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Influence of Methylprednisolone on Plasma Homocysteine Levels in Cadaveric Renal Transplant Recipients
Influence of Methylprednisolone on Plasma Homocysteine Levels in Cadaveric Renal Transplant Recipients C. Libetta, V. Sepe, M. Zucchi, P. Pisacco, V. Portalupi, G. Adamo, G. Soccio, and A. Dal Canton ABSTRACT The aim of the present study was to investigate plasma homocysteine levels in renal transplant recipients in the course of steroid-based or steroid-free immunosuppression. Data from 32 patients were retrospectively analyzed according to the steroid immunosuppressive regimen. The 20 recipients on methylprednisolone (MP) plus cyclosporine (CyA) or tacrolimus (TRL) (n ⫽ 20) showed similar creatinine levels when compared with those on calcineurin inhibitors plus mycophenolate mofetil (MMF; n ⫽ 12), (1.6 ⫾ 1.5 vs 1.6 ⫾ 0.4 mg/dL; P ⫽ NS) but significantly higher total plasma homocysteine (tHcy) levels (28.5 ⫾ 12.5 vs 16.3 ⫾ 5.5 mol/L; P ⬍ .05). No differences of tHcy levels have been observed when patients were analyzed according to CyA- or TRL-based immunosuppression regardless of MP or MMF associations. Our data suggest that recipients, particularly those on steroid-based immunosuppression, should receive homocysteine-lowering treatment early after transplantation.
T
HE INCIDENCE of cardiovascular disease (CVD) is about fivefold greater in renal transplant recipients compared to the general population.1 Hyperhomocysteinemia (hHcy) is a recognized independent risk factor for atherosclerosis, increasing the risk of CVD in patients with chronic renal disease.2 Contradictory data have suggested that anticalcineurin immunosuppression determines plasma tHcy levels in these patients,3,4 and possibly a lowering effect of mycophenolic acid on tHcy levels.5 Studies on the possible modulatory effect of steroids on tHcy levels are still not available. The aim of the present work was to analyze the influence of steroidbased immunosuppression on tHcy levels.
Table 1. Plasma Levels From 32 Renal Transplant Recipients Analyzed According to Steroid or Steroid-Free Immunosuppression
n Creatinine (mg/dL) Folic acid (ng/mL) Vitamin B12 (pg/mL) THcy (mol/L)
MP
Steroid-Free
20 1.6 ⫾ 1.5 3.7 ⫾ 1.5 483 ⫾ 152 28.5 ⫾ 12.5
12 1.6 ⫾ 0.4 3.1 ⫾ 0.9 552 ⫾ 149 16.3 ⫾ 5.5*
MP, patients on methylprednisolone plus cyclosporine or tacrolimus; steroidfree, patients on cyclosporine or tacrolimus plus mycophenolate mofetil; tHcy, total plasma homocysteine. *P ⬍ .05 vs MP.
