Plasmapheresis‐resistant acute humoral rejection successfully treated with anti‐C5 antibody

Even if kidney graft survival has improved during the last decades, sensitized pediatric patients are an emerging problem. We describe a 17‐yr‐old male who lost his first graft due to chronic rejection becoming hyperimmunized (CDC PRA 99.61%). A desensitization protocol based on high‐dose IVIG, PP, and two Mabthera^® infusions was performed with minor response (CDC PRA post‐desensitization 80%). One month after his second non‐living transplant, he developed a biopsy‐proven AMR; post‐transplant immunological monitoring showed the presence of donor‐specific anti‐DQ5 antibodies (DSA, MFI 20.000). He received methylprednisolone pulses and 45 PP sessions without clinical response; eculizumab was then used to salvage a kidney undergoing severe PP‐resistant rejection. A biopsy performed after the fourth eculizumab infusion showed complete resolution of AMR. Eculizumab infusions were then continued for the first year post‐transplantation. Two yr after transplantation, graft function is stable. Anti‐C5 therapy may represent an effective therapeutic option in pediatric patients with PP‐resistant AMR.     

De novo therapy with everolimus and reduced‐exposure cyclosporine following pediatric kidney transplantation: A prospective,multicenter, 12‐month study

Prospective data regarding the de novo use of everolimus following kidney transplantation in children are sparse. In a prospective, 12‐month, single‐arm, open‐label study, pediatric kidney transplant patients received everolimus (target trough concentration ≥3 ng/mL) with reduced‐exposure CsA and corticosteroids, with or without basiliximab induction. Sixteen of the 18 patients completed the study on‐treatment. Age range was 2–16 yr (mean 10.9 yr); eight patients received a living donor graft. Mean (s.d.) everolimus level was 7.4 (3.1) ng/mL during the first 12 months post‐transplant. There were no cases of BPAR, graft loss, or death during the study. Protocol biopsies were performed at month 12 in seven patients, with subclinical (untreated) acute rejection diagnosed in one case. Mean (s.d.) estimated GFR (Schwartz formula) was 98 (34) mL/min/1.73 m² at month 12. Three patients experienced one or more serious adverse events with a suspected relation to study medication. One patient discontinued study medication due to post‐transplant lymphoproliferative disease (5.6%). Everolimus with reduced‐dose CsA and corticosteroids achieved good efficacy and renal function and was well tolerated in this small cohort of pediatric kidney transplant patients. Controlled trials are required to answer remaining questions about the optimal use of everolimus in this setting.     

Impaired graft survival in pediatric renal transplant recipients with donor‐specific antibodies detected by solid‐phase assays

Verghese PS, Smith JM, McDonald RA, Schwartz SM, Nelson KA, Warner PR. Impaired graft survival in pediatric renal transplant recipients with donor‐specific antibodies detected by solid‐phase assays. Pediatr Transplantation 2010: 14:730–734. © 2010 John Wiley & Sons A/S. Abstract: SAB assays have increased the sensitivity and specificity to detect HLA alloantibodies, but there is uncertainty about the clinical relevance of SAB‐positive alloantibodies when the FCXM is negative. We performed a retrospective study to evaluate the clinical significance of SAB‐detected DSA in 82 pediatric recipients of a first kidney transplant between January 2000 and December 2005 who had a negative pretransplant FCXM. Pretransplant sera were evaluated by SAB for DSA. Graft loss and rejection between patients with (DSA+) and without DSA (DSA?) were compared. DSA were detected in 13.9%. Eighty percent of DSA+ subjects were DD transplant recipients vs. 56.9% in the DSA? cohort. The RR of graft loss in DSA+ vs. DSA? was 3.3 (95% CI, 1.4–7.9) and in DD was 4.3 (95% CI 1.4–13.1). By Cox regression, the HR of graft loss in DSA+ vs. DSA? was 2.8 (95% CI 0.7–10.9; p = 0.14) and in DD was 5.1 (95% CI 1–25.6; p = 0.05). Acute rejection occurred in 60% in the DSA+ vs. 44.4% in DSA? (p = 0.5). SAB‐detected DSA was associated with impaired renal allograft survival in pediatric renal transplant recipients. Impaired graft survival in pediatric renal transplant recipients with DSA detected by solid‐phase assays.     

