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actors Involved in Baseline Hyperhomocysteinemian Renal Transplantation

.M. Dı́az, Z. Sainz, I. Gich, L.L. Guirado, T. Puig, A. Oliver, R. Montañés, E. Chuy, and R. Solà

ABSTRACT

Hyperhomocysteinemia (hyperHcy) is one cardiovascular risk. The objective of this studywas to establish the prevalence demographic, and clinical and analytical factors related tohyperhomocysteinemia among renal transplant patients. The mean Hcy level was 17.3�mol/L; the prevalence of hyperHcy was 61.2%. The population was categorized ashyperHcy and normal-homocysteinemia (Hcy) patients. Those subjects with hyperHcywere mostly men, with lower intraerythrocyte folate and vitamin B12 levels, higherfibrinogen levels, and poorer renal function. Multivariate evaluation showed that creati-nine clearance, plasma intraerythrocyte folate and vitamin B12 levels, and plasmafibrinogen levels were independently associated with Hcy levels. Even though the Hcy levelwas slightly higher among patients who suffered a posttransplantation cardiovascular

event, this was statistically significant.

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URVIVAL OF RENAL grafts has progressively in-creased over the last few years. The most frequent

auses of renal graft loss are death of the patient with aunctional graft (basically cardiovascular in etiology) andhronic graft nephropathy.1 In addition to the well-knownactors of cardiovascular risk (diabetes, hypertension, dys-ipidemia, and smoking habit), other aspects are gainingncreasing importance, particularly hyperhomocysteinemiahyperHcy).2 HyperHcy is one factor of cardiovascular riskn the general population, which has been associated withoronary mortality.3 Some studies have shown an inverseelationship between homocysteine levels and the degree ofenal function.4 However, data on prevalence, predisposingactors and prognosis of hyperHcy in patients with renalransplants are sparse and inconclusive.5,6 The objective ofhis study was to establish the prevalence, demographics,nd clinical and analytical factors related to hyperHcy intable patients with renal transplants, and to assess whetheratients with hyperHcy were more prone to a cardiovascu-

ar event.

ATIENTS AND METHODS

n this observational, prospective analysis we studied 209 patientsith renal transplants (139 men [66.5%] and 70 women [33.5%]) ofean age 52 years (standard deviation [SD] 13.8), carrying a

unctional graft for over 1 year and with a mean posttransplanta-ion follow-up of 5 years. The data set included demographics,osttransplantation atherosclerotic cardiovascular diseases, and

actors influencing homocysteine metabolism. E

2005 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 37, 3799–3801 (2005)

To avoid interference with other data (homocysteinemia (Hcy),ntraerythrocyte folate, and vitamin B12 levels), none of the pa-ients was receiving treatment with either folic acid or vitamin Bomplex. The technology to determine Hcy, vitamin B12, and folatelasma levels was chemoluminescence. HyperHcy has been defineds plasma homocysteine levels greater than 15 �mol/L. Continuousariables were expressed as mean values with SDs between brack-ts. For categorical variables the results were expressed as percent-ges. Chi-square and Student t tests were used in bivariate studies.

stepwise multivariate study was performed with logistic regres-ion with creatinine clearance chosen as the indicator of the renalunction, since there was colinearity with plasma creatinine).ignificance was considered when P � .05.

ESULTS

he mean Hcy level of the entire population was 17.3mol/L (6.7, 0.7 to 37.1) with intraerythrocyte folate levelsf 426 nmol/L (299, 62 to 1754) and vitamin B12 levels of50 pmol/L (152, 112 to 1600). The prevalence of hyperho-ocysteinemia was 61.2% (95% confidence interval [CI]

From the Renal Transplantation Unit (J.M.D., Z.S., L.L.G., E.C.,.S.), Nephrology Department, Fundació Puigvert; Epidemiologyepartment (J.G., T.P.), Hospital de la Santa Creu i Sant Pau;nd Laboratory Service (A.O., R.M.), Fundació Puigverts Univer-itat Autónoma Barcelona, Barcelona, Spain.Address reprint requests to J.M. Dı́az, Renal Transplantationnit, Nephrology Department, Fundació Puigverts Universitatutónoma Barcelona, Cartagena, 340.08025 Barcelona, Spain.

