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Successful Therapy of Chronic Renal Allograft Failure by Enhanced Immunosuppression
Successful Therapy of Chronic Renal Allograft Failure by Enhanced Immunosuppression V. Kliem, T. Tiroke, G. Ehlerding, O. Eberhard, M. Behrend, U. Frei, K.M. Koch, R. Pichlmayr, and R. Brunkhorst
T
HE IMPACT of immunologic1,2 and nonimmunologic factors3– 6 on the development of chronic allograft failure in renal transplant recipients treated with cyclosporine (CyA) and prednisolone is controversially discussed. The observations that episodes of acute rejection as well as low CyA doses ,5 mg/kg/d7 and suboptimal histocompatibility between donor and organ recipient8 are correlated with increased incidence of chronic allograft failure are in favor of the hypothesis that immunologic mechanisms cause the chronic rejection process. An immunosuppressive protocol including azathioprine (Aza) was reported to be associated with less histologic signs of chronic rejection 2 years posttransplant as compared with CyA/steroid-based therapy.9 Furthermore, higher immunosuppression in kidney recipients with slowly deteriorating graft function by a conversion to triple therapy including Aza showed promising results.10,11 However, trials on higher patient numbers with use of standardized conversion criteria and prospective studies are lacking. Thus, it was the aim of this study to investigate the impact of a standardized conversion from double immunosuppression with CyA/prednisolone to a triple-drug regimen including Aza on chronic progressive allograft failure in renal transplant patients. In addition, the safety of the conversion protocol regarding acute rejection episodes and side effects was tested. PATIENTS AND METHODS The present study includes all kidney recipients who were converted from double immunosuppression to triple-drug therapy including Aza between January 1987 and November 1994 because of slowly progressing chronic renal allograft failure. Inclusion criteria were (1) an increase in the serum creatinine value of .50 mmol/L during an interval of 6 months preconversion, (2) a serum creatinine value between 150 and 450 mmol/L at time of conversion, (3) a time interval of .12 months between transplantation and conversion, and (4) exclusion of acute rejection, acute CyA nephrotoxicity, or recurrent renal disease by graft biopsy and clinical evaluation. Exclusion criteria were (1) an episode of acute graft rejection within 6 months preconversion, (2) acute pyelonephritis within the last 6 months, chronic infectious diseases, or septicemia posttransplant, (3) chronic active liver disease, (4) a history of drug-induced bone marrow depression or a white blood cell count ,4000/mL or a red blood cell count ,9 g/dL at time of conversion, and (5) allopurinol treatment. Of the 80 renal trans-
plant recipients who complied with the criteria of the study, 60 were analyzed retrospectively (RT) and 20 were prospectively surveyed (PT). Immunosuppression consisted of CyA 10 mg/kg/d (adjusted to trough levels between 150 and 200 ng/mL within the first 3 months) and prednisolone 1 mg/kg/d, tapered to 0.1 mg/kg/d within 3 months. In the long run, the patients received CyA (trough levels 100 to 150 ng/mL) plus prednisolone (7.5 mg/d maintenance dose). Biopsy-proven acute graft rejection was treated with intravenous (IV) bolus doses of 0.5 to 1 g methylprednisolone (3 to 5 days). Patients with resistant rejection received antithymocyte globulin (ATG) or OKT3. The switch to triple-drug therapy was performed according to the following protocol. Day 1: Increase of prednisolone dose from 7.5 to 30 mg/d, no change of CyA dose, and additional treatment with Aza (1.5 to 2 mg/kg/d). Day 14: Reduction of CyA to about two thirds of the former dose. During the following weeks, CyA doses were adjusted to maintain trough levels of 70 to 90 ng/mL and prednisolone was reduced by 5 mg per week to 15 mg/d, subsequently further reduced by 2.5 mg per week to the maintenance dose of 7.5 mg/d. After conversion, all patients were seen monthly for 3 months and thereafter every 3 months at our outpatient clinic. The following data were regularly obtained: blood pressure, serum creatinine value, full blood count, liver enzymes, cholesterol, grade of proteinuria, and CyA trough levels (assessed by a monoclonal-specific radioimmunoassay [RIA] kit, Sandoz, Basel, Switzerland). Casual blood pressure recordings were performed at time of conversion and 6 as well as 12 months afterwards. For statistical analysis, a two-tailed t test for pairs was performed to compare the preconversion data with those obtained during the follow-up. Significance was assumed at P , .05.