PATIENTS AND METHODS We retrospectively analyzed data from 32 consecutive cadaveric recipients according to the immunosuppressive regimen. Steroidbased immunosuppression was associated with cyclosporine (CyA) or tacrolimus (TRL). A steroid-free regimen instead combined CyA or TRL with mycophenolate mofetil (MMF). Data were also analyzed according to CyA or TRL immunosuppression regardless MP or MMF associations. All patients were on a methylprednisolone (MP) plus CyA regimen for 6 months after kidney transplantation. Fifty percent of them were then shifted from CyA to TRL according to a randomization table prepared by our Department of Epidemiology. Six months after transplantation patients without a pretransplant history of autoimmune disease underwent slow steroid withdrawal with MMF introduced into the immunosuppressive regimen. At the time of sampling patients on MMF had all been on MP for at least 6 months after kidney transplantation and all had been on a steroid-free regimen with MMF for at least 6 months. CyA doses were adjusted to maintain trough levels (C0) between 150 and 200 ng/mL during the
first year and between 100 and 150 ng/mL after the first year of transplantation. Therapeutic ranges for TRL were maintained between 10 and 12 ng/mL during the first 3 posttransplantation months and between 8 and 10 ng/mL thereafter. MMF was administered at a standard dose of 1000 mg twice daily. Data from acutely ill patients were not included in the analysis. Folate or vitamin B supplements were never administered during the follow-up period. Plasma levels of creatinine, folic acid, vitamin B12, and tHcy were measured in all patients. THcy levels, including homocysteine-homocysteine disulfide and mixed homocysteine-cysteine disulfide, were measured in samples From the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Address reprint requests to Vincenzo Sepe, MD, PhD, Fondazione IRCCS Policlinico San Matteo, Nephrology, Dialysis, Transplantation, Ple Golgi 2, Pavia 27100, Italy. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.149
Transplantation Proceedings, 38, 2893–2894 (2006)
2893
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LIBETTA, SEPE, ZUCCHI ET AL
Table 2. Plasma Levels From 32 Renal Transplant Recipients According to Cyclosporine- or Tacrolimus-Based Immunosuppression
n Creatinine (mg/dL) Folic acid (ng/mL) Vitamin B12 (pg/mL) THcy (mol/L)
CyA
TRL
14 1.6 ⫾ 0.5 3.5 ⫾ 1.6 511 ⫾ 163 19.3 ⫾ 4.8
18 1.6 ⫾ 0.8 4.1 ⫾ 1.9 497 ⫾ 152 22.9 ⫾ 11.7
Table 4. General Characteristics of 32 Renal Transplant Recipients Analyzed According to Cyclosporine or Tacrolimus-Based Immunosuppression
n Sex (M; F) Age (y) Follow-up (mo)
CyA
TRL
14 10; 4 48 ⫾ 16 17 ⫾ 15
18 11; 7 48 ⫾ 18 17 ⫾ 12
CyA, cyclosporine; TRL, tacrolimus; follow-up, months after transplantation.
CyA, cyclosporine; TRL, tacrolimus; tHcy, total plasma homocysteine.
from fasting patients using high-performance liquid chromatography (HPLC) analysis with fluorimetric detection. Plasma creatinine levels were similar in all groups regardless stratification for MP or anticalcineurin immunosuppression. We did not adjust tHcy levels for renal function (Tables 1 and 2). The data are presented as mean values ⫾ standard deviations.
RESULTS
Similar plasma creatinine levels were observed in patients analyzed according to MP or steroid-free immunosuppression (Table 3). No differences were observed for folic acid and vitamin B12 plasma levels between MP and steroid-free patients (Table 2). Steroid-free patients treated with MMF plus CyA or TRL showed significantly lower tHcy levels compared with patients on steroid-based immunosuppression (Table 1). We also analyzed the 32 recipients according to CyA or TRL regardless of MP or MMF combinations (Table 4). No differences were observed when folic acid, vitamin B12, and tHcy plasma levels were compared between the two groups (Table 2). DISCUSSION
Our results confirmed that despite complete or partial recovery of renal function high levels of tHcy were observed in renal transplant recipients. These data were consistent with previous studies4 showing mild to moderate hHcy in these patients compared with the general population. It suggested that folate and/or vitamin B supplements should be implemented early after kidney transplantation. The influence of immunosuppressive drugs on tHcy levels in the course of kidney transplantation has been analyzed by several authors. Calcineurin inhibition appeared to be a determinant of tHcy only in an early work by Arnadottir et al,6 although several recent work Table 3. General Characteristics of 32 Renal Transplant Recipients Analyzed According to Steroid or Steroid-Free Immunosuppression
n Sex (M; F) Age (y) Follow-up (mo)
MP
Steroid-Free
20 12; 8 47 ⫾ 17 18 ⫾ 12
12 9; 3 49 ⫾ 18 19 ⫾ 11
MP, patients on methylprednisolone plus cyclosporine or tacrolimus; steroidfree, patients on a cyclosporine or tacrolimus plus mycophenolate mofetil; follow-up, months after transplantation.