Evaluation of the current post‐transplantation Human Leukocyte Antigen antibody screening in pediatric renal transplant recipients

The necessity of post‐transplant monitoring for donor‐specific antibodies (DSAs) is unclear. This study evaluates the clinical relevance of post‐transplantation donor‐specific HLA antibodies in pediatric renal transplant recipients, aiming at better stratification of patients at risk of graft dysfunction and better recommendations for post‐transplant monitoring. A cohort of 68 pediatric kidney recipients, involving 76 transplantations between 2004 and 2014, was studied retrospectively. All patients were screened for HLA antibodies at 1, 3, 6, and 12 months after transplantation and yearly thereafter. Samples testing positive were further analyzed to detect DSA. A biopsy was performed on clinical indication. We studied the baseline characteristics of the patients with biopsy, with DSA, and with rejection. We assessed the effect of post‐transplant DSA on clinical outcome, including antibody‐mediated acute rejection and GFR decrease. In our cohort, the prevalence of DSA was 19% (13/68 transplantations). Most patients with HLA antibodies after transplantation were DSA‐positive (76%; 13/17). A clear association between DSA and subsequent rejection was found. At the end of the study period, a significantly lower GFR was found in patients with biopsy, DSA, or rejection. Based on our observations, we recommend routine post‐transplantation screening for HLA and DSA. The presence of DSA justifies a renal biopsy even in the absence of clinical signs of rejection.     

Successful living‐related renal transplantation in a patient with factor H antibody‐associated atypical hemolytic uremic syndrome

CFH‐Ab‐associated aHUS requires different diagnostic and therapeutic approaches and then the genetically defined aHUS forms. The risk of post‐transplant recurrence with graft dysfunction in CFH‐Ab aHUS is not well documented. It is suggested that recurrence can be expected if a significant CFH‐Ab load persists at the time of transplantation. A pretransplant procedure to reduce CFH‐Ab titer seems reasonable, but accurate recommendations are lacking. Whether further prophylactic interventions after transplantation are necessary has to be decided on an individual basis. We report the case of a late diagnosed CFH‐Ab HUS with initial ESRD and a successful living‐related renal transplantation over a post‐transplant period of four and a half years on the basis of a prophylactic pretransplant IVIG admission.     

The impact of recipient BKV shedding before transplant on BKV viruria,DNAemia, and nephropathy post‐transplant: A prospective study

We previously demonstrated that detectable BKV replication in donor urine pretransplant was significantly associated with post‐transplant recipient BKV viremia. In this 4‐year prospective study, we assessed whether recipient BKV replication pretransplant was associated with post‐transplant viremia/BKV nephropathy. We studied 220 primary adult and pediatric organ transplant recipients for 490 person‐years and 2100 clinical visits. BKV viruria was detectable in 28 (16%), 26 adults and two children; and viremia in none pretransplant. Post‐transplant viruria occurred in all recipients with pretransplant BKV viruria, significantly more than in recipients without pretransplant viruria on univariate (P<.005) and multivariate analysis including type of organ transplanted and immunosuppression type (P .008). Time to post‐transplant viruria was significantly shorter in recipients with pretransplant viruria (P .01). By univariate and multivariate analysis, BKV viruria in recipients pretransplant did not impact post‐transplant BKV viremia (P=.97 and .97, respectively) even when stratified by type of organ transplant (kidney P=.6; liver P=.5). The peak serum and urine BKV PCR post‐transplant were not significantly different in patients with pretransplant BKV viruria and no one developed BK nephropathy. In conclusion, recipient BKV viruria prior to transplant predicts post‐transplant viruria but not viremia or BKV nephropathy.     

