- Email: [email protected]
Living Donor Kidney Transplantation: Impact of Differentiated Immunosuppressive Regimen
Living Donor Kidney Transplantation: Impact of Differentiated Immunosuppressive Regimen H.H. Wolters, St. Heidenreich, C. Dame, J.G. Brockmann, N. Senninger, and C.F. Krieglstein ABSTRACT Introduction. Recipients of related (R) and unrelated (NR) living donor kidney transplantations (LDKTX) receive immunosuppressive (IS) therapy 5 days in advance in order to achieve low rates of acute rejection episodes. We herein report the different IS regimens for R and NR transplants as well as acute rejection and primary function rates. Methods. Ninety-five LDKTX (69% R, 31% NR) were performed with mean cold ischemia time (CIT) of 145 ⫾ 32 minutes. In R-LDKTX mean age of recipients was 31 ⫾ 12.5 years. This cohort included 41 men and 25 women whose mean age was 50 ⫾ 11.1 years. The therapeutic regimen for R-LDKTX included CyA/MMF/prednisone; for NR-LDKTX, FK/MMF/prednisone. Among the recipients of NR grafts the mean recipient age was 51 ⫾ 8.5 years. This cohort included 23 men and 6 women whose donor mean age was 50 ⫾ 8.8 years. The mean HLA mismatch among R-LDKTX (2.3) was significantly less than that in the NR-LDKTX cohort (3.51). Results. At a mean follow-up of 35 months, 94.7% of grafts were functioning. DGF was seen in only one recipient (1%). Three grafts were lost due to acute (R) or chronic (NR) rejection or to multiorgan failures. Two recipients died with functioning grafts. Biopsyproven rejection episodes were observed in 17.2% of NR-LDKTX and 9% of R-LDKTX. In R-LDKTX 50% of rejection episodes were corticoid-sensitive, while 33% needed ATG, and 16% were treated by a switch to FK. In NR-LDKTX 20% of rejections were corticoid-sensitive, 40% needed ATG, and 40% were treated with rapamycin rescue therapy. Conclusion. Although HLA mismatching is significantly different between R- and NR-LDKTX, no difference in outcome was observed, which may be due to the specific therapeutic regimen and short CIT.
I
NCREASINGLY CENTERS are performing living donor kidney transplantation (LDKTX) using related or unrelated donators as a result of the constantly increasing demand for renal allografts due to the profound shortage.1,2 As LDKTX is a well-known procedure, the immunosuppressive medication starts 5 days in advance. To face the problem of worse HLA-matching in unrelated LDKTX, we treat related and unrelated transplant recipients with different immunosuppressive regimens, as we report in our experience with 95 consecutive cases here. PATIENTS AND METHODS Between 1993 and 2003, 95 consecutive living donor kidney transplantations (LDKTX) were performed after donor evaluations including blood group, HLA matching, extensive medical exami-
nations, including angiography and extensive psychological evaluation, which means at least two consultations. In 66 cases (69%) a genetically related person was suitable for living donation; in 29 recipients (31%) an unrelated person. Among related (R-) LDKTX (n ⫽ 66) the mean recipient age was 31 ⫾ 12.5 years (41 men, 25 women). Since many cases were parent-child relationships, the mean donor age was higher than the recipient age (50 ⫾ 11.1 years). Eighty-five percent (n ⫽ 56) of R-LDKTX received a first organ; 11% (7) a second; and 4% (3) a From the Departments of General Surgery (H.H.W., C.D., J.G.B., N.S., C.F.K.) and Inner Medicine (St. H.); University of Münster, Münster, Germany. Address reprint requests to Heiner H. Wolters, MD, Department of General Surgery, University of Münster, Waldeyerstrasse 1, D-48149 Münster; Germany. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.09.022
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1616
Transplantation Proceedings, 37, 1616 –1617 (2005)
DIFFERENTIATED IMMUNOSUPPRESSIVE REGIMENS third graft. The immunosuppressive regimen in R-LDKTX consisted of CyA/MMF/prednisone starting 5 days prior to KTX. The CyA trough level was set at 150 to 200 ng/mL, the MMF dose at 2 g/d, and prednisone tapered from 1 g to 20 mg/d by day 7. Among the 23 men and six women who received unrelated (NR-) LDKTX the mean recipient age was 51 ⫾ 8.5 years and donor age 50 ⫾ 8.8 years. Eighty-nine percent (26) of these NR-LDKTX received their first graft and 11% (3) their second graft. In NR-LDKTX the immunosuppressive regimen started 5 days prior to KTX and consisted of FK/MMF/prednisone setting an FK trough level of 8 to 12 ng/mL with 2 g/d MMF and prednisone tapered from 1 g to 20 mg/d on day 7. The mean HLA mismatch among R-LDKTX (2.3) was significantly lower than NR-LDKTX (3.51). The harvesting procedure used an anterior extraperitoneal approach with a first warm ischemic time (WIT) of 30 ⫾ 12 seconds, a mean CIT of 145 ⫾ 32 minutes, and a second WIT of 20 ⫾ 4.2 minutes.
