Kidney International, Vol. 56, Suppl. 71 (1999), pp. S-235–S-237

Immunosuppression enhances atherogenicity of lipid profileafter transplantation

THOMAS QUASCHNING, TILL MAINKA, MATTHIAS NAUCK, LARS CHRISTIAN RUMP,CHRISTOPH WANNER, and ANNETTE KRAMER-GUTH

Departments of Medicine, Divisions of Nephrology, Universities of Wurzburg and Freiburg, and Department of ClinicalChemistry, University of Freiburg, Freiburg, Germany

Immunosuppression enhances atherogenicity of lipid profile Renal transplantation has significantly improved pa-after transplantation. tient prognosis in chronic renal failure. However, in-

Background. Patients after renal transplantation exhibit high creasing attention is drawn to the high incidence of car-cardiovascular morbidity and mortality because of the accumu-diovascular morbidity and mortality in renal transplantlation of cardiovascular risk factors such as hypertension orrecipients [1]. The reason for this may be the accumula-dyslipidemia. To elucidate the influence of immunosuppressive

therapy on hyperlipidemia, we studied serum lipids and lipo- tion of risk factors for cardiovascular disease, such asproteins in renal transplant patients who received prednisone hypertension and dyslipidemia. Besides other contribut-and either azathioprine or cyclosporine or triple immunosup- ing factors, post-transplant dyslipidemia may be relatedpressive therapy.

to immunosuppressive treatment with corticosteroidsMethods. Serum lipids and lipoprotein levels were measured[2], cyclosporine [3], azathioprine, or combinations ofin 216 renal transplant patients (81 female and 135 male) with

stable graft function of 4.8 6 2.3 years (range six months to those drugs. Although the impact of dyslipidemia oneight years) after transplantation. Patients were divided into long-term graft and patient survival in renal transplantthree groups according to one of the following immunosuppres- recipients is generally accepted [4], the influence of im-sive regimens: (a) prednisone and azathioprine, (b) prednisone

munosuppressive drugs, namely cyclosporine, on dyslipi-and cyclosporine, or (c) prednisone, azathioprine, and cyclospo-demia is discussed controversially [5], and mechanisms ofrine. Healthy, age- and sex-matched subjects served as controls.

In addition to measurement of total serum lipids, lipoproteins post-transplant dyslipidemia are only poorly understoodwere isolated by preparative ultracentrifugation, and lipids [6]. This study was designed to evaluate lipid metabolismwere determined in very low-density lipoprotein (VLDL), low- in well-characterized renal transplant recipients on threedensity lipoprotein (LDL), and high-density lipoprotein (HDL) common immunosuppressive regimens in comparisondensity classes.

with matched controls. It therefore quantifies distinctResults. Total serum triglycerides, VLDL, and LDL triglyc-changes in serum lipids and composition of lipoproteinserides, as well as VLDL cholesterol were elevated in all renal

transplant patients, but elevation was pronounced in female by using preparative ultracentrifugation.patients. In contrast to total serum cholesterol, which was sig-nificantly increased in only female patients, elevation of LDL-triglyceride/apo B ratio was more marked in male patients. METHODSPatients in group A exhibited only mild hypertriglyceridemia, Overnight fasting blood was drawn from 216 renalwhereas triglyceride enrichment in VLDL and LDL was more

transplant recipients (81 female and 135 male) with func-distinct in group B and was most pronounced in patients oftioning renal graft 4.8 6 2.3 years after transplantationgroup C. Furthermore, hypertriglyceridemia increased with the

dose of administered prednisone. (range six months to eight years). Lipoproteins were iso-Conclusions. Immunosuppressive therapy in renal trans- lated by preparative ultracentrifugation [7], and serum

plant patients leads to accumulation of triglyceride-enriched lipids and lipoproteins were determined enzymaticallyVLDL and LDL. Triglyceride enrichment in LDL indicates(Boehringer Mannheim, Germany). Patients received onethe accumulation of small, dense LDLs, which are known toof the following immunosuppressive regimens: (a) predni-bear enhanced atherosclerotic risk. This study provides data

that underline the use of individually adjusted immunosuppres- sone and azathioprine (N 5 22), (b) prednisone and cy-sive therapy and steroid-sparing protocols in renal transplant closporine (N 5 74), or (c) prednisone, azathioprine, andpatients to improve their atherogenic lipoprotein profile. cyclosporine (N 5 120). Three hundred twenty-eight

healthy age- and sex-matched subjects served as controls.Patients and control subjects on lipid-lowering therapyKey words: cardiovascular risk factors, dyslipidemia, immunosuppres-

sive therapy, renal transplantation. were excluded, and data were analyzed in respect toconcomitant medication. Hypertension was defined as 1999 by the International Society of Nephrology

