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Leukocytopheresis therapy for chronic renal allograft rejection
Leukocytopheresis Therapy for Chronic Renal Allograft Rejection S. Tomikawa, Y. Ando, Y. Nomura, and Y. Bech
D
ESPITE improvements in early survival of renal allografts associated with advances in current immunosuppressive protocols, there has been no change in longterm graft survival and chronic renal allograft rejection (CR) is the most common cause of late failure of kidney allografts. Attention has been focused on the prevention and management of CR, but there is no established means of prevention or treatment of CR.1 Therefore, a new effective treatment of CR is indispensable for the improvement in long-term allograft survival. Recently, the effectiveness of leukocytopheresis (LCP) performed with a leukocyte removal filter is reported for the inflammatory diseases, such as inflammatory bowel disease2 and rheumatoid arthritis,3 in which the immunologic mechanism seems to be concerned in the occurrence. We therefore examined the effectiveness of LCP for the patients with biopsy-proven CR after kidney transplantation. PATIENTS AND METHODS To study the efficacy of LCP, LCP therapy was applied to five patients with established chronic renal allograft rejection diagnosed both on a histologic and clinical basis (Table 1). In all cases, the immunosuppressive drug was not changed throughout the LCP therapy. Three patients (case 1, 2, and 3) were selected to apply LCP because of the progressive increase in the level of serum creatinine (sCr) more than 2.5 mg/dL (two cases associated with proteinuria) and another two patients (case 4 and 5) were because of proteinuria with a sCr level below 2 mg/dL. We obtained informed consent from all patients who participated in this clinical trial. LCP therapy was performed with a leukocyte removal filter, Cellsorba (Asahi Medical Co), and nafamostat mesilate (Torii Pharmaceutical Co) was used as an anticoagulant. In each LCP procedure, a total of 3000 mL of blood was filtered and returned to patient at a flow rate of 50 mL/min for 60 min. LCP therapy was
administered five times at 2- to 3-day intervals as intensive therapy and 6 to 12 times over a 2-week interval as maintenance therapy. As an index to the therapy effect, sCr and urinary excretion of protein were examined. The graft function was expressed by reciprocal sCr, and the change in the graft function was expressed by the slope of the regression line of reciprocal sCr of the pretreatment observation period, the therapeutic period, and the posttreatment observation period. In addition, the number of circulating leukocyte and T-lymphocyte surface markers (CD3, CD4, CD8, CD25, CD38, CD71, and HLA-DR) were measured before and after the first, third, and fifth procedures. Data shown were mean ⫾ SD, and statistical analysis was done by Student’s paired t test.
RESULTS
LCP procedures were tolerated by all patients. There was no serious complication, and routine laboratory tests were normal except for the decrease in temporary numbers of platelets immediately after procedures. The change of the level of sCr and the urinary protein excretion before, during, and after the treatment was shown in Fig 1. The patient, case 1, showed slowing of the progressive increase in the level of sCr and decrease of the degree of proteinuria after three LCP therapy treatments, which followed the intensive therapy. Because 2 months after this treatment, the level of sCr and the degree of proteinuria increased again, LCP therapy (nine times) was administered in an interval of 2 weeks. The patient responded to this additional treatment. The progressive increase in the level of sCr was From the Department of Surgery, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Address reprint requests to Dr S. Tomikawa, Department of Surgery, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan.
Table 1. Clinical Feature of Patients with LCP Treatment
Case
Age (y)
Sex
Time from Transplant to LCP Therapy (y)
1 2 3 4 5
31 38 39 39 48
M M M F M
8.3 11.6 4.6 11.1 4.3
Episode of Acute Rejection
Previous Treatment for Chronic Rejection
sCr Immediately Before LCP Therapy (mg/dL)
Proteinuria Immediately Before LCP Therapy (g/d)
(⫺) (⫹) (⫹) (⫹) (⫺)
CYA dose up DSG Pr dose up (⫺) MP pulse DSG
2.6 4.3 3.0 1.6 1.7
2.38 1.38 0.07 1.74 2.23
CYA, cyclosporine; DSG, deoxyspergualin; Pr, prednisolone; MP, methyl-prednisolone.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01386-5
Transplantation Proceedings, 32, 1761–1764 (2000)
1761
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TOMIKAWA, ANDO, NOMURA ET AL
Fig 1. The change of the level of sCr and the urinary protein excretion before, during, and after the treatment. LCP e, LCP therapy was administered five times at 2- to 3-day intervals as intensive therapy. LCP e e e, LCP therapy was administered 6 to 12 times over a 2-week interval as maintenance therapy that followed the intensive therapy.The progressive increase in the level of sCr was prevented throughout the treatment in case 1, 2, and 3. The degree of proteinuria diminished after the intensive therapy in all cases but returned to the pretreatment values in three cases during or after the maintenance therapy.
