- Email: [email protected]
The Effect of Sirolimus in the Development of Chronic Allograft Nephropathy
OUTCOMES
The Effect of Sirolimus in the Development of Chronic Allograft Nephropathy A. Gürkan, S. Kaçar, U. Erdog˘du, C. Varılsüha, G. Kandemir, C. Karaca, and F. Akman ABSTRACT Purpose. The effect of sirolimus (SRL) in renal function was studied in renal transplant recipients. Patients and Methods. We studied 20 patients who underwent live related kidney transplantation 1 to 2 years prior under cyclosporine (CsA) treatment and displayed serum creatinine values between 2 and 3 mg/dL. The patients were randomized into 2 groups prospectively. The calcineurin inhibitors (CNI) group continued taking CsA; the SRL group underwent a switch from CsA to SRL. Biopsies were performed to assess chronic allograft nephropathy (CAN) findings and TGF1 in the transplanted kidneys at the beginning and the end of the study. Creatinine clearance, serum creatinine, and proteinuria values were detected in the beginning as well as at 1, 3, 6, and 12 months later. Results. At the beginning of the study, the creatinine clearance and serum creatinine levels were 52.21 mL/min and 2.05 mg/dL in the CNI group and 47.76 mL/min and 2.13 mg/dL in the SRL group, respectively. At 12 months, these values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Creatinine clearance values between the 2 groups at 12 months were statistically different. Although it was not significant, there was a tendency toward decreases inflammatory infiltration and TGF1 levels in the SRL group compared with the CNI group on the second biopsies. Conclusion. Pathologic findings of CAN development, serum creatinine, and creatinine clearance values were ameliorated in the SRL group. We concluded that SRL positively affected long-term graft survival.
From the S.B. Tepecik Teaching Hospital, Organ Transplantation Center, and Micro Private Pathology Center, Izmir, Turkey. 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2007.11.005 114
Address reprint requests to Alp Gu¨rkan, MD, FACS, Ali Cetinkaya Bul. No: 18 D: 2 Alsancak Izmir, Turkey, 35220. E-mail: [email protected] © 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 114 –116 (2008)
SIROLIMUS
115
K
IDNEY transplantation is the best choice for treatment of end-stage renal disease because it prolongs survival,1 improves quality of life,2 and is less costly compared with dialysis.2 Almost half of kidney failures are due to progressive chronic allograft nephropathy (CAN).3,4 Although patients can return to dialysis after failure of a transplanted kidney, loss of the kidney is associated with increased risk of death5 and cost2 as well as decreased quality of life.2 Sirolimus (SRL) is believed to be free of nephrotoxicity.6,7 Nowadays there is increasing tendency to convert patients from calcineurin inhibitors (CNI) to SRL in many transplantation centers. However, the appropriate timing of the conversion is uncertain. The purpose of this study was to examine the efficacy of SRL to improve renal dysfunction before establishment of CAN. PATIENTS AND METHODS We analyzed 20 patients who underwent live related kidney transplantation 1 to 2 years ago, using a cyclosporine (CsA)-based immunosuppressive protocol, who displayed serum creatinine values between 2 and 3 mg/dL without proteinuria and who did not experience acute rejection episodes within 6 months. The patients were prospectively randomized into 2 groups, the CNI group continued taking CsA; the SRL group discontinued CsA and were switched to SRL. All patients were followed for 12 months. Tru-cut biopsies were performed on the transplanted kidneys at the beginning and at the end of the study. In all of the patients, creatinine clearance, serum creatinine, proteinuria, blood pressure, alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, trigliderides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and blood sugar values were measured at the beginning as well as at 1, 3, 6, and 12 months. The values were compared within the same group and between the groups at each study interval. In addition, hematoxylin eosin and periodic acid Schiff showing and TGF1 immunochemical reactions were performed on renal biopsy specimens. We examined the biopsies semiquantitatively based upon the CADI score and the presence of TGF1. Differences between groups were tested using an unpaired two-tailed Student t test; the relationship between variables was examined with linear regression analysis.