RESULTS
The time between transplantation and conversion therapy was 38 (median 5 to 160) months, median follow-up after conversion to triple immunosuppression was 53 (19 to 108; RT) and 16 (13 to 18; PT) months. Aza dose was 1.6 6 0.4 mg/kg/d, while CyA dose was reduced by approximately 22%. Renal graft biopsy was performed in all PT patients and in 35 of 60 RT patients, revealing in all cases tubular From Abteilung Nephrologie and Klinik fu¨r Abdominal und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany. Address reprint requests to Dr Volker Kliem, Abteilung Nephrologie, Medizinische Hochschule Hannover, Carl-NeubergStraße 1, D-30625 Hannover, Germany.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00212-7
Transplantation Proceedings, 30, 1207–1209 (1998)
1207
1208
atrophy and interstitial fibrosis as well as in 65% of the cases a so-called benign nephrosclerosis and in 40% of the cases a transplant glomerulopathy. All 80 patients showed an increase in the value in serum creatinine from an average of 202 6 47 to 264 6 63 mmol/L during the 6 months before conversion. Among these 80 patients, two groups could clearly be separated with respect to response in renal graft function after conversion: (1) group A included 60 patients (45 RT and 15 PT) who showed a significant improvement in graft function after the switch from a mean serum creatinine value of 259 6 53 to 218 6 44 mmol/L and achieved stable graft function and (2) group B consisted of 20 patients (15 RT and 5 PT) who displayed a progressive decline in renal function despite triple therapy, with an increase in the serum creatinine value of .100 mmol/L during the following 12 months. Thirteen of these 20 patients lost their graft within 2 years after conversion. During the 18 months before initiation of triple therapy, renal graft function deteriorated in both groups (A and B) without significant difference. With regard to age, gender, pretransplant dialysis time, HLA match, graft cold ischemia time, the number of rejections, and optiminum serum creatinine value posttransplant, no significant differences were found between groups A and B. Significant differences between responders (A) and nonresponders (B) at the time of conversion were found for proteinuria (0.65 vs 2.4 mg/d) and for casual blood pressure values (140/85 vs 156/91 mm Hg; number of antihypertensive agents was comparable in both groups). The CyA trough levels were similar for both groups shortly after transplantation as well as immediately before and after initiation of triple therapy. Also the Aza doses given did not differ. After conversion, neither acute rejections nor severe infections occurred. No disturbances of liver and pancreas function were seen. Total cholesterol levels did not differ significantly between both groups shortly after transplantation as well as at time of switch. Bone marrow toxicity from Aza occurred in 8 of 80 (10%) cases and led to dose reduction in four of them. In none of the patients the drug had to be permanently withdrawn because of leukopenia. Fifteen of 80 (19%) patients received erythropoietin for therapy of renal anemia after conversion to triple-drug therapy. DISCUSSION
As primary regimen after renal transplantation, triple immunosuppression including Aza provides comparable graft survival rates as therapy with CyA/steroids. The rationale for the triple-drug regimen is that the three drugs are believed to complement each other in preventing graft rejection, so that maintenance therapy at low doses with an associated reduction in side effects becomes possible.12 The conversion from CyA/steroid-treated kidney recipients with slowly progressing chronic allograft failure to triple therapy including Aza could gain stable graft function anew, thus on the one hand by enhancing the immunosuppression by Aza while on the other hand by mitigating CyA effects on the
KLIEM, TIROKE, EHLERDING ET AL
already damaged graft as a consequence of CyA dose reduction. As mentioned, in primary triple-immunosuppressed patients 2 years after renal transplantation, less histologic signs of chronic rejection were found as compared with CyA/steroid treatment, even if the graft survival rates were comparable.9 However, Leaker et al13 reported a striking increase of infections under triple therapy and Salaman et al14 described some cases with fatal outcome. In agreement with other reports regarding conversion to triple therapy,10,11 the absence of severe complications due to infections and of disturbances of liver or pancreatic functions as well as of bone marrow depression leading to discontinuation of Aza treatment in our study can be explained by the relatively low Aza dose and overall moderate immunosuppression. Rejection episodes have been reported due to conversion from CyA/steroids to triple therapy, in particular when the CyA dose was reduced by more than 50%.15 According to our data, however, a switch to triple immunosuppression with a reduction