prevented and the degree of proteinuria was decreased during the maintenance therapy, and it continued after the discontinuation of LCP therapy. In two patients (case 2 and 3), the maintenance therapy was started 2 or 2.5 months after the intensive therapy. The progressive increase in the level of sCr was prevented throughout the treatment in both cases, but the effect was not continued after the discontinuation of LCP therapy. The degree of proteinuria diminished after the intensive therapy in all cases but returned to the pretreatment values in three cases during or after the maintenance therapy. The changes in the number of circulating leukocyte and T-lymphocyte surface markers during the first and the fifth procedure are shown in Table 2. The leukocyte count in circulating blood decreased to about 25% of previous value 30 minutes after LCP was started, and it was almost
recovered to the previous value at the end of the 60-minute procedure. After every LCP procedure, the percentage of lymphocyte significantly decreased (P ⬍ .01), and the percentage of neutrophoils significantly increased (P ⬍ .01) compared with the pretreatment values. The flow cytometry results showed that the percentage of CD3⫹ cells decreased and the percentage of CD38⫹ cells and CD8⫹CD38⫹ cells increased after the fifth LCP procedure significantly. DISCUSSION
There is no effective therapy for CR, which is a dominant reason for late allograft loss even with current immunosuppressive protocols. We previously reported the effect of deoxyspergualin on chronic rejection in renal transplanta-
LEUKOCYTOPHERESIS AND RENAL ALLOGRAFT REJECTION
1763
Table 2. Change in the Number of Circulating Leukocyte and T-Lymphocyte Surface Markers
WBC(/mm3) Lymphocyte(%) Neutrophil(%) CD3(%) CD4(%) CD8(%) CD25(%) CD38(%) CD71(%) HLADR(%) CD3⫹CD25⫹(%) CD3⫹CD38⫹(%) CD3⫹CD71⫹(%) CD3⫹HLADR⫹(%) CD4⫹CD25⫹(%) CD4⫹CD38⫹(%) CD4⫹CD71⫹(%) CD4⫹HLADR⫹(%) CD8⫹CD25⫹(%) CD8⫹CD38⫹(%) CD8⫹CD71⫹(%) CD8⫹HLADR⫹(%)
Pre
First LCP 30 min
Post
Pre
Fifth LCP Post
7680 ⫾ 1750 28.5 ⫾ 11.4 61.9 ⫾ 9.5 84.3 ⫾ 6.3 39.0 ⫾ 5.8 46.8 ⫾ 7.7 14.7 ⫾ 6.5 18.8 ⫾ 9.2 1.3 ⫾ 0.4 27.3 ⫾ 8.0 13.1 ⫾ 6.6 7.3 ⫾ 4.6 0.6 ⫾ 0.5 21.0 ⫾ 6.1 10.0 ⫾ 3.5 5.6 ⫾ 3.6 0.4 ⫾ 0.1 5.1 ⫾ 2.4 4.4 ⫾ 8.5 5.7 ⫾ 2.3 0.2 ⫾ 0.1 13.1 ⫾ 4.2
1780 ⫾ 670 52.6 ⫾ 21.5 41.2 ⫾ 20.4 — — — — — — — — — — — — — — — — — — —
7580 ⫾ 3460 16.9 ⫾ 12.2* 77.4 ⫾ 12.0* 80.3 ⫾ 4.9 36.9 ⫾ 12.4 43.3 ⫾ 16.3 9.6 ⫾ 4.7 19.8 ⫾ 7.1 1.7 ⫾ 0.7 26.5 ⫾ 8.5 8.0 ⫾ 4.5 7.2 ⫾ 4.8 0.8 ⫾ 0.5 19.3 ⫾ 8.8 7.9 ⫾ 3.8 5.1 ⫾ 3.9 0.6 ⫾ 0.2 4.4 ⫾ 1.4 0.6 ⫾ 0.4 5.5 ⫾ 1.8 0.3 ⫾ 0.3 13.1 ⫾ 5.7
7260 ⫾ 1470 26.9 ⫾ 11.1 62.8 ⫾ 11.0 82.6 ⫾ 6.7 37.5 ⫾ 5.6 48.5 ⫾ 7.4 9.0 ⫾ 4.7 22.0 ⫾ 11.0 1.8 ⫾ 0.6 31.8 ⫾ 6.5 7.7 ⫾ 4.6 9.7 ⫾ 6.5 0.8 ⫾ 0.3 26.1 ⫾ 6.6 7.7 ⫾ 4.3 6.3 ⫾ 4.7 0.6 ⫾ 0.1 5.4 ⫾ 1.1 0.8 ⫾ 0.2 8.0 ⫾ 2.4 0.5 ⫾ 0.2 15.9 ⫾ 5.2
7510 ⫾ 4400 13.3 ⫾ 9.0* 79.4 ⫾ 7.4* 77.7 ⫾ 3.8** 37.3 ⫾ 8.2 44.1 ⫾ 10.0 11.6 ⫾ 6.2 25.3 ⫾ 9.6** 2.7 ⫾ 1.1 30.1 ⫾ 9.1 8.7 ⫾ 4.6 9.3 ⫾ 6.4 1.2 ⫾ 0.5 21.7 ⫾ 6.8 8.0 ⫾ 4.1 6.4 ⫾ 5.1 1.1 ⫾ 0.6 5.0 ⫾ 1.2 0.8 ⫾ 0.5 7.5 ⫾ 1.4** 0.3 ⫾ 0.2 14.5 ⫾ 4.6
*P ⬍ .01 vs pre 1st LCP. **P ⬍ .05 vs pre 1st LCP.
tion,4 but the effect did not continue in the long term. So, a new effective treatment of CR is indispensable for the improvement in long-term allograft survival. Clinically, CR is characterized by a progressive deterioration of renal function occurring more than 6 months after transplantation. There is no doubt that nonimmunologic factors may play a role in the development or in the worsening of late graft dysfunction, immunologically medi-
