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revalence Evolution and Impact of Cardiovascular Risk Factors onllograft and Renal Transplant Patient Survival

.M. Dı́az, I. Gich, X. Bonfill, R. Solà, L. Guirado, C. Facundo, Z. Sainz, T. Puig, I. Silva, and J. Ballarín

ABSTRACT

Objective. The prevalence of traditional cardiovascular risk factors in renal transplan-tation is high. Studying the evolution of cardiovascular risk factors over time may help usto design better strategies to control them. The relative impact of traditional cardiovas-cular risk factors on allograft survival and mortality in transplant recipients is not clear.This study was performed to determine the incidence and risk factors for allograft survivaland mortality among renal transplant patients.Patients and Methods. We enrolled 250 patients who had undergone transplantationbetween 1980 and 2004. They were followed for various periods, and we analyzed theimpact of traditional and nontraditional risk factors on renal allograft survival.Results. The prevalence of hypertension was �80% during all the follow-up periods. Bloodpressure diminished, antihypertensive drug prescription increased, and 15% of patients hadadequate blood pressure control during follow-up. The prevalence of pretransplant diabetesmellitus was 6.8%; the incidence of posttransplant diabetes mellitus (PTDM) was 14.2%. Theprevalence of PTDM increased over the course of patient evolution. The prevalence ofdyslipidemia was in all cases �70%; total cholesterol and low-density lipoprotein (LDL)-cholesterol decreased; prescription of statins increased; and the percentage of patients withgood lipid control also increased. The 25% prevalence of active smoking at the time oftransplantation decreased to 13.6% at 10 years posttransplantation. The mean patientfollow-up was 8 � 4.6 years. Sixty-five patients (26%) lost their grafts and 40 (16%) died duringfollow-up. Donor age, exercise, diastolic blood pressure, renal function, and albumin levelswere independent risk factors for graft loss. Charlson comorbidity index at transplantation,recipient and donor ages, exercise, diastolic blood pressure, and LDL-cholesterol posttrans-plantation were independent risk factors for mortality among renal transplant recipients.Conclusion. Blood pressure and lipid control improved during follow-up, however,insufficiently among renal transplant patients. The prevalence of diabetes graduallyincreased, and the incidence of smoking cessation was low. Diastolic blood pressure,exercise, and albuminemia were the most significant modifiable cardiovascular risk factorsfor renal allograft survival. Diastolic blood pressure, LDL-cholesterol level, and exercisewere the most relevant modifiable cardiovascular risk factors for the survival of renal

transplant patients.

From the Department of Nephrology (J.M.D., R.S., L.G., C.F.,.S., I.S., J.B.), Fundació Puigvert, and Department of Clinicalpidemiology and Public Health (I.G., X.B., T.P.), Hospital de laanta Creu i Sant Pau, Universitat Autònoma de Barcelona, Bar-elona, Spain; Red Renal de Investigación Española (REDinREN)J.M.D., L.G., C.F., J.B.), Madrid, Spain; CIBER Epidemiologia y

Heart Failure Research Network (REDINSCOR) (T.P.), Madrid,Spain.

Address reprint requests to Juan Manuel Dı́az, Department ofNephrology, Fundació Puigvert, Universitat Autònoma de Bar-celona, Cartagena, 340, 08025, Barcelona, Spain. E-mail: jdiaz@

alud Pública (CIBERESP) (I.G., X.B., R.S.), Madrid, Spain; andfundacio-puigvert.es

2009 by Elsevier Inc. All rights reserved. 0041-1345/09/$–see front matter60 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2009.06.134

ransplantation Proceedings, 41, 2151–2155 (2009) 2151

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2152 DÍAZ, GICH, BONFILL ET AL

RADITIONAL CARDIOVASCULAR risk factors,such as hypertension (HTN), diabetes, dyslipidemia,

nd smoking, are more common among renal transplantecipients than the general population.1,2 These risk factorsncrease the risk of cardiovascular disease in this popula-ion, and reduce allograft and patient survivals.3–5 Studyinghe evolution of cardiovascular risk factors over time mayelp us to design better strategies for their control. Despiteecent advances in immunosuppressive therapy, improve-ents in long-term graft survival have not been commen-

urate with observed 1-year graft survivals.6 Those improve-ents are necessary to develop better, more specific

trategies to improve allograft survivals. The survival ofidney transplant patients has increased steadily over time,ut death is the most common cause of graft loss in manyublished studies. Recent reports3 have emphasized theole of nontraditional cardiovascular risk factors in renalransplant patients. However, the relative impact of tradi-ional and nontraditional cardiovascular risk factors onllograft survival and mortality is not entirely clear. Knowl-dge of the relative contribution of cardiovascular riskactors on renal allograft and renal transplant patienturvivals may help to steer resources to the most importantodifiable factors.