of the CyA dose by only 20% to 25% and applying transiently higher steroid doses was not ensued by the risk of acute graft rejection. In our study, approximately 75% of the kidney recipients with chronic allograft failure reached stable graft function anew after initiation of triple therapy, whereas in 25% after transient improvement, graft function continued to deteriorate despite conversion. The rate of proteinuria and casual blood pressure values were significantly higher already preconversion in the nonresponders and may serve as predictors for outcome after switch. Thus, in the nonresponders, alloantigen-independent mechanisms, in particular hypertension,3,6 could contribute to chronic allograft failure. Beside the grade of proteinuria and hypertension, we were not able to find any predictors for the success of conversion to triple therapy. Nevertheless, the results of conversion in a large number of patients from a CyA-based double-drug therapy to an enhanced immunosuppression including Aza are encouraging in slowly progressing chronic renal allograft failure and are in agreement with preliminary results.10,11 In conclusion, in up to 75% of CyA/steroid-treated kidney recipients with chronic allograft failure and impending graft loss, renal failure can be avoided by conversion to triple therapy including Aza - being a therapy with low risk regarding acute graft rejections and adverse effects - and stable graft function can be achieved in the long-term course after switch. These findings support the role of immunologic factors in the development of chronic renal allograft failure. REFERENCES 1. Matas AJ, Burke JF, DeVault GA, et al: J Am Soc Nephrol 4 (suppl 1):S23, 1994 2. Lemstro ¨m K, Koskinen P, Ha¨yry P: Kidney Int 48 (suppl 52):S2, 1995 3. First MR, Neylan F, Rocher LL, et al: J Am Soc Nephrol 4 (suppl 1):S30, 1994 4. Paul LC, Benediktsson H: Kidney Int 48 (suppl 52):S34, 1995
CHRONIC RENAL ALLOGRAFT FAILURE 5. Guijarro C, Massy ZA, Kasiske BL: Kidney Int 48 (suppl 52):S56, 1995 6. Tullius SG, Bechstein WO, Nieminen M, et al: Nephrol Dial Transplant 11:1913, 1996 7. Almond PS, Matas A, Gillingham KJ, et al: Transplantation 55:752, 1993 8. Opelz G for the collaborative transplant study: Transplant Int 5 (suppl 1):S621, 1991 9. Isoniemi HM, Ahonen J, Tikkanen MJ, et al: 55:494, 1993 10. Rocher LL, Hodgson RJ, Merion RM, et al: Transplantation 47:249, 1989
1209 11. Pasqual J, Marce´n R, Orofino L, et al: Transplantation 52:276, 1991 12. Simmons RL, Canafax DM, Strand M, et al: Transplant Proc 17 (suppl 1):26, 1985 13. Leaker B, Neild GH, Rudge C, et al: Transplant Proc 21:1548, 1989 14. Salaman JR, Griffin PJA, Ross WB, et al: Transplant Proc 19:1935, 1987 15. Taube D, Marsden J, Palmer A, et al: Transplant Proc 22:1251, 1990
T
HE IMPACT of immunologic1,2 and nonimmunologic factors3– 6 on the development of chronic allograft failure in renal transplant recipients treated with cyclosporine (CyA) and prednisolone is controversially discussed. The observations that episodes of acute rejection as well as low CyA doses ,5 mg/kg/d7 and suboptimal histocompatibility between donor and organ recipient8 are correlated with increased incidence of chronic allograft failure are in favor of the hypothesis that immunologic mechanisms cause the chronic rejection process. An immunosuppressive protocol including azathioprine (Aza) was reported to be associated with less histologic signs of chronic rejection 2 years posttransplant as compared with CyA/steroid-based therapy.9 Furthermore, higher immunosuppression in kidney recipients with slowly deteriorating graft function by a conversion to triple therapy including Aza showed promising results.10,11 However, trials on higher patient numbers with use of standardized conversion criteria and prospective studies are lacking. Thus, it was the aim of this study to investigate the impact of a standardized conversion from double immunosuppression with CyA/prednisolone to a triple-drug regimen including Aza on chronic progressive allograft failure in renal transplant patients. In addition, the safety of the conversion protocol regarding acute rejection episodes and side effects was tested. PATIENTS AND METHODS The present study includes all kidney recipients who were converted from double immunosuppression to triple-drug therapy including Aza between January 1987 and November 1994 because of slowly progressing chronic renal allograft failure. Inclusion criteria were (1) an increase in the serum creatinine value of .50 mmol/L during an interval of 6 months preconversion, (2) a serum creatinine value between 150 and 450 mmol/L at time of conversion, (3) a time interval of .12 months between transplantation and conversion, and (4) exclusion of acute rejection, acute CyA nephrotoxicity, or recurrent renal disease by graft biopsy and clinical evaluation. Exclusion criteria were (1) an episode of acute graft rejection within 6 months preconversion, (2) acute pyelonephritis within the last 6 months, chronic infectious diseases, or septicemia posttransplant, (3) chronic active liver disease, (4) a history of drug-induced bone marrow depression or a white blood cell count ,4000/mL or a red blood cell count ,9 g/dL at time of conversion, and (5) allopurinol treatment. Of the 80 renal trans-