RESULTS
After a mean follow-up of 35 months, 94.7% (90) of grafts were functional. Delayed graft function was only seen in one recipient (1%) who needed five dialyses. Upon followup, two grafts were lost due to acute (R-LDKTX) or chronic (NR-LDKTX) rejection. One graft was lost when the patient developed multiorgan failure after severe impairment of the cardiovascular system posttransplantation. Two recipients died with functioning grafts due to cardiovascular complications. Among NR-LDKTX biopsy-proven rejection episodes were observed in 17.2%. Of these rejections 20% were corticoid-sensitive and treated with pulse therapy for 3 days. Forty percent of the primary rejections were treated with ATG after corticosteroid failure. After antibody failure (ATG and OKT3) the cases were treated with rapamycin rescue therapy, which turned out to be effective in these circumstances. In R-LDKTX biopsyproven rejections were only diagnosed in 9% with 50% being corticoid-sensitive and 16% successfully treated by a switch to tacrolimus therapy. Again some rejections (33%) turned out to be corticoid- and tacrolimus-resistant but were successfully treated with ATG. DISCUSSION
To deal with the shortage of grafts it has been suggested to use organs from living donors.3,4 More and more transplant
1617
centers offer living donor kidney transplantation, and their number is increasing. Since some of the patients on the waiting list do not have a suitable or willing living related donor,5 the unrelated donor has also been employed. However, this entails a worse HLA mismatch with poorer long-term kidney function in living unrelated KTX, based upon observations with cadaveric organs. In our center dismal kidney function in NR-LDKTX was not detected, although the significantly worse HLA-match was confirmed. In living donation immunosuppressive therapy can start prior to KTX. In our center we start our regimen 5 days in advance for the recipient to achieve the desired trough level on the day of transplantation. However, NR-LDKTX recipients showed a higher rate of biopsy-proven rejections than R-LDKTX. Nevertheless, in terms of risk of PTLD and infections, we would not use induction therapy in NR-LDKTX as reported by others.6 Further graft loss for chronic rejection may be prevented by early calcineurin withdrawal, although we recognize the risk of late acute rejection.6 In conclusion, our living donation program is safe for related as well as for unrelated donors and yields satisfactory transplant outcomes. The worse HLA mismatches in unrelated donors seem to demand a different immunosuppressive regimen to address the increased risk of acute rejection episodes.
REFERENCES 1. Cohen B, Persijn GG: Trends in organ donation. Transplant Proc 29:3301, 1997 2. Spital A: Ethical and political issues in altruistic living and cadaveric organ donation. Clin Transplant 11:77, 1997 3. Drukker A: Organ donation and kidney sales. Lancet 352:483, 1998 4. Lawrence R: Abuse of live related kidney transplantation. Nephrol Dial Transplant 12:2028, 1997 5. Khajehdehi P: Living non-related versus related renal transplantation—its relationship to the social status, age and gender of recipient and donors. Nephrol Dial Transplant 14:2621, 1999 6. Humar A, Durand B, Gillingham K, et al: Living unrelated donors in kidney transplants: better long-term results than with non-HLA-identical living related donors? Transplantation 69:1942, 2000
I
NCREASINGLY CENTERS are performing living donor kidney transplantation (LDKTX) using related or unrelated donators as a result of the constantly increasing demand for renal allografts due to the profound shortage.1,2 As LDKTX is a well-known procedure, the immunosuppressive medication starts 5 days in advance. To face the problem of worse HLA-matching in unrelated LDKTX, we treat related and unrelated transplant recipients with different immunosuppressive regimens, as we report in our experience with 95 consecutive cases here. PATIENTS AND METHODS Between 1993 and 2003, 95 consecutive living donor kidney transplantations (LDKTX) were performed after donor evaluations including blood group, HLA matching, extensive medical exami-
nations, including angiography and extensive psychological evaluation, which means at least two consultations. In 66 cases (69%) a genetically related person was suitable for living donation; in 29 recipients (31%) an unrelated person. Among related (R-) LDKTX (n ⫽ 66) the mean recipient age was 31 ⫾ 12.5 years (41 men, 25 women). Since many cases were parent-child relationships, the mean donor age was higher than the recipient age (50 ⫾ 11.1 years). Eighty-five percent (n ⫽ 56) of R-LDKTX received a first organ; 11% (7) a second; and 4% (3) a From the Departments of General Surgery (H.H.W., C.D., J.G.B., N.S., C.F.K.) and Inner Medicine (St. H.); University of Münster, Münster, Germany. Address reprint requests to Heiner H. Wolters, MD, Department of General Surgery, University of Münster, Waldeyerstrasse 1, D-48149 Münster; Germany. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.09.022
