blood Pressure Control According to the Prevalence of Diabetes in Renal Transplant Recipients

Blood Pressure Control According to the Prevalence of Diabetes in Renal Transplant Recipients E. Zbroch, J. Malyszko, I. Glowinska, D. Maciorkowska, G. Kobus, and M. Mysliwiec ABSTRACT Hypertension is one of the most frequent complications of renal transplantation. About 70% to 90% of this population display either high blood pressure (BP) or require antihypertensive therapy. Diabetes mellitus is also a common finding among kidney transplant recipients. The aim of the study was to assess the BP control among kidney transplant recipients according to the prevalence of diabetes. This retrospective analysis included 172 renal transplant recipients of overall mean age 50 years and 51% males. Hypertension was present in 79% of patients. About one-third of the studied population showed abnormal blood pressures based on office measurements. The cohort was divided into two groups according to the presence of diabetes: group 1, diabetic patients (n 14) versus group 2, nondiabetics (n 158). Nondiabetic patients were significantly older than diabetic ones (61.5 versus 49 years; P.05) and their time after renal transplantation was longer (98.83 versus 67.33 months, P.05). There was no difference in regard to hypertension prevalence, mean BP value, percentage of abnormal ( 140/90 mm Hg) BP values or glomerular filtration rate. Diabetic patients were prescribed less steroid. The main hypotensive drug used in whole cohort and in no-diabetic patients was a beta-blocker (n 64, 37%; n 4, 28%), patients with diabetes used beta-blockers and angiotensinconverting enzyme inhibitors at the same frequency (n 60, 37%). The main causative factor for hypertension appeared to be the calcineurin inhibitor. More aggressive antihypertensive treatment using combined drugs, including RAS blockers, might provide adequate BP control among renal transplant subjects with high cardiovascular risk. AS EARLY AS THE FRAMINGHAM STUDY, conducted in 1961, hypertension (HTN) and diabetes were identified as the main risk factors for cardiovascular diseases. 1 HTN is a common disorder among patients with both types of diabetes. 2,3 It about 33% of persons with 20 years and about 70% at 40 years of diabetes type 1. 2 Among newly diagnosed diabetes type 2 cases, about 40% are hypertensive. 4 HTN is also one of the most frequent complications of renal transplantation; about 70% to 90% of this population displays either high blood pressure (BP) or requires antihypertensive therapy. 5 An abnormal BP is a potent nonimmunologic risk factor that directly relates to patient and graft survivals. 6 Uncontrolled HTN not only leads to de novo congestive heart failure and coronary heart disease, but also may contribute to a reduced glomerular filtration rate (GFR). HTN after renal transplantation derives from the interactions of a variety of factors, some of which are related to the transplanted kidney, or the native kidneys or immunosuppressive medications. It increases over time after transplantation. 6 Diabetes mellitus is also a common finding in kidney transplant recipients. Type 2, new-onset diabetes mellitus after transplantation is a serious condition enhancing cardiovascular risk, affecting longterm allograft survival and increasing complication. It occurs among 2% to 53% of all solid organ transplantations with a component like HTN, attributable to the immunosuppressive medications. 7 Therefore, effective hypotensive and hypoglycemic treatment of renal transplant patients is a major mission of daily practice. 8 The aim of the present study was to assess BP control among kidney transplant recipients according to the prevalence of diabetes. From the Department of Nephrology and Transplantology with Dialysis Center, Medical University, Bialystok, Poland. Address reprint requests to Professor Jolanta Malyszko, Department of Nephrology and Transplantology, Medical University 15-540 Bialystok, Zurawia14, Poland. E-mail: jolmal@poczta.onet.pl 0041-1345/13/$ see front matter 2013 by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.transproceed.2012.05.089 360 Park Avenue South, New York, NY 10010-1710 200 Transplantation Proceedings, 45, 200 204 (2013)