Pediatric ABO‐incompatible kidney transplantation: Evolving with the advancing apheresis technology: A single‐center experience

Recent literature has endorsed favorable outcomes following ABOi kidney transplantation in pediatric population. Nevertheless, reluctance to pursue an ABOi still remains pervasive. This could be ascribed to various legitimate reasons, namely less extensive pediatric ABOi data, technical difficulties encountered during PP, cost restraints, and concerns regarding higher rates of antibody‐mediated rejection, infectious complications, and post‐transplant lymphoproliferative disorder as compared to adults. However, given the similar excellent outcomes of both ABOi and ABOc kidney transplantation, clinicians should consider this option sooner if a compatible donor or swap is not available. Here, we describe the outcomes of three pediatric ABOi performed at our institute in India (from 2014 till now), wherein distinct apheresis modalities had been employed in each desensitization protocol, and our techniques evolved with advancing science in apheresis. This case series includes India's first published pediatric ABO‐incompatible transplant (Case 2) and the youngest child to undergo ABO‐incompatible renal transplant in SAARC nations (Case 3).     

Impact of active antibody‐mediated rejection treatment on donor‐specific antibodies in pediatric kidney transplant recipients

AMR is a major cause of graft loss after kidney transplantation. We evaluated a retrospective cohort of 13 pediatric kidney transplant patients diagnosed with active AMR. All 13 patients were treated with plasmapheresis (PP), IVIg, and rituximab. Anti‐HLA DSAs were measured at the time of transplantation, AMR diagnosis, 30 days post‐rejection treatment, 90 days post‐rejection treatment, and 24 ± 12 months post‐AMR. A total of 68 DSAs were identified from 13 patients at the time of active AMR diagnosis. The primary objective of this study was to differentiate treatment response rates between class I and class II anti‐HLA DSA post‐AMR treatment. Overall, DSAs were significantly reduced at 30 days, and the reduction was sustained at 90 days post‐treatment, even for class II anti‐HLA and strongly positive DSAs. A significant difference between class I and class II anti‐HLA DSA was observed at 30 days; however, between class significance was lost at 90‐day follow‐up due to continued class II anti‐HLA DSA treatment response. Low DSA strength was predictive of treatment response. eGFR demonstrated significant improvement 90 days after AMR diagnosis compared to the initial value at the time of AMR, and the effect was sustained for 12 months. These results suggest that the AMR treatment is effective in pediatric kidney transplant recipients with an early diagnosis of active AMR across both class I and class II anti‐HLA DSAs.     

AST‐to‐platelet ratio index in non‐invasive assessment of long‐term graft fibrosis following pediatric liver transplantation

Long‐term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post‐transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long‐term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10‐yr follow‐up and fibrosis was graded using the Ishak scoring system, with S3‐6 denoting “significant fibrosis.” APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post‐transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non‐invasive adjunct in the assessment of significant graft fibrosis in the long‐term follow‐up of pediatric liver transplant survivors.     

A longitudinal retrospective analysis of left ventricular mass in a cohort of pediatric kidney transplant recipients

Childhood end‐stage kidney disease is associated with increased risk for early adulthood cardiovascular (CV) morbidity and mortality. Increased LVM is an early indicator of CV disease. Previous studies have suggested that LVM decreases after kidney transplantation; however, trends have been inconsistent. A single center retrospective longitudinal cohort analysis of LVM, documented annually, starting before kidney transplantation for up to 10 yr after transplantation was performed. BP documented by annual 24‐h ambulatory monitoring studies, and BMI values were also reviewed. Twenty‐seven children followed for a mean period of 5.3 yr were included. Depending on definition of LVH, its prevalence pretransplant and in the first years post‐transplant was up to 33% dropping to 0–25% thereafter. Individual longitudinal LVM z‐score trends were highly variable but generally trended toward the mean immediately after transplant and toward negative values in the following years. BP was stable during the follow‐up period while mean annual BMI increased in the first‐year post‐transplant but declined thereafter. In a cohort of pediatric renal transplant recipients, prevalence of LVH decreased after transplant; however, individual longitudinal LVM trends were highly variable among patients. Prospective studies are needed to correlate individual LVM trends with outcomes.     