ATIENTS AND METHODS

e enrolled 250 patients who had undergone transplantationetween 1980 and 2004. Sample selection was performed byandomly selecting 25% of these patients each year. The follow-uperiods after transplantation were 1, 3, and 6 months, as well as 1,, 3, 5, 10, 15, and 20 years.

ariables

he cardiovascular risk factors were age, gender, blood pressureBP), lipids, diabetes, smoking, obesity, exercise, albuminemia,emoglobin, homocysteinemia, serum C-reactive protein, and his-ory of cardiovascular events before transplantation. Transplant-pecific risk factors were time and modality of dialysis, presence ofelayed graft function, acute rejection episodes, immunosuppres-ive regimen, proteinuria, and renal function. HTN, diabetes, andyslipidemia were defined based on current clinical practice guide-

ines (The Seventh Report of the Joint National Committee onrevention, Detection, Evaluation, and Treatment of High Bloodressure; American Diabetes Association Guidelines; Third Re-ort of the Expert Panel on Detection, Evaluation, and Treatmentf High Blood Cholesterol in Adults). A BP lower than 130/80 mmg and a low-density lipoprotein (LDL)-cholesterol lower than 2.6mol/L were both considered good control.

tatistical Analysis

e calculated the quantitative mean values in the first year, usingalues obtained at months 1, 3, 6, and 12 posttransplantation. Therst 5-year quantitative mean values were calculated using thealues obtained at years 2, 3, and 5, as well as the mean during therst year after renal transplantation. An evolution-over-time anal-sis was performed by one-way analysis of variance (ANOVA) inhe case of quantitative variables, and the McNemar test for

ategorical variables.

Differences between groups were tested with the chi-square testor dichotomous variables, and Student t test for continuousariables. The variables with significance upon univariate analysesP � .1) were used to perform a multivariate analysis by means ofogistic regression with the forward stepwise variable inclusion

ethod. Two multivariate models were assessed. The first modelncluded variables capable of changing over the course of the firstear (time-dependent covariates) plus the constant variables (time-onstant covariates). The second model included variables capablef changing over the first 5 years plus the constant variables. In allases, the significance level was set at 5% (� � .05), and thepproximation used was bilateral. Statistical analysis was per-ormed using SPSS version 15.0.

ESULTS

he mean patient follow-up after renal transplantation was� 4.6 years. The mean patient age at the time of

ransplantation was 47.7 � 14.2 years with 65.2% of patientsen and 34.8% women. The initial immunosuppressive

trategy changed over time. All patients received steroids,ut 76.6% were prescribed cyclosporine and 23.4% tacroli-us, with 49.1% azathioprine versus 50.9% mycophenolateofetil, and 57.6% either mono- or polyclonal antibodiesithin the first month either as induction or acute rejection

reatment.Table 1 shows the results of the variables analyzed within

he BP field. The prevalence of HTN was always �80%; itncreased significantly between years 1 and 5, remainingtable between years 5 and 10. Systolic BP, diastolic BP, andulse pressure were reduced during follow-up. In the coursef this period, the quantity of daily antihypertensive agentsas greater, as well as the number of patients receiving

Table 1. Time Evolution of Variables Associated With BloodPressure and Lipids

Variable

Years Posttransplantation

P1 5 10

ystolic BP (mm Hg) 140.7 136.4 135.5 �.001iastolic BP (mm Hg) 81.3 79.3 78.5 �.001ulse pressure (mm Hg) 59.5 57.2 57.1 .015*ypertension (%) 84.9 92.5 93.3 .027*ntihypertensive drugs per day 0.9 1.3 1.6 �.001harmacological treatment (%) 70.0 85.2 86.8 �.001*CE inhibitors (%) 30.0 47.2 51.3 .001*iuretics (%) 12.9 13.1 11.8 .523alcium channel blockers (%) 39.2 42.6 48.7 .392lpha-blockers (%) 15.5 15.3 15.8 .845ngiotensin II antagonist (%) 4.3 9.7 9.2 .006*eta-blockers (%) 15.9 23.9 28.9 .052P control (%) 15.0 16.0 14.9 .523holesterol (mmol/L) 5.6 5.5 5.3 �.001DL-cholesterol (mmol/L) 1.5 1.5 1.6 .107DL-cholesterol (mmol/L) 3.8 3.6 3.3 �.001riglycerides (mmol/L) 1.6 1.6 1.6 .539yslipidemia (%) 82.7 78.6 76.6 .481tatins (%) 24.0 44.0 40.0 �.001*ipid control (%) 18.8 31.3 27.1 1.000