HYPERTENSION AND DIABETES 201 PATIENTS AND METHODS This retrospective analysis of medical documentation of 172 renal transplant recipients of mean age 50 years included 51% males and 49% females. We examined the medical history of hypertension and diabetes, the time of transplantation as well as the hypotensive and immunosuppressive treatments. Diabetes was diagnosed before transplantation in two type 1 diabics, both of whom were blind and, one also had toe amputations versus for type 2 cases wherein, it was the cause of end-stage kidney failure. In contrast as new-onset diabetes mellitus was observed in eight subjects after transplantation. Diabetic controls was judged by HbA1c target values below 7% as assessed by HPLC (high-pressure liquid chromatography). BP was measured twice (in the beginning and in the end; the mean value was the count), during each routine visit to the Outpatient Transplant Unit in the sitting position after 5- minute rest, using a manual sphygmomanometer with an arm cuff. We analyzed the arithmetic average of median values from three visits. Routine visits were scheduled every 2 to 3 months. The laboratory tests included red blood count, hemoglobin, creatinine, total cholesterol, triglycerides as well as cyclosporine or tacrolimus level. GFR was estimated using the simplified MDRD formula. The type and dose of hypotensive and immunosuppressive drugs the number and were analyzed in relation to BP control. According to the guidelines of Polish and European Society of Hypertension, 9 an abnormal BP was a value 140/90 mm Hg. HTN was defined as a hypotensive drug prescription or an abnormal BP. The hypotensive drugs included calcium channel blockers (CCB), angiotensinconverting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), beta-blockers (BB), and diuretics. The immunosuppressive regimen of prevalent kidney transplant recipients consisted of calcineurin inhibitors (CNI), in combination with prednisone and azathioprine or mycophenolate mofetil. The study group was divided according to the presence of diabetes: group I diabetics versus group II nondiabetics. Statistical Analysis Data were expressed as mean values standard deviations (SD). The data were analyzed using Statistica 7.0 computer software. Examination of the distribution normality of variables employed the W Shapiro-Wilk test. The data were also transformed logarithmically to achieve a normal distribution, whenever possible. Normally distributed measurements are reported as mean values SD; nonnormally distributed data, as median and minimal maximal values. P.05 was considered statistically significant. RESULTS The mean age of the studied group was 50 years with 51% (n 88) men. HTN was present in 79% of patients. The overall mean BP was 130/80 mm Hg. The studied cohort was divided according to group I with diabetes (n 14, 8%) versus group II without diabetes (n 158). Group I patients were significantly older (P.05) and their time after renal transplantation longer (98.83 versus 67.33 months, P.05). There was no difference between them in the presence of HTN, mean BP value, percentage of abnormal ( 140/90 mm Hg) BPs, GFR, or laboratory tests, including cyclosporine or tacrolimus level. The analysis of the kind of immunosuppressive therapy revealed lower doses of steroids in the diabetic group. The characteristics of the groups are demonstrated in Table 1. The following hypotensive drugs were used: BB (37%), CCB (27%), ACEI (23%), and diuretics (12%). The main hypotensive drug among patients without diabetes was a BB (28%), followed by CCB (21%), ACEI (21%), and diuretics (14%). For patients with diabetes, they were BB and ACEI in the same frequency (37%) followed by CCB (28%) and diuretics (12%). One was the mean number of hypotensive Table 1. Clinical and Biochemical Characteristics of the Studied Kidney Transplant Recipients According to the Presence of Diabetes Whole Study Group (n 172) Group I Patients With Diabetes (n 14; 8%) Group II Patients Without Diabetes (n 158) P Age (y) 48.13 13.7 59.29 11.1 47.14 13.5.0001 Male (%) 88 (51%) 8 (57%) 80 (57%) NS Time after kidney transplantation (mos) 73.83 57.4 98.08 47.7 71.72 57.7.038 egfr (ml/min/1.73 m 2 ) 63.53 27.9 55.87 24.9 64.21 28.1 NS Creatinine (mg/dl) 1.36 0.7 1.39 0.4 1.36 0.8 NS Erythrocyte count (mln/ml) 4.22 0.6 4.32 0.5 4.21 0.6 NS Hemoglobin (g/dl) 12.79 1.8 13.04 1.7 12.77 1.8 NS Total cholesterol (mg/dl) 198.19 42.9 173.67 7.6 199.77 43.8 NS Triglycerides (mg/dl) 140.36 69.0 134.8 31.7 140.67 70.6 NS Serum cyclosporin level (ng/ml) 201.95 216.8 141.87 26.9 207.01 225.0 NS Blood pressure (mm Hg) Systolic 127.70 1.6 130.36 7.9 127.47 11.7 NS Diastolic 78.63 8.5 77.5 4.3 78.73 8.8 NS Blood pressure 140/90 mm Hg 44 (25%) 3 (21%) 41 (25%) NS Presence of hypertension 153 (79%) 11 (78%) 123 (77%) NS Use of calcineurin inhibitors 167 (97%) 14 (100%) 153 (96%) NS Use of mycophenolate mofetil 124 (72%) 9 (64%) 115 (72%) NS Use of azathioprine 29 (16%) 2 (14%) 27 (17%) NS Use of steroids 111 (64%) 6 (40%) 105 (66%).023 egfr, estimated glomerular filtration rate; NS, not significant.