Bortezomib in the treatment of antibody‐mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study

Antibody‐mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody‐mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy‐proven antibody‐mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty‐three patients received bortezomib for antibody‐mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow‐up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post‐bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty‐six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune‐dominant donor‐specific antibody, 1‐3 months after the first dose of bortezomib. Non‐life‐threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life‐threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3‐6 months in pediatric kidney transplant recipients with antibody‐mediated rejection.     

Good outcome of the single‐center pediatric kidney transplant program in Abu Dhabi

Renal transplantation is the treatment of choice for ESRD in children. It is associated with better quality of life, growth of children, and improved long‐term survival. The aim of the study was to evaluate the outcomes of pediatric renal transplantation at a tertiary care center in UAE. A retrospective chart review was undertaken for all the pediatric renal transplants performed at Sheikh Khalifa Medical City, Abu Dhabi, UAE, over the past 9 years. The study evaluated the demographic data, outcomes, and complications of pediatric renal transplantation. The post‐transplantation outcomes including surgical complications, documented infections, graft rejection, graft and patient survival, effect on growth, and eGFR were reviewed. Between 2010 and 2018, 30 pediatric patients underwent renal transplantation. The follow‐up period ranged from 1 to 9 years with a mean of 3.3 years. The mean age of the patients at the time of transplant was 9.8 years, and 56.7% were males. Prior to the transplantation, the majority of the recipients were on peritoneal dialysis (70.0%). Main source of renal donation at our center was from LRD, chiefly from parents. Patient survival at 1 and 5 years was 100% and 96.7%, respectively. Graft survival at 1 and 5 years was 96.7% and 83.3%, respectively. During the 9‐year follow‐up period, 5 (16.7%) recipients experienced rejection episode. This study demonstrates that during 5‐year period, pediatric kidney transplantation program has achieved optimal patient (96.7%) and graft (83.3%) survival rates and is comparable to well‐established centers.     

Pretransplant six‐minute walk test predicts peri‐ and post‐operative outcomes after pediatric lung transplantation

The purpose of the pretransplant assessment in lung transplantation is to determine a patient's need for transplant as well as their potential survival post‐procedure. In 2005, the UNOS introduced the LAS, a calculation based on multiple physiologic measures to determine need and likelihood for survival. Measures include NYHA class and the 6‐MWT. Some adult studies indicate a positive correlation with 6‐MWT and waiting list survival. In pediatric/adolescent patients, there are minimal data regarding the predictive value of physiologic markers in either wait list survival or post‐transplant outcome. A retrospective cohort study of 60 consecutive lung transplantations from 1990 to 2008 was performed at a pediatric tertiary care facility. Functional pretransplant assessments were abstracted from the medical record and compared with outcomes after transplantation. Results: a 6‐MWT of >1000 ft (305 m) prior to transplantation correlated with a shorter ICU stay (7 vs. 11 days, p = 0.046) and fewer days of mechanical ventilation (2 vs. 4, p = 0.04). A pretransplant 6‐MWT greater than 750 ft (229 m) correlated with shorter overall hospitalization (37 vs. 20 days, p = 0.03). Measuring pretransplant 6‐MWT tests for pediatric patients is valuable in predicting peri‐operative outcomes after lung transplantation.     