*Year 1 vs year 5.

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CARDIOVASCULAR RISKS IN RENAL TRANSPLANTATION 2153

hese agents, particularly renin-angiotensin system inhibi-ors. Approximately 15% of patients showed adequate BPontrol.

The prevalence of pretransplant diabetes was 6.8%, andhe incidence of posttransplant diabetes mellitus (PTDM)as 14.2%. The prevalence of PTDM increased in theourse of the follow-up with the onset of new cases.

Table 1 also shows the results of the lipid area. Therevalence of dyslipidemia was in all cases �70%, remain-

ng stable over time. Total cholesterol and LDL-cholesterolecreased and the percentage of patients receiving statins

ncreased gradually. The percentage of patients with goodipid control also increased over time.

Twenty-five percent of patients were active smokers athe time of transplantation, 26.8% were former smokers,nd 48.2% had never smoked. The prevalence of activemokers went down to 21.6% over the first month post-ransplantation, remaining stable over the first 5 years. Therevalence continued to diminish gradually thereafter,eaching 13.6% at 10 years posttransplantation; however,hese differences were not significant (P � .063).

During follow-up, 26.1% (95% confidence interval [CI]0.6–31.4) of patients lost their renal allografts. Of the 65ffected patients, 40 (61.5%) died with a functioning graft;8.5% experienced chronic allograf nephropathy; 7.7% hadurgical complications, 6.2% due to acute rejection and.2% due to de novo glomerulonephritis or recurrence ofhe primary disease.

Table 2 shows the results of risk factors for graft loss.xercise was a protective factor, whereas donor age andiastolic BP within the first year of transplantation were riskactors for renal allograft loss. Also, diastolic BP, renalunction, and albumin levels throughout the first 5 yearsere crucial to predict long-term renal allograft survival.n additional study after patient death-censored analysis

onfirmed acute rejection (P � .004; odds ratio [OR] 9.3; CI.02–42.8) and hemoglobin level (P � .002; OR 0.94; CI.91–0.98) also to be risk factors for renal allograft survival.After renal transplantation, 40 patients (16%; 95% CI

1.5–20.5) died, the most frequent cause being cardiovas-ular (42.5%), followed by infectious (27.5%) and neoplas-ic (25%). Table 3 shows the mortality results. We observedhat exercise was a protective factor and that recipient age,harlson index at the time of transplantation, and diastolicP during the first year after transplantation were risk

Table 2. Risk Factors for Graft Loss (Multivariate Analysis)

P OR CI

nalysis during the first yearExercise (yes/no) .018 0.21 0.06–0.76Donor age �.001 1.06 1.03–1.09Diastolic BP .008 1.12 1.03–1.21

nalysis during the first 5 yearsDiastolic BP �.001 1.23 1.12–1.34Glomerular filtration rate .050 0.97 0.93–1.00

tAlbumin .010 0.76 0.62–0.94

actors. Also, the multivariate analysis suggested that donorge, diastolic BP, and LDL-cholesterol predicted long-termenal transplant patient survival.

ISCUSSION

s in other studies,5,7,8 we observed the prevalence of HTNlways to be �80%, independent of the time after renalransplantation. Modifications to the prescription of anti-ypertensive drugs sought to improve long-term BP controlsing the renoprotective and cardioprotective effects ofenin-angiotensin system inhibitors. The degree of BPontrol was unsatisfactory despite the fact that our controlequirements were more rigorous than those of othertudies.8,9 Improving the degree of BP control is basic, asTN in its early stages has been associated with reduces

urvival of both the graft and the transplant recipient.The prevalence of pretransplant diabetes was similar to

hat shown by a Spanish collaborative study,10 but differentrom other studies that have analyzed patients with ahorter evolution,11,12 highlighting the ever-increasing num-er of diabetic patients who currently undergo transplanta-ion.