RESULTS
At the beginning of the study, the creatinine clearances were measured at 52.21 mL/min and 47.76 mL/min in the CNI and the SRL groups, respectively (P ⫽ .374). The levels of serum creatinine were 2.05 mg/dL in the CNI and 2.13 mg/dL in the SRL group, respectively (P ⫽ .744). At the first month, the values were 50.2 mL/min and 2.18 mg/dL in the CNI group and 50.1 mL/min and 1.98 mg/dL in the SRL group, respectively. At 12 months, the values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Comparisons of the creatinine clearances and serum creatinine values between the beginning and end of the study were significantly different (P ⫽ .037 and .031, respectively). The creatinine clearance values between the 2 groups at 12 months were also significant (P ⫽ .002). Creatinine clearance curves for both groups starting be-
Fig 1. The GFR curves of both groups.
tween 1 year before the study (months before study as shown with negative quotation) and during the study are shown in Figure 1. Blood sugar, HDL, LDL, cholesterol, ALT, AST, triglyceride, and systolic and diastolic blood pressure levels were not different between or within groups during the study. Although at the beginning of the study, daily urinary protein excretion levels were similar in both groups (19.22 mg/L in the CNI group; 17.83 mg/L in the SRL group), a difference became statistically significant (P ⫽ .039) at the end of 12 months (25.78 mg/L in the CNI group; 40.67 mg/L in the SRL group). On the second biopsies, there was a tendency for a decreased inflammatory infiltrate and reduced level of TGF1 in the SRL compared with the CNI group. In the SRL group, only 1 patient seemed to show an increased TGF1 expression, whereas the others were unchanged. In the CNI group, all of the patients (except 1) showed elevated TGF1 expression. The mean CADI scores were 7 and 7 in both groups at the beginning of the study, whereas at the end of the study the mean CADI scores were 12 and 9 for CNI and SRL groups, respectively. DISCUSSION
The main cause of kidney dysfunction at 1 year after transplantation is CAN, which is characterized by impaired renal function along with pathologic changes of interstitial fibrosis, tubular atrophy, and intimal thickening in the arteries.8 Nankivell et al9 reports 94% of the patients in whom protocol biopsies were performed revealed signs of CAN. Although the pathogenesis of CAN is uncertain, many immune and nonimmune factors contribute. CNI nephrotoxicity is thought to be a major nonimmune factor in the pathogenesis of CAN.3,10,11 Various studies have shower that renal function is improved by CNI withdrawal or minimization.12,13 The conversion of a CNI-based protocol to a non-nephrotoxic regimen also must maintain an adequate immunosuppressive effect. It has been demonstrated that early CsA withdrawal followed by SRL-based protocols provided significant improvement in renal histology and function in the first 3 years.14 Timing of the conversion is still controversial. As stated in the study by
116
Nankivell et al,9 CAN develops in 3 distinctive periods. CNI toxicity is clearly shown in this third period, during which immunological insults are diminished. It seems wise to withdraw CNI and convert to a non-nephrotoxic regimen for adequate immunosuppressive therapy after 1 year, unless there is the presence of severe proteinuria (⬎800 mg/dL). Although the number of the patients was small, our study before CAN development showed beneficial effects of conversion to SRL on CADI score and TGF1 expression. CAN can be diagnosed in protocol biopsy specimens even before clinical features point to graft dysfunction.5,15 Protocol biopsies have thus become a common practice as a useful tool to predict chronic allograft damage.7,15,16 The CADI score system,15 has shown a good correlation with long-term graft function. In the study by Ortiz et al,16 changes in CADI score over 6 months distinguished patients early with progressive histologic allograft damage even before serum creatinine elevation. TGF1 is stated to be a good marker for fibrogenesis17; it is believed to have an important role in the pathogenesis, of CAN18,19, in which interstitial fibrosis is a major histological feature. In many studies17–19 TGF1 expression levels correlated with Banff histopathological grades, CsA toxicity, acute rejection events, CAN, and clinical outcome as well. In contrast, other studies have not been able to show a correlation with the cause of allograft failure.20 Although we were not able to do a statistical analysis in our study due to the small number of patients, TGF1 expression was not elevated in the SRL group patients during the study. Glomerular fitration rate levels of these patients were increased at the end of the study. In the CNI group, TGF1 expression was elevated in all of the patients except 1 with a good correlation with glomerular fitration rate decline. In conclusion, serum creatinine, creatinine clearance, and TGF1 expression, which are believed to reflect CAN development, were ameliorated in the SRL group. Based upon these findings, we concluded that SRL positively affected long-term graft survival. Larger studies should be performed to correlate TGF1 expression levels and longterm graft survival. REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting
