Dyslipoproteinemia in renal transplantation.RV Gunjotikar, SP Taskar, AF Almeida, VN Acharya
Dept. of Nephrology, KEM Hospital, Parel, Bombay, Maharashtra.
Twenty-seven live related donor renal allograft recipients were evaluated for dyslipoproteinemia. Twenty-two patients received dual immunosuppression with prednisolone and azathioprine. Five patients received cyclosporin as well. Total cholesterol (Tch), triglycerides (TG), HDL cholesterol (HDLch), LDL cholesterol (LDLch) and VLDL cholesterol (VLDLch) levels were estimated. Fifteen (56%) patients showed significant lipoprotein abnormalities. Renal allograft recipients showed significantly lower levels of Tch (p < 0.05) and LDLch (p < 0.05) and higher levels of TG (p < 0.005) and HDLch (p < 0.05). Diet and beta blockers did not influence lipoprotein levels. A significant negative correlation was noted between post-transplant duration and Tch, TG and VLDLch levels. Increased TG levels were associated with increase in weight and higher daily prednisolone dosage at the time of evaluation. The study confirms the existence of dyslipoproteinemia in renal allograft recipients.
Keywords: Adolescent, Adult, Azathioprine, administration &dosage,Cyclosporine, administration &dosage,Female, Human, Hyperlipidemia, etiology,Immunosuppressive Agents, administration &dosage,Kidney Transplantation, Lipoproteins, blood,Male, Middle Age, Postoperative Complications, etiology,Prednisolone, administration &dosage,Transplantation, Homologous,
Atherosclerotic disorders and cardiovascular events contribute to significant post-transplant morbidity and mortality,,,,. Though many metabolic abnormalities of uraemia are reversed by successful transplantation, lipid abnormalities appear to progress in many patient. Lipid abnormalities have been shown to affect cyclosporin pharmacokinetics as well,. There is a dearth of reports in Indian literature on post-transplant dyslipoproteinemia.
There is evidence that the dyslipoproteinemia that exists in an Indian population (amongst chronic renal failure patients) differs from that in the West. Hence, this study was carried out to assess the lipid abnormalities in post transplant patients.
Twenty-seven live related donor renal allograft recipients with satisfactory graft function (serum creatinine < 1.2 mg%) were included in the study. Renal allograft recipients with diabetes mellitus, liver dysfunction, overt thyroid dysfunction and nephrotic range proteinuria were excluded. Immunosuppression consisted of prednisolone and azathioprine. Five patients received cyclosporin in addition. Prednisolone was administered initially in a dose of 2 mg/kg body weight and reduced to a maintenance dose of 10-15 mgs/day Azathioprine doses ranged from an initial 5 mg/kg to a maintenance dose of 2-3 mg/kg. Cyclosporin was administered with a starting dose of 5-6 mg/kg gradually reduced to about 3 mg/kg at 6 months. Anti-rejection therapy comprised of 1 gm bolus doses of methyl prednisolone (‘pulse’ steroids) on 3 days or a high dose oral steroids (3 mg/kg) or dexamethasone (3 mg/kg) for 3 doses.
All patients were evaluated clinically and with laboratory studies, which included complete hemogram, urinalysis, renal function tests, and liver function tests. Records were screened for details of past and present medications. A detailed dietary assessment of calorie consumption, fats and types of fat was done. No dietary restrictions other than curtailed salt intake were in force.
For lipoprotein analysis, 5 ml heparinised blood was collected by venepuncture after an overnight fast. The plasma was separated by centrifugation at 3000 rpm. Plasma total cholesterol (Tch) and triglyceride (TG) were estimated by Abell's and van Handel and Zilverschmidt's methods respectively. The lipoprotein electrophoresis was performed on agarose gel (0.75% w/v) using bicarbonate buffer at pH 8.6 (0.05 m/L). Lipoprotein fractions were separated by the method of lipid research clinic programme whereas the cholesterol content was measured by the method described by Rudel and Morris. Lipoprotein levels were compared with age and sex matched healthy subjects. Lipoprotein levels exceeding mean + SD for age and sex matched healthy subjects was considered abnormal.
