Multivisceral Transplantation / 대한이식학회지

Small bowel transplantation is the most rapidly evolving area of the solid organ transplantation. Pathophysiologic nature of the intestinal failure leads various surgical options performing intestinal transplantation, e.g. isolated intestine, liver and intestine, and multivisceral transplantation. Because of high dosing of immunogenic tissue from the allograft, prevention and treatment of the acute rejection is still one of the main hurdles to improve clinical outcome after transplantation. With the contribution of refining surgical skills, novel immunosuppressive therapy, and upgraded patient management before and after transplantation, clinical outcome has been improved significantly for last decade. The indication of the intestinal transplantation, however, still remained to use this novel treatment option as a life- saving procedure in intestinal failure patients and not to be justified for pre-emptive intestinal transplantation. Intestinal or multivisceral transplantation has so many unveiled areas, which warrants additional vigorous study.

Intestinal and Multivisceral Transplantation

Intestinal transplantation has been established as a treatment option for patients that suffer from intestinal failure with complications from total parenteral nutrition. It is still rapidly evolving and just reached a landmark of 1, 000 cases worldwide. Intestinal allografts can be transplanted as isolated, combined with the liver or as a part of a multivisceral allograft. Tacrolimus-based immunosuppression regimens have been used universally with improved outcomes. Clinical outcome in intestinal transplantation has improved significantly over time, impacted by refinement of surgical technique and novel immunosuppression. However rejection, infection, and technical complications still remain the most difficult barrier to improve patient and graft survival.

Effect of Mycophenolic Acid and Rapamycin on the Proliferation of Glomerular Mesangial Cell of Rat

PURPOSE: Excess proliferation of mesenchymal cells such as vascular smooth muscle cells and glomerular mesangial cells, cause transplant vascular sclerosis and glomerulosclerosis, which are typical pathological lesions of chronic allograft dysfunction. Mycophenoic acid (MPA) and rapamycin (RPM) were recently reported to have strong anti-proliferative potentials toward vascular smooth muscle cells. However, the potential effects of these drugs, either alone or in combination, on glomerular mesangial cells, remain to be reported. METHODS: Primary cultured mesangial cells, from Sprague-Dawley rats, were isolated, and stimulated with 10ng/ml of PDGF. The test drugs MPA and RPM were administered at various concentrations, either alone or in combination, 15 minutes before the addition of the PDGF. The cell proliferation was assessed by [3H]-thymidine incorporation. RESULTS: The PDGF effectively stimulated the proliferation of the mesangial cells. The MPA inhibited the proliferation in a dose-dependent manner. In comparison to the stimulated control, the MPA (above 500 nM) showed a significant inhibitory effect. The IC50 of the MPA, against PDGF-stimulated mesangial cell proliferation, was between 500 nM and 1microM. The RPM, at 10 nM, showed a significant inhibitory effect. In a linear regression analysis, the RPM was supposed to suppress the mesangial proliferation in a dose-dependent manner (P<0.05). The pattern of inhibition for the MPA and RPM combination was very similar to that of either the MPA or the RPM alone. Both the MPA and RPM were shown to independently suppress the mesangial proliferation from a multiple regression analysis (R2=0.415, P<0.001). CONCLUSION: We demonstrated that MPA and RPM significantly inhibited the proliferation of glomerular mesangial cells, and that these effects were well maintained when used in combination. Our data indicate that both MPA and RPM have unique potentials in preventing the development of transplant mesangial proliferation in renal transplant recipients.

Effect of Mycophenolic Acid and Rapamycin on the Proliferation and Collagen Synthesis of the Vascular Smooth Muscle Cell of Rat / 대한이식학회지

PURPOSE: Vascular smooth muscle cell (VSMC) proliferation and extracellular matrix protein accumulation play important roles in chronic allograft vasculopathy. Mycophenolic acid (MPA) or rapamycin (RPM) was reported to inhibit VSMC proliferation in vitro and in vivo. However, effects of MPA or RPM on collagen synthesis of VSMCs, and the combined effects of MPA and RPM treatment on VSMC proliferation are not yet reported. METHODS: VSMCs isolated from the aorta of Sprague-Dawley rats were cultured with EMEM supplemented with 10% fetal bovine serum and insulin/ transferrin. Growth arrested and synchronized cells were pretreated with test drugs (alone or combination of various concentrations of MPA and RPM) 1 hour before the addition of 10 ng/ml PDGF. Cell proliferation was assessed by [H3]- thymidine incorporation, and collagen synthesis by [H3]- proline incorporation. RESULTS: PDGF increased cell proliferation and collagen synthesis by 3.4- and 2.1-fold, respectively, compared to control. MPA at above 100 nM or RPM at above 1 nM effectively inhibited PDGF-induced cell proliferation and collagen synthesis. The IC50 of MPA or RPM against PDGF-stimulated cell proliferation was between 100 nM and 1 micrometer or between 1 nM and 10 nM, respectively. The combination of MPA and RPM showed additive effects on PDGF-induced VSMC proliferation in a multiple regression analysis (R2=0.508, P<0.05). CONCLUSION: The present study demonstrated that MPA or RPM significantly inhibited PDGF-induced VSMC proliferation. These independent phenomena were well maintained as suggested by additive effects after combination treatment. PDGF-induced collagen synthesis was also effectively suppressed by the treatment of MPA or RPM.