S-235

Quaschning et al: Lipid profile after renal transplantationS-236

Table 1. Lipid levels

NTX Controls

Male Female Total Male Female TotalN 5 135 N 5 81 N 5 216 N 5 201 N 5 127 N 5 328

Serum TG 2.1860.64a 2.3360.52a 2.2460.69a 1.9260.32 1.39 60.31 1.71 60.38Serum chol 5.8661.36 6.19 61.11a 5.9861.48 5.62 61.01 5.54 61.06 5.59 61.27VLDL TG 1.4760.82a 1.4960.62a 1.4860.93a 1.3060.28 0.75 60.23 1.08 60.37VLDL chol 0.8860.22a 0.9660.19a 0.9160.31a 0.6260.14 0.36 60.09 0.52 60.19LDL TG 0.4760.17a 0.5160.19a 0.4960.22a 0.3660.11 0.38 60.12 0.37 60.15LDL chol 3.6361.12 3.68 60.93 3.65 61.26 3.76 60.65 3.63 60.67 3.71 60.82HDL TG 0.2560.09 0.31 60.13 0.27 60.15 0.24 60.07 0.26 60.09 0.25 60.12HDL chol 1.3360.34 1.53 60.32 1.41 60.37 1.24 60.31 1.58 60.34 1.37 60.44LDL TG/apoB 0.4560.13a 0.4960.14a 0.4760.18a 0.3360.06 0.37 60.13 0.35 60.16

Data are given in mmol/liter as mean 6 sem. Abbreviations are: Tg, triglycerides; chol, cholesterol; VLDL, very-low density lipoproteins; LDL, low densitylipoproteins; HDL, high density lipoproteins; apoB, apolipoprotein B.

a P , 0.005 vs. controls

whereas VLDL cholesterol was elevated parallel to theincrease in VLDL triglycerides (Table 1), indicating thepredominance of qualitative changes in LDL and quanti-tative changes in VLDL. Enhancement of triglyceride-rich VLDL was pronounced in female patients. In addi-tion, serum cholesterol was found to be increased in bothgenders, but elevation was significant in only female sub-jects. Patients on prednisone and azathioprine exhibitedonly minor elevation of triglycerides in VLDL and LDL,whereas hypertriglyceridemia was more severe in patientswho received prednisone and cyclosporine and was mostpronounced in patients on triple therapy. Triglycerideenrichment increased with the administered dose of pred-nisone and was even more distinct in patients with cyclospo-rine levels higher than 120 ng/ml, independent of steroid

Fig. 1. Low-density lipoprotein (LDL) triglycerides in male (open bar, therapy. Furthermore, subgroup analysis revealed aggra-N 5 201) and female (hatched bar, N 5 127) control subjects (Co); vation of dyslipidemia in patients on b-blocker therapy.male (open bar, N 5 16) and female (hatched bar, N 5 6) patients onprednisone and azathioprine (A); male (open bar, N 5 38) and female(hatched bar, N 5 36) patients on prednisone and cyclosporine (B); andmale (open bar, N 5 81) and female (hatched bar, N 5 39) patients on DISCUSSIONprednisone, azathioprine, and cyclosporine (C). Data are given as mean 6

This study demonstrates distinct changes in serumsem for P , 0.005 (d d) vs. controls, and for P , 0.005 (s) vs. (A).lipid and lipoprotein concentration and composition re-lated to immunosuppressive therapy after renal trans-plantation. Post-transplant dyslipidemia appears to be

documented blood pressure of more than 140/90 mm Hg qualitatively and quantitatively dependent on gender,on the day of blood drawing. Serum lipid and lipoprotein immunosuppressive drug, and dose. Although some for-levels are presented as mean 6 sem (Table 1). Differ- mer studies focused mainly on elevation of serum choles-ences between groups were assessed by Student’s two- terol, our data underline the presence of a remarkablesided, unpaired t-test for continuous data and by analysis

increase in triglycerides after renal transplantation inof frequency (chi-squared) for categorical data.