202 ZBROCH, MALYSZKO, GLOWINSKA ET AL drugs among all subjects regardless of diabetes diagnosis. The whole cohort of renal transplant recipients was analyzed according to the type of immunosuppressive therapy. CNI were prescribed for 97% (N 167) of patients. More of them were hypertensive compared with subjects free of CNI (98%; n 130 versus 92% n 36, P.04) and their mean BP value was higher (130/80 versus 120/70 mm Hg, P.05). They more frequently displayed diabetes (8%, n 14 versus 0%) or increased total cholesterol concentrations (Table 2). Steroids were used by 64% (n 111) of renal transplant recipients. Patients on steroid therapy showed a shorter time after transplantation than those withdrawn from this drug. Steroids users revealed a lower estimated GFR. The mean fasting glucose was lower and prevalence of diabetes less among the group not receiving steroids. DISCUSSION Hypertension and diabetes are main factors related to cardiovascular mortality and morbidity among the general population. 10 Kidney transplant patients are often affected by abnormal BP and impaired glucose tolerance, which directly relate to patient and graft survivals. 2,7 Hillebrand et al 11 suggested that BP control is a key target to achieve long-term graft survival, which was longer among subjects with well-controlled BP. HTN is one of the most frequent complications of renal transplantation; about 70% to 90% of this population either displayed a high BP or requires antihypertensive therapy. 1 Our cohort included 79% of kidney transplant recipients to be hypertensive. There are some discrepancies in the target BP for these patients. According to ESH/ESC and JNC 7 guidelines, the target BP should be less than 140/90 mm Hg in the general population. 12,13 However neither JNC 7 nor ESH/ESC guidelines, including the latest update from 2009, make recommendations for solid organ transplant recipients. The NICE guidelines (Guideline 1.9 C-CVD for hypertension in renal transplant patients) recommend a target BP lower than 130/80 mm Hg, similar to that in the 2009 KDIGO (Kidney Disease Improving Global Outcomes) guidelines. 14 However, NICE and KDIGO guidelines are based only on expert opinion of good practice. There have been no randomized prospective studies estimating the target BP in renal transplant recipients. The latest guidelines of the Polish Society of Hypertension, in 2011, have increased the target BP to 140/90 mm Hg, even among subjects with higher cardiovascular risk such as transplant patients. 9,15 For our cohort of kidney transplant recipients, we adopted that target value of BP observing abnormal BP ( 140/90 mm Hg) among 25% of patients, regardless of the presence of diabetes. Using the same criteria, Basiratnia et al 16 reported a higher BP in 25.7% of 66 kidney transplant recipients. Małyszko et al, 17 comparing BP control in two groups of high cardiovascular risk subjects coronary heart disease and kidney allograft recipients, demonstrated an abnormal value (above 130/80 mm Hg) in 60% of transplanted patients. Examining 1666 renal transplant recipients Kasikse et al 18 observed a BP below 140/90 mm Hg only in almost half of them (55%). However, the method of BP measurement may play a role, not only in the general population, but also among transplanted patients. Basiratnia et al 16 verified that the casual method of office BP measurement showed 8/17 subjects who were hypertensive to be normotensive by ambulatory BP monitoring (ABPM). Comparing office blood pressure and ABPM, Paripovic et al 19 observed ABPM to discuss 24% with masked hypertension and 21% with hidden uncontrolled HTN. Diabetes can lead to cardiovascular diseases and may affect blood pressure control. In a study of 369 treated subjects on chronic hemodialysis, Agarwal 20 observed the presence of diabetes to be associated with an higher rate of predialysis BP. We also observed a similar relation according to the presence of diabetes in our previous study of BP control among hemodialysis patients. 