Patients with end-stage renal disease (ESRD), particularly

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1 Renal Transplantation Is Not Associated with Regression of Left Ventricular Hypertrophy: A Magnetic Resonance Study Rajan K. Patel,* Patrick B. Mark,* Nicola Johnston, Ellon McGregor, Henry J. Dargie, and Alan G. Jardine* *BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; and Departments of Renal Medicine and Cardiology, Western Infirmary, Glasgow, United Kingdom Background and objectives: Patients with end-stage renal failure (ESRD) have an increased risk of premature cardiovascular (CV) disease. Left ventricular hypertrophy is an independent risk factor for CV events and death in ESRD. Renal transplantation has been associated with reduction in CV risk and echocardiographic regression of left ventricular hypertrophy. However, echocardiography overestimates LV mass in ESRD patients. Cardiac magnetic resonance (CMR) provides more detailed, volume-independent, measures of cardiac structure. Changes in LV mass measured by CMR after renal transplantation were studied. Design, setting, participants, & measurements: Fifty patients underwent CMR on two occasions. Twenty-five were transplanted before the second scan. CMR was performed to measure LV mass index (LVMI), ejection fraction, end-diastolic and end-systolic volumes. Changes were expressed as percentage change over time. Patients with CV events between scans (e.g., acute coronary syndrome, myocardial infarction) were excluded. All transplant patients had serum creatinine <150 mol/l. Results: There was no significant change in LVMI between patients who underwent renal transplantation and those who remained on dialysis (transplanted mean, 2.75%/yr, 9.1 versus dialysis, 3.6%/yr 16.7). In addition, there were no significant changes in end-diastolic volume (transplant, 0.1%/yr 19.5 versus not transplanted, 3.4%/yr 31.5), end-systolic volume (transplanted mean, 15.2%/yr 65.2 versus not transplanted, 3.0%/yr 55.5), or ejection fraction (transplant, 2.1%/yr 11.9 versus not transplanted, 0.4%/yr 5.3). Conclusions: Renal transplantation is not associated with significant regression of LVMI on CMR compared with patients who remain on the transplant waiting list. Clin J Am Soc Nephrol 3: , doi: /CJN Patients with end-stage renal disease (ESRD), particularly those requiring dialysis and transplantation, have an increased risk of premature cardiovascular disease (CVD; (1)). Left ventricular hypertrophy (LVH) is a common feature of patients with ESRD, a component of uremic cardiomyopathy, and an independent risk factor for sudden cardiac death, heart failure, and cardiac arrhythmias in the general population and dialysis patients (2,3). Furthermore, successful renal transplantation (RT) is associated with lower cardiovascular morbidity and mortality compared with patients who remain on the transplant waiting list (4) and has been reportedly associated with significant echocardiographic regression of LVH (5,6). However, accurate echocardiographic estimation of left ventricular (LV) mass in ESRD patients is difficult because of large variation in intravascular (and hence intraventricular) volume during the interdialytic period and during dialysis therapy (7). Furthermore, geometric assumptions made during calculation Received March 22, Accepted June 17, Published online ahead of print. Publication date available at Correspondence: Prof. Alan G Jardine, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, United Kingdom. Phone: ; Fax: ; a.g.jardine@ clinmed.gla.ac.uk of LV mass from conventional M mode echocardiography dimensions (8) result in greater inaccuracies because of geometric LV distortion in patients with LVH and ESRD (representing the majority of patients). Cardiac magnetic resonance (CMR) provides more detailed, volume-independent, measurement of cardiac structure and is considered the gold standard for assessing ventricular dimensions in patients, including those with stage 5 chronic kidney disease (9 11). The aim of this study was to compare changes in LV structure and function between patients that had undergone RT and those that remained on the transplant waiting list. Materials and Methods Patients Since 2002 (9,11), we have used CMR as part of the standard assessment of patients for RT. The renal transplant unit at the Western Infirmary, Glasgow provides transplant services to a population of 2.8 million people in the west of Scotland. The transplant waiting list has 300 to 400 patients at any time point; approximately 100 to 120 new patients are waitlisted and approximately 70 adult transplants are performed annually. In this study, patients were invited for repeat CMR scan. CMR assessment was performed in 25 patients accepted onto the transplant waiting list who were successfully transplanted, and another 25 patients accepted for transplantation, who remained on the waiting list. Copyright 2008 by the American Society of Nephrology ISSN: /

