Cadaveric Renal Allograft Recipients Research Articles

Spectrum of asymptomatic bacteriuria in renal allograft recipients and its short-term effect on graft outcome: Experience of a Tertiary Care Center from Northwest India

Introduction: Asymptomatic bacteriuria (AB) is not uncommon after renal transplantation with limited data from developing countries; we did this study to assess the microbiological spectrum and its short-term graft outcome in our tertiary care center. Materials and Methods: It is a prospective observational study. We included all the patients who underwent renal transplantation over a period of 18 months, from January 2016 to June 2017. Patients who had indwelling urinary catheter beyond 5 days posttransplant and those with persistent graft dysfunction within 6 months of transplant were excluded from the study. Results: A total of 67 patients were included in the study with a mean age of 33.78 ± 8.91 years and a male-to-female ratio of 7:1; live-related donors were 36 (53.73%), live unrelated were 19 (28.35%), and 12 (17.91%) were cadaveric renal allograft recipients (RARs). Twenty-eight (41.79%) patients had 42 episodes of AB over 6 months of follow-up. The maximum episodes occurred within 1 month of postrenal transplantation, and 42 out of 67 (62.68%) RARs had bacterial growth in their double-J ureteral stents (USs). The most frequently isolated pathogen from urine was Escherichia coli (n = 14, 33.33%), whereas Pseudomonas aeruginosa (n = 10, 23.80%) was in US culture (USC). The prevalence of AB was higher in cadaveric RARs compared to live RARs (83.33% vs. 32.72%, P = 0.001) and with bacterial growth in the USC compared to those who did not show any growth in USs (57.14% vs. 16.0%, P = 0.001). However, the estimated glomerular filtration rate between those with AB and those without at 6 months of follow-up (66.36 ± 14.98 vs. 66.10 ± 13.83 ml/min/1.73 m2, P = 0.943) was not different. Conclusion: AB is not uncommon in RARs and it is more common in cadaveric RARs and those with growth in US culture without compromise in allograft function at 6 months postrenal transplant.

TRANSLATIONAL CELLULAR IMMUNOTHERAPY FOR CADAVERIC KIDNEY ALLOGRAFT IN UROLOGICAL PATIENTS

Представлен первый отечественный опыт применения трансляционной клеточной иммунотерапии у реципиентов после аллотрансплантации трупной почки. Приведен анализ клинических, лабораторных и иммунологических данных, а также результаты протокольной биопсии трансплантата на 30-е и 180-е сутки после операции. Выявлены клинико-лабораторные, иммунологические и гистологические преимущества у больных основной группы. Установлены некоторые механизмы, раскрывающие возможности формирования иммунологической толерантности.

Bone Marrow–derived Endothelial Progenitor Cells and Endothelial Cells May Contribute to Endothelial Repair in the Kidney Immediately After Ischemia–Reperfusion

In ischemic acute kidney injury, renal blood flow is decreased. We have previously shown that reperfused, transplanted kidneys exhibited ischemic injury to vascular endothelium and that preservation of peritubular capillary endothelial integrity may be critical to recovery from ischemic injury. We hypothesized that bone marrow-derived (BMD) endothelial progenitor cells (EPCs) might play an important role in renal functional recovery after ischemia. We tested this hypothesis in recipients of cadaveric renal allografts before and for 2 weeks after transplantation. We found that the numbers of circulating CD34-positive EPCs and CD146-positive endothelial cells (ECs) decreased immediately after ischemia-reperfusion. In renal allograft tissues obtained 1 hr after reperfusion, CD34-positive cells were more frequently observed along the endothelial lining of peritubular capillaries compared with non-ischemic controls. Moreover, 0-17.5% of peritubular capillary ECs were of recipient origin. In contrast, only 0.1-0.7% of tubule cells were of recipient origin. Repeat graft biopsy samples obtained 35 and 73 days after transplant did not contain capillary ECs of recipient origin, whereas 1.4% and 12.1% of tubule cells, respectively, were of recipient origin. These findings suggest that BMD EPCs and ECs may contribute to endothelial repair immediately after ischemia-reperfusion.