The Results of Renal Transplantation after Lymphocyte Cross-match Negative Conversion by Combination Therapy with Plasmapheresis, Intravenous Gamma Globulin and Potent Immunosuppresants in Patients with Positive LCM / 대한이식학회지

PURPOSE: It is well-known that kidney transplantation cannot be done if recipient has circulating antibodies showing positive lymphocyte cross-match (LCX) to organ donor. In the United States and European countries, the incidence of positive LCX to cadaveric donors in patients who are on the waiting list is up to 20~40%. Unfortunately, these patients also show high rate of positive LCX to live donors when they have donor candidates in their family members and have to be on dialysis until compatible donor comes up. Recently, Eugene J Schweitzer and his associates at the University of Maryland used the combination therapy with plasmapheresis, intravenous gamma globulin and potent immunosuppression to induce negative conversion of LCX in patients who were LCX positive to their living donors and reported the good results after the trial. We did the combination therapy in patients who had positive LCX to their living donors and reported the results. METHODS: Seven patients, four women and three men who showed positive LCX to their living donors, underwent the conversion trials between January 1 and July 31, 2002. The mean age of patients was 43.86 (35~60) and the duration of dialyses varies from 9 to 120 months. We used combination therapy with plasmapheresis, intravenous gamma globulin injection, tacrolimus, mycophenolate mofetil (MMF) and steroids. Plasmapheresis had been done on every other day up to 6 times to induce negative conversion of LCX. If patient continue to show positive LCX to donor after 6 times of plasmapheresis, we stopped the therapy. The numbers of plasmapheresis varies from two to six times. Kidney transplantations were preformed immediately after negative conversion of LCX as a semi-elective procedures. Five to ten day courses of ATG (or OKT3) were used as an induction immunosuppression after transplantation and tacrolimus, MMF, and steroids were used as a maintenance immunosuppression. RESULTS: We could achieve negative conversion of LCX in six out of seven patients, and kidney transplantations were performed in these 6 patients successfully. There was no hyperacute rejection during the operations, but three patients developed acute rejection episodes during their early postoperative periods. Steroid pulse therapies were used as a primary therapy to treat acute rejection and all three patients showed complete recovery of their graft function after the treatments. Baseline serum creatinine level varies from 1.0 mg/dl to 1.9 mg/dl with 3 to 6 months follow-up periods after transplantations. We could not induce negative conversion in one patient and he remained on hemodialysis. CONCLUSION: We did successful kidney transplantations in six patients who achieved negative conversion of LCX to their donors after the combination therapy with plasmapheresis and potent immunosuppression. All patients showed excellent graft function since their operations and did not have any significant complications except three reversible acute rejection episodes. According to the results, although it is preliminary, we recommend the use of the combination therapy in patient who has LCX positive living donor. Further long-term study with more numbers of patients is needed for the evaluation of the efficacy of this trial.

Granzyme B and TIA-1 Expression in Chronic and Acute on Chronic Renal Allograft Rejection

Although active inflammation may be deleterious and indicate immunologic activation in chronically rejected grafts, the underlying mechanism of tissue destruction has been little studied. Twenty-four cases of chronic rejection (CR) with or without acute rejection (AR) were stained with antibodies against CD3, CD8, CD68, granzyme B and TIA-1, and the number of positive cells were counted. Eleven cases of AR served as controls. The number of CD3 and CD8 positive cells increased in the acute on CR group compared to the CR group. About a half of CD3 positive T cells were CD8 positive in both groups, however, the proportion of TIA-1 or granzyme B positive cells was higher in the acute on CR group. The numbers of CD3, CD68, granzyme B and TIA-1 positive cells were higher in the AR group than the acute on CR group, however, no significant difference was found between the two groups. Serum creatinine level and proteinuria at the time of biopsy and the percentages of late onset AR and graft failure rate were higher in the acute on CR group than the CR group. Summarizing, these results suggest that infiltration of activated T cells containing cytotoxic granules plays a role in graft destruction in acute on CR.