The prevalence of PTDM was 14.2%, ie, a lower percent-ge than those reported by US study groups,13,14 but similaro that reported in Spain.10 In fact, over the variousosttransplantation periods, the global prevalence of dia-etic patients (before and after transplantation) was alwayslose to 15%, a higher prevalence than the overall Spanishopulation, which is around 10%.15

The growing use of statins and the resulting diminutionf total cholesterol and LDL-cholesterol levels probablyeflect endeavors toward long-term control of cholesterolevels. However, only 30% of our patients were well con-rolled in the long term. The reason for this poor control,articularly over the first year posttransplantation, wasrobably due to scant statin use. However, it is not easy tobtain LDL-cholesterol values �2.6 mmol/L in renal trans-lant patients; statin and ezetimibe administration must

ncrease, and dietary and physical exercise recommenda-ions should be insisted upon. Other studies have shownower degrees of control (7%–27%) than those obtained byur group.16,17

Based on our results, the prevalence of smoking at the

Table 3. Risk Factors for Mortality (Multivariate Analysis)

P OR CI

nalysis during the first yearExercise (yes/no) .040 0.11 0.01–0.91Recipient age �.001 1.13 1.06–1.20Charlson index at transplantation .045 1.73 1.01–2.96Diastolic BP .002 1.13 1.05–1.23

nalysis during the first 5 yearsDonor age .025 1.09 1.01–1.17Diastolic BP .005 1.31 1.09–1.58LDL-cholesterol .038 5.40 1.10–26.5

ime of transplantation was 25%. This prevalence was

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2154 DÍAZ, GICH, BONFILL ET AL

ardly modified shortly after transplantation; it only de-reased to around 14% at 10 years after the procedure.ccording to various studies, between 15% and 50% ofatients ceased smoking at the time of transplantation.18,19

ur data have suggested that we should try to offer moreesources to reduce the prevalence of smoking among renalransplant patients. It is also critical to insist on smokingessation immediately after transplantation.

The results of our study have shown that 26.1% ofatients lost their renal allografts during follow-up; theost frequent cause was patient death, while the secondost frequent cause was chronic allograft nephropathy.ur data are opposed to those of a study in Italy20 in which

he main cause of allograft loss was chronic allograftephropathy. As suggested by Prommool et al,21 discrep-ncies between published studies may be explained by theact that graft survival depends on many variables thatvolve over time following transplantation. Thus, when thessessment was performed in the longer term (beyond 5ears), patient death was the most frequent cause of renalllograft loss. This observation agrees with the data fromur study, in which the mean follow-up was 8 years.Diastolic BP was one of the basic predictive variables of

enal allograft evolution, independent of the degree ofenal function. These data were consistent in a substudyhat censored patient death. Our results agreed with thosef a series of studies4,8,22 which concluded that BP, primar-

ly during the early stages of transplantation (�1 year), wasesponsible for reduced renal allograft survival. Conse-uently, when indicated, antihypertensive treatment shoulde established as early as possible. Attempts should bendertaken to attain the objectives recommended by cur-ent guidelines.

In contrast, we observed exercise to be a protective factoror renal allograft progression. This finding should beighlighted as the medical literature lacks references to it.atients in our study who lost their renal allografts dis-layed lower hemoglobin levels, but this was a conclusiveactor only in the substudy wherein death was censored.ther studies have supported the hypothesis that anemic

atients are prone to graft loss.23 Our data also showed thatenal function is poorer at all times during follow-up amongatients who lose their renal allografts, as shown by othertudies.20,21,24

The 16% mortality observed in our study showed cardio-ascular diseases to be the most frequent cause of death.ur data are similar to previous studies.1 Blood pressure iscrucial factor in the evolution of renal transplant patients

ccording to other authors.8,25 In our experience, theDL-cholesterol level in the first 5 years after renal trans-lantation was an important predictive factor of mortality.n other published studies there are discrepancies. Sometudies have shown that dyslipidemia decreases patienturvival,26–28 and others have not reached this conclu-ion29,30; however, the first set included larger sample sizeshan the others. Moreover, regular physical exercise was a

rotective factor in patient evolution, which is important to

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ighlight since only one study31 revealed a greater percent-ge of sedentary patients among those who succumbeduring follow-up. Our results suggested that the Charlson