2 1808 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: , 2008 Table 1. Clinical data for patients Not Transplanted (n 25) Transplanted (n 25) P Age 52.7 ( 10.4) 45.9 ( 14.4) 0.06 Male 15 (62.5) 20 (80) 0.18 Diabetes mellitus 4 (16) 5 (20) 0.11 Past history IHD 6 (24) 4 (16) 0.48 Hypertension 24 (96) 22 (88) 0.29 Heart failure 3 (12) 1 (4) 0.29 Smoking status Never 8 (32) 16 (64) Yes 11 (44) 6 (24) 0.08 Ex 6 (24) 3 (12) No. on hemodialysis 12 (48) 10 (44) 0.41 Time on RRT before CMR1 (yr) 2.31 ( 2.6) 3.01 ( 3.0) 0.47 Drug history ESA CMR1 20 (80) 18 (72) 0.51 CMR2 20 (80) 1 (4) Beta blocker CMR1 8 (32) 11 (44) 0.38 CMR2 19 (76) 15 (60) Aspirin CMR1 6 (24) 9 (36) 0.36 CMR2 10 (40) 9 (36) 0.77 ACE-I/AIIRA CMR1 7 (28) 6 (26) 0.75 CMR2 8 (32) 9 (36) 0.77 Calcium channel antagonist CMR1 2 (8) 7 (28) 0.06 CMR2 4 (16) 6 (24) 0.48 Other clinical data Mean SBP CMR1 139 ( 17.2) 135 ( 20.1) 0.40 CMR2 145 ( 20.5) 147 ( 17.4) 0.31 Mean DBP CMR1 81 ( 12.3) 78 ( 11.5) 0.41 CMR2 77 ( 13.2) 81 ( 13.1) 0.35 Mean BSA (m 2 ) 1.86 ( 0.19) 1.88 ( 0.19) 0.80 Mean BMI (kg/m 2 ) CMR ( 4.0) 26.1 ( 5.2) 0.79 CMR ( 4.1) 27.0 ( 5.7) 0.92 Mean hemoglobin (g/dl) CMR ( 1.8) 11.9 ( 1.9) 0.61 CMR ( 7.0) 12.8 ( 2.3) 0.89 Mean hematocrit CMR ( 0.05) 0.37 ( 0.06) 0.22 CMR ( 0.05) 0.39 ( 0.06) 0.26 Data are presented as number (%) or mean SD. Tests of significance are t test or 2. IHD, ischemic heart disease; RRT, renal replacement therapy; ESA, erythropoiesis stimulating agent; CMR, cardiac MRI; ACE-I, angiotensin-converting enzyme inhibitor; AIIRA, angiotensin II receptor antagonist; SBP, systolic blood pressure (expressed in mmhg); DBP, diastolic blood pressure; BSA, body surface area; BMI, body mass index. CMR Technique and Analysis CMR was performed using a 1.5-Tesla MRI scanner (Sonata, Siemens, Erlangan, Germany) with LV mass and function assessed as described previously (9). In hemodialysis patients, CMR was consistently performed 24 h after the end of the last dialysis session. Patients on peritoneal dialysis were studied at their dry weight, according to

3 Clin J Am Soc Nephrol 3: , 2008 LVH and Renal Transplantation 1809 Table 2. Cardiac MRI results for baseline (CMR1) and second scan (CMR2) Not Transplanted (n 25) Transplanted (n 25) P Mean time between CMRs (yr) 2.4 ( 1.1) 2.8 ( 1.2) 0.14 Mean time transplant to CMR2 (yr) 1.8 ( 0.9) Ejection fraction (%) CMR ( 12.2) 66.3 ( 11.5) 0.56 CMR ( 11.5) 67.1 ( 12.2) 0.52 LVMI (g/m 2 ) CMR (75.1, 113.5) 94.7 (77.2, 108.7) 0.96 CMR (69.3, 112.1) 99.1 (79.1, 119.9) 0.27 cedv (ml/m 2 ) CMR ( 31.4) 69.3 ( 18.9) 0.51 CMR ( 18.9) 62.3 ( 18.6) 0.59 cesv (ml/m 2 ) CMR ( 23.3) 24.3 ( 20.6) 0.55 CMR ( 17.4) 25.4 ( 20.7) 0.51 % change ejection fraction/yr 2.1 ( 11.9) 0.4 ( 5.3) 0.34 % change LVMI/yr 3.6 ( 16.7) 2.75 (9.1) 0.10 % change EDV/yr 3.4 ( 31.5) 0.1 ( 19.5) 0.64 % change ESV/yr 3.0 ( 55.5) 15.2 ( 65.2) 0.48 LVH CMR1 17 (68) 17 (68) 1.00 CMR2 15 (60) 19 (76) 0.23 LVSD CMR1 5 (20) 3 (12) CMR2 2 (8) 2 (8) LV dilatation CMR1 5 (20) 4 (16) CMR2 1 (4) 0 Data are mean ( SD), except for LVMI on MRI where median (interquartile range) is shown. Tests of significance are t test and 2 except LVMI on MRI for where Mann-Whitney is used. LVMI, left ventricular mass index; cedv, corrected enddiastolic volume; cesv, corrected end-systolic volume. clinical charts. A fast imaging with steady-state precession (true FISP) sequence was used to acquire cine images in long axis planes (vertical long axis, horizontal long axis, LV outflow tract) followed by sequential short axis LV cine loops (8-mm slice thickness, 2-mm gap between slices) from the atrioventicular ring to the apex. Imaging parameters, which were standardized for all subjects, included repetition time/echo time/flip angle/voxel size/field of view 3.14 ms/1.6 ms/60 / mm/340 mm. LV function was analyzed by two observers, blinded to patient clinical characteristics (including transplantation status), from short axis cine loops using manual tracing of epicardial and endocardial end-systolic and end-diastolic contours with endsystolic and end-diastolic volumes and LV mass calculated using analysis software (Argus, Siemens). Time between scans for both groups was calculated from the difference between dates of CMRs. Because of interpatient variation in time between CMR scans, changes were expressed as percentage change per