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1616
Transplantation Proceedings, 37, 1616 –1617 (2005)
DIFFERENTIATED IMMUNOSUPPRESSIVE REGIMENS third graft. The immunosuppressive regimen in R-LDKTX consisted of CyA/MMF/prednisone starting 5 days prior to KTX. The CyA trough level was set at 150 to 200 ng/mL, the MMF dose at 2 g/d, and prednisone tapered from 1 g to 20 mg/d by day 7. Among the 23 men and six women who received unrelated (NR-) LDKTX the mean recipient age was 51 ⫾ 8.5 years and donor age 50 ⫾ 8.8 years. Eighty-nine percent (26) of these NR-LDKTX received their first graft and 11% (3) their second graft. In NR-LDKTX the immunosuppressive regimen started 5 days prior to KTX and consisted of FK/MMF/prednisone setting an FK trough level of 8 to 12 ng/mL with 2 g/d MMF and prednisone tapered from 1 g to 20 mg/d on day 7. The mean HLA mismatch among R-LDKTX (2.3) was significantly lower than NR-LDKTX (3.51). The harvesting procedure used an anterior extraperitoneal approach with a first warm ischemic time (WIT) of 30 ⫾ 12 seconds, a mean CIT of 145 ⫾ 32 minutes, and a second WIT of 20 ⫾ 4.2 minutes.
RESULTS
After a mean follow-up of 35 months, 94.7% (90) of grafts were functional. Delayed graft function was only seen in one recipient (1%) who needed five dialyses. Upon followup, two grafts were lost due to acute (R-LDKTX) or chronic (NR-LDKTX) rejection. One graft was lost when the patient developed multiorgan failure after severe impairment of the cardiovascular system posttransplantation. Two recipients died with functioning grafts due to cardiovascular complications. Among NR-LDKTX biopsy-proven rejection episodes were observed in 17.2%. Of these rejections 20% were corticoid-sensitive and treated with pulse therapy for 3 days. Forty percent of the primary rejections were treated with ATG after corticosteroid failure. After antibody failure (ATG and OKT3) the cases were treated with rapamycin rescue therapy, which turned out to be effective in these circumstances. In R-LDKTX biopsyproven rejections were only diagnosed in 9% with 50% being corticoid-sensitive and 16% successfully treated by a switch to tacrolimus therapy. Again some rejections (33%) turned out to be corticoid- and tacrolimus-resistant but were successfully treated with ATG. DISCUSSION
To deal with the shortage of grafts it has been suggested to use organs from living donors.3,4 More and more transplant
1617
centers offer living donor kidney transplantation, and their number is increasing. Since some of the patients on the waiting list do not have a suitable or willing living related donor,5 the unrelated donor has also been employed. However, this entails a worse HLA mismatch with poorer long-term kidney function in living unrelated KTX, based upon observations with cadaveric organs. In our center dismal kidney function in NR-LDKTX was not detected, although the significantly worse HLA-match was confirmed. In living donation immunosuppressive therapy can start prior to KTX. In our center we start our regimen 5 days in advance for the recipient to achieve the desired trough level on the day of transplantation. However, NR-LDKTX recipients showed a higher rate of biopsy-proven rejections than R-LDKTX. Nevertheless, in terms of risk of PTLD and infections, we would not use induction therapy in NR-LDKTX as reported by others.6 Further graft loss for chronic rejection may be prevented by early calcineurin withdrawal, although we recognize the risk of late acute rejection.6 In conclusion, our living donation program is safe for related as well as for unrelated donors and yields satisfactory transplant outcomes. The worse HLA mismatches in unrelated donors seem to demand a different immunosuppressive regimen to address the increased risk of acute rejection episodes.
REFERENCES 1. Cohen B, Persijn GG: Trends in organ donation. Transplant Proc 29:3301, 1997 2. Spital A: Ethical and political issues in altruistic living and cadaveric organ donation. Clin Transplant 11:77, 1997 3. Drukker A: Organ donation and kidney sales. Lancet 352:483, 1998 4. Lawrence R: Abuse of live related kidney transplantation. Nephrol Dial Transplant 12:2028, 1997 5. Khajehdehi P: Living non-related versus related renal transplantation—its relationship to the social status, age and gender of recipient and donors. Nephrol Dial Transplant 14:2621, 1999 6. Humar A, Durand B, Gillingham K, et al: Living unrelated donors in kidney transplants: better long-term results than with non-HLA-identical living related donors? Transplantation 69:1942, 2000