GU¨RKAN, KAÇAR, ERDOG˘DU ET AL transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725, 1999 2. Laupacis A, Keown P, Pus N, et al: A study of the quality life and cost-utility of renal transplantation. Kidney Int 50:235, 1996 3. US Renal Data System: Available at: www.usrds.org 4. Ojo AO, Hanson JA, Wolfe RA, et al: Long-term survival in renal transplant recipients with graft function. Kidney Int 57:307, 2000 5. Chapman JR: Longitudinal analysis of chronic allograft nephropathy; clinicopathologic correlations. Kidney Int 99:S108, 2005 6. Morales JM, Andres A, Rengel M, et al: Influence of cyclosporin or tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. Nephrol Dial Transplant 16:121, 2001 7. Saunders RN, Metcalfe MS, Nicholson ML: Rapamycin in transplantation: a review of the evidence. Kidney Int 70:3, 2001 8. Knoll G, Muirhead N, Trpeski L, et al: Patient survival following renal transplant failure in Canada. Am J Transplant 5:1719, 2005 9. Nankivell BJ, Borrows RJ, Fung CL, et al: The natural history of chronic allograft nephropathy. N Eng J Med 349:2326, 2003 10. de Mattos A, Olyaei A, Bennett W: Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 35:333, 2000 11. Joosten S, van Kooten C, Paul L: Pathogenesis of chronic allograft rejection. Transplant Int 16:137, 2003 12. Weir MR, Blahut S, Drachernburg C, et al: Late calcineurin inhibitor withdrawal as a strategy to prevent graft loss in patients with suboptimal kidney transplant function. Am J Nephrol 24:379, 2004 13. Vitko S, Tedesco H, Eris J, et al: Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 4:626, 2004 14. Mota A, Arias M, Taskinen EI, et al: Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 4:1869, 2004 15. Isoniemi H, Krogerus L, von Willebrand E, et al: Histopathologic findings in well-functioning, long-term renal allografts. Kidney Int 41:155, 1992 16. Ortiz F, Paavonen T, Törnroth T, et al: Predictors of renal allograft histologic damage progression. J Am Soc Nephrol 16:817, 2005 17. Pribylova-Hribova P, Kotsch K, Lodererova A, et al: TGF-1 mRNA upregulation influences chronic renal allograft dysfunction. Kidney Int 69:1872, 2006 18. Nicholson ML, Waller JR, Bicknell GR: Renal transplant fibrosis correlates with intragraft expression of tissue inhibitor of metaloproteinase messenger RNA. Br J Surg 89:933, 2002 19. Ishimura T, Ishida T, Fujisawa M: Significance of early biopsy in pediatric kidney transplantation. Aktuel Urol 34:234, 2003 20. Coupes BM, Newstead CG, Short CD, et al: Transforming growth factor 1 in renal allograft recipients. Transplantation 57:1727, 1994
The Effect of Sirolimus in the Development of Chronic Allograft Nephropathy A. Gürkan, S. Kaçar, U. Erdog˘du, C. Varılsüha, G. Kandemir, C. Karaca, and F. Akman ABSTRACT Purpose. The effect of sirolimus (SRL) in renal function was studied in renal transplant recipients. Patients and Methods. We studied 20 patients who underwent live related kidney transplantation 1 to 2 years prior under cyclosporine (CsA) treatment and displayed serum creatinine values between 2 and 3 mg/dL. The patients were randomized into 2 groups prospectively. The calcineurin inhibitors (CNI) group continued taking CsA; the SRL group underwent a switch from CsA to SRL. Biopsies were performed to assess chronic allograft nephropathy (CAN) findings and TGF1 in the transplanted kidneys at the beginning and the end of the study. Creatinine clearance, serum creatinine, and proteinuria values were detected in the beginning as well as at 1, 3, 6, and 12 months later. Results. At the beginning of the study, the creatinine clearance and serum creatinine levels were 52.21 mL/min and 2.05 mg/dL in the CNI group and 47.76 mL/min and 2.13 mg/dL in the SRL group, respectively. At 12 months, these values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Creatinine clearance values between the 2 groups at 12 months were statistically different. Although it was not significant, there was a tendency toward decreases inflammatory infiltration and TGF1 levels in the SRL group compared with the CNI group on the second biopsies. Conclusion. Pathologic findings of CAN development, serum creatinine, and creatinine clearance values were ameliorated in the SRL group. We concluded that SRL positively affected long-term graft survival.