-mail: jdiaz@fundacio-puigvert.es

0041-1345/05/$–see front matterdoi:10.1016/j.transproceed.2005.10.056

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3800 DÍAZ, SAINZ, GICH ET AL

4.6 to 67.8). Within the group of patients with hyperHcy,ost (91%) presented with moderate hyperHcy (15 to 30mol/L levels), whereas only 9% had levels higher than 30mol/L.Once the population was categorized according to Hcy

evels those with hyperHcy were mostly men, mostly aged,aving lower intraerythrocyte folate and vitamin B12 levels,igher fibrinogen levels, and poorer renal function (Table 1).No relationship was found with the other parameters:

moking habit, diabetes, arterial hypertension, dyslipide-ia, albuminemia, or C-reactive protein.Even though the Hcy level was slightly higher among

atients receiving cyclosporine compared to those receivingacrolimus (17.8 �mol/L vs 17.1 �mol/L), the difference wasot statistically significant (P � .39).Multivariate evaluation showed that creatinine clearance,

lasma intraerythrocyte folate and vitamin B12 levels, asell as plasma fibrinogen level were independently associ-ted with the Hcy level (Table 1).

Since glomerular filtration is a significant factor, when werouped the population over the base of their renal functionpplying the current K/DOKI (Kidney Disease Outcomeuality Initiative) definitions (Table 2), we observed a

rogressive increase in Hcy at the stages of chronic renalisease (stage 1: 12.5 �mol/L; stage 2: 14.5 �mol/L; stage 3:8.1 �mol/L; stage 4: 25.4 �mol/L). However, a filtrationate below 60 mL/min was basically the one at which theifferences were more noticeable, since there were noifferences between patients in stages 1 and 2 but thereere between these two groups and patients in stages 3 and 4.Following renal transplantation and prior to Hcy baseline

Table 1. Results According to C

Univariate study

Normal Hcy HyperHcy

ge (y) 47.4 (11.9) 54.2 (14.3)ender (men) 55% 73.6%olic (nmol/L) 475 (342) 396 (266)

12 (pmol/L) 379 (192) 332 (118)ibrinogen (g/L) 3.48 (0.97) 3.92 (0.93)RP (mg/L) 4.22 (5) 5.9 (10.1)lbumin (g/L) 42.7 (3.6) 43 (3.7)reatinine (�mol/L) 112 (34) 166 (67)reatinine clearance (mL/min) 72 (23) 50 (22)roteinuria � 0.3 g/day 18.8% 40.6%

Co, colinearity with creatinine clearance.

Table 2. Hcy Levels in Stages of Chronic Kidney Diseases

StageGlomerular

filtration (mL/min) nHomocysteine

(�mol/L)

1 �90 17 12.5 (SD 4.7)2 60–89 72 14.5 (SD 5.2)3 30–59 95 18.1 (SD 6.0)4 15–29 25 25.4 (SD 6.0)5 �15 0

sP � .001 intergroups, except nonsignificant (.168) between stages 1 and 2.

etermination, 16% of the patients had experienced aonfatal cardiovascular event. The Hcy level was slightlyut not significantly higher among patients who suffered aosttransplantation cardiovascular event (18.6 �mol/L vs6.9 �mol/L); (P � .195).

ISCUSSION

yperHcy prevalence in our study was 61.2%, but usuallyhe extent was moderate since only approximately 5% ofatients showed Hcy levels higher than 30 �mol/L. Othertudies have noted similar results.7 The Hcy level was notssociated with the albumin level in our study, probablyecause most of our patients did not suffer from hypoalbu-inemia. As happens with other groups,8 we have not been

ble to show an independent association between hyperHcynd CRP.