21 In the present study there were no difference in BP control and the prevalence of HTN between the groups with versus without diabetes. What is even more interesting, diabetic patients were Table 2. Clinical and Biochemical Characteristics of the Studied Kidney Transplant Recipients According to the Use of Calcineurin Inhibitors/Steroids Whole Group (n 172) Use of Calcineurin Inhibitors (n 167) Without Calcineurin Inhibitors (n 5) P Blood pressure (mm Hg) Systolic 127.70 1.6 127.99 11.6 118 4.5.006 Diastolic 78.63 8.5 78.77 8.6 74 5.5.036 Total cholesterol (mg/dl) 198.19 42.9 199.47 42.9 157.13 14.7.027 Presence of hypertension 153 (79%) 130 (98%) 36 (92%).0443 Presence of diabetes 14 (8%) 14 (8%) 0 (0%) NS Use of Steroids (n 111) Without Steroids (n 61) Time after kidney transplantation (mons) 73.83 57.4 66.4 57.2 87.17 55.8.009 Creatinine (mg/dl) 1.36 0.7 1.4 0.7 1.29 0.8.037 egfr (ml/min/1.73 m 2 ) 63.53 27.9 60.62 27.5 68.69 28.0.036 Fasting glucose (mg/dl) 101.6 39.3 98.78 38.4 113.69 49.7.0078 Presence of diabetes 14 (8%) 6 (5%) 8 (13%).023 egfr, estimated glomerular filtration rate; NS, not significant.

HYPERTENSION AND DIABETES 203 significantly older and their time after transplantation longer compared with those without diabetes. Only 40% of them compared to 66% of patients without diabetes were prescribed glucocorticosteroids, due to the tendency to complete withdrawal in long-term allografts. Our diabetic patients included those with diabetes type 1 and 2 as well as with new-onset diabetes after transplantation, which was more frequently diagnosed among patients prescribed tacrolimus, or were older, or were obese or overweight (data not shown). CNI, especially cyclosporine, play predominant roles in the pathophysiology of posttransplant HTN. The hypertensive effect of CNI depends on increased systemic vascular resistance due to arterial vasoconstriction. 5,6 CNI also reduce GFR and increase tubular reabsorption of sodium leading to salt and water retention and rise in BP. 6 CNI, especially tacrolimus, shows diabetogenic qualities. 22 The recent cross-sectional, multicenter study of Bohlke et al 23 confirmed that cyclosporine and glucocorticosteroids were independent predictors of high BP after kidney transplantation. We also reaffirmed this relationship: the CNI group was more often hypertensive or diabetic. Beside modifying their life style most kidney allograft recipients, require antihypertensive agents to treat HTN. 5 In a study of BP among 119 patients after renal transplantation, Wadei et al 24 described 71% to use two hypotensive drugs. In our cohort, the mean number of antihypertensive agents was one. Małyszko et al 17 reported that a study group of hypertensive patients after kidney transplantation required a mean of three hypotensive drugs. In turn, a Korean study of BP control in 3859 patients with type 2 diabetes, documented 65.4% to require monotherapy while 24.7% were prescribed two hypotensive agents. 25 No particular class of antihypertensive drugs is recommended for kidney transplant recipients. The choice of a drugs depends not only on their efficacy and tolerance but also their possible impact on the renal graft and their pharmacological interference with the immunosuppressive therapy. 6 CCB, particular dihydropyridine, are the most frequently prescribed hypotensive class of medications for patients after renal transplantation, namely 80% of subjects studied by Małyszko et al. 17 Another classes of hypotensive regimens useful in patients after transplantation are ACEI and ARB. Assessing BP control after heart compared with kidney transplantation Przybylowski et al 26 and ACEI were prescribed for 40%. Among our cohort the most used hypotensive drug was a BB. Among diabetic, the second was a CCB or ACEI. Patients without diabetes used BB and ACEI at the same frequency; in second position was CCA among that group. Type 2 diabetic Korean patients showed the main hypotensive drug to be an ARB (52.8%) and then a CCA (21.8%) with BB only used by 10.4%. 25 Due to prevalence of cardiac disease in this population BB are widely used for chronic kidney disease, particularly associated with hyperactivity of the sympathetic nervous system. 27 This phenomena may have influenced the wide use of BB among our cohort of kidney patients. In conclusion, HTN is a common finding in renal transplant recipients. About one-third of the studied population had an abnormal BP based on the office BP measurements. 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