Eight‐year follow‐up in pediatric living donor kidney recipients receiving alemtuzumab induction

Recipient lymphocytes are crucial for direct and indirect pathways of allorecognition. We proposed that the administration of alemtuzumab several weeks pretransplantation could eradicate peripheral lymphatic cells and promote donor‐specific acceptance. This was a single‐center, retrospective review of 101 consecutive living donor kidney transplantations in pediatric patients (age 7 months—18 years), performed between September 2006 and April 2010. IS protocol included two 30 mg doses of alemtuzumab: The first was given 12‐29 days prior to transplantation, and the second at the time of transplantation. Maintenance IS was based on combination of low‐dose CNI and mycophenolate, with steroids tapered over the first 5 days post‐transplantation. Patients were followed for 7.8±1.3 years, and protocol biopsies were taken 1 month, 1, 3, and 5 years post‐transplant. The Kaplan‐Meier 8‐year patient and graft survival rates in the cyclosporine‐treated patients were 82.0±7.3% and 71.6±7.3, and in the tacrolimus‐treated patients were 97.2±5.4 and 83.8±6.0%. Biopsy‐proven acute rejection developed in 35% of cyclosporine‐treated patients and in 8% of tacrolimus‐treated patients. Alemtuzumab pretreatment prior to LRD kidney transplantation, followed by maintenance immunosuppression with tacrolimus and MMF, is associated with reasonable long‐term results in pediatric patients.     

Eosinophilic density in graft biopsies positive for rejection and blood eosinophil count can predict development of post‐transplant digestive tract eosinophilia

EGID is a known post‐transplant complication. Its etiology has been related to antirejection medication, but other factors may also play a role as only few transplant recipients develop EGID despite standardized treatment. This study aimed to determine whether EGID is associated with rejection events and with a specific phenotype of the rejection‐positive graft biopsies in children with solid organ transplant. All patients with liver, heart, and kidney transplant followed at our institution were included in the study. Digestive tract eosinophilia was more common in heart and liver recipients and was a rare event after renal transplantation. Subjects with EGID had higher incidence of rejection and elevated peripheral blood AEC. The first rejection event and high AEC values preceded EGID diagnosis in the majority of patients. Histologically, the initial rejection‐positive graft biopsy revealed accentuated eosinophilia in EGID patients compared with non‐EGID cohort, which correlated with higher blood eosinophil counts at the time of first rejection episode. Prominent graft tissue and peripheral blood eosinophilia prior to EGID diagnosis suggests a predisposition for eosinophil activation in patients with post‐transplant digestive eosinophilic disorder. These parameters can be used as markers for subsequent development of EGID.     

Determinants of graft survival in pediatric and adolescent live donor kidney transplant recipients: a single center experience

To study the independent determinants of graft survival among pediatric and adolescent live donor kidney transplant recipients. Between March 1976 and March 2004, 1600 live donor kidney transplants were carried out in our center. Of them 284 were 20 yr old or younger (mean age 13.1 yr, ranging from 5 to 20 yr). Evaluation of the possible variables that may affect graft survival were carried out using univariate and multivariate analyses. Studied factors included age, gender, relation between donor and recipient, original kidney disease, ABO blood group, pretransplant blood transfusion, human leukocyte antigen (HLA) matching, pretransplant dialysis, height standard deviation score (SDS), pretransplant hypertension, cold ischemia time, number of renal arteries, ureteral anastomosis, time to diuresis, time of transplantation, occurrence of acute tubular necrosis (ATN), primary and secondary immunosuppression, total dose of steroids in the first 3 months, development of acute rejection and post-transplant hypertension. Using univariate analysis, the significant predictors for graft survival were HLA matching, type of primary urinary recontinuity, time to diuresis, ATN, acute rejection and post-transplant hypertension. The multivariate analysis restricted the significance to acute rejection and post-transplant hypertension. The independent determinants of graft survival in live-donor pediatric and adolescent renal transplant recipients are acute rejection and post-transplant hypertension.     