serum, LDL, and VLDL.Triglyceride-rich LDLs are known to be smaller and

RESULTS exhibit higher density than control LDLs [8]. Becausealteration of size and density contributes to configura-Total serum triglycerides were elevated in all renaltional changes, small, dense LDL exhibit reduced recep-transplant patients. Lipid analysis of lipoprotein densitytor-specific uptake and therefore bear increased athero-classes revealed an increase in low-density lipoproteingenicity [9]. This corresponds with the finding that(LDL) (Fig. 1) and very LDL (VLDL) triglycerides ashypertriglyceridemia is considered to be an independentan underlying mechanism of post-transplant hypertri-risk factor for cardiovascular disease [10].glyceridemia. In LDL, enrichment of triglycerides oc-

curred without significant changes in LDL cholesterol, Even though other observations are consistent with

Quaschning et al: Lipid profile after renal transplantation S-237

our data, some authors failed to prove a significant asso- REFERENCESciation between post-transplant dyslipidemia and the ad- 1. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ:ministration of cyclosporine [5]. Conflicting results may Cardiovascular disease after renal transplantation. J Am Soc

Nephrol 7:158–165, 1996originate from variations in methodology, variations in2. Vathsala A, Weinberg RB, Schoenberg L, Grevel J, Goldsteinimmunosuppressive regimens, and the use of antihyper-

RA, Vanburen CT: Lipid abnormalities in cyclosporine-predni-tensive agents, as well as the small-sized groups of pa- sone-treated renal transplant patients. Transplantation 48:37–43,

1989tients in most of the studies.3. Kuster GM, Drexel H, Bleisch JA, Rentsch K, Pei P, Bins-Despite remaining controversies about the mecha-

wanger U: Relation of cyclosporine blood levels to adverse effectsnisms and quality of adverse affects of immunosuppres- on lipoproteins. Transplantation 57:1479–1483, 1994sion after renal transplantation on lipid metabolism, it 4. Bumgardner GL, Wilson GA, Tso PL, Henry ML, Elkhammas

EA, Davies EA, Qiu W, Ferguson RM: Impact of serum lipidsis no doubt that wherever dyslipidemia occurs, it goeson long-term graft and patient survival after renal transplantation.along with reduction of graft and patient survival [4] andTransplantation 60:1418–1421, 1995

enhanced cardiovascular morbidity and mortality [1]. 5. Aakhus S, Dahl K, Wideroe TE: Hyperlipidemia in renal trans-Therefore, monitoring of serum lipids after renal trans- plant patients. J Int Med 239:407–415, 1996

6. Massy ZA, Kasiske BL: Post-transplant hyperlipidemia: Mecha-plantation is important and should be considered as be-nism and management. J Am Soc Nephrol 7:971–977, 1996ing one criterion for individual choice and dosage of

7. Wanner C, Horl WH, Luley CH, Wieland H: Effects of HMG-immunosuppressive agents. CoA reductase inhibitors in hypercholesterolemic patients on he-

modialysis. Kidney Int 39:754–760, 1991Additionally, lipid-lowering therapy is warranted in8. Deckelbaum RJ, Galeano NF: Hyperlipidemia, Small low densityrenal transplant patients with an atherogenic lipid profile

lipoprotein, Atherogenicity. Small dense low density lipoprotein:and multiple risk factors [6]. It appears to be useful in Formation and potential mechanisms for atherogenicity. Isr J Medthose patients without cardiovascular disease (primary Sci 32:464–468, 1996

9. Krauss RM: Dense low density lipoproteins and coronary arteryprevention) and is mandatory in those with establisheddisease. Am J Cardiol 75:53B–57B, 1995coronary artery disease (secondary prevention).

10. Hanefeld M, Fischer S, Julius U, Schulze J, SchwanebeckU, Schnechel H, Ziegelasch HJ, Lindner J: Risk factors forReprint requests to Thomas Quaschning, M.D., Department of Medi-myocardial infarction and death in newly detected NIDDM: Thecine, Division of Nephrology, University of Wurzburg, Josef-Schneider-Diabetes Intervention Study, 11-year follow-up. Diabetologia 39:Str. 2, D-97080 Wurzburg, Germany.1577–1583, 1996E-mail: quaschning@gmx.de