The correlation coefficients were calculated by Spearman's rank correlation test. Two tailed student T test was used for inter group comparison.
Twenty-seven patients with renal transplant (M:26; F:1) were studied, 23 of who had post-transplant hypertension. 15 patients received beta blocking agents as a part of their anti hypertensive regimen. The characteristics of these 27 patients are shown in [Table - 1].
The analysis of the lipoprotein parameters is shown in [Table - 2].
Fifteen (56%) patients showed elevated TG, VLDIch or low HDLch alone or in combination. Eleven (41%) patients showed low Tch, TG, LDLch or elevated HDLch alone or in combination. Lipoprotein profile was normal in a single patient.
As compared to age and sex matched healthy subjects, [Table - 3] renal allograft recipients showed significantly lower levels of Tch (P < 0.05) and LDLch (p < 0.05), higher levels of TG (p < 0.005) and HD Lch (0.05 < p < 0-03).
The differences in VLDLch were not significant. The details of lipoprotein profile are shown in [Table - 4]. Diet did not differ significantly in normo-and dyslipoproteinemic patients. Therapy with beta blockers too did not alter lipoprotein profile. The number of patients in each group being too few assessment of effect of age, sex and cyclosporin therapy [Table - 5] was not possible.
Statistically significant negative correlation was seen between duration after transplantation and Tch, TG and VLDLch levels. HDLch levels did not show such a correlation. TG levels increased with increasing body weight and daily prednisolone dose at the time of evaluation. No such correlation was observed with cumulative corticosteroid dose and weight gain after transplantation.
Accelerated atherosclerosis accounts for a major proportion of morbidity and mortality in renal transplant recipients,,,. Vascular disease, common to hyperlipidemic patients, is responsible for 10-40% deaths after renal transplantation,. Though significant post-transplant hyperlipidemia has been widely documented,,,, normal lipid profile in these patients has been reported too,. The incidence of hypercholesterolemia ranges from 16 to 78% and that of hypertriglyceridemia between 9 to 66% in conventionally treated renal allograft recipients. It must however be noted that criteria used for defining hyperlipidemia are not uniform,. In the present study, hyperlipidemia was noted in 56% of renal transplant patients with the main abnormality being hypertriglyceridemia (n=l 3) (15%). LDLch was reduced in 4 (15%) patients.
These findings agree with other studies,,,,. The Tch levels peak at 4-10 months post transplant and decline between 12-36 months. The TG levels peak at 4-12 months after an initial fall in the first month following transplantation,,. In this study, the lipoprotein levels (Tch, TG and VI-DI-ch) which correlated negatively with duration after transplantation indicate a gradual fall with increasing post-transplant duration -a finding in other studies too,,,.
Similar to other workers,,,, renal transplant patients in the present study showed higher levels of TG as compared to age and sex matched healthy controls. Another important observation noted in our study was a higher level of HDLch in renal transplant recipients,,,. In this study, hyperlipidemia was not as severe in contrast to other studies,. A different dietary pattern in Indian population could be responsible for this difference.
As noted by other workers,,,,, a positive correlation between daily prednisolone dosage and TG levels was observed. HDLch levels increased with time after transplantation as noted in another study. A fall in HDLch level was also found by other workers. Tch, TG levels correlated positively with body weight at the time of evaluation in this and other studies,,.
The role of cyclosporine in post-transplant hyperlipidemia is still unclear although some workers have implicated cyclosporin in its causation,. A correlation has been observed between TG and Tch levels with cyclosporin dose,, and cyclosporin trough levels, by various workers. Vatsala et al found severe hyperlipidemia in cyclosporin treated patients but the incidence was not high. Greater severity was probably related to a higher age, body weight and graft dysfunction.
This study confirms the existence of a post-transplant dyslipoproteinemia. However, the role of cyclosporin needs to be evaluated further.
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]