From the S.B. Tepecik Teaching Hospital, Organ Transplantation Center, and Micro Private Pathology Center, Izmir, Turkey. 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2007.11.005 114
Address reprint requests to Alp Gu¨rkan, MD, FACS, Ali Cetinkaya Bul. No: 18 D: 2 Alsancak Izmir, Turkey, 35220. E-mail: [email protected] © 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 114 –116 (2008)
SIROLIMUS
115
K
IDNEY transplantation is the best choice for treatment of end-stage renal disease because it prolongs survival,1 improves quality of life,2 and is less costly compared with dialysis.2 Almost half of kidney failures are due to progressive chronic allograft nephropathy (CAN).3,4 Although patients can return to dialysis after failure of a transplanted kidney, loss of the kidney is associated with increased risk of death5 and cost2 as well as decreased quality of life.2 Sirolimus (SRL) is believed to be free of nephrotoxicity.6,7 Nowadays there is increasing tendency to convert patients from calcineurin inhibitors (CNI) to SRL in many transplantation centers. However, the appropriate timing of the conversion is uncertain. The purpose of this study was to examine the efficacy of SRL to improve renal dysfunction before establishment of CAN. PATIENTS AND METHODS We analyzed 20 patients who underwent live related kidney transplantation 1 to 2 years ago, using a cyclosporine (CsA)-based immunosuppressive protocol, who displayed serum creatinine values between 2 and 3 mg/dL without proteinuria and who did not experience acute rejection episodes within 6 months. The patients were prospectively randomized into 2 groups, the CNI group continued taking CsA; the SRL group discontinued CsA and were switched to SRL. All patients were followed for 12 months. Tru-cut biopsies were performed on the transplanted kidneys at the beginning and at the end of the study. In all of the patients, creatinine clearance, serum creatinine, proteinuria, blood pressure, alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, trigliderides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and blood sugar values were measured at the beginning as well as at 1, 3, 6, and 12 months. The values were compared within the same group and between the groups at each study interval. In addition, hematoxylin eosin and periodic acid Schiff showing and TGF1 immunochemical reactions were performed on renal biopsy specimens. We examined the biopsies semiquantitatively based upon the CADI score and the presence of TGF1. Differences between groups were tested using an unpaired two-tailed Student t test; the relationship between variables was examined with linear regression analysis.
RESULTS
At the beginning of the study, the creatinine clearances were measured at 52.21 mL/min and 47.76 mL/min in the CNI and the SRL groups, respectively (P ⫽ .374). The levels of serum creatinine were 2.05 mg/dL in the CNI and 2.13 mg/dL in the SRL group, respectively (P ⫽ .744). At the first month, the values were 50.2 mL/min and 2.18 mg/dL in the CNI group and 50.1 mL/min and 1.98 mg/dL in the SRL group, respectively. At 12 months, the values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Comparisons of the creatinine clearances and serum creatinine values between the beginning and end of the study were significantly different (P ⫽ .037 and .031, respectively). The creatinine clearance values between the 2 groups at 12 months were also significant (P ⫽ .002). Creatinine clearance curves for both groups starting be-
Fig 1. The GFR curves of both groups.
tween 1 year before the study (months before study as shown with negative quotation) and during the study are shown in Figure 1. Blood sugar, HDL, LDL, cholesterol, ALT, AST, triglyceride, and systolic and diastolic blood pressure levels were not different between or within groups during the study. Although at the beginning of the study, daily urinary protein excretion levels were similar in both groups (19.22 mg/L in the CNI group; 17.83 mg/L in the SRL group), a difference became statistically significant (P ⫽ .039) at the end of 12 months (25.78 mg/L in the CNI group; 40.67 mg/L in the SRL group). On the second biopsies, there was a tendency for a decreased inflammatory infiltrate and reduced level of TGF1 in the SRL compared with the CNI group. In the SRL group, only 1 patient seemed to show an increased TGF1 expression, whereas the others were unchanged. In the CNI group, all of the patients (except 1) showed elevated TGF1 expression. The mean CADI scores were 7 and 7 in both groups at the beginning of the study, whereas at the end of the study the mean CADI scores were 12 and 9 for CNI and SRL groups, respectively. DISCUSSION
The main cause of kidney dysfunction at 1 year after transplantation is CAN, which is characterized by impaired renal function along with pathologic changes of interstitial fibrosis, tubular atrophy, and intimal thickening in the arteries.8 Nankivell et al9 reports 94% of the patients in whom protocol biopsies were performed revealed signs of CAN. Although the pathogenesis of CAN is uncertain, many immune and nonimmune factors contribute. CNI nephrotoxicity is thought to be a major nonimmune factor in the pathogenesis of CAN.3,10,11 Various studies have shower that renal function is improved by CNI withdrawal or minimization.12,13 The conversion of a CNI-based protocol to a non-nephrotoxic regimen also must maintain an adequate immunosuppressive effect. It has been demonstrated that early CsA withdrawal followed by SRL-based protocols provided significant improvement in renal histology and function in the first 3 years.14 Timing of the conversion is still controversial. As stated in the study by