plant recipients who complied with the criteria of the study, 60 were analyzed retrospectively (RT) and 20 were prospectively surveyed (PT). Immunosuppression consisted of CyA 10 mg/kg/d (adjusted to trough levels between 150 and 200 ng/mL within the first 3 months) and prednisolone 1 mg/kg/d, tapered to 0.1 mg/kg/d within 3 months. In the long run, the patients received CyA (trough levels 100 to 150 ng/mL) plus prednisolone (7.5 mg/d maintenance dose). Biopsy-proven acute graft rejection was treated with intravenous (IV) bolus doses of 0.5 to 1 g methylprednisolone (3 to 5 days). Patients with resistant rejection received antithymocyte globulin (ATG) or OKT3. The switch to triple-drug therapy was performed according to the following protocol. Day 1: Increase of prednisolone dose from 7.5 to 30 mg/d, no change of CyA dose, and additional treatment with Aza (1.5 to 2 mg/kg/d). Day 14: Reduction of CyA to about two thirds of the former dose. During the following weeks, CyA doses were adjusted to maintain trough levels of 70 to 90 ng/mL and prednisolone was reduced by 5 mg per week to 15 mg/d, subsequently further reduced by 2.5 mg per week to the maintenance dose of 7.5 mg/d. After conversion, all patients were seen monthly for 3 months and thereafter every 3 months at our outpatient clinic. The following data were regularly obtained: blood pressure, serum creatinine value, full blood count, liver enzymes, cholesterol, grade of proteinuria, and CyA trough levels (assessed by a monoclonal-specific radioimmunoassay [RIA] kit, Sandoz, Basel, Switzerland). Casual blood pressure recordings were performed at time of conversion and 6 as well as 12 months afterwards. For statistical analysis, a two-tailed t test for pairs was performed to compare the preconversion data with those obtained during the follow-up. Significance was assumed at P , .05.
RESULTS
The time between transplantation and conversion therapy was 38 (median 5 to 160) months, median follow-up after conversion to triple immunosuppression was 53 (19 to 108; RT) and 16 (13 to 18; PT) months. Aza dose was 1.6 6 0.4 mg/kg/d, while CyA dose was reduced by approximately 22%. Renal graft biopsy was performed in all PT patients and in 35 of 60 RT patients, revealing in all cases tubular From Abteilung Nephrologie and Klinik fu¨r Abdominal und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany. Address reprint requests to Dr Volker Kliem, Abteilung Nephrologie, Medizinische Hochschule Hannover, Carl-NeubergStraße 1, D-30625 Hannover, Germany.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00212-7
Transplantation Proceedings, 30, 1207–1209 (1998)
1207
1208
atrophy and interstitial fibrosis as well as in 65% of the cases a so-called benign nephrosclerosis and in 40% of the cases a transplant glomerulopathy. All 80 patients showed an increase in the value in serum creatinine from an average of 202 6 47 to 264 6 63 mmol/L during the 6 months before conversion. Among these 80 patients, two groups could clearly be separated with respect to response in renal graft function after conversion: (1) group A included 60 patients (45 RT and 15 PT) who showed a significant improvement in graft function after the switch from a mean serum creatinine value of 259 6 53 to 218 6 44 mmol/L and achieved stable graft function and (2) group B consisted of 20 patients (15 RT and 5 PT) who displayed a progressive decline in renal function despite triple therapy, with an increase in the serum creatinine value of .100 mmol/L during the following 12 months. Thirteen of these 20 patients lost their graft within 2 years after conversion. During the 18 months before initiation of triple therapy, renal graft function deteriorated in both groups (A and B) without significant difference. With regard to age, gender, pretransplant dialysis time, HLA match, graft cold ischemia time, the number of rejections, and optiminum serum creatinine value posttransplant, no significant differences were found between groups A and B. Significant differences between responders (A) and nonresponders (B) at the time of conversion were found for proteinuria (0.65 vs 2.4 mg/d) and for casual blood pressure values (140/85 vs 156/91 mm Hg; number of antihypertensive agents was comparable in both groups). The CyA trough levels were similar for both groups shortly after transplantation as well as immediately before and after initiation of triple therapy. Also the Aza doses given did not differ. After conversion, neither acute rejections nor severe infections occurred. No disturbances of liver and pancreas function were seen. Total cholesterol levels did not differ significantly between both groups shortly after transplantation as well as at time of switch. Bone marrow toxicity from Aza occurred in 8 of 80 (10%) cases and led to dose reduction in four of them. In none of the patients the drug had to be permanently withdrawn because of leukopenia. Fifteen of 80 (19%) patients received erythropoietin for therapy of renal anemia after conversion to triple-drug therapy. DISCUSSION
