| Abstract|| |
Since the introduction of monitoring levels of immunosuppressive medications in our service in July 2000, 1088 kidney transplant patients were received for therapeutic drug monitoring and regular follow-up. The aim of this study was to retrospectively analyze the data on these renal graft patients in Algeria and correlate with our 12 years' experience with calcineurin inhibitor (CNI) measurements. In addition, during this period, we also examined other biochemical parameters. The analysis was focused on the difference of effect of cyclosporin A (CsA; 623 patients) and Tacrolimus (Tac; 465 patients) on lipid and glucose metabolism and their side-effects, if any, on the renal function. The mean age at the time of transplantation was 36.1 years. A great majority of the transplanted kidneys had been taken from living related donors (88.6%). Three-quarters of all grafts were transplanted in our country (79.5%). Dyslipidemia and renal dysfunction were the most common adverse effects of CsA and Tac exposure, with a frequency of 21.4% and 10.3%, respectively. Both the CNIs had a similar effect on the lipid levels. The highest incidence occurred at 3-12 months after renal graft. Tac seemed to have more side-effects on glycemia, causing the onset of diabetes mellitus more than two-fold than CsA (6.9% vs. 3.1%). A significant difference was observed during 12-24 months after transplantation. However, Tac was associated with the most favorable effects on renal function estimated with the Modification of Diet in Renal Disease (MDRD) formula.
|How to cite this article:|
Yargui L, Chettouh H, Boukni H, Mokhtari N, Berhoune A. Metabolic status of 1088 patients after renal transplantation: Assessment of twelve years monitoring in Algiers Mustapha Hospital. Saudi J Kidney Dis Transpl 2014;25:177-84
|How to cite this URL:|
Yargui L, Chettouh H, Boukni H, Mokhtari N, Berhoune A. Metabolic status of 1088 patients after renal transplantation: Assessment of twelve years monitoring in Algiers Mustapha Hospital. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Nov 13];25:177-84. Available from: http://www.sjkdt.org/text.asp?2014/25/1/177/124568
| Introduction|| |
Kidney transplantation is now considered as the treatment of choice for most patients with end-stage renal disease. In Algeria, the prevalence of patients on renal replacement therapy was estimated as 351 per million population in 2011; 90% were on hemodialysis and 10% were on peritoneal dialysis. About 1000 kidney transplantations were performed from 1986 to 2011.  Earlier, therapeutic drug monitoring (TDM) was fairly new and Algerian physicians were sending blood samples to specialized laboratories in Tunisia or France. It is to be noticed that, during those years, adopted healthcare priorities were different to those prevalent in other countries. However, over the last decade, significant efforts have been made to improve the quality of healthcare and to decrease disparities. As a result, suitable equipment and reagents have been provided to make TDM facilities available in many centers across Algeria TDM of calcineurin inhibitors (CNIs) was initiated in our laboratory in July 2000.  ,  We started with a single, fully automated Random Access Clinical Chemistry Analyser, Hitachi 902 (Roche Diagnostics Corp, Indianapolis, USA) and a high-pressure liquid chromatograph (Waters Corp., Milford, USA). Over the years, X-pand Plus analyzer (Siemens Corporation, Deerfield, IL, USA) has been added to combat the increasing number of renal transplants and requests for TDM.
| Materials and Methods|| |
The present study is based on our experience over 12 years' TDM of Cyclosporine A (CsA) and Tacrolimus (Tac) and the measurements of other biochemical parameters that were carried out to get an overview of the metabolic status of renal transplant patients on follow-up in our laboratory. The objective of this retrospective study was to analyze the data and correlate the CNI measurements and side-effects of CsA and Tac, analyzing their impacts on glycemia, plasma lipids and renal function. The analysis was focused on the differences of effect of CsA (623 patients) and Tac (465 patients) on lipid and glucose metabolism and their side-effects, if any, on the renal function.
Since 24 July 2000, 1088 patients referred from 11 transplantation centers across Algeria on treatment with either CsA or Tac were received in our laboratory for TDM and regular follow-up. This study excluded patients who had second renal transplantation (n = 3), liver transplantation (n = 16) or multiple organ transplantation (n = 1) and those who had glycemia ≥126 mg/dL at the first routine visit (n = 10). No patients were on hypocholesterolemic drugs.
Population characteristics (name, surname, date of birth, age at transplantation, gender, pre-transplant dialysis duration, donor types, country where the grafting was performed and the underlying disease) were collected on the basis of an interview with each patient during one of the monitoring visits at our department. Informed consent had been obtained for all patients. For the medical information (induction therapy and drug dosage), an official "patient document" was transmitted to clinicians and were received completed.