116
Nankivell et al,9 CAN develops in 3 distinctive periods. CNI toxicity is clearly shown in this third period, during which immunological insults are diminished. It seems wise to withdraw CNI and convert to a non-nephrotoxic regimen for adequate immunosuppressive therapy after 1 year, unless there is the presence of severe proteinuria (⬎800 mg/dL). Although the number of the patients was small, our study before CAN development showed beneficial effects of conversion to SRL on CADI score and TGF1 expression. CAN can be diagnosed in protocol biopsy specimens even before clinical features point to graft dysfunction.5,15 Protocol biopsies have thus become a common practice as a useful tool to predict chronic allograft damage.7,15,16 The CADI score system,15 has shown a good correlation with long-term graft function. In the study by Ortiz et al,16 changes in CADI score over 6 months distinguished patients early with progressive histologic allograft damage even before serum creatinine elevation. TGF1 is stated to be a good marker for fibrogenesis17; it is believed to have an important role in the pathogenesis, of CAN18,19, in which interstitial fibrosis is a major histological feature. In many studies17–19 TGF1 expression levels correlated with Banff histopathological grades, CsA toxicity, acute rejection events, CAN, and clinical outcome as well. In contrast, other studies have not been able to show a correlation with the cause of allograft failure.20 Although we were not able to do a statistical analysis in our study due to the small number of patients, TGF1 expression was not elevated in the SRL group patients during the study. Glomerular fitration rate levels of these patients were increased at the end of the study. In the CNI group, TGF1 expression was elevated in all of the patients except 1 with a good correlation with glomerular fitration rate decline. In conclusion, serum creatinine, creatinine clearance, and TGF1 expression, which are believed to reflect CAN development, were ameliorated in the SRL group. Based upon these findings, we concluded that SRL positively affected long-term graft survival. Larger studies should be performed to correlate TGF1 expression levels and longterm graft survival. REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting
GU¨RKAN, KAÇAR, ERDOG˘DU ET AL transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725, 1999 2. Laupacis A, Keown P, Pus N, et al: A study of the quality life and cost-utility of renal transplantation. Kidney Int 50:235, 1996 3. US Renal Data System: Available at: www.usrds.org 4. Ojo AO, Hanson JA, Wolfe RA, et al: Long-term survival in renal transplant recipients with graft function. Kidney Int 57:307, 2000 5. Chapman JR: Longitudinal analysis of chronic allograft nephropathy; clinicopathologic correlations. Kidney Int 99:S108, 2005 6. Morales JM, Andres A, Rengel M, et al: Influence of cyclosporin or tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. Nephrol Dial Transplant 16:121, 2001 7. Saunders RN, Metcalfe MS, Nicholson ML: Rapamycin in transplantation: a review of the evidence. Kidney Int 70:3, 2001 8. Knoll G, Muirhead N, Trpeski L, et al: Patient survival following renal transplant failure in Canada. Am J Transplant 5:1719, 2005 9. Nankivell BJ, Borrows RJ, Fung CL, et al: The natural history of chronic allograft nephropathy. N Eng J Med 349:2326, 2003 10. de Mattos A, Olyaei A, Bennett W: Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 35:333, 2000 11. Joosten S, van Kooten C, Paul L: Pathogenesis of chronic allograft rejection. Transplant Int 16:137, 2003 12. Weir MR, Blahut S, Drachernburg C, et al: Late calcineurin inhibitor withdrawal as a strategy to prevent graft loss in patients with suboptimal kidney transplant function. Am J Nephrol 24:379, 2004 13. Vitko S, Tedesco H, Eris J, et al: Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 4:626, 2004 14. Mota A, Arias M, Taskinen EI, et al: Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 4:1869, 2004 15. Isoniemi H, Krogerus L, von Willebrand E, et al: Histopathologic findings in well-functioning, long-term renal allografts. Kidney Int 41:155, 1992 16. Ortiz F, Paavonen T, Törnroth T, et al: Predictors of renal allograft histologic damage progression. J Am Soc Nephrol 16:817, 2005 17. Pribylova-Hribova P, Kotsch K, Lodererova A, et al: TGF-1 mRNA upregulation influences chronic renal allograft dysfunction. Kidney Int 69:1872, 2006 18. Nicholson ML, Waller JR, Bicknell GR: Renal transplant fibrosis correlates with intragraft expression of tissue inhibitor of metaloproteinase messenger RNA. Br J Surg 89:933, 2002 19. Ishimura T, Ishida T, Fujisawa M: Significance of early biopsy in pediatric kidney transplantation. Aktuel Urol 34:234, 2003 20. Coupes BM, Newstead CG, Short CD, et al: Transforming growth factor 1 in renal allograft recipients. Transplantation 57:1727, 1994