Diminished NO generation by injured endothelium and loss of macula densa nNOS may contribute to sustained acute kidney injury after ischemia-reperfusion

In postischemic acute kidney injury (AKI) or acute renal failure, a dissipation of glomerular filtration pressure is associated with an altered renal vascular tone and reactivity, as well as a loss of vascular autoregulation. To test the hypothesis that renal nitric oxide (NO) generation reflects endothelial damage in the kidney after ischemia-reperfusion, we quantified the urinary NO levels and identified the site of its generation in postischemic AKI. Subjects were 50 recipients of cadaveric renal allografts: 15 with sustained AKI and 35 with recovering renal function. Urine and blood samples were obtained after transplant, and intraoperative allograft biopsies were performed to examine NO synthases (NOSs) in the kidney. In the sustained AKI group, urinary nitrite and nitrate excretion (in mumol/g urine creatinine) was lower (12.3 +/- 1.8 and 10.0 +/- 1.4 on postoperative days 0 and 3) than in the recovery group [20.0 +/- 3.6 and 35.1 +/- 5.3 (P < 0.005 vs. sustained AKI on days 0 and 3) on postoperative days 0 and 3]. Endothelial NOS expression diminished from the peritubular capillaries of 6 of 7 subjects in the sustained AKI group but from only 6 of 16 subjects in the recovery group. No differences were observed in the inducible NOS staining pattern between the two groups. Neuronal NOS staining was rarely observed in the macula densae of subjects but was prominent in control tissues. These findings suggest that a diminished NO generation by injured endothelium and loss of macula densa neuronal NOS could impair the vasodilatory ability of the renal vasculature and contribute to the reduction in the glomerular filtration rate in postischemic AKI.

Enzymuria and low molecular weight protein excretion as the differentiating marker of complications in the early post kidney transplantation period

Renal function in the early post-transplantation period depends largely on factors affecting the kidney prior to implantation. Function of the graft may be also disturbed by the most common complications of the early post-operative period such as acute graft rejection (AGR), acute tubular necrosis (ATN) and may be modified by nephrotoxic action of cyclosporine A (CsA). Evaluation of excretion of enzymes and low molecular weight proteins (LMWP) may help in the differentiation of these complications. Aim Comparison of the urinary excretion of markers of tubular injury in patients with AGR, ATN, or patients with stable graft function (SGF) was made and differences between groups and correlations between markers and cold ischemia time (CIT), warm ischemia time (WIT) and blood trough level of cyclosporine A (CsA0) were determined. Material and methods In 60 cadaveric renal allograft recipients in the early post-transplantation period urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and B isoenzyme (NAG-B), alanylaminopeptidase (AAP), gamma-glutamyltransferase (GGT), alpha and pi isoenzymes of glutathione S-transferase (alpha-GST, pi-GST), retinol binding protein (RBP) and beta2- microglobulin (beta2M), were analyzed. Results NAG and NAB-B activities were higher in ATN (P<0.05, P<0.01) and in AGR (P<0.005, P<0.02) than in SGF. Excretion of pi-GST was higher in AGR than in SGF (P<0.0002) or ATN (P<0.007). CIT and WIT in patients with ATN were higher (P<0.05) than in SGF group. In ATN patients, correlations of CIT with RBP (P<0.05) and pi-GST (P<0.05), and WIT with RBP (P<0.05), and pi-GST (P<0.001) were found. Conclusions High urinary NAG and NAG B excretion characterizes ATN and AGR patients. Evaluating urinary excretion of pi-GST may be helpful in differentiating AGR from ATN. However, taking into account ischemia time is necessary in interpreting the pi-GST value in early post transplant period.