Factors Affecting the First 3-year Quality of Graft Function after Live Donor Kidney Transplantation

PURPOSE: We designed this study to identify the risk factors affecting the quality of graft after live donor kidney transplantation. METHODS: The study cohort included 259 adult patients who had been followed up for an average of 37 months after transplantation. Cyclosporine (CsA) and steroids were used as main immunosuppressive agents. Seven variables [HLA match, numbers of acute rejection (AR) within post-transplant 1 year, blood type compatibility, use of anti-lymphocyte antibody, age of donor (DA), age of recipient, and the donor kidney weight to recipient body weight ratio (KW/BW)] were examined by multiple regression analysis during the first 3 years. Serum creatinine (Scr), creatinine clearance rate (Ccr) and the 24 hours urinary excretion of protein (24 UP) were used as parameters. RESULTS: AR, DA, or KW/BW independently affected the quality of graft function. Scr, Ccr, or 24 UP at post-transplant 1 year was strongly correlated with AR (p<0.0001, p=0.002, or p=0.002, respectively). However, Scr, Ccr, or 24 UP at post-transplant 3 years was strongly affected by KW/BW (p<0.0001, p<0.0001, or p=0.008, respectively) or DA (p<0.0001, p=0.001, or p=0.039, respectively). CONCLUSION: Non-immunologic factors independently affected the graft function through the study periods. The impact of non-immunologic factors on the function of the graft increased year by year. During renal allocation, KW/BW and DA should be included as reference indices to improve the long-term graft function.

Postprandial Hepatic Volume Change: Spiral CT Evaluation in Case of Liver Cirrhosis

PURPOSE: To investigate the usefulness of evaluating liver cirrhosis through the measurement of liver volume. MATERIALS AND METHODS: In a control group(20 normal subjects) and 20 cirrhotic patients, variations in liver volume before and after a meal were obtained. A case-control study was conducted between the two groups. RESULTS: In the control group, the range of increased liver volume after the meal was 67-186ml. Mean increased liver volume was 119.3ml, the range of percentage increase was 6-12% and the mean percentage increase was 9.89%. In cirrhotic patients, the range of increased liver volume after the meal was 1-20ml. Mean increased liver volume was 6.9ml, the range of percentage increase was 0-1.9% and the mean percentage increase was 0.65%. Compared with the control group, cirrhotic patients showed a much smaller increase in liver volume (p<0.01). CONCLUSION: Difference in variation of liver volume between a control group and cirrhotic patients before and after a meal can be used for the evaluation of liver cirrhosis.

Ratio of Kidney Weight to Recipient Weight Correlates with the 3-Year Graft Function / 대한이식학회지

Reduced renal mass, increased recipient body size, and their mismatching are the potential risk factor to explain the non-immunologic graft dysfunction. Present study was designed to assess the effect of mismatch between donor kidney weight (KW) and recipient body weight (BW) on the 3-year graft function in live donor renal transplantation (TX) patients (pts) who were operated before Nov. 1995 under cyclosporine. To remove immunologic injuries and effect of glomerulonephritis (GN), the pts experiencing episode of acute rejection or showing post-TX biopsy-proven GNs were excluded. A total of 82 pts cohort was identified and followed up till Nov. 1998. The donor KW after cold flushing, BW of recipient at TX, and renal parameters at 3-year post-TX such as serum creatinine (Scr), creatinine clearance ratio (CCR) and 24-hour urinary excretion of protein (24UP) were recorded. First, any correlation between the index value of the KW/BW ratio and each parameters was studied by the regression analysis, and secondly, the pts were stratified into 3 groups by the KW/BW ratio (3.5 4.0) and compared with each parameters by ANOVA test. Scr, CCR, and 24 UP was well correlated with the ratio KW/BW (p4.0) have significantly lower Scr, higher CCR and lower 24 UP compared with pts showing medium or low ratio. In conclusion, the mismatch between the donor KW and recipient BW has a substantial effect on the medium term graft function. Since estimating the kidney volume by CT scan or ex vivo after bench surgery is simple and easily applicable in clinical practice, KW/BW ratio is to be considered for the selection or allocation of potential donor in both cadaveric and living donor TX programs.

Efficacy of Tacrolimus in Primary Kidney Transplant Patients: Multi-center, Open-label, Prospective Study / 대한이식학회지