ndex at the time of transplantation was a critical factor forhe mortality of renal transplant patients. Other publishedtudies have supported this idea: one showed that theharlson index was the best comorbidity index correlatedith the survival of renal transplant patients,32 and another,

hat patients with a Charlson index greater than 5 experi-nced worse survival.33

In conclusion, the prevalence of traditional cardiovascu-ar risk factors among renal transplant patients is highuring follow-up. Over time there is wider (yet insufficient)P and lipid control, as well as a progressively increasingrevalence of diabetes and a low incidence of smokingessation. Diastolic BP, exercise, and albuminemia were theost significant modifiable cardiovascular risk factors for

enal allograft survival. Diastolic BP, LDL-cholesterol level,nd physical activity were the most significant modifiableardiovascular risk factors for patient survival.

EFERENCES

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eart disease in renal transplant recipients: a prospective study.idney Int 66:441, 20044. Opelz G, Dohler B: Improved long-term outcomes after renal

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mprovement in renal allograft survival despite a marked decreasen acute rejection rates over the most recent era. Am J Transplant:378, 20047. Diaz JM, Sainz Z, Guirado LL, et al: Risk factors for

ardiovascular disease after renal transplantation. Transplant Proc5:1722, 20038. Kasiske BL, Anjum S, Shah R, et al: Hypertension after

idney transplantation. Am J Kidney Dis 43:1071, 20049. Opelz G, Wujciak T, Ritz E: Association of chronic kidney

raft failure with recipient blood pressure. Collaborative Trans-lant Study. Kidney Int 53:217, 199810. Martinez-Castelao A, Hernandez MD, Pascual J, et al:etection and treatment of post kidney transplant hyperglycemia:Spanish multicenter cross-sectional study. Transplant Proc 37:

813, 200511. Schiel R, Heinrich S, Steiner T, et al: Long-term prognosis of

atients after kidney transplantation: a comparison of those with orithout diabetes mellitus. Nephrol Dial Transplant 20:611, 200512. de Mattos AM, Prather J, Olyaei AJ, et al: Cardiovascular

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CARDIOVASCULAR RISKS IN RENAL TRANSPLANTATION 2155

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enal transplant recipients. Transplant Proc 36:108, 200419. Kasiske BL, Klinger D: Cigarette smoking in renal trans-

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idney allograft failure. Kidney Int 62:1848, 200221. Prommool S, Jhangri GS, Cockfield SM, et al: Time depen-

ency of factors affecting renal allograft survival. J Am Soc Nephrol1:565, 200022. Mange KC, Feldman HI, Joffe MM, et al: Blood pressure

nd the survival of renal allografts from living donors. J Am Socephrol 15:187, 200423. Winkelmayer WC, Kewalramani R, Rutstein M, et al: Phar-acoepidemiology of anemia in kidney transplant recipients. J Am

oc Nephrol 15:1347, 200424. Hariharan S, McBride MA, Cherikh WS, et al: Post-transplant

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25. Tutone VK, Mark PB, Stewart GA, et al: Hypertension,ntihypertensive agents and outcomes following renal transplanta-ion. Clin Transplant 19:181, 2005

26. Aakhus S, Dahl K, Wideroe TE: Cardiovascular morbiditynd risk factors in renal transplant patients. Nephrol Dial Trans-lant 14:648, 199927. Wissing KM, Abramowicz D, Broeders N, et al: Hypercho-

esterolemia is associated with increased kidney graft loss caused byhronic rejection in male patients with previous acute rejection.ransplantation 70:464, 200028. Roodnat JI, Mulder PG, Zietse R, et al: Cholesterol as an

ndependent predictor of outcome after renal transplantation.ransplantation 69:1704, 200029. Kasiske BL, Chakkera HA, Roel J: Explained and unex-

lained ischemic heart disease risk after renal transplantation.Am Soc Nephrol 11:1735, 200030. Booth JC, Joseph JT, Jindal RM: Influence of hypercholes-

erolemia on patient and graft survival in recipients of kidneyransplants. Clin Transplant 17:101, 2003

31. Aakhus S, Dahl K, Wideroe TE: Cardiovascular disease intable renal transplant patients in Norway: morbidity and mortalityuring a 5-yr follow-up. Clin Transplant 18:596, 200432. Jassal SV, Schaubel DE, Fenton SS: Baseline comorbidity in

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