Rescue Therapy by Immunoadsorption in Combination With Tacrolimus and Mycophenolate Mofetil for C4d-Positive Acute Humoral Renal Allograft Rejection

The aim of this study was to investigate the efficacy of immunoadsorption (IA) in combination with tacrolimus (TAC; 0.14 to 0.16 mg/kg/d) and mycophenolate mofetil (MMF; 1.5 to 2.0 g/d) rescue therapy for C4d-positive acute humoral rejection in nine cadaveric renal allograft recipients. Initial Panel reactive antibody (PRA-I and PRA-II levels were as high as 28.8% ± 16.2% and 15.3% ± 8.9%, IA therapy significantly decreased PRA-I and PRA-II levels to 5.9% ± 2.9% and 2.2% ± 0.6%, respectively. Total serum immunoglobulin levels were markedly decreased. Repeated allograft renal biopsy in nine patients revealed remission of acute humoral rejection (AHR), and the deposition of C4d disappeared and reduced. With a mean follow-up of 29.4 ± 5.4 months, patient and allograft survivals were 100%, and renal function remained stable with a mean serum creatinine of 1.1 ± 0.3 mg/dL. Our findings suggested that a therapeutic approach combining IA and TAC and MMF rescue improved the outcomes of AHR.

Triple therapy in cadaver renal transplantation.

One hundred consecutive first (n = 72) and regrafted (n = 28) cadaver renal allograft recipients were immunosuppressed with cyclosporin, azathioprine and prednisolone (triple therapy) and followed for a median of 17.3 months (range, 7-26 months). Actuarial patient survival at 12 and 24 months was 97.7 per cent. Actuarial graft survival at 12 and 24 months was 79.5 per cent (first graft recipients 81.3 per cent and regrafted recipients 75 per cent). HLA-DR matching significantly improved graft survival which was 93 per cent at 1 year in patients given HLA-DR compatible kidneys, compared with 83 and 54 per cent, respectively, in patients who received kidneys mismatched for one or two HLA-DR antigens. There were 0.8 (s.d. = 0.7) episodes of acute rejection per patient during the first 3 months after transplantation. Triple therapy provides effective immunosuppression without evidence of over immunosuppression and reduces the incidence of cyclosporin side-effects. Although acute nephrotoxicity was uncommon, serum creatinine remained elevated 6 and 12 months after transplantation.

Impacts of donor and recipient's SNP of cytokine and cytokine receptor on early acute renal allograft rejection

To investigate the impact of donor and recipient's SNP of cytokine and cytokine receptor on early acute rejection after renal transplantation. (1) 129 cases of cadaveric renal allograft recipients were divided into two groups according to the presence or absence of acute graft rejection. The distribution of 21 single nucleotide polymorphisms in cytokines and cytokine receptors gene were compared between two groups as well as latent factors affecting the development of acute rejection. (2) Based on the result of HLA-DR matching between donor and recipient, the recipients with AR were stratified into two conditions, 0-1 locus mismatched (0-1MM) and completely mismatched (2MM). By aids of SPSS 11.5 software, association analysis was assessed using Kruskal Wallis test, 2 x 2 or 2 x n contingency table, the Chi-square test. (1) Of 129 recipients of renal transplantation, 39 developed acute graft rejection (30.2%). (2) Compared with recipients without acute rejection, the number of HLA-DR mismatching was significantly higher in rejection group. (3) In rejection group and non-rejection group, the gene polymorphism distribution was significantly different. (4) 0-1MM group and 2MM group were various in the gene polymorphism distribution. In the whole, the susceptibility of acute rejection after renal transplantation may be predicted by the donor and recipient's SNP of cytokine and cytokine receptor.

Prevalence of Osteoporosis in Patients After Renal Transplantation: Results from a Single Center