Introduction of tacrolimus has been accepted as one of the major advance in the management of rejection following solid organ transplantation. This open-label, multi-center study is designed to confirm the efficacy of tacrolimus in primary kidney transplantation. A total of 64 renal transplant recipients were recruited from 4 medical centers, and received dual drug therapy consists of tacrolimus and low-dose corticosteroids after kidney transplantation. Tacrolimus was started 2 days prior to the transplantation with the dosage of 0.2 mg/kg/day. Daily dose of tacrolimus was modulated to maintain the trough blood level between 15 ng/ml and 20 ng/ml for the first 3 months and between 10 ng/ml and 15 ng/ml for the next 3 months after the transplantation. Steroid pulse therapy with methylprednisolone was used as a first line modality of acute rejection treatment. Steroid resistant rejection was treated with anti- lymphocyte agents. Post-transplant diabetes mellitus was defined as the cases when patients who had no history of glucose intolerance need the use of oral hypoglycemics and/or insulin for 30 days or longer to control their hyperglycemia after transplantation. There were 51 live donor and 13 cadaveric donor transplantations. Live donor transplantation consisted with 33 related (10 HLA identical, 23 HLA haplo- identical) and 18 unrelated pairs. Mean age of the patients was 39.4 9.6 (range; 22-58). There were 36 male and 28 female patients. There were 21 acute rejection episodes in 17 patients (26.6%) during the first 6 months after transplantation. Six patients were treated with anti-lymphocyte agents, and 4 patients showed complete response but 2 episodes (9.5%) showed partial rescue. Six-month patient and graft survivals were 100% and 98.4%, respectively. A total of 18 patients (28.1%) experienced glucose intolerance during the study period. Tacrolimus showed satisfactory efficacy in primary kidney transplantation. Long-term follow up is needed for further evaluation of efficacy and safety.

Effectiveness of Cipol-N(R) in Primary Living Donor Kidney Transplant Patients: Open-Label, Multi-Center Study / 대한이식학회지

Cyclosporine (CsA) has been one of the main immunosuppressants after kidney transplantation since its introduction in Korea. There was remarkable improvement of graft survival in kidney transplantation with CsA, compared with azathioprine. Cipol-N(R)(Chong Kun Dang, Korea), microemulsion gelatin capsule formulation of CsA, is a new generic drug. This pure domestic brand of CsA was tested for bioequivalence in healthy adults compared with the reference drug of the same formulation, Sandimmun-Neoral(R)(Novartis, Switzerland) in 1997. This open-label, multi-center study is designed to evaluate the efficacy of Cipol-N(R) in primary kidney transplant recipients for 6 months after transplantation. A total of 59 patients from 4 medical centers were enrolled in the study. Maintenance immunosuppressive protocol was based on CsA and steroid dual therapy, which was induced 2 days prior to the operation. Acute rejection was diagnosed with clinical or pathological clue. Clinical criteria for the diagnosis of acute rejection were oliguria, graft swelling and tenderness, rising serum creatinine, fever, and papillary swelling and increased vascular resistant index on Doppler ultrasonography. Steroid pulse therapy was used as primary treatment. Steroid resistant acute rejection was treated with anti-lymphocyte agents such as OKT3, ATG, or ALG. The primary efficacy endpoint was onset of acute rejection or treatment failure, defined as graft loss, death, or premature termination from the study for any reason. Incidence and severity of acute rejection, actual survival rate of patient and graft, function of the graft, pharmacokinetics of the Cipol-N(R), and the primary efficacy variables were evaluated 6 months after transplantation. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. Mean age of the patients was 37.1 10.4 years old. Male and female ratio was 42:17. There were 38 related pairs, which included 5 HLA identical and 33 HLA haplo-identical matches, and 21 unrelated pairs. A total of 10 patients were withdrawn from the study before post- transplant 6 months. The causes for premature withdrawal were patient's request without specific reason (6), partially rescued acute rejection (3), and patient's death (1). There were 27 episodes of acute rejection in 25 patients, which were diagnosed clinically (11) and pathologically (16). Steroid pulse therapy and anti-lymphocyte agent were used in 24 and 3 cases respectively. There were 4 patients, who showed partial rescue but no graft loss due to acute rejection. Patient and graft survival was 98.3% at post-transplant 6 months. Serum creatinine concentration showed 1.3-1.7 mg/dl all through the study period, which meant relatively stable graft function. Mean daily doses of Cipol-N(R) at post-transplant 1 and 6 months were 325 and 300 mg respectively. With this short term study, we can report that Cipol-N(R) showed relatively good efficacy in primary living donor kidney transplantation. Further study is needed for the evaluation of long term efficacy and safety.

Effectiveness of Cipol-N(R) in Primary Living Donor Kidney Transplant Patients: Open-Label, Multi-Center Study / 대한이식학회지