ated chronic rejection is by far the most important cause of late graft failure. We tried LCP therapy in the patients with CR in which such immunologic mechanism seemed to be concerned. In this study, the slope of the reciprocal sCr regression line during the treatment in three patients with a sCr level more than 2.5 mg/dL at the initiation of the treatment became less steep (the slope turned positive in two cases) as compared to that of the pretreatment period.
Fig 2. The regression line of reciprocal sCr before, during, and after LCP treatment. The slope of the reciprocal sCr regression line during the treatment in three patients became less steep (the slope turned positive in two cases) as compared with that of the pretreatment period. In case 1, slowed progression of graft dysfunction continued, whereas in two cases (case 2 and 3), the slope steepened again after the discontinuation of LCP therapy.
1764
In case 1, a slowed rate of the progression of graft dysfunction continued after the discontinuation of LCP therapy. In two cases (case 2 and 3), the slope steepened again after the discontinuation of LCP therapy. The investigators who reported that the LCP therapy was effective for the inflammatory disease have indicated the involvement of an activated T cell in peripheral blood.2,3 Our study showed that the percentage of CD3⫹ cells decreased and the percentage of CD38⫹ cells and CD8⫹CD38⫹ cells increased after the fifth LCP procedure significantly. But the number of patients is very small, and it is necessary to perform a careful investigation in the future. In this study, after every LCP procedure the percentage of lymphocytes significantly decreased (P ⬍ .01), and the percentage of neutrophoils significantly increased (P ⬍ .01) compared with the pretreatment values. Since the leukocyte
TOMIKAWA, ANDO, NOMURA ET AL
removal filter we used removes nearly all of the leukocytes passing through, the increased neutrophils in circulating blood indicates the possibility that these cells play a major role in the effectiveness of LCP therapy. In conclusion, although the optimum frequency of LCP therapy still has to be established, our present results indicate that LCP is a new effective therapy for the patient with chronic renal allograft rejection. REFERENCES 1. Hostetter TH: Kidney Int 46:266, 1994 2. Sawada K, Ohnishi K, Fukui S, et al: J Gastroenterol 30:322, 1995 3. Fujita S: Jpn J Clin Immun 13:268, 1990 4. Nomura Y, Tomikawa S, Beck Y, et al: Transplant Proc 30:3580, 1998
D
ESPITE improvements in early survival of renal allografts associated with advances in current immunosuppressive protocols, there has been no change in longterm graft survival and chronic renal allograft rejection (CR) is the most common cause of late failure of kidney allografts. Attention has been focused on the prevention and management of CR, but there is no established means of prevention or treatment of CR.1 Therefore, a new effective treatment of CR is indispensable for the improvement in long-term allograft survival. Recently, the effectiveness of leukocytopheresis (LCP) performed with a leukocyte removal filter is reported for the inflammatory diseases, such as inflammatory bowel disease2 and rheumatoid arthritis,3 in which the immunologic mechanism seems to be concerned in the occurrence. We therefore examined the effectiveness of LCP for the patients with biopsy-proven CR after kidney transplantation. PATIENTS AND METHODS To study the efficacy of LCP, LCP therapy was applied to five patients with established chronic renal allograft rejection diagnosed both on a histologic and clinical basis (Table 1). In all cases, the immunosuppressive drug was not changed throughout the LCP therapy. Three patients (case 1, 2, and 3) were selected to apply LCP because of the progressive increase in