did not confirm this finding.2 When we analyzed the data according to MP or MMF immunosuppression, tHcy levels appeared significantly higher in patients treated with MP plus calcineurin inhibition compared with MMF plus CyA or TRL. A possible explanation could be related to an unknown modulatory effect of MMF on homocysteine metabolism.5 How MP instead might eventually affect tHcy levels could be explained by effects on Hcy metabolism. A recent paper by Faggiano et al7 showed high tHcy levels among patients with Cushing’s disease, explaining this finding as an indirect effect of glucocorticoid-induced insulin resistance or increased glucagon levels on cystathionine -synthase, an enzyme within the pathway of homocysteine metabolism. An influence on insulin resistance has recently been reviewed by Desouza et al.8 Our results were also consistent with previous work showing no evidence of CyA or TRL on tHcy levels.2 In conclusion, our findings confirmed that complete or partial recovery of renal function in renal transplant recipients was associated with hHcy, suggesting that folate and/or vitamin B supplements should be administered early after kidney transplantation. Finally, our data showed that MP increased tHcy levels when compared to steroid-free regimens, possibly caused by the influence of glucocorticoids on insulin metabolism. REFERENCES 1. Kasiske B: Risk factors for accelerated atherosclerosis in renal transplanted recipients. Am J Med 84:985, 1988 2. Friedman AN, Rosenberg IH, Selhub J, et al: Hyperhomocysteinemia in renal transplant recipients. Am J Transplant 2:308, 2002 3. Laures AS, Gomez E, Baltar J, et al: Risk factors for cardiovascular disease during the first 2 years after renal transplantation. Transplant Proc 37:3778, 2005 4. Laures AS, Gomez E, Alvarez V, et al: Influence of anticalcineurinic therapy in plasma homocysteine levels of renal transplant recipients: a prospective study. Transplant Proc 35:1739, 2003 5. Ignatescu MC, Kletzmayr J, Fodinger M, et al: Influence of mycophenolic acid and tacrolimus on homocysteine metabolism. Kidney Int 61:1894, 2002 6. Arnadottir M, Hultberg B, Wahlberg J, et al: Serum total homocysteine concentration before and after renal transplantation. Kidney Int 54:1380, 1998 7. Faggiano A, Melis D, Alfieri R, et al: Sulfur amino acids in Cuscing’s disease: insight in homocysteine and taurine levels in patients with active and cured disease. J Clin Endocrinol Metab 90:6616, 2005 8. Desouza C, Keebler M, McNamara DB, et al: Drugs affecting homocysteine metabolism. Impact on cardiovascular risk. Drugs 62:605, 2002
T
HE INCIDENCE of cardiovascular disease (CVD) is about fivefold greater in renal transplant recipients compared to the general population.1 Hyperhomocysteinemia (hHcy) is a recognized independent risk factor for atherosclerosis, increasing the risk of CVD in patients with chronic renal disease.2 Contradictory data have suggested that anticalcineurin immunosuppression determines plasma tHcy levels in these patients,3,4 and possibly a lowering effect of mycophenolic acid on tHcy levels.5 Studies on the possible modulatory effect of steroids on tHcy levels are still not available. The aim of the present work was to analyze the influence of steroidbased immunosuppression on tHcy levels.
Table 1. Plasma Levels From 32 Renal Transplant Recipients Analyzed According to Steroid or Steroid-Free Immunosuppression
n Creatinine (mg/dL) Folic acid (ng/mL) Vitamin B12 (pg/mL) THcy (mol/L)
MP
Steroid-Free
20 1.6 ⫾ 1.5 3.7 ⫾ 1.5 483 ⫾ 152 28.5 ⫾ 12.5
12 1.6 ⫾ 0.4 3.1 ⫾ 0.9 552 ⫾ 149 16.3 ⫾ 5.5*
MP, patients on methylprednisolone plus cyclosporine or tacrolimus; steroidfree, patients on cyclosporine or tacrolimus plus mycophenolate mofetil; tHcy, total plasma homocysteine. *P ⬍ .05 vs MP.
