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Biopsy-proven resolution of steroid-resistant acute rejection with basiliximab therapy in a renal allograft recipient
Biopsy-Proven Resolution of Steroid-Resistant Acute Rejection With Basiliximab Therapy in a Renal Allograft Recipient H.K. Goh and W.C. Lye
A
CUTE RENAL allograft rejection is a common complication after transplantation and occurs in up to 30% to 50% of kidney transplants.1 Steroid-resistant rejections occur in up to 20% of kidney transplants.1 Steroidresistant rejections were usually treated with either monoclonal or polyclonal anti-lymphocyte or anti-thymocyte antibodies with a success rate of up to 85% of cases.2 To our knowledge, there has been no report on the use of the anti-interleukin-2 receptor antibodies in the treatment of acute steroid-resistant rejections. We report a patient who developed a biopsy-confirmed steroid-resistant acute rejection after a spouse kidney transplantation. Treatment with two courses of intravenous methylprednisolone and conversion from azathioprine to mycophenolate mofetil failed to reverse the rejection. Two doses of basiliximab were given with biopsy-proven successful reversal of rejection. CASE REPORT
A 55-year old, 60 kg Bangladeshi man with end-stage renal disease had a spouse kidney transplantation in Singapore. The patient’s immediate posttransplantation immunosuppression consisted of steroids, azathioprine, and tacrolimus. Oral tacrolimus was started at a dose of 6.0 mg twice a day (0.2 mg/kg per day), initial azathioprine dose was 125 mg/day for the first week followed by 75 mg/day. His other medications included carvedilol, amlodipine, isosorbide mononitrate, and ticlopidine. His transplanted kidney functioned immediately with an initial urine output of 5.0 L/d. On the second posttransplant day, his 12-hour whole blood trough tacrolimus level was 15.6 g/L. On the fifth posttransplant day, his serum creatinine was 1.2 mg/dL, and on the 8th posttransplant day, his serum creatinine was 1.6 mg/dL and rose to 3.0 mg/dL on the 12th posttransplant day. Ultrasonography of the graft was normal and a diethylenetriamine-pentacetic acid (DTPA) scan revealed good perfusion with impaired isotope uptake. On the 15th posttransplant day, a transplant kidney biopsy showed features of marked acute renal allograft rejection consistent with a Banff Grade 2 of 3. The biopsy specimen showed foci of well-defined tubulitis with marked diffuse cellular interstitial infiltration of lymphocytes, macrophages, and polymorphs, and patchy areas of hemorrhages. No definite vasculitis was seen. He was treated with three intravenous doses of methylprednisolone 500 mg per day. On the 20th
posttransplant day, his serum creatinine decreased to 2.4 mg/dL. However, his serum creatinine started to rise again and reached 4.6 mg/dL on the 26th posttransplant day. His trough tacrolimus level was 12.2 g/L. On the 27th posttransplant day, a second kidney biopsy showed ongoing features of predominantly cellular acute renal allograft rejection consistent with a Banff Grade 2 of 3. There was moderate diffuse interstitial infiltration of lymphocytes, plasma cells, and macrophages with foci of tubulitis. A diagnosis of steroid-resistant rejection was made and antilymphocyte antibody treatment was offered. The patient refused because of his fear of opportunistic infections. Instead he opted for the conversion from azathioprine to mycophenolate mofetil 750 mg bid as rescue therapy. His serum creatinine gradually decreased over a period of three weeks. On his 50th posttransplant day, his serum creatinine was 2.7 mg/dL and remained stable over the next three months. Five months posttransplant, his serum creatinine rose to 4.0 mg/dL. His trough tacrolimus level was 12.9 g/L. A third renal allograft biopsy showed features of acute cellular renal allograft rejection consistent with a Banff Grade 1 of 3. There were foci of tubulitis with lymphocytic infiltration of the epithelial cells and cellular infiltration of the interstitium by lymphocytes, mononuclear cells, and eosinophils. He was given three doses of intravenous methylprednisolone at a dose of 500 mg per day. Two weeks after the administration of steroids, his serum creatinine was still 3.4 mg/dL. A diagnosis of failure of acute rejection reversal was made. Despite counseling, the patient refused anti-lymphocyte antibody therapy for treatment of his refractory rejections. The possibility of using basilixamab was offered to the patient and informed consent was obtained. Two doses of basiliximab at a dose of 20 mg per day were infused four days apart without any adverse reactions. Four weeks after administering basiliximab, his serum creatinine was 3.1 mg/dL. Three months after the use of basiliximab and 9 months posttransplant, his serum creatinine was 2.4 mg/dL. A follow-up fourth renal allograft biopsy showed foci of tubular atrophy and interstitial fibrosis without any evidence of tubulitis. There was minimal From the Division of Nephrology, Department of Medicine (H.K.G), National University Hospital and Centre for Kidney Diseases (W.C.L), Mount Elizabeth Medical Center, Singapore.