the level of serum creatinine (sCr) more than 2.5 mg/dL (two cases associated with proteinuria) and another two patients (case 4 and 5) were because of proteinuria with a sCr level below 2 mg/dL. We obtained informed consent from all patients who participated in this clinical trial. LCP therapy was performed with a leukocyte removal filter, Cellsorba (Asahi Medical Co), and nafamostat mesilate (Torii Pharmaceutical Co) was used as an anticoagulant. In each LCP procedure, a total of 3000 mL of blood was filtered and returned to patient at a flow rate of 50 mL/min for 60 min. LCP therapy was
administered five times at 2- to 3-day intervals as intensive therapy and 6 to 12 times over a 2-week interval as maintenance therapy. As an index to the therapy effect, sCr and urinary excretion of protein were examined. The graft function was expressed by reciprocal sCr, and the change in the graft function was expressed by the slope of the regression line of reciprocal sCr of the pretreatment observation period, the therapeutic period, and the posttreatment observation period. In addition, the number of circulating leukocyte and T-lymphocyte surface markers (CD3, CD4, CD8, CD25, CD38, CD71, and HLA-DR) were measured before and after the first, third, and fifth procedures. Data shown were mean ⫾ SD, and statistical analysis was done by Student’s paired t test.
RESULTS
LCP procedures were tolerated by all patients. There was no serious complication, and routine laboratory tests were normal except for the decrease in temporary numbers of platelets immediately after procedures. The change of the level of sCr and the urinary protein excretion before, during, and after the treatment was shown in Fig 1. The patient, case 1, showed slowing of the progressive increase in the level of sCr and decrease of the degree of proteinuria after three LCP therapy treatments, which followed the intensive therapy. Because 2 months after this treatment, the level of sCr and the degree of proteinuria increased again, LCP therapy (nine times) was administered in an interval of 2 weeks. The patient responded to this additional treatment. The progressive increase in the level of sCr was From the Department of Surgery, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Address reprint requests to Dr S. Tomikawa, Department of Surgery, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan.
Table 1. Clinical Feature of Patients with LCP Treatment
Case
Age (y)
Sex
Time from Transplant to LCP Therapy (y)
1 2 3 4 5
31 38 39 39 48
M M M F M
8.3 11.6 4.6 11.1 4.3
Episode of Acute Rejection
Previous Treatment for Chronic Rejection
sCr Immediately Before LCP Therapy (mg/dL)
Proteinuria Immediately Before LCP Therapy (g/d)
(⫺) (⫹) (⫹) (⫹) (⫺)
CYA dose up DSG Pr dose up (⫺) MP pulse DSG
2.6 4.3 3.0 1.6 1.7
2.38 1.38 0.07 1.74 2.23
CYA, cyclosporine; DSG, deoxyspergualin; Pr, prednisolone; MP, methyl-prednisolone.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01386-5
Transplantation Proceedings, 32, 1761–1764 (2000)
1761
1762
TOMIKAWA, ANDO, NOMURA ET AL
Fig 1. The change of the level of sCr and the urinary protein excretion before, during, and after the treatment. LCP e, LCP therapy was administered five times at 2- to 3-day intervals as intensive therapy. LCP e e e, LCP therapy was administered 6 to 12 times over a 2-week interval as maintenance therapy that followed the intensive therapy.The progressive increase in the level of sCr was prevented throughout the treatment in case 1, 2, and 3. The degree of proteinuria diminished after the intensive therapy in all cases but returned to the pretreatment values in three cases during or after the maintenance therapy.