PATIENTS AND METHODS We retrospectively analyzed data from 32 consecutive cadaveric recipients according to the immunosuppressive regimen. Steroidbased immunosuppression was associated with cyclosporine (CyA) or tacrolimus (TRL). A steroid-free regimen instead combined CyA or TRL with mycophenolate mofetil (MMF). Data were also analyzed according to CyA or TRL immunosuppression regardless MP or MMF associations. All patients were on a methylprednisolone (MP) plus CyA regimen for 6 months after kidney transplantation. Fifty percent of them were then shifted from CyA to TRL according to a randomization table prepared by our Department of Epidemiology. Six months after transplantation patients without a pretransplant history of autoimmune disease underwent slow steroid withdrawal with MMF introduced into the immunosuppressive regimen. At the time of sampling patients on MMF had all been on MP for at least 6 months after kidney transplantation and all had been on a steroid-free regimen with MMF for at least 6 months. CyA doses were adjusted to maintain trough levels (C0) between 150 and 200 ng/mL during the
first year and between 100 and 150 ng/mL after the first year of transplantation. Therapeutic ranges for TRL were maintained between 10 and 12 ng/mL during the first 3 posttransplantation months and between 8 and 10 ng/mL thereafter. MMF was administered at a standard dose of 1000 mg twice daily. Data from acutely ill patients were not included in the analysis. Folate or vitamin B supplements were never administered during the follow-up period. Plasma levels of creatinine, folic acid, vitamin B12, and tHcy were measured in all patients. THcy levels, including homocysteine-homocysteine disulfide and mixed homocysteine-cysteine disulfide, were measured in samples From the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Address reprint requests to Vincenzo Sepe, MD, PhD, Fondazione IRCCS Policlinico San Matteo, Nephrology, Dialysis, Transplantation, Ple Golgi 2, Pavia 27100, Italy. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.149
Transplantation Proceedings, 38, 2893–2894 (2006)
2893
2894
LIBETTA, SEPE, ZUCCHI ET AL
Table 2. Plasma Levels From 32 Renal Transplant Recipients According to Cyclosporine- or Tacrolimus-Based Immunosuppression
n Creatinine (mg/dL) Folic acid (ng/mL) Vitamin B12 (pg/mL) THcy (mol/L)
CyA
TRL
14 1.6 ⫾ 0.5 3.5 ⫾ 1.6 511 ⫾ 163 19.3 ⫾ 4.8
18 1.6 ⫾ 0.8 4.1 ⫾ 1.9 497 ⫾ 152 22.9 ⫾ 11.7
Table 4. General Characteristics of 32 Renal Transplant Recipients Analyzed According to Cyclosporine or Tacrolimus-Based Immunosuppression
n Sex (M; F) Age (y) Follow-up (mo)
CyA
TRL
14 10; 4 48 ⫾ 16 17 ⫾ 15
18 11; 7 48 ⫾ 18 17 ⫾ 12
CyA, cyclosporine; TRL, tacrolimus; follow-up, months after transplantation.
CyA, cyclosporine; TRL, tacrolimus; tHcy, total plasma homocysteine.
from fasting patients using high-performance liquid chromatography (HPLC) analysis with fluorimetric detection. Plasma creatinine levels were similar in all groups regardless stratification for MP or anticalcineurin immunosuppression. We did not adjust tHcy levels for renal function (Tables 1 and 2). The data are presented as mean values ⫾ standard deviations.