Osteopenia and bone loss are major complications after renal transplantation. Clinical data in the Asian population are lacking. We prospectively studied the changes in bone mineral density (BMD) of 31 cadaveric renal allograft recipients using dual energy X-ray absorptiometry (DEXA) within 2 weeks after transplantation and then at 1 year post transplantation. One year after transplantation, the mean bone mineral reduction at the lumbar spine was 6.3 ± 4.9% (osteopenia in 32.2% of patients and osteoporosis in 6.5%). For the femoral neck, there was a 4.3 ± 5.5% decrease in BMD (osteopenia in 38.7% of patients and osteoporosis in 3.2%). For total hip, there was a 4.8 ± 3.6% decrease in BMD (osteopenia in 25.8% of patients and osteoporosis in 3.2%). Decrease in BMD at the femoral neck and total hip correlated with the cumulative dosage of steroid (femoral neck: r = −0.36, p = 0.048; total hip: r = −0.4, p = 0.026). Compared with patients without rejection, patients with a history of acute rejection received higher cumulative doses of steroid, and sustained a greater decrease in BMD at the femoral neck and total hip: median percentage (interquartile range) decrease in femoral neck BMD was 7.7% (−12.8 to −6.3) versus 4.4% (−6.5 to −0.065), p = 0.016; decrease in total hip BMD was 8.2% (−11.22 to −6.7) versus 3.4% (−6.92 to −1.4), p = 0.03. There was no correlation between BMD changes and cumulative dosage of cyclosporine A, azathioprine, tacrolimus, duration of dialysis, changes in body mass index, creatinine or parathyroid hormone levels. Reduction of BMD after renal transplantation is common. The cumulative dosage of prednisolone correlates with bone loss at the femoral neck and total hip. Patients with a history of acute rejection suffered from more bone loss after 1 year compared to patients without rejection.

Prevention of Early Acute Rejection With Daclizumab and Triple Immunosuppression in Cadaveric Renal Allograft Recipients

We carried out a prospective study of the safety and efficacy of daclizumab combined with triple immunosuppression in adult recipients of at least one HLA-mismatched cadaveric renal allograft. All studied patients received the same immunosuppression: a daclizumab infusion of 1 mg/kg immediately before transplantation, and at 2, 4, 6, and 8 weeks following the transplantation. Infusion of cyclosporine (CsA) (0.08 mg/kg/h) was started at the time of the operation and continued by CsA microemulsion (CsA-Neoral), 3 mg/kg twice daily on day 2, methylprednisolone, 0.4 mg/kg intravenously at operation, and mycophenolate mofetil started on day 1. The dose of CsA-Neoral was adjusted to maintain target blood trough levels. Oral methylprednisolone was tapered by 4 mg per week to achieve a maintenance dose of 0.08 mg/kg/day. Fifty-five patients, with a mean age of 48 +/- 11 years, were studied. Six of them received a second renal allograft. The mean donor age was 38 +/- 14 years. Mean cold ischemia time was 19.5 +/- 6.5 h, mean value of HLA-antigen mismatches was 2.7 +/- 0.9, mean latest PRA value was 3 +/- 7%. Fifteen patients experienced delayed graft function. During a follow-up period of 3 months three acute rejection episodes occurred. One patient died because of systemic aspergillosis. After 3 months mean serum creatinine was 104 +/- 38 micromol/L. Five renal allografts failed, one of them due to rejection. Patient and graft survival was 98.2% and 90.9%, respectively. Daclizumab with this triple therapy represents safe and efficient immunosuppression strategy, demonstrated with low incidence of early acute rejection episodes and an acceptable adverse event profile in cadaveric renal allograft recipients.

Variation of CD4 + and CD8 + T Lymphocytes as Predictor of Outcome in Renal Allograft Recipients Who Developed Acute Respiratory Distress Syndrome Caused by Cytomegalovirus Pneumonia

Introduction We investigated the variation of CD4 + and CD8 + T lymphocytes in renal allograft recipients who developed acute respiratory distress syndrome (ARDS) caused by cytomegalovirus (CMV) infection and their relationship to patients outcome. Methods Twenty one cadaveric renal allograft recipients who developed ARDS caused by CMV infection were enrolled in this study. CD4 + and CD8 + T lymphocytes were examined in peripheral blood on five occasions: the admission day (day 0) to ICU as ARDS, day 5, day 10, day 15 in ICU, and discharge day. A value taken in the second month after transplantation was assumed to be the preinfection value. Results Among 13 surviving patients, the numbers of CD4 + and CD8 + T cells and their ratio increased as the patients recovered. The numbers of CD4 + T cells increased significantly on day 10, day 15, and at discharge day compared with day 0 ( P < .05). The number of CD8 + T cells on discharge day and the ratios after day 10 were also significantly higher than those on day 0 ( P < .05). In eight nonsurviving patients, the numbers of CD4 + and CD8 + T cells and their ratio was similar to day 0. The number of CD4 + and CD8 + cells after day 5 and their ratio after day 10 were significantly lower than those of survival group ( P < .05). Conclusion The variations of CD4 + and CD8 + T lymphocytes and their ratio are useful indicators of the severity of disease and the outcome of patients with CMV infections accompanying ARDS after renal transplantation. Nevertheless, it may be helpful to evaluate the efficiency of ongoing treatment methods in these patients.