As primary regimen after renal transplantation, triple immunosuppression including Aza provides comparable graft survival rates as therapy with CyA/steroids. The rationale for the triple-drug regimen is that the three drugs are believed to complement each other in preventing graft rejection, so that maintenance therapy at low doses with an associated reduction in side effects becomes possible.12 The conversion from CyA/steroid-treated kidney recipients with slowly progressing chronic allograft failure to triple therapy including Aza could gain stable graft function anew, thus on the one hand by enhancing the immunosuppression by Aza while on the other hand by mitigating CyA effects on the
KLIEM, TIROKE, EHLERDING ET AL
already damaged graft as a consequence of CyA dose reduction. As mentioned, in primary triple-immunosuppressed patients 2 years after renal transplantation, less histologic signs of chronic rejection were found as compared with CyA/steroid treatment, even if the graft survival rates were comparable.9 However, Leaker et al13 reported a striking increase of infections under triple therapy and Salaman et al14 described some cases with fatal outcome. In agreement with other reports regarding conversion to triple therapy,10,11 the absence of severe complications due to infections and of disturbances of liver or pancreatic functions as well as of bone marrow depression leading to discontinuation of Aza treatment in our study can be explained by the relatively low Aza dose and overall moderate immunosuppression. Rejection episodes have been reported due to conversion from CyA/steroids to triple therapy, in particular when the CyA dose was reduced by more than 50%.15 According to our data, however, a switch to triple immunosuppression with a reduction of the CyA dose by only 20% to 25% and applying transiently higher steroid doses was not ensued by the risk of acute graft rejection. In our study, approximately 75% of the kidney recipients with chronic allograft failure reached stable graft function anew after initiation of triple therapy, whereas in 25% after transient improvement, graft function continued to deteriorate despite conversion. The rate of proteinuria and casual blood pressure values were significantly higher already preconversion in the nonresponders and may serve as predictors for outcome after switch. Thus, in the nonresponders, alloantigen-independent mechanisms, in particular hypertension,3,6 could contribute to chronic allograft failure. Beside the grade of proteinuria and hypertension, we were not able to find any predictors for the success of conversion to triple therapy. Nevertheless, the results of conversion in a large number of patients from a CyA-based double-drug therapy to an enhanced immunosuppression including Aza are encouraging in slowly progressing chronic renal allograft failure and are in agreement with preliminary results.10,11 In conclusion, in up to 75% of CyA/steroid-treated kidney recipients with chronic allograft failure and impending graft loss, renal failure can be avoided by conversion to triple therapy including Aza - being a therapy with low risk regarding acute graft rejections and adverse effects - and stable graft function can be achieved in the long-term course after switch. These findings support the role of immunologic factors in the development of chronic renal allograft failure. REFERENCES 1. Matas AJ, Burke JF, DeVault GA, et al: J Am Soc Nephrol 4 (suppl 1):S23, 1994 2. Lemstro ¨m K, Koskinen P, Ha¨yry P: Kidney Int 48 (suppl 52):S2, 1995 3. First MR, Neylan F, Rocher LL, et al: J Am Soc Nephrol 4 (suppl 1):S30, 1994 4. Paul LC, Benediktsson H: Kidney Int 48 (suppl 52):S34, 1995
CHRONIC RENAL ALLOGRAFT FAILURE 5. Guijarro C, Massy ZA, Kasiske BL: Kidney Int 48 (suppl 52):S56, 1995 6. Tullius SG, Bechstein WO, Nieminen M, et al: Nephrol Dial Transplant 11:1913, 1996 7. Almond PS, Matas A, Gillingham KJ, et al: Transplantation 55:752, 1993 8. Opelz G for the collaborative transplant study: Transplant Int 5 (suppl 1):S621, 1991 9. Isoniemi HM, Ahonen J, Tikkanen MJ, et al: 55:494, 1993 10. Rocher LL, Hodgson RJ, Merion RM, et al: Transplantation 47:249, 1989
1209 11. Pasqual J, Marce´n R, Orofino L, et al: Transplantation 52:276, 1991 12. Simmons RL, Canafax DM, Strand M, et al: Transplant Proc 17 (suppl 1):26, 1985 13. Leaker B, Neild GH, Rudge C, et al: Transplant Proc 21:1548, 1989 14. Salaman JR, Griffin PJA, Ross WB, et al: Transplant Proc 19:1935, 1987 15. Taube D, Marsden J, Palmer A, et al: Transplant Proc 22:1251, 1990