Cyclosporine (CsA) has been one of the main immunosuppressants after kidney transplantation since its introduction in Korea. There was remarkable improvement of graft survival in kidney transplantation with CsA, compared with azathioprine. Cipol-N(R)(Chong Kun Dang, Korea), microemulsion gelatin capsule formulation of CsA, is a new generic drug. This pure domestic brand of CsA was tested for bioequivalence in healthy adults compared with the reference drug of the same formulation, Sandimmun-Neoral(R)(Novartis, Switzerland) in 1997. This open-label, multi-center study is designed to evaluate the efficacy of Cipol-N(R) in primary kidney transplant recipients for 6 months after transplantation. A total of 59 patients from 4 medical centers were enrolled in the study. Maintenance immunosuppressive protocol was based on CsA and steroid dual therapy, which was induced 2 days prior to the operation. Acute rejection was diagnosed with clinical or pathological clue. Clinical criteria for the diagnosis of acute rejection were oliguria, graft swelling and tenderness, rising serum creatinine, fever, and papillary swelling and increased vascular resistant index on Doppler ultrasonography. Steroid pulse therapy was used as primary treatment. Steroid resistant acute rejection was treated with anti-lymphocyte agents such as OKT3, ATG, or ALG. The primary efficacy endpoint was onset of acute rejection or treatment failure, defined as graft loss, death, or premature termination from the study for any reason. Incidence and severity of acute rejection, actual survival rate of patient and graft, function of the graft, pharmacokinetics of the Cipol-N(R), and the primary efficacy variables were evaluated 6 months after transplantation. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. Mean age of the patients was 37.1 10.4 years old. Male and female ratio was 42:17. There were 38 related pairs, which included 5 HLA identical and 33 HLA haplo-identical matches, and 21 unrelated pairs. A total of 10 patients were withdrawn from the study before post- transplant 6 months. The causes for premature withdrawal were patient's request without specific reason (6), partially rescued acute rejection (3), and patient's death (1). There were 27 episodes of acute rejection in 25 patients, which were diagnosed clinically (11) and pathologically (16). Steroid pulse therapy and anti-lymphocyte agent were used in 24 and 3 cases respectively. There were 4 patients, who showed partial rescue but no graft loss due to acute rejection. Patient and graft survival was 98.3% at post-transplant 6 months. Serum creatinine concentration showed 1.3-1.7 mg/dl all through the study period, which meant relatively stable graft function. Mean daily doses of Cipol-N(R) at post-transplant 1 and 6 months were 325 and 300 mg respectively. With this short term study, we can report that Cipol-N(R) showed relatively good efficacy in primary living donor kidney transplantation. Further study is needed for the evaluation of long term efficacy and safety.

Long-term (>10 years) Result of Kidney Transplantation between HLA Identical Siblings / 대한이식학회지

Degree of HLA matching between donor and recipient is a well-known risk factor affecting the renal allograft function and survival. This study presents long-term clinical outcomes of kidney transplantation between HLA identical siblings from a single center. A total of 60 patients (pts), who has been followed up more than 10 years were identified and constituted the cohort of this study. The graft and patient survival were estimated with Kaplan-Meier's analysis method. Causes of graft loss and pts' death, episode of acute and chronic rejection, allograft function, and long-term complications were reviewed from medical records. Before 1984, azathioprine (AZA) and steroids were used for immunosuppression, but cyclosporine (regular oral solution, regular capsules or microemulsion preparation) and a low dose steroid has been the mainstay of immunosuppression since 1984. Earlier 37 pts were treated with AZA/steroids protocol (AZA group) and later 23 pts were immunosuppressed with cyclosporine (CsA)/steroids protocol (CsA group). Mean duration of follow-up months was 151 in AZA and 114 in CsA group respectively. Mean age of recipients at the time of transplantation was 34.1 years in AZA and 34.7 years in CsA group. Ten year graft survival in each group were 67.6% and 65.2% (p=0.672) and patient survival were 82.7% and 80.0% (p=0.833) respectively. Adoption of CsA/steroids protocol since 1984 did not significantly improve the graft and patient survival comparing AZA/steroids protocol. During the period, 12 patients died of various causes. The leading causes of patient death were cerebrovascular disease (3) and infection (3). Twenty-two grafts were lost: 13 in AZA and 9 in CsA group. The common causes of graft loss were pts' death with functioning graft (12), chronic rejection (5), and poor compliance (4). We could not find any differences in the causes of mortality and graft loss between the AZA and CsA groups. Mean serum creatinine in the chronic rejection-free pts at post-transplant 10 year were 1.4 and 1.3 mg/dl in or CsA group. CsA/steroids protocol did not improve the long-term outcome in HLA matched pairs. Long surviving transplant recipients continue to experience a variety of medical and surgical complications. For this reason, continued follow-up by experienced medical personnel is essential. Measures need to be taken to prevent and manage these late complications. Continued investigation into new and better immunosuppressive modalities is essential in an attempt to prevent the long-term consequences of maintenance immunosuppression.