37 Prevention of Early Acute Rejection with Daclizumab and Triple Immunosuppression in Cadaveric Renal Allograft Recipients

We assessed the safety and efficacy of daclizumab combined with triple immunosuppression in adult recipients of at least 1 HLA‐mismatched cadaveric renal allograft. All studied patients received equal immunosuppression: daclizumab infusion of 1 mg/kg immediately before transplantation and at 2, 4, 6 and 8 weeks following the transplantation, infusion of cyclosporine (CyA) (0.08 mg/kg/hr) started at operation and continued by CyA‐Neoral, 3 mg/kg b.i.d. on day 2, methylprednisolone, 0.4 mg/kg i.v. at operation, and mycophenolate mofetil started on day 1. CyA‐Neoral dose was adjusted to maintain blood trough levels of 100–170 ng/mL (FPIA, monoclonal). Oral methylprednisolone was tapered by 4 mg per week to achieve maintenance dose of 0.08 mg/kg/day. 39 patients, with mean age of 49 ± 10 years (SD; range 26–66 years), were studied. Three of them received a second renal allograft. The mean donor age was 38 ± 13 years (range 16–58 years). Mean cold ischemia time was 19.0 ± 6.5 h (range 9.5–39.5 h), mean value of HLA‐antigen mismatches was 2.7 ± 1.0 (range 1–5), mean latest PRA value was 3 ± 8% (range 0–47%). Ten patients experienced delayed graft function. During follow‐up of 3 months one acute rejection episode was observed, vascular type, treated with OKT3. One patient experienced a hypersensitivity reaction to daclizumab, which despite precautionary measures required early interruption of the 5th infusion dose. In two patients CMV disease, requiring hospitalisation, was successfully treated. No malignancies were detected. After 3 months mean serum creatinine was 102.2 ± 24.0 µmol/L (range 63–152 µmol/L). 2 renal allografts were removed, but not for rejection. Patient and graft survival was 100% and 94.9%, respectively. We conclude that daclizumab with this triple therapy represents a safe and efficient immunosuppression strategy, demonstrated with low incidence of early acute rejection episodes, excellent allograft function, acceptable adverse event profile and high short‐term survival rate.

36 Prevention of Early Acute Rejection with Basiliximab and Triple Immunosuppression in Cadaveric Renal Allograft Recipients

We assessed the efficacy and safety of basiliximab combined with triple immunosuppression in adult recipients of at least 1 HLA‐mismatched cadaveric renal allograft. All studied patients, transplanted between October 1999 and December 2003, received equal immunosuppression: 20 mg infusion of basiliximab on day 0 and on day 4, infusion of cyclosporine (CyA) (0.08 mg/kg/h) started at operation and continued by CyA‐Neoral, 3 mg/kg b.i.d. on day 2, methylprednisolone, 0.4 mg/kg i.v. at operation, and mycophenolate mofetil started on day 1. CyA‐Neoral dose was adjusted to maintain blood trough levels of 150–250 ng/mL (FPIA, monoclonal). Oral methylprednisolone was tapered by 4 mg per week to achieve a maintenance dose of 0.08 mg/kg/day. A total of 153 patients, with mean age of 46 ± 11 years (SD; range 18–65 years), were studied. Thirteen of them received second renal allograft. The mean donor age was 37 ± 14 years (range 6–61 years). Mean cold ischemia time was 22.0 ± 8.0 h (range 7.0–41.0 h), mean value of HLA‐antigen mismatches was 3.0 ± 0.9 (range 1–5), mean latest PRA value was 8 ± 14% (range 0–85%). 47 patients experienced delayed graft function. During a follow‐up of 3 months no acute rejection episode occurred. Four renal allografts were removed, but not for rejection. One patient died because of sepsis. In one patient life‐threatening CMV disease was successfully treated. One malignancy (skin basal cell carcinoma) was detected. Hypersensitivity reactions and cytokine‐release syndrome were not observed. After 3 months mean serum creatinine was 111 ± 36 µmol/L (range 53–238 µmol/L). Patient and graft survival was 99.3% and 97.4%, respectively. We conclude that basiliximab with this triple therapy is an efficient and safe immunosuppression strategy, demonstrated with absence of early acute rejection episodes, excellent allograft function, acceptable adverse event profile and high short‐term survival rate.