We have found significantly increased plasma fibrinogenevels among patients with hyperHcy—the clinical signifi-ance of which needs to be elucidated. Even though onetudy found differences according to the type of antical-ineurin therapy,9 we did not confirm this, perhaps because,n contrast to that study, the plasma creatinine values in ourtudy were similar among cyclosporine- versus tacrolimus-reated patients.

As can be inferred from the multivariate analysis, Hcyatients display poorer renal function, lower plasma in-raerythrocyte folate and vitamin B12 levels, and higherlasma fibrinogen levels. Glomerular filtration was the mostowerful independent variable. These data agree with othertudies4,7 that also suggest that the vitamin status has lessmpact on Hcy than renal function. The results obtainedpon categorizing patients according to their renal functionuggest that it is reasonable to determine Hcy in thoseatients with creatinine clearances below 60 mL/min.Although those patients who had experienced a nonfatal

ardiovascular event had higher Hcy levels, the differenceas not statistically significant. Among the general popula-

ion, a moderate Hcy increase is a cardiovascular riskactor.8 The studies suggesting that hyperHcy may be aardiovascular risk factor in renal transplantation are

orized Homocysteine (n � 209)

Multivariate study

P Coef. B P OR 95% CI OR

�.001 NS.04 0.837 .037 2.309 1.052–5.067.062 �0.002 .005 0.998 0.997–0.999.029 �0.003 .04 0.997 0.994–1.000.004 0.478 .019 1.612 1.082–2.403.2 NS.45 NS

�.001 Co�.001 �0.001 �.001 0.954 0.937–0.971

.001 NS

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parse; however, one trial7 showed that patients with a

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FACTORS IN HYPERHOMOCYSTEINEMIA 3801

ardiovascular event (including death) had higher Hcyevels, even though the mean levels were 21.2 �mol/L (ie,igher than those in our study). The authors of the above-entioned trial reported a 6% increase in cardiovascular

isease with each �mol/L Hcy increase.In conclusion, the prevalence of hyperHcy in renal trans-

lantation was 61.2% (95% CI 51.6 to 67.8). The Hcylasma levels significantly depended upon the gender, theegree of renal function, as well as the plasma folate anditamin B12 and fibrinogen levels. Hyperhomocysteinemicatients have a poorer renal function, lower folate anditamin B12 levels, and higher plasma fibrinogen levels.

EFERENCES

1. U.S. Renal Data System: USRDS 2000, Annual Report, 20002. Kasiske BL: Epidemiology of cardiovascular disease after

enal transplantation. Transplantation 72:S5, 2001

3. Schnyder G, Roffi M, Flammer Y, et al: Effect of homocysteine-

owering therapy with folic acid, vitamin B12 and vitamin B6 on clinicalcp

utcome after percutaneous coronary intervention. JAMA 288:973,002

4. Friedman A, Bostom A, Selhub J, et al: The kidney andomocysteine metabolism. J Am Soc Nephrol 12:2181, 20015. Ducloux D, Ruedin C, Gibey R, et al: Prevalence, determi-

ants, and clinical significance of hyperhomocysteinemia in renal-ransplantation recipients. Nephrol Dial Transplant 13:2890, 1998

6. Arnadottir M, Hultberg B, Wahlberg J, et al: Serum totalomocysteine concentration before and after renal transplantation.idney Int 54:1380, 19987. Ducloux D, Motte G, Challier B, et al: Serum total homocys-

eine and cardiovascular disease occurrence in chronic, stable renalransplantation recipients: a prospective study. J Am Soc Nephrol1:134, 20008. Suliman M, Stenvinkel P, Barany P, et al: Hyperhomocysteine

nd its relationship to cardiovascular disease in ESRD: influence ofypoalbuminemia, malnutrition, inflammation, and diabetes melli-us. Am J Kidney Dis 41(Suppl 1):89, 2003

9. Laurés AS, Gómez E, Alvarez V, et al: Influence of antical-

ineurinic therapy in plasma homocysteine levels of renal trans-lantation recipients. Transplant Proc 35:1739, 2003