prevented and the degree of proteinuria was decreased during the maintenance therapy, and it continued after the discontinuation of LCP therapy. In two patients (case 2 and 3), the maintenance therapy was started 2 or 2.5 months after the intensive therapy. The progressive increase in the level of sCr was prevented throughout the treatment in both cases, but the effect was not continued after the discontinuation of LCP therapy. The degree of proteinuria diminished after the intensive therapy in all cases but returned to the pretreatment values in three cases during or after the maintenance therapy. The changes in the number of circulating leukocyte and T-lymphocyte surface markers during the first and the fifth procedure are shown in Table 2. The leukocyte count in circulating blood decreased to about 25% of previous value 30 minutes after LCP was started, and it was almost
recovered to the previous value at the end of the 60-minute procedure. After every LCP procedure, the percentage of lymphocyte significantly decreased (P ⬍ .01), and the percentage of neutrophoils significantly increased (P ⬍ .01) compared with the pretreatment values. The flow cytometry results showed that the percentage of CD3⫹ cells decreased and the percentage of CD38⫹ cells and CD8⫹CD38⫹ cells increased after the fifth LCP procedure significantly. DISCUSSION
There is no effective therapy for CR, which is a dominant reason for late allograft loss even with current immunosuppressive protocols. We previously reported the effect of deoxyspergualin on chronic rejection in renal transplanta-
LEUKOCYTOPHERESIS AND RENAL ALLOGRAFT REJECTION
1763
Table 2. Change in the Number of Circulating Leukocyte and T-Lymphocyte Surface Markers
WBC(/mm3) Lymphocyte(%) Neutrophil(%) CD3(%) CD4(%) CD8(%) CD25(%) CD38(%) CD71(%) HLADR(%) CD3⫹CD25⫹(%) CD3⫹CD38⫹(%) CD3⫹CD71⫹(%) CD3⫹HLADR⫹(%) CD4⫹CD25⫹(%) CD4⫹CD38⫹(%) CD4⫹CD71⫹(%) CD4⫹HLADR⫹(%) CD8⫹CD25⫹(%) CD8⫹CD38⫹(%) CD8⫹CD71⫹(%) CD8⫹HLADR⫹(%)
Pre
First LCP 30 min
Post
Pre
Fifth LCP Post
7680 ⫾ 1750 28.5 ⫾ 11.4 61.9 ⫾ 9.5 84.3 ⫾ 6.3 39.0 ⫾ 5.8 46.8 ⫾ 7.7 14.7 ⫾ 6.5 18.8 ⫾ 9.2 1.3 ⫾ 0.4 27.3 ⫾ 8.0 13.1 ⫾ 6.6 7.3 ⫾ 4.6 0.6 ⫾ 0.5 21.0 ⫾ 6.1 10.0 ⫾ 3.5 5.6 ⫾ 3.6 0.4 ⫾ 0.1 5.1 ⫾ 2.4 4.4 ⫾ 8.5 5.7 ⫾ 2.3 0.2 ⫾ 0.1 13.1 ⫾ 4.2
1780 ⫾ 670 52.6 ⫾ 21.5 41.2 ⫾ 20.4 — — — — — — — — — — — — — — — — — — —
7580 ⫾ 3460 16.9 ⫾ 12.2* 77.4 ⫾ 12.0* 80.3 ⫾ 4.9 36.9 ⫾ 12.4 43.3 ⫾ 16.3 9.6 ⫾ 4.7 19.8 ⫾ 7.1 1.7 ⫾ 0.7 26.5 ⫾ 8.5 8.0 ⫾ 4.5 7.2 ⫾ 4.8 0.8 ⫾ 0.5 19.3 ⫾ 8.8 7.9 ⫾ 3.8 5.1 ⫾ 3.9 0.6 ⫾ 0.2 4.4 ⫾ 1.4 0.6 ⫾ 0.4 5.5 ⫾ 1.8 0.3 ⫾ 0.3 13.1 ⫾ 5.7
7260 ⫾ 1470 26.9 ⫾ 11.1 62.8 ⫾ 11.0 82.6 ⫾ 6.7 37.5 ⫾ 5.6 48.5 ⫾ 7.4 9.0 ⫾ 4.7 22.0 ⫾ 11.0 1.8 ⫾ 0.6 31.8 ⫾ 6.5 7.7 ⫾ 4.6 9.7 ⫾ 6.5 0.8 ⫾ 0.3 26.1 ⫾ 6.6 7.7 ⫾ 4.3 6.3 ⫾ 4.7 0.6 ⫾ 0.1 5.4 ⫾ 1.1 0.8 ⫾ 0.2 8.0 ⫾ 2.4 0.5 ⫾ 0.2 15.9 ⫾ 5.2
7510 ⫾ 4400 13.3 ⫾ 9.0* 79.4 ⫾ 7.4* 77.7 ⫾ 3.8** 37.3 ⫾ 8.2 44.1 ⫾ 10.0 11.6 ⫾ 6.2 25.3 ⫾ 9.6** 2.7 ⫾ 1.1 30.1 ⫾ 9.1 8.7 ⫾ 4.6 9.3 ⫾ 6.4 1.2 ⫾ 0.5 21.7 ⫾ 6.8 8.0 ⫾ 4.1 6.4 ⫾ 5.1 1.1 ⫾ 0.6 5.0 ⫾ 1.2 0.8 ⫾ 0.5 7.5 ⫾ 1.4** 0.3 ⫾ 0.2 14.5 ⫾ 4.6