Novel rescue therapy for C4d‐positive acute humoral renal allograft rejection

To investigate the efficacy of immunoadsorption (IA) in combination with tacrolimus (TAC) and mycophenolate mofetil (MMF) rescue therapy for C4d-positive acute humoral rejection (AHR) of renal transplants. Six of 185 cadaveric renal allograft recipients transplanted at our institute developed AHR over a mean period of 4.8 +/- 0.8 d after operation. The ages ranged from 35 to 51 yr (mean 42.6 +/- 5.6 yr). C4d deposits in peritubular capillaries (PTC) and accumulation of granulocytes in PTC were observed. IA with staphylococcal protein A and TAC-MMF combination therapy were given. After subjected to IA for 6.3 +/- 1.03 sessions combined with TAC (0.14-0.16 mg/kg/d) and MMF (1.5 g/d) therapy, renal function recovered in all the patients. The mean duration of treatment when serum creatinine decreased was 14 +/- 2.9 d. The pre-IA panel reactive antibody reactivity was as high as 50.2 +/- 6.1%, and was significantly reduced to 8.3 +/- 2.9% after IA. Repeated allograft kidney biopsy in four of six patients revealed a favorable remission of AHR. With a mean follow-up of 18.8 +/- 5.46 months, patient and allograft survival are 100%, renal function remained stable with a mean serum creatinine of 1.2 +/- 0.22 mg/dL. The optimal treatment for alloantibody-mediated AHR remains undefined. Our findings suggest that a therapeutic approach combining IA and TAC-MMF rescue has excellence to improve the outcome of AHR.

Improved clinical outcomes in Chinese renal allograft recipients receiving lower dose immunosuppressants.

The application of potent immunosuppressants has decreased the incidence of acute rejection and increased short- and long-term graft survival; however, these drugs cause a variety of complications. In China, many transplant centers have adopted the immunosuppressive protocols based on the white population, neglecting the differences between the races. The purpose of this study was to explore a suitable immunosuppressive regimen for Chinese renal allograft recipients. Two hundred cadaveric renal allograft recipients who underwent transplantation between July 1999 and October 2001 were observed. Before October 2000, 104 recipients received the conventional dose of immunosuppressants; thereafter, 96 recipients received lower dose treatment. Doses of immunosuppressive agents, the incidence of acute rejection and pulmonary infection, and patient and graft survival rates were compared between the two groups. Doses of mycophenolate mofetil (MMF) and cyclosporine A (CsA) administered in the conventional dose group were significantly higher than in the lower dose group at 3 months posttransplant, as was prednisone at 6 months posttransplant. The incidence of acute rejection and subclinical rejection that was biopsy-proven or diagnosed by clinical manifestations was 17.3% and 19.8%, respectively, in the conventional dose group and the lower dose group within the first 6 months, and no significant difference was noted (P=0.55). The incidence of pulmonary infection, especially severe infection, was much higher in the conventional treatment group (40.1% and 26.9%, respectively) than that in the lower dose group (11.5% and 5.2%, respectively), and the differences were statistically significant (P<0.001). The corresponding 1-year survival rate of patients was 87.4% and 97.9% (P<0.01), and that of renal grafts was 85.5% and 96.9% (P<0.01), for patients receiving conventional dose and lower dose immunosuppressive drugs, respectively. The rate of death with a functioning allograft caused by infection in the conventional dose group was significantly higher than that in the lower dose group (12.5% vs. 0%, P<0.01). The regimen of lower dose MMF, CsA, and prednisone in combination can significantly reduce the incidence of pulmonary infection, especially severe pulmonary infection, without increasing the incidence and severity of allograft rejection.