Induction therapy included antithymocyte globulin (Thymoglobulin, Genzyme) or basiliximab (Simulect, Novartis). The majority of patients received 100-500 mg of intravenous methylprednisolone pre-operatively and treatment with oral prednisolone was started at 20 mg/day, which was tapered to a dose of 15 mg at 18 days and to 10 mg at one month.
Six hundred and twenty-three patients started on Cyclosporine (Sandimune Neoral, Novartis) at a dose of 2.5-6 mg/kg twice daily tapered to a trough level of whole-blood concentration of 150-300 ng/mL for the first three months and 70-150 ng/mL thereafter. The remaining patients (n = 465) started on Tac (Prograf, Hikma) at a dose of 0.075-0.15 mg/kg twice daily tapered to a whole-blood concentration of 8- 15 ng/mL for the first three months and 6-8 ng/mL thereafter.
Mycophenolate mofetil (Cellcept, Roche) was used for all patients at a dose of 2 g BID for the first month and 1 g BID thereafter.
For assessment of CsA and Tac levels, patients were sent to us according to the monitoring frequency approved by the nephrologists: One to two visits a week for the first three months post-transplant until the patient got stable. Then, one visit every one to two months or whenever clinically indicated. Blood sampling was performed 12 h after the previous dose of CsA or Tac for trough level monitoring (CsA C 0 or Tac C 0 ). For CsA C 2 , blood samples were collected within 15 min of the 2-h post-dose time point. Sensitivity of CsA and Tac measurement methods were 10.1 ng/mL and 1.0 ng/mL, respectively. Intra-day and inter-day variations for the low, medium and high drug concentrations were less than 10%, as described previously. ,
In addition to drug determinations, other tests were performed to check the adverse effects of immunosuppressants (creatinine for nephrotoxicity, liver function, lipids, glucose and electrolytes for possible metabolic changes). Parameters determined but not assessed were ASAT, ALAT, Bilirubine, γ-GT, urea and electrolytes.
Fasting plasma glucose (Glu), total cholesterol (TC) and triglyceride (TG) levels were measured by routine automated enzymatic methods.
The diagnosis criteria of impaired fasting glucose (IFG) and new-onset diabetes mellitus (NODM) were defined according to the American Diabetes Association (ADA 2010 and WHO 2011).
Lipid target values were adopted as established by the National Cholesterol Education Program (NCEP). Acceptable (normal or desirable) plasma levels were <200 mg/dL for cholesterol total and <150 mg/dL for triglycerides. Results were compared with data collected from a control group of 75 healthy volunteers aged 42 ± 7 years.
Serum creatinine concentration (Cr) was determined by the kinetic alkaline picrate method. This method had been standardized with isotope dilution mass spectrometry (IDMS) (Roche Hitachi) according to the manufacturer's instructions. Glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease (MDRD) formula.  GFR estimation was used as a marker to assess the renal function rate and as a screening test that would enhance the probability of developing kidney disease. GFR less than 60 mL/min/1.73 m 2 was the value accepted by the National Kidney to identify individuals with clinically significant chronic kidney disease. 
| Statistical Analysis|| |
Results are reported as frequencies (percentages) or mean ± standard deviation. The 95% confidence interval for all percentages was assessed. Descriptive variables were compared using Wilcoxon's signed rank test, Fisher's exact test or a chi test as appropriate. Differences for which the P-value was <0.05 were considered to be significant.
| Results|| |
The mean age at transplantation date of the 1088 patients was 36.1 ± 14.5 years. Nearly two-thirds of the patients were men (62.3%). A great majority of the transplanted kidneys had been taken from living related donors (88.6%). Three-quarters of all grafts were performed in our country (79.5%). The median follow-up duration was about 59 months (range: 5 days to 12 years). Demographic patient data details are shown in [Table 1].
Summary of results
Dyslipidemia and renal dysfunction were the most commonly observed adverse effects of CsA and Tac exposure, with a frequency of 21.4% and 10.3%, respectively. Both the CNIs had an equivalent impact on lipid disorders. The incidence of renal dysfunction was significantly higher among CsA-treated patients than those receiving Tac (13.8% vs. 5.6%, P <0.05). NODM occurred in 3.1% of patients receiving CsA compared with 6.9% patients receiving Tac (P <0.05). All results are summarized in [Table 2].