Post‐renal transplant erythrocytosis: A case report

PTE is defined as hematocrit >51% or hemoglobin >17 g/dL after renal transplantation. Risk factors include native kidneys with adequate erythropoiesis pretransplant, smoking, renal artery stenosis, and cyclosporine treatment. We report the case of a 14‐yr‐old female kidney transplant patient, with triple therapy immunosuppression and stable graft function who developed PTE at 12 months post‐transplant with hemoglobin 17.3 g/dL, hematocrit 54.2%, stable graft function, and normotensive with normal cardiac echocardiogram and erythropoietin levels. The only risk factor found was tobacco use. As she had no spontaneous improvement, enalapril treatment was started at 19 months post‐transplant with a hemoglobin level of 17.5 g/dL and hematocrit 53%; by 23 months post‐transplant, hemoglobin lowered to 15 g/dL and hematocrit to 44.5% and continued to be in normal range thereafter. PTE is a rare condition in childhood and can be successfully treated with enalapril.     

Quantiferon‐Cytomegalovirus assay: A potentially useful tool in the evaluation of CMV‐specific CD8+ T‐cell reconstitution in pediatric hematopoietic stem cell transplant patients

Pediatric HSCT recipients are at high risk for CMV reactivation due to their immature immune system and therapy following transplantation. Reconstitution of CMV‐specific T‐cell immunity is associated with control and protection against CMV. The clinical utility of monitoring CMV‐specific CMI to predict CMV viremia in pediatric HSCT patients using the Quantiferon‐CMV (QIAGEN^®) test was investigated prospectively. Thirty‐seven pediatric allogeneic HSCT recipients were enrolled from 3/2010‐6/2012. CMV viremia was detected via weekly real‐time PCR. The Quantiferon‐CMV test was conducted pretransplant, early after transplantation, 30, 90 , 180 , 270, and 360 days post‐transplantation. The incidence of CMV viremia was 51% (19/37) with half of the episodes within ≤30 days post‐transplant. Fifteen patients showed CMV‐specific immunity (average of 82 days). The cumulative incidence of CMV reactivation in patients who developed CMV‐specific immunity was lower than those who did not (15% vs 53%; P = .023). The ROC statistical analysis showed that the AUC was 0.725 in predicting viremia, for Quantiferon‐CMV test. In this cohort, the Quantiferon‐CMV assay was a valuable method for identifying pediatric HSCT patients at high risk for CMV viremia, suggesting potential clinical utility to individualize patient's management post‐transplant.     

Long‐term impact of respiratory viral infection after pediatric lung transplantation

Liu M, Mallory GB, Schecter MG, Worley S, Arrigain S, Robertson J, Elidemir O, Danziger‐Isakov LA. Long‐term impact of respiratory viral infection after pediatric lung transplantation.
Pediatr Transplantation 2010: 14:431–436. © 2010 John Wiley & Sons A/S. Abstract: To evaluate the epidemiology and to investigate the impact of RVI on chronic allograft rejection after pediatric lung transplantation, a retrospective study of pediatric lung transplant recipients from 2002 to 2007 was conducted. Association between RVI and continuous and categorical risk factors was assessed using Wilcoxon rank‐sum tests and Fisher’s exact tests, respectively. Association between risk factors and outcomes were assessed using Cox proportional hazards models. Fifty‐five subjects were followed for a mean of 674 days (range 14–1790). Twenty‐eight (51%) developed 51 RVI at a median of 144 days post‐transplant (mean 246; range 1–1276); 41% of infections were diagnosed within 90 days. Twenty‐five subjects developed 39 LRI, and eight subjects had 11 URI. Organisms recovered included rhinovirus (n = 14), adenovirus (n = 10), parainfluenza (n = 10), influenza (n = 5), and RSV (n = 4). Three subjects expired secondary to their RVI (two adenovirus, one RSV). Younger age and prior CMV infection were risks for RVI (HR 2.4 95% CI 1.1–5.3 and 17.0; 3.0–96.2, respectively). RVI was not associated with the development of chronic allograft rejection (p = 0.25) or death during the study period. RVI occurs in the majority of pediatric lung transplant recipients, but was not associated with mortality or chronic allograft rejection.