Duffy antigen receptor and genetic susceptibility of African Americans to acute rejection and delayed function

The unique distribution of the alleles for the Duffy antigen receptor complex (DARC) that binds to chemokines may be associated with the rates of acute rejection and delayed allograft function (DGF) among African Americans. A prospective, multicenter cohort study enrolled 222 African American recipients of cadaveric renal allografts from eight adult transplant centers. Subjects were typed by allele-specific polymerase chain reaction (ASPCR) for the polymorphism at position 535 that determines the level of transcription. Associations of DARC genotypes were examined in Cox hazards models with episodes of acute rejection and in logistic regression models with the development of DGF. FyB Null homozygosity was observed among 67% of the recipients. Fifteen percent of the study cohort experienced at least one episode of acute rejection, and the incidence of DGF was 42.5%. The number of FyB Null alleles and FyB Null homozygosity had no detectable association with the rate of acute rejection (P > 0.50) or with the development of DGF (P > 0.50). The susceptibility of African American recipients to acute rejection and to DGF was not confirmed to be associated with DARC alleles or genotype. Future studies should exclude a potential role of donor-related DARC in transplant outcomes.

C4d-positive acute humoral renal allograft rejection: Rescue therapy by immunoadsorption in combination with tacrolimus and mycophenolate mofetil

Objective We investigated the efficacy of immunoadsorption (IA) in combination with tacrolimus (FK506) and mycophenolate mofetil (MMF) rescue therapy for C4d-positive acute humoral rejection (AHR) of renal transplants. Methods Six of 185 cadaveric renal allograft recipients developed AHR at a mean of 4.8 ± 0.8 days after the operation. C4d deposits were observed in peritubular capillaries (PTC) with accumulation of granulocytes. IA with staphylococcal protein A and FK506-MMF combination therapy were administered. Results After treatment with IA for 6.3 ± 1.03 sessions combined with FK506 (0.14 to 0.16 mg · kg −1 · d −1) and MMF (1.5 g/d) therapy, renal function recovered in all the patients. The mean duration of treatment to a serum creatinine decrease was 14 ± 2.9 days. The pre-IA panel reactive antibody reactivity (PRA) peaked at 50.2% ± 6.1%, and was significantly reduced to 8.3% ± 2.9% after IA. In four of six patients repeat allograft biopsy revealed a remission of AHR. With a mean follow-up of 18.8 ± 5.46 months, patient and allograft survival are 100% and renal function remains stable with a mean serum creatinine of 1.2 ± 0.22 mg/dL. Conclusion The optimal treatment for alloantibody-mediated AHR remains uncertain. Our findings suggest that a therapeutic approach combining IA and FK506-MMF rescue improves the outcome of AHR.

CLINICAL RELEVANCE OF HLA ANTIBODY (SPECIFICITY AND TITER) AND DONOR SPECIFIC FLOW CYTOMETRY CROSSMATCHES IN SIROLIMUS TREATED RENAL ALLOGRAFT RECIPIENTS