Long-term (>10 years) Result of Kidney Transplantation between HLA Identical Siblings / 대한이식학회지

Degree of HLA matching between donor and recipient is a well-known risk factor affecting the renal allograft function and survival. This study presents long-term clinical outcomes of kidney transplantation between HLA identical siblings from a single center. A total of 60 patients (pts), who has been followed up more than 10 years were identified and constituted the cohort of this study. The graft and patient survival were estimated with Kaplan-Meier's analysis method. Causes of graft loss and pts' death, episode of acute and chronic rejection, allograft function, and long-term complications were reviewed from medical records. Before 1984, azathioprine (AZA) and steroids were used for immunosuppression, but cyclosporine (regular oral solution, regular capsules or microemulsion preparation) and a low dose steroid has been the mainstay of immunosuppression since 1984. Earlier 37 pts were treated with AZA/steroids protocol (AZA group) and later 23 pts were immunosuppressed with cyclosporine (CsA)/steroids protocol (CsA group). Mean duration of follow-up months was 151 in AZA and 114 in CsA group respectively. Mean age of recipients at the time of transplantation was 34.1 years in AZA and 34.7 years in CsA group. Ten year graft survival in each group were 67.6% and 65.2% (p=0.672) and patient survival were 82.7% and 80.0% (p=0.833) respectively. Adoption of CsA/steroids protocol since 1984 did not significantly improve the graft and patient survival comparing AZA/steroids protocol. During the period, 12 patients died of various causes. The leading causes of patient death were cerebrovascular disease (3) and infection (3). Twenty-two grafts were lost: 13 in AZA and 9 in CsA group. The common causes of graft loss were pts' death with functioning graft (12), chronic rejection (5), and poor compliance (4). We could not find any differences in the causes of mortality and graft loss between the AZA and CsA groups. Mean serum creatinine in the chronic rejection-free pts at post-transplant 10 year were 1.4 and 1.3 mg/dl in or CsA group. CsA/steroids protocol did not improve the long-term outcome in HLA matched pairs. Long surviving transplant recipients continue to experience a variety of medical and surgical complications. For this reason, continued follow-up by experienced medical personnel is essential. Measures need to be taken to prevent and manage these late complications. Continued investigation into new and better immunosuppressive modalities is essential in an attempt to prevent the long-term consequences of maintenance immunosuppression.

Significance of Functional Graft Survival Rate

Patient death with a functioning graft(DFG) has been a predominant cause of graft loss. According to conventional graft survival(C-GS) analysis, DFG is considered as a graft failure. However, such survival analysis may obscure immunologic graft loss and distort the overall graft results as well as risk factors affecting the graft survivals. In functional graft survival(F-GS) analysis, the DFG is considered as censored data(in which the graft survived until patient death) which is more closely related with the immunologic graft loss. We designed our study to identify the differences and significance of F-GS compared to C-GS. From April 1984 to October 1995, 1242 living donor kidney transplantations under cyclosporine were performed at Yonsei University Medical Center. At least a 1-year follow-up was possible in all the patients. The graft survival rate was calculated by both C-GS and F-GS analyses. The recipient's and the donor's ages, the donor-recipient relationship, the degree of HLA matching, the degree of ABO blood type matching, the episodes of acute rejection within 1 year, and the presence of diabetes mellitus were monitored as risk factors affecting the graft survival in the two analysis methods. Univariate and multivariate analyses for risk factors were done by the Kaplain-Meier method and the Cox proportional harzard model. The C-GS rate were 96.3% at 1 year, 81.8% at 5 years, and 58.4% at 10 years compared to 98.5%, 88.1%, and 67.9%, respectively in the F-GS analysis. Elderly recipients(> or =50), elderly donors(> or =50), presence of acute rejection within 1 year post-transplant, ABO blood type minor mismatching, and diabetic recipients were risk factors affecting long-term graft survival in the C-GS analysis. However, elderly recipients and diabetic recipients were no longer considered as risk factors in the F-GS analysis. In fact, elderly recipients or diabetic recipients showed equal or even better graft survivals in the F-GS analysis compared with younger or non-diabetic recipients. The differences between the C-GS and the F-GS analyses in such subgroups suggests that the primary cause of graft loss in these groups was non-immunologic. Death with functioning graft(DFG) needs to be considered in analyzing kidney-transplant outcomes. Hence, we propose that all transplant graft survival data be presented in two ways, by conventional and functional graft analyses.

Tacrolimus(FK-506) Nephrotoxicity and the Effect of alpha-Tocopherol in the Rat Renal Isograft / 대한이식학회지