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/01/$–see front matter PII S0041-1345(01)02368-5
Transplantation Proceedings, 33, 3213–3214 (2001)
3213
3214
chronic inflammatory cellular infiltration and a marked decrease in the number of inflammatory cells compared to the earlier biopsies. The biopsy features were consistent with chronic allograft injury without any evidence of acute rejection. One year posttransplant, his serum creatinine had decreased to 1.9 mg/dL. DISCUSSION
Despite advances in immunosuppressive therapy, acute rejections still occur in 30% to 50% of renal allograft recipients.1 Basiliximab is a chimeric anti-interleukin-2 receptor monoclonal antibody that has been shown to be effective in reducing acute cellular rejection rates in renal allograft recipients in both the North American and European multicenter studies.3,4 However, there have been no reports on its use in the treatment of acute renal allograft rejections. Traditionally, polyclonal anti-lymphocyte or monoclonal anti-CD3 receptor antibodies were used to treat steroid-resistant rejections with a success rate of up to 85%. Our patient had biopsy-confirmed acute renal allograft rejections that were refractory to treatment with
GOH AND LYE
conventional doses of methylprednisolone and the use of tacrolimus and mycophenolate mofetil. An anti-lymphocyte antibody would be the treatment of choice, but the patient refused because he was concerned about the risk of contracting an opportunistic infection in his home country. The use of basiliximab was an empiric decision, and its efficacy was unexpected. It is possible that basiliximab may have exerted its anti-rejection effects by blocking the IL-2 receptors of the activated T-lymphocytes after partial suppression of the activated immune system with steroids. Further studies are needed to determine whether there is a role for the use of anti-IL-2 receptor antibodies in the treatment of acute rejections. REFERENCES 1. Matas AJ, Gillingham KJ, Payne WD, et al: Transplantation 57:857, 1994 2. Jogose JT, Bailey RR, Lynn KL, et al: Nephron 77:298, 1997 3. Kahan BD, Rajagopalan PR, Hall M: Transplantation 67:276, 1999 4. Nashan B, Moore R, Amlot P, et al: Lancet 350:1193, 1997
A
CUTE RENAL allograft rejection is a common complication after transplantation and occurs in up to 30% to 50% of kidney transplants.1 Steroid-resistant rejections occur in up to 20% of kidney transplants.1 Steroidresistant rejections were usually treated with either monoclonal or polyclonal anti-lymphocyte or anti-thymocyte antibodies with a success rate of up to 85% of cases.2 To our knowledge, there has been no report on the use of the anti-interleukin-2 receptor antibodies in the treatment of acute steroid-resistant rejections. We report a patient who developed a biopsy-confirmed steroid-resistant acute rejection after a spouse kidney transplantation. Treatment with two courses of intravenous methylprednisolone and conversion from azathioprine to mycophenolate mofetil failed to reverse the rejection. Two doses of basiliximab were given with biopsy-proven successful reversal of rejection. CASE REPORT
A 55-year old, 60 kg Bangladeshi man with end-stage renal disease had a spouse kidney transplantation in Singapore. The patient’s immediate posttransplantation immunosuppression consisted of steroids, azathioprine, and tacrolimus. Oral tacrolimus was started at a dose of 6.0 mg twice a day (0.2 mg/kg per day), initial azathioprine dose was 125 mg/day for the first week followed by 75 mg/day. His other medications included carvedilol, amlodipine, isosorbide mononitrate, and ticlopidine. His transplanted kidney functioned immediately with an initial urine output of 5.0 L/d. On the second posttransplant day, his 12-hour whole blood trough tacrolimus level was 15.6 g/L. On the fifth posttransplant day, his serum creatinine was 1.2 mg/dL, and on the 8th posttransplant day, his serum creatinine was 1.6 mg/dL and rose to 3.0 mg/dL on the 12th posttransplant day. Ultrasonography of the graft was normal and a diethylenetriamine-pentacetic acid (DTPA) scan revealed good perfusion with impaired isotope uptake. On the 15th posttransplant day, a transplant kidney biopsy showed features of marked acute renal allograft rejection consistent with a Banff Grade 2 of 3. The biopsy specimen showed foci of well-defined tubulitis with marked diffuse cellular interstitial infiltration of lymphocytes, macrophages, and polymorphs, and patchy areas of hemorrhages. No definite vasculitis was seen. He was treated with three intravenous doses of methylprednisolone 500 mg per day. On the 20th