O425 Aims: We have previously suggested that renal allograft recipients with Flow PRA identified pretransplant (Tx) IgG HLA antibodies (Ab) were at significant risk for rejection and recipients with both HLA Ab and a positive (+) donor specific flow cytometry crossmatch (FCXM) experienced both rejection and graft loss. However, not all of the Ab (+), FCXM (+) grafts were lost. Methods: To understand why not all of these grafts were lost to rejection sera from Ab (+) and FCXM (+) recipients were evaluated for HLA Ab specificity and titer (strength of Ab) with results compared to rejection and graft loss. We studied 16 Sirolimus treated recipients of cadaveric donor renal allografts who were transplanted following negative IgG anti-human globulin (AHG) crossmatches (testing the most reactive historical and pre-Tx sera). Results: All 16 recipients experienced acute humoral rejections between days 7-21 post-Tx. Retrospective testing of pre-Tx sera revealed that all 16 recipients had Flow PRA identified donor specific IgG HLA Ab and donor specific FCXM reactivity. Rejections were treated with plasmapheresis and OKT-3, thymoglobulin and/or IVIG. Reversal of these acute humoral rejections was achieved in 69% (11/16) of the recipients as evidenced by a mean fall in serum creatinine (SCr) from 6.4 ± 2.9 to 1.4 ± 0.5 mg/dl. However, 31% (5/16) of the grafts were lost to rejection. To try and understand whether there were any immune differences between successful and failed grafts, we studied the pre-Tx sera from twelve of the sixteen recipients for HLA Ab titer. Pre-tx sera from four recipients who lost their grafts did not reach their end point titers until 1:256, 1:256, 1:512 and 1:1024. In contrast, pre-Tx sera from eight recipients who kept their grafts lost Ab reactivity at titers of 1:8, 1:8, 1:8, 1:8, 1:16, 1:16, 1:16 and 1:32 respectively. While all 16 recipients presented with what may be considered immune contraindications (+ donor specific IgG HLA Abs and a (+) donor specific FCXM), those patients with lower antibody titers responded to rejection therapy. Conclusions: These data suggest that the strength of Ab reactivity (Ab titer) may be important in identifying high risk recipients who may be amenable to desensitization protocols and/or therapeutic intervention resulting in prevention or successful reversal of antibody mediated rejections.

A randomized, placebo-controlled trial of IGF-1 for delayed graft function: A human model to study postischemic ARF

Insulin-like growth factor (IGF-1) has been shown in animal models to accelerate recovery from acute renal failure (ARF). However, a therapeutic trial of recombinant human (rh) IGF-1 in patients with ARF in the intensive care unit (ICU) failed to demonstrate efficacy [1]. Such patients often had multiple organ failure, recurrent renal injury, and a delay of several days before commencing treatment. To circumvent these confounding factors, we randomized recipients of cadaveric renal allografts to immediate (<5 hours) rhIGF-1 versus placebo therapy (100 mg/kg subcutaneously twice a day for 6 days). Preliminary observations 3 hours posttransplantation in an additional 44 patients revealed a creatinine clearance < or = 20 mL/min to predict protracted ARF. Thus, this value was used to determine study eligibility. Creatinine clearance prior to commencing treatment was not significantly different between the two groups (8 +/- 5 mL/min for IGF-1 and 7 +/- 6 mL/min for placebo; P = 0.39). Inulin clearance on day 7, the primary outcome measure, was 21 +/- 22 mL/min and 19 +/- 19 mL/min in the IGF-1 (N = 19) and placebo (N = 24) groups, respectively (P = 0.67). Secondary outcome measures, including nadir serum creatinines after 6 weeks and need for dialysis, also did not differ between the two groups. We performed an analysis of statistical power using the placebo arm of the trial. Defining a twofold increase above placebo in day 7 glomerular filtration rate (GFR) as of meaningful biologic significance, we determined that the modest sample size used in the present study is adequate. We, thus, conclude that (1) IGF-1 treatment is unlikely to benefit ARF and (2) the transplanted kidney is a good model to screen new agents for ARF that have demonstrated promise in animal trials.

Bicêtre hospital experience with sirolimus-based therapy in human renal transplantation: the sirolimus European renal transplant study

In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly ( P ≤ .05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities were reported significantly more often with sirolimus, which included hypertriglyceridemia (51% vs 12%), hypercholesterolemia (44% vs 14%), thrombocytopenia (37% vs 0%), leukopenia (39% vs 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/mL. Occurrence of cytomegalovirus was comparable (14% vs 12%), but incidence of herpes simplex (24% vs 10%, P = .08) and pneumonia (17% vs 2%, P = .03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs 33%). Two malignancies were observed with CsA, none with sirolimus. Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from that of CsA.