RESULTS
Similar plasma creatinine levels were observed in patients analyzed according to MP or steroid-free immunosuppression (Table 3). No differences were observed for folic acid and vitamin B12 plasma levels between MP and steroid-free patients (Table 2). Steroid-free patients treated with MMF plus CyA or TRL showed significantly lower tHcy levels compared with patients on steroid-based immunosuppression (Table 1). We also analyzed the 32 recipients according to CyA or TRL regardless of MP or MMF combinations (Table 4). No differences were observed when folic acid, vitamin B12, and tHcy plasma levels were compared between the two groups (Table 2). DISCUSSION
Our results confirmed that despite complete or partial recovery of renal function high levels of tHcy were observed in renal transplant recipients. These data were consistent with previous studies4 showing mild to moderate hHcy in these patients compared with the general population. It suggested that folate and/or vitamin B supplements should be implemented early after kidney transplantation. The influence of immunosuppressive drugs on tHcy levels in the course of kidney transplantation has been analyzed by several authors. Calcineurin inhibition appeared to be a determinant of tHcy only in an early work by Arnadottir et al,6 although several recent work Table 3. General Characteristics of 32 Renal Transplant Recipients Analyzed According to Steroid or Steroid-Free Immunosuppression
n Sex (M; F) Age (y) Follow-up (mo)
MP
Steroid-Free
20 12; 8 47 ⫾ 17 18 ⫾ 12
12 9; 3 49 ⫾ 18 19 ⫾ 11
MP, patients on methylprednisolone plus cyclosporine or tacrolimus; steroidfree, patients on a cyclosporine or tacrolimus plus mycophenolate mofetil; follow-up, months after transplantation.
did not confirm this finding.2 When we analyzed the data according to MP or MMF immunosuppression, tHcy levels appeared significantly higher in patients treated with MP plus calcineurin inhibition compared with MMF plus CyA or TRL. A possible explanation could be related to an unknown modulatory effect of MMF on homocysteine metabolism.5 How MP instead might eventually affect tHcy levels could be explained by effects on Hcy metabolism. A recent paper by Faggiano et al7 showed high tHcy levels among patients with Cushing’s disease, explaining this finding as an indirect effect of glucocorticoid-induced insulin resistance or increased glucagon levels on cystathionine -synthase, an enzyme within the pathway of homocysteine metabolism. An influence on insulin resistance has recently been reviewed by Desouza et al.8 Our results were also consistent with previous work showing no evidence of CyA or TRL on tHcy levels.2 In conclusion, our findings confirmed that complete or partial recovery of renal function in renal transplant recipients was associated with hHcy, suggesting that folate and/or vitamin B supplements should be administered early after kidney transplantation. Finally, our data showed that MP increased tHcy levels when compared to steroid-free regimens, possibly caused by the influence of glucocorticoids on insulin metabolism. REFERENCES 1. Kasiske B: Risk factors for accelerated atherosclerosis in renal transplanted recipients. Am J Med 84:985, 1988 2. Friedman AN, Rosenberg IH, Selhub J, et al: Hyperhomocysteinemia in renal transplant recipients. Am J Transplant 2:308, 2002 3. Laures AS, Gomez E, Baltar J, et al: Risk factors for cardiovascular disease during the first 2 years after renal transplantation. Transplant Proc 37:3778, 2005 4. Laures AS, Gomez E, Alvarez V, et al: Influence of anticalcineurinic therapy in plasma homocysteine levels of renal transplant recipients: a prospective study. Transplant Proc 35:1739, 2003 5. Ignatescu MC, Kletzmayr J, Fodinger M, et al: Influence of mycophenolic acid and tacrolimus on homocysteine metabolism. Kidney Int 61:1894, 2002 6. Arnadottir M, Hultberg B, Wahlberg J, et al: Serum total homocysteine concentration before and after renal transplantation. Kidney Int 54:1380, 1998 7. Faggiano A, Melis D, Alfieri R, et al: Sulfur amino acids in Cuscing’s disease: insight in homocysteine and taurine levels in patients with active and cured disease. J Clin Endocrinol Metab 90:6616, 2005 8. Desouza C, Keebler M, McNamara DB, et al: Drugs affecting homocysteine metabolism. Impact on cardiovascular risk. Drugs 62:605, 2002