posttransplant day, his serum creatinine decreased to 2.4 mg/dL. However, his serum creatinine started to rise again and reached 4.6 mg/dL on the 26th posttransplant day. His trough tacrolimus level was 12.2 g/L. On the 27th posttransplant day, a second kidney biopsy showed ongoing features of predominantly cellular acute renal allograft rejection consistent with a Banff Grade 2 of 3. There was moderate diffuse interstitial infiltration of lymphocytes, plasma cells, and macrophages with foci of tubulitis. A diagnosis of steroid-resistant rejection was made and antilymphocyte antibody treatment was offered. The patient refused because of his fear of opportunistic infections. Instead he opted for the conversion from azathioprine to mycophenolate mofetil 750 mg bid as rescue therapy. His serum creatinine gradually decreased over a period of three weeks. On his 50th posttransplant day, his serum creatinine was 2.7 mg/dL and remained stable over the next three months. Five months posttransplant, his serum creatinine rose to 4.0 mg/dL. His trough tacrolimus level was 12.9 g/L. A third renal allograft biopsy showed features of acute cellular renal allograft rejection consistent with a Banff Grade 1 of 3. There were foci of tubulitis with lymphocytic infiltration of the epithelial cells and cellular infiltration of the interstitium by lymphocytes, mononuclear cells, and eosinophils. He was given three doses of intravenous methylprednisolone at a dose of 500 mg per day. Two weeks after the administration of steroids, his serum creatinine was still 3.4 mg/dL. A diagnosis of failure of acute rejection reversal was made. Despite counseling, the patient refused anti-lymphocyte antibody therapy for treatment of his refractory rejections. The possibility of using basilixamab was offered to the patient and informed consent was obtained. Two doses of basiliximab at a dose of 20 mg per day were infused four days apart without any adverse reactions. Four weeks after administering basiliximab, his serum creatinine was 3.1 mg/dL. Three months after the use of basiliximab and 9 months posttransplant, his serum creatinine was 2.4 mg/dL. A follow-up fourth renal allograft biopsy showed foci of tubular atrophy and interstitial fibrosis without any evidence of tubulitis. There was minimal From the Division of Nephrology, Department of Medicine (H.K.G), National University Hospital and Centre for Kidney Diseases (W.C.L), Mount Elizabeth Medical Center, Singapore.
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/01/$–see front matter PII S0041-1345(01)02368-5
Transplantation Proceedings, 33, 3213–3214 (2001)
3213
3214
chronic inflammatory cellular infiltration and a marked decrease in the number of inflammatory cells compared to the earlier biopsies. The biopsy features were consistent with chronic allograft injury without any evidence of acute rejection. One year posttransplant, his serum creatinine had decreased to 1.9 mg/dL. DISCUSSION
Despite advances in immunosuppressive therapy, acute rejections still occur in 30% to 50% of renal allograft recipients.1 Basiliximab is a chimeric anti-interleukin-2 receptor monoclonal antibody that has been shown to be effective in reducing acute cellular rejection rates in renal allograft recipients in both the North American and European multicenter studies.3,4 However, there have been no reports on its use in the treatment of acute renal allograft rejections. Traditionally, polyclonal anti-lymphocyte or monoclonal anti-CD3 receptor antibodies were used to treat steroid-resistant rejections with a success rate of up to 85%. Our patient had biopsy-confirmed acute renal allograft rejections that were refractory to treatment with
GOH AND LYE
conventional doses of methylprednisolone and the use of tacrolimus and mycophenolate mofetil. An anti-lymphocyte antibody would be the treatment of choice, but the patient refused because he was concerned about the risk of contracting an opportunistic infection in his home country. The use of basiliximab was an empiric decision, and its efficacy was unexpected. It is possible that basiliximab may have exerted its anti-rejection effects by blocking the IL-2 receptors of the activated T-lymphocytes after partial suppression of the activated immune system with steroids. Further studies are needed to determine whether there is a role for the use of anti-IL-2 receptor antibodies in the treatment of acute rejections. REFERENCES 1. Matas AJ, Gillingham KJ, Payne WD, et al: Transplantation 57:857, 1994 2. Jogose JT, Bailey RR, Lynn KL, et al: Nephron 77:298, 1997 3. Kahan BD, Rajagopalan PR, Hall M: Transplantation 67:276, 1999 4. Nashan B, Moore R, Amlot P, et al: Lancet 350:1193, 1997