There have been many reports about oxygen free radical injury as a pathogenetic mechanism of CyA nephrotoxicity, but few reports have investigated the relationship between Tacrolimus(FK-506) nephrotoxicity and oxygen free radical injury. Therefore, we decided to evaluate the relationship between Tacrolimus nephrotoxicity and oxygen free radicals, to examine the protective effect of alpha-tocopherol as an antioxidant, and finally to determine the histological changes of these injuries. En bloc resection of the left kidney, left renal artery including a portion of aorta, left renal vein with vena cava, and left ureter including a portion of bladder from male Lewis rats was done, and then preserved in UW solution and stored in the refrigerator at 4oC for 24 hours. After right nephrectomy in the recipients, the harvested organs were transplanted into the right peritoneal cavity using end-to-side anastomoses of the aorta and inferior vena cava between the recipient and donor under a microscope. Also, end-to-end anastomosis of the partly-resected bladders was made between the recipient and donor. After transplantations, rats were divided into 4 groups(I~IV). 2 mg of Tacrolimus per kilogram body weight was injected intramuscularly daily into groups II and III. alpha-Tocopherol was injected intraperitoneally daily in the amount of 20 mg/kg from 2 days prior to transplantation in groups III and IV. The control group(I) received the same amount of saline. 5 or 6 rats from each group were sacrificed at 3 days, 7 days, and 14 days after transplantation, respectively. The grafted and native kidneys were removed for histopathologic examination and the measurement of malondialdehyde(MDA) using a modified TBA method(Ohkawa). Both morphologic renal tubular injury and the increase of MDA due to cold ischemia-reperfusion were highest at 3 days after transplantation, then were alleviated after 7 days. The inhibitory effect of alpha-tocopherol to renal tubular damage from cold ischemia-reperfusion began to appear after 1 week, and was distinct 2 weeks after transplantation. The degree of renal tubular damage was the most severe in Tacrolimus nephrotoxicity, and the frequency of tubulointerstitial nephritis increased with the passage of time, as compared with the ischemia-reperfusion injury(group I). With alpha-tocopherol treatment, ischemia-reperfusion injury as well as Tacrolimus nephrotoxicity was decreased or healed 2 weeks after transplantation, and the amount of MDA was markedly decreased after 1 week. In summary, Tacrolimus nephrotoxicity prolonged the duration of acute tubular necrosis and caused tubulointerstitial nephritis in the rat renal isograft model, which may be the result of aggravation of ischemia-reperfusion injury. That the renal damage due to cold ischemia-reperfusion and Tacrolimus administration was reduced by alpha- tocopherol, indicates that oxidative injury is a pathogenetic mechanism of Tacrolimus nephrotoxicity in this model.

The Impact of Acute Rejection on Long-Term Graft Outcome in Renal Allograft Recipient / 대한이식학회지

Acute rejection after renal transplantation is still the most common cause of graft failure during the early post-transplant period. To determine whether an acute rejection episode adversely affects long-term graft survival, we retrospectively analyzed our single center patients population of 1266 consecutive living donor kidney transplantations performed between April 1984 and October 1995. Five hundred twenty three recipients(41.3%) experienced 711 acute rejection episodes. Among these 711 episodes, 92.6% were respond to anti-rejection therapy and treatment failure rate was 7.6%. Late onset acute rejection, which developed 1 year after transplantation, showed poor treatment response(79.7%). There was statistically significant difference of graft survival rate between acute rejection free group and acute rejection group. Furthermore, the frequency of acute rejection, response rate the steroid pulse therapy and the degree of remission affected the graft survival rate. Donor source impacted on the development of acute rejection-33.1% in living related donor, 39.9% in living unrelated donor and 57.1% in cadaveric donor transplantation. In living related donor kidney transplantations, HLA identical pairs(11%) showed less acute rejection episodes than HLA haplo-identical pairs(38.7%). In living unrelated donor kidney transplantations, HLA antigen match adversely affected the acute rejection rate-43.9%, 35.8% and 30.6% in 1~2, 3 and 4~5 Ag match group, respectively. ABO blood group compatibility, recipient's age and compatibility of HLA DR Ag did not influenced to the development of acute rejection. These results suggest that the acute rejection could be a major determinant of long-term graft outcome.

Tacrolimus(FK-506) Nephrotoxicity and the Effect of alpha-Tocopherol in the Rat Renal Isograft / 대한이식학회지