*P ⬍ .01 vs pre 1st LCP. **P ⬍ .05 vs pre 1st LCP.
tion,4 but the effect did not continue in the long term. So, a new effective treatment of CR is indispensable for the improvement in long-term allograft survival. Clinically, CR is characterized by a progressive deterioration of renal function occurring more than 6 months after transplantation. There is no doubt that nonimmunologic factors may play a role in the development or in the worsening of late graft dysfunction, immunologically medi-
ated chronic rejection is by far the most important cause of late graft failure. We tried LCP therapy in the patients with CR in which such immunologic mechanism seemed to be concerned. In this study, the slope of the reciprocal sCr regression line during the treatment in three patients with a sCr level more than 2.5 mg/dL at the initiation of the treatment became less steep (the slope turned positive in two cases) as compared to that of the pretreatment period.
Fig 2. The regression line of reciprocal sCr before, during, and after LCP treatment. The slope of the reciprocal sCr regression line during the treatment in three patients became less steep (the slope turned positive in two cases) as compared with that of the pretreatment period. In case 1, slowed progression of graft dysfunction continued, whereas in two cases (case 2 and 3), the slope steepened again after the discontinuation of LCP therapy.
1764
In case 1, a slowed rate of the progression of graft dysfunction continued after the discontinuation of LCP therapy. In two cases (case 2 and 3), the slope steepened again after the discontinuation of LCP therapy. The investigators who reported that the LCP therapy was effective for the inflammatory disease have indicated the involvement of an activated T cell in peripheral blood.2,3 Our study showed that the percentage of CD3⫹ cells decreased and the percentage of CD38⫹ cells and CD8⫹CD38⫹ cells increased after the fifth LCP procedure significantly. But the number of patients is very small, and it is necessary to perform a careful investigation in the future. In this study, after every LCP procedure the percentage of lymphocytes significantly decreased (P ⬍ .01), and the percentage of neutrophoils significantly increased (P ⬍ .01) compared with the pretreatment values. Since the leukocyte
TOMIKAWA, ANDO, NOMURA ET AL
removal filter we used removes nearly all of the leukocytes passing through, the increased neutrophils in circulating blood indicates the possibility that these cells play a major role in the effectiveness of LCP therapy. In conclusion, although the optimum frequency of LCP therapy still has to be established, our present results indicate that LCP is a new effective therapy for the patient with chronic renal allograft rejection. REFERENCES 1. Hostetter TH: Kidney Int 46:266, 1994 2. Sawada K, Ohnishi K, Fukui S, et al: J Gastroenterol 30:322, 1995 3. Fujita S: Jpn J Clin Immun 13:268, 1990 4. Nomura Y, Tomikawa S, Beck Y, et al: Transplant Proc 30:3580, 1998