Patient metabolic status
As shown in [Figure 1], plasma lipids were significantly elevated in all groups compared with controls. The occurrence of dyslipidemia versus time after transplantation was found to be the same for both CsA and Tac patients. The higher incidence occurred within three and 12 months after renal graft. Cholesterol concentrations increased slightly at three months after transplant and had a tendency to increase at a higher rate thereafter. The rate of triglyceride concentrations remained steady, and was similar in both groups.
|Figure 1: Plasma lipids in the control group and CsA- and Tac-treated patients.|
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Fifty-one patients had developed NODM [Table 3]. Based on the transplantation date, the incidence of NODM was the same (P = NS) in each cohort for both early (<1 year) and late (>2 years) post-transplantation periods. However, during the time between 12 and 24 months, the incidence was significantly higher among Tac-treated patients than among those receiving CsA (P <0.05). No difference in CNI concentrations was observed between non-diabetic and diabetic patients in both the CsA and the Tac groups [Table 3]. All patients diagnosed with NODM were followed-up by a diabetes specialist. Recently, nine patients were switched from Tac to CsA. They showed an improvement in HbA 1c control without normalization of glycemia (preliminary results, data not shown). As presented in [Figure 2], GFR <60 mL/min was observed more frequently in the CsA group. Most of the cases were seen after two years post-transplantation; 6.7% in the CsA-treated patients compared with 2.25% in the Tac group.
|Table 3: Patient glucose profiles according to calcineurin inhibitors measurements and the time after transplantation.|
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| Discussion|| |
The number of kidney transplant recipients has increased considerably in our country during the recent years, mostly after 2006. As a result of a sustained program, more than 65 cases per year are being performed, mainly using kidneys from living related donors. In this study, only 79 patients (6.9% of the total patient population) have undergone cadaveric donor transplantation abroad, mainly in France, Jordan, Iraq and Saudi Arabia. The relatively young age of the patients at transplantation (mean = 36 years) is explained by the age distribution of our general population. Algeria's population in January 2011 was estimated at 3.1 million habitants, and only 7.9% was over 60 years old. The etiology of native kidney disease in these patients was unknown in 90%.
Hyperlipidemia including increased TC and TG was seen in 21.4% of the patients. The observed dyslipidemia might be related to the immunosuppressive agents. In addition, the similar incidence seen in both CsA- and Tac-treated patients suggests an equal effect of CsA and Tac on lipid disorders. In previously reported comparative studies, Tac has been shown to affect lipid metabolism to a lesser extent than CsA. ,, However, thus far, there have been only a few studies trying to address the mechanisms of these effects. CsA-treated animals showed a significant reduction in the levels of hepatic enzyme, cholesterol 7a-hydroxylase, involved in the rate-limiting step in conversion of cholesterol to bile acid, which is the principal pathway of cholesterol catabolism. In addition, in kidney transplant patients, a reduction of lipolytic activity both in liver and skeletal muscle can contribute to elevation of TG level.  Recently, it has been observed that CsA concentration correlated positively with LDL levels and the expression of CD36 on peripheral blood monocytes, whereas Tac showed no significant effect on serum lipid level.  There is no doubt that whenever dyslipidemia occurs, it goes along with increased cardiovascular morbidity and mortality. Therefore, pharmacological therapy of dyslipidemia seems crucial after a trial with diet alone.
NODM is another common complication after kidney transplantation that is associated with an increased number of cardiovascular diseases, graft failure and patient death. , In this study, the incidence of NODM of 4.7% observed is similar to those reported in recent years, ,,, but notably lower than those published before the last decade.  A decreasing incidence of NODM is probably due to the importance given to the early identification of patients presenting a risk of developing any form of post-transplant hyperglycemia and to the prevention of diabetes occurrence. Several risk factors for NODM have been characterized, including older age, body weight excess, hepatitis C positivity, family history of diabetes, transplantation of a deceased donor organ and the use of corticosteroids.
Regarding CNIs, our results are similar to several studies where it has been shown that Tac compared with CsA is associated with a significantly higher incidence of NODM. ,,,,,, This observation has been confirmed recently in a randomized controlled trial.  Insulin resistance appears in patients receiving CNI. Tac inhibits insulin secretion to a greater extent than CsA-based regimens. However, unlike some other series,  in our study, the only significant difference between the Tac and CsA groups occurred within 12-24 months post-transplantation, not before or after.
It is well known that chronic allograft nephropathy (CAN) is a common cause of graft loss. However, many studies have reported that CNI nephrotoxicity plays a major role in late allograft deterioration and dysfunction.  It is important to notice that CAN is a multifactorial process that leads to a progressive glomerular sclerosis, an interstitial fibrosis and a tubular atrophy. Recently, authors suggest that chronic antibody-mediated rejection and recurrent glomerular disease are the major contributors. , In addition, the effect of non-immunological factors such as infections, hypertension and hypertensive drugs should also be considered.