There have been many reports about oxygen free radical injury as a pathogenetic mechanism of CyA nephrotoxicity, but few reports have investigated the relationship between Tacrolimus(FK-506) nephrotoxicity and oxygen free radical injury. Therefore, we decided to evaluate the relationship between Tacrolimus nephrotoxicity and oxygen free radicals, to examine the protective effect of alpha-tocopherol as an antioxidant, and finally to determine the histological changes of these injuries. En bloc resection of the left kidney, left renal artery including a portion of aorta, left renal vein with vena cava, and left ureter including a portion of bladder from male Lewis rats was done, and then preserved in UW solution and stored in the refrigerator at 4oC for 24 hours. After right nephrectomy in the recipients, the harvested organs were transplanted into the right peritoneal cavity using end-to-side anastomoses of the aorta and inferior vena cava between the recipient and donor under a microscope. Also, end-to-end anastomosis of the partly-resected bladders was made between the recipient and donor. After transplantations, rats were divided into 4 groups(I~IV). 2 mg of Tacrolimus per kilogram body weight was injected intramuscularly daily into groups II and III. alpha-Tocopherol was injected intraperitoneally daily in the amount of 20 mg/kg from 2 days prior to transplantation in groups III and IV. The control group(I) received the same amount of saline. 5 or 6 rats from each group were sacrificed at 3 days, 7 days, and 14 days after transplantation, respectively. The grafted and native kidneys were removed for histopathologic examination and the measurement of malondialdehyde(MDA) using a modified TBA method(Ohkawa). Both morphologic renal tubular injury and the increase of MDA due to cold ischemia-reperfusion were highest at 3 days after transplantation, then were alleviated after 7 days. The inhibitory effect of alpha-tocopherol to renal tubular damage from cold ischemia-reperfusion began to appear after 1 week, and was distinct 2 weeks after transplantation. The degree of renal tubular damage was the most severe in Tacrolimus nephrotoxicity, and the frequency of tubulointerstitial nephritis increased with the passage of time, as compared with the ischemia-reperfusion injury(group I). With alpha-tocopherol treatment, ischemia-reperfusion injury as well as Tacrolimus nephrotoxicity was decreased or healed 2 weeks after transplantation, and the amount of MDA was markedly decreased after 1 week. In summary, Tacrolimus nephrotoxicity prolonged the duration of acute tubular necrosis and caused tubulointerstitial nephritis in the rat renal isograft model, which may be the result of aggravation of ischemia-reperfusion injury. That the renal damage due to cold ischemia-reperfusion and Tacrolimus administration was reduced by alpha- tocopherol, indicates that oxidative injury is a pathogenetic mechanism of Tacrolimus nephrotoxicity in this model.

The Impact of Acute Rejection on Long-Term Graft Outcome in Renal Allograft Recipient / 대한이식학회지

Acute rejection after renal transplantation is still the most common cause of graft failure during the early post-transplant period. To determine whether an acute rejection episode adversely affects long-term graft survival, we retrospectively analyzed our single center patients population of 1266 consecutive living donor kidney transplantations performed between April 1984 and October 1995. Five hundred twenty three recipients(41.3%) experienced 711 acute rejection episodes. Among these 711 episodes, 92.6% were respond to anti-rejection therapy and treatment failure rate was 7.6%. Late onset acute rejection, which developed 1 year after transplantation, showed poor treatment response(79.7%). There was statistically significant difference of graft survival rate between acute rejection free group and acute rejection group. Furthermore, the frequency of acute rejection, response rate the steroid pulse therapy and the degree of remission affected the graft survival rate. Donor source impacted on the development of acute rejection-33.1% in living related donor, 39.9% in living unrelated donor and 57.1% in cadaveric donor transplantation. In living related donor kidney transplantations, HLA identical pairs(11%) showed less acute rejection episodes than HLA haplo-identical pairs(38.7%). In living unrelated donor kidney transplantations, HLA antigen match adversely affected the acute rejection rate-43.9%, 35.8% and 30.6% in 1~2, 3 and 4~5 Ag match group, respectively. ABO blood group compatibility, recipient's age and compatibility of HLA DR Ag did not influenced to the development of acute rejection. These results suggest that the acute rejection could be a major determinant of long-term graft outcome.

Treatment of Transplant Renal Artery Stenosis with Expandable Metal Stent / 대한이식학회지

We report our experience of endoluminal expandable stent placement for the treatment of post- transplant renal artery stenosis. Fourty years old male patient, underwent living donor renal allograft 16 months ago, was admitted due to uncontrollable hypertension and gradual graft dysfunction. On the past history, he had had acute rejection at post-transplant day 4 and it had been treated successfully with steroid pulse therapy. After then, he have been relatively doing well and the graft function has shown normal with serum creatinine of 1.1 mg/dl. His blood pressure has been marked 140/90 mmHg, which has been well controlled with amlodipine (calcium channel blocker) and atenolol (beta blocker). On the physical examination, there was no briut on the iliac fossa and blood pressure was 190/110 mmHg. Serum creatinine was 2.0 mg/dl and blood renin level showed 15.61 ng/ml in supine postion, 11.51 ng/ml in erect postion, which were about 10 times above the normal range, respectively. With the impression of post-transplant renal artery stenosis, angiography was performed. The angiogram showed nearly complete transplant renal artery stenosis(about 90% of the lumen) at the anastomotic site. Expandable metal stent was indwelled successfully into the endolumen of transplant renal artery. After this precedure, the blood pressure of this patient was down to 130/80 mmHg and serum creatinine was stabilized to 1.1 mg/dl. Percutaneous endoluminal stent procedures for resistant transplant renal artery stenosis is promising. Longer follow-up periods are necessary for true evaluation of this procedure.