year. Data Collection Mean hemoglobin and blood pressure were calculated from monthly measurements 3 months before and after CMR scanning. Blood pressure measurements taken immediately before start of hemodialysis were recorded. Statistical Analysis Statistical analysis was performed using SPSS version 13.0 (SPSS, Chicago, IL). Data are expressed as mean SD or median and interquartile range. Comparisons were made between those patients who received a transplant and those who remained on the waiting list by t test (for normal data) or Mann-Whitney test (for non-normal data). Results Fifty patients were studied. The mean time between the CMR studies was 2.8 yr for those transplanted and 2.4 yr for those remaining on the waiting list. No patients had cardiac events (myocardial infarction, acute coronary syndrome, cardiac arrhythmias) between scans. All transplanted patients had serum creatinine 150 mol/l at the time of second scanning. The demographic data are presented in Table 1. This shows that patients who received a transplant were younger yrs versus yrs (P 0.06). However, there was no significant difference in the number of patients who were male, who had diabetes, a past history of ischemic heart disease, hypertension, heart failure, or in the smoking status (although there was a trend toward nonsmokers in the trans-

4 1810 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: , 2008 planted group). Forty-eight percent of patients who were not transplanted were on in-center hemodialysis at the time of first CMR scan, compared with 56% of those who received a transplant. At the time of first scan, there was no significant difference in duration on renal replacement therapy between both groups (not transplanted, yr versus transplanted, yr; P 0.47). The distribution of cardioactive drugs was not statistically significant different between groups. The only noted change was that only one patient was on ESA after transplantation, compared with 80% of those who remained on the waiting list. Systolic blood pressure was higher after transplantation and during transplant assessment. However, there was no significant difference in systolic or diastolic blood pressure between those transplanted or those remaining on the waiting list, nor was there a particular change in the number of antihypertensive agents. Hemoglobin was well controlled on dialysis, and there was no significant difference between groups after transplantation. There was no difference in any of the cardiac parameters measured (Table 2; Figure 1): ejection fraction, LV mass index (LVMI), corrected end-diastolic and end-systolic volumes, before transplantation or at follow-up. If anything, there is a small reduction in LVMI ( 3.6%/yr) in dialysis patients and a small increase associated with transplantation (2.8%/yr). However, none of the measured cardiac parameters achieved statistical significance. The proportion of patients with LVH was 68% in both groups and did not change significantly on follow-up. Discussion Patients with end-stage renal failure have a greatly increased risk of CVD. However, the pattern of CVD differs from the general population with a disproportionate increase in sudden cardiac death and the relatively smaller increase in myocardial infarction. There is a general consensus that this excess risk is likely due to changes in LV structure and function that together have been labeled uremic cardiomyopathy (12). The most common form of this is LVH, which may be particularly severe and associated with cardiac fibrosis. Cardiac fibrosis leads to chaotic conduction and probably provides the link between uremic cardiomyopathy and sudden, presumed arrhythmic, death. Patients with a successful transplant have reduced cardiac risk compared with patients who remain on dialysis (4); however, this still remains higher than the general population. A number of studies have suggested that transplantation may be associated with regression of LVH. However, there are conflicting results, and echocardiography is unreliable in patients on hemodialysis because of changes in intravascular volume (13). These inaccuracies are avoided with CMR scanning because of detailed characterization of the LV borders. Furthermore, echocardiography assumes an approximately cubic shape of the left ventricle when calculating LVMI (8) using standard M mode measurements. This method has been validated in normal hearts; however, it may not be valid in ESRD patients because of pressure and volume overload leading to eccentric LV remodelling (14). In view of this, we have performed the present study using Figure 1. (A) Mean percentage change ejection fraction