As shown above, other than GFR, in this study, there is no data providing information on rejection rate, transplant glomerulopathy, results of kidney biopsy and proteinuria. It will be wrong to attribute change in renal function only to either CsA or Tac. It is possible that chronic progressive CNI toxicity exists, but probably it is not the only predominant cause of late renal dysfunction after transplantation.
Finally, monitoring of CNI must be carried out periodically to diagnose and manage the metabolic abnormalities after renal transplantation. Measurement of plasma lipids, glycemia, serum creatinine, proteinuria and kidney biopsy (when indicated) should be carried out as routine along with the drug monitoring measurements. Identification of high-risk patients and implementation of measures to recognize and treat the associated dyslipidemia and NODM will improve both long-term patient and graft outcomes.
| References|| |
|1.||Haddoum F. Declaration of the president of Algerian Society of Nephrology Dialysis and Transplantation in SanteMag 2012;3:49. |
|2.||Yargui L, Berhoune A. The Emit Tacrolimus assay: Development of application protocol for Roche Hitachi 902 analyzer. Ann Biol Clin 2008;66:657-64. |
|3.||Yargui L, Berhoune A. Monitoring of C0 and C2 blood concentrations of cyclosporine on the Roche Hitachi 902 analyzer. Transplant Proc 2009;41:3713-9. |
|4.||American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011; 34 Suppl 1:562-9. |
|5.||Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. |
|6.||Myers GL, Miller WG, Coresh J, et al. Recommendations for improving serum creatinine measurement: A report from the laboratory working group of the National Kidney Disease Education Program. Clin Chem 2006;52:5-18. |
|7.||Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;16:461-70. |
|8.||National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266. |
|9.||Quaschning T, Mainka T, Nauck M, Rump LC, Wanner C, Krämer-Guth A. Immunosuppression enhances atherogenicity of lipid profile after transplantation. Kidney Int 1999;71: S235-7. |
|10.||Deleuze S, Garrique V, Delmas S, et al. New onset dyslipidemia after renal transplantation: Is there a difference between Tacrolimus and cyclosporine? Transplant Proc 2006;38:2311-3. |
|11.||Badiou S, Cristol JP, Mourad G. Dyslipidemia following kidney transplantation: Diagnosis and treatment. Curr Diab Rep 2009;4:305-11. |
|12.||Vaziri ND, Liang K, Azad H. Effect of cyclosporine on HMG-CoA reductase, cholesterol 7a-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expessions. J Pharm Exp Ther 2000;294:778-83. |
|13.||Jiang Y, Xie XB, Peng LK, et al. Dyslipidemia in human kidney transplant recipients receiving cyclosporine and Tacrolimus is associated with different expression of CD36 on peripheral blood monocytes. Transplant Proc 2011;43:1612-5. |
|14.||Revanur VK, Jardine AG, Kingsmore DB, Jaques BC, Hamilton DH, Jindal RM. Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation. Clin Transplant 2001;15:89-94. |
|15.||Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3:178-85. |
|16.||Kamar N, Mariat C, Delahousse M, et al. Diabetes mellitus after kidney transplantation: A French multicentre observational study. Nephrol Dial Transplant 2007;22:1986-93. |
|17.||Valderhaug TG, Hjelmesaeth J, Rollag H, Leivestad T, Røislien J, Jenssen T. Reduced incidence of new-onset posttransplantation diabetes mellitus during the last decade. Transplantation 2007;84:1125-30. |
|18.||Veroux M, Corona D, Giuffrida G, et al. New-onset diabetes mellitus after kidney transplantation: The role of immunosuppression. Transplant Proc 2008;40:1885-7. |
|19.||Hornum M, Jorgensen KJ, Hansen JM, et al. New-onset diabetes mellitus after kidney transplantation in Danemark. Clin J Am Soc Nephrol 2010;5:709-16. |
|20.||Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Posttransplantation diabetes: A systematic review of the literature. Diabetes Care 2002;25:583-92. |
|21.||Vincenti F, Friman S, Scheuemann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7:1506-14. |
|22.||Van Duijnhoven EM, Christiaans MH, Boots JM, Nieman FH, Wolffenbuttel BH, Van Hooff JP. Glucose metabolism in the first three years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression. J Am Soc Nephrol 2002; 13:213-20. |
|23.||Gaston RS. Chronic calcineurin inhibitor nephrotoxicity: Reflections on an evolving paradigm. Clin J Am Soc Nephrol 2009;4:2029-34. |
|24.||Ganji MR, Haririan A. Chronic allograft dysfunction Major contributing factors. Iranian J Kidney Dis 2012;2:88-93. |
|25.||Matas AJ. Chronic progressive calcineurin nephrotoxicity: An overstated concept. Am J Transplant 2011;11:687-92. |
Biochemistry Central Laboratory, Mustapha Hospital, Algiers
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]