per year (with 95% confidence intervals). No transplant, 2.1%/yr (11.9); transplant, 0.4%/yr (5.3); P (B) Mean percentage change LVMI per year (with 95% confidence interval). No transplant, 3.6%/yr (16.7); transplant 2.8%/yr (9.1); P CMR imaging to provide accurate, volume-independent assessment of LV mass. The study shows that there is no significant change in LVMI in patients who are well controlled and survive on hospital hemodialysis for a period of 2 to 3 yr. Similarly, patients who underwent successful transplantation over the same time scale showed no change in LV mass. Although the current study is limited by small sample size and variability in timing of scans, it is the first study to serially evaluate the LVs of patients who have undergone RT using CMR. The greater precision of CMR permits smaller studies than echocardiography (15). Furthermore, interdialytic changes of hemodialysis patients were reduced by standardizing the timing of CMR (24 h after end of last hemodialysis session) for both scans. CVD, particularly sudden cardiac death, remains the major cause of mortality after RT (16,17), and this study supports a possible role for LVH. These findings cast doubt on the revers-

5 Clin J Am Soc Nephrol 3: , 2008 LVH and Renal Transplantation 1811 ibility of LVH in this population, and it is likely that prevention, by tight blood pressure control, in the earliest phases of progressive renal disease with the aim of preventing development of LVH will be a more successful strategy. Moreover, it seems likely that the previous positive results are artifactual resulting from normalization of intravascular volume after successful transplantation. Acknowledgments This study was supported by the Darlinda s Charity for Renal Research. Rajan Patel (FS/08/030/24993), Patrick Mark, and Nicola Johnston are funded by the British Heart Foundation. Disclosures None. References 1. Baigent C, Burbury K, Wheeler D: Premature cardiovascular disease in chronic renal failure. Lancet 356: , Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322: , Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray D, Barre PE: Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int 49: , Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341: , Montanaro D, Gropuzzo M, Tulissi P, Vallone C, Boscutti G, Mioni R, Risaliti A, Baccarani U, Adani GL, Sainz M, Lorenzin D, Bresadola F, Mioni G: Effects of successful renal transplantation on left ventricular mass. Transplant Proc 37: , Dudziak M, Debska-Slizien A, Rutkowski B: Cardiovascular effects of successful renal transplantation: a 30-month study on left ventricular morphology, systolic and diastolic functions. Transplant Proc 37: , Stewart GA, Foster J, Cowan M, Rooney E, McDonagh T, Dargie HJ, Rodger RS, Jardine AG: Echocardiography overestimates left ventricular mass in hemodialysis patients relative to magnetic resonance imaging. Kidney Int 56: , Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation 55: , Stewart GA, Mark PB, Johnston N, Foster JE, Cowan M, Rodger RS, Dargie HJ, Jardine AG: Determinants of hypertension and left ventricular function in end stage renal failure: a pilot study using cardiovascular magnetic resonance imaging. Clin Physiol Funct Imaging 24: , Bottini PB, Carr AA, Prisant LM, Flickinger FW, Allison JD, Gottdiener JS: Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens 8: , Mark PB, Johnston N, Groenning BA, Foster JE, Blyth KG, Martin TN, Steedman T, Dargie HJ, Jardine AG: Redefinition of uremic cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging. Kidney Int 69: , Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, Barre PE: Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 47: , Hunold P, Vogt FM, Heemann UW, Zimmermann U, Barkhausen J: Myocardial mass and volume measurement of hypertrophic left ventricles by MRI-study in dialysis patients examined before and after dialysis. J Cardiovasc Magn Reson 5: , Mark PB, Patel RK, Jardine AG: Are we overestimating left ventricular abnormalities in end-stage renal disease? Nephrol Dial Transplant 22: , Keenan NG, Pennell DJ: CMR of ventricular function. Echocardiography 24: , Rigatto C: Clinical epidemiology of cardiac disease in renal transplant recipients. Semin Dial 16: , Collins AJ, Foley R, Herzog C, Chavers B, Gilbertson D, Ishani A, Kasiske B, Liu J, Mau LW, McBean M, Murray A, St Peter W, Xue J, Fan Q, Guo H, Li Q, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Wang C, Weinhandl E, Zaun D, Zhang R, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L: Excerpts from the United States Renal Data System 2007 annual data report. Am J Kidney Dis 51[Suppl]: S1 S320, 2008