Plasmapheresis treatment of antibody‐mediated rejection in an A2 donor to O pediatric liver transplant recipient

Martin T, Schwartz J, Demetris A, Comstock J, Lowichik A, Book L. Plasmapheresis treatment of antibody‐mediated rejection in an A2 donor to O pediatric liver transplant recipient.
Pediatr Transplantation 2011: 15:E15–E18. © 2009 John Wiley & Sons A/S. Abstract: It is safe to transplant kidneys from blood group A2 donors into O recipients if the latter have low titers of anti‐A antibodies. However, in liver transplantation, O and B recipients of A2 donor livers are not routinely screened for anti‐blood group antibodies because of the immuno‐absorptive capacity of the liver and the low incidence of antibody‐mediated rejection. Herein, we report a rare case of combined cell and antibody‐mediated rejection in a pediatric blood group O recipient of an A2 donor liver, and rescue of the allograft using PP and IVIG.     

Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss

Sutherland SM, Chen G, Sequeira FA, Lou CD, Alexander SR, Tyan DB. Complement‐fixing donor‐specific antibodies identified by a novel C1q assay are associated with allograft loss.
Pediatr Transplantation 2012: 16: 12–17. © 2011 John Wiley & Sons A/S. Abstract: Long‐term outcomes following renal transplantation remain disappointing. Recently, interest has focused on the antibody‐mediated component of allograft injury and the deleterious effects of DSA. We applied a novel C1q solid‐phase assay in parallel with the standard IgG SAB assay to identify DSA with the potential to activate complement by binding C1q. Among 193 consecutive renal transplants at our center, 19.2% developed de novo DSA following transplantation. Of the patients with DSA, 43% had antibodies that bound C1q in vitro [C1q(+) DSA]. Patients with C1q(+) DSA were more likely to develop allograft loss than patients with DSA that did not bind C1q (46.7% vs. 15%; p = 0.04); patients with C1q(+) DSA were nearly six times more likely to lose their transplant than those with C1q(?) DSA. Additionally, patients with C1q(+) DSA who underwent allograft biopsy were more likely to demonstrate C4d deposition (50% vs. 8%; p = 0.03) and meet criteria for acute rejection (60% vs. 17%; p = 0.02) when compared with patients with DSA that did not bind C1q. These data suggest that DSA with the ability to activate complement, as determined by this novel C1q assay, are associated with greater risk of acute rejection and allograft loss.     

Immune monitoring of pediatric heart transplant recipients through serial donor specific antibody testing — An initial experience and review of the literature

Heart transplantation is the best therapy for patient with end stage heart failure from cardiomyopathy or congenital heart disease that is not amenable to further surgical palliation. However, the development of rejection, cardiac allograft vasculopathy, and graft failure limit long term survival. Standard tools to assess for these complications include Echo, ECG, endomyocardial biopsy, and coronary angiography. However, the measurement of anti-HLA antibodies before and after transplantation is emerging in the clinical management of pediatric heart transplant recipients. It has been demonstrated that the presence of anti-HLA antibodies prior to transplantation and the development of de novo donor specific antibodies are both associated with poor outcomes. Detection of donor specific antibodies may be useful to monitor highly sensitized patients post transplant and to diagnose and guide clinical decision making in the treatment of antibody mediated rejection. Immunologic monitoring for the presence of these antibodies can be integral to ongoing surveillance. This paper will review the role of the immune system in heart transplantation, discuss concepts of pretransplant allosensitization and post transplant donor specific antibodies, and, finally will review clinical scenarios in which immunologic monitoring through donor specific antibody testing can be helpful.     

Antibody depletion for the treatment of crossmatch‐positive pediatric heart transplant recipients

Sensitization to HLA is a risk factor for adverse outcomes after heart transplantation. Requiring a negative prospective CM results in longer waiting times and increased waitlist mortality. We report outcomes in a cohort of sensitized children who underwent transplant despite a positive CDC CM+ using a protocol of antibody depletion at time of transplant, followed by serial IVIG administration. All patients <21 yrs old who underwent heart transplantation at Boston Children's Hospital from 1/1998 to 1/2011 were included. We compared freedom from allograft loss, allograft rejection, and serious infection between CM+ and CM? recipients. Of 134 patients in the cohort, 33 (25%) were sensitized prior to transplantation and 12 (9%) received a CM+ heart transplant. Serious infection in the first post‐transplant year was more prevalent in the CM+ patients compared with CM? patients (50% vs. 16%; p = 0.005), as was HD‐AMR (50% vs. 2%; p < 0.001). There was no difference in freedom from allograft loss or any rejection. At our center, children transplanted despite a positive CM had acceptable allograft survival and risk of any rejection, but a higher risk of HD‐AMR and serious infection.     

De novo phyllodes tumor in an adolescent female after liver transplantation

Cheng F, Qin J‐J, Yu M‐N, Zhang F, Li X‐C, Sun B‐C, Kong L‐B, Wang X‐H. De novo phyllodes tumor in an adolescent female after liver transplantation.
Pediatr Transplantation 2011: 15:E12–E14. © 2009 John Wiley & Sons A/S. Abstract: Phyllodes tumor of the breast is a rare disease constituting 0.3–0.9% of all breast neoplasms. Occurring mainly in females aged 35 to 55 yr, the disease is especially rare among adolescent females. There is no published literature about de novo phyllodes tumor after liver transplantation. Here we describe a case of de novo phyllodes tumors in an adolescent female after liver transplantation from a living donor for Wilson disease.     

Attenuation of rat chronic small bowel allograft rejection by n‐3 polyunsaturated fatty acids is associated with reduced expression of graft IL‐15

Interleukin‐15 was found to play key roles in various immunological processes including chronic rejection after renal and cardiac transplantation. n‐3 polyunsaturated fatty acids (n‐3 PUFA) have shown beneficial effects to chronic allograft rejection. The objective of this study is to search the possible mechanism of this inhibitory effect in chronic small bowel allograft rejection. Animals were divided into three groups: isograft (CsA + corn oil‐supplemented diet); allograft (CsA + corn oil‐supplemented diet); and allograft (CsA + fish oil‐supplemented diet). Donor intestines from F344 rats were transplanted orthotopically into Lewis rat recipients. CsA was administered at 5 mg/kg/day for 2 wk post‐operatively. Post‐transplant weight was recorded. Histopathological changes and graft IL‐15 expression were measured on POD 90. Chronic small bowel allograft rejection developed on POD 90. n‐3 PUFA significantly decreased the score of chronic rejection and increased the post‐operative weight gain rate. This attenuation is associated with reduced graft IL‐15 expression. n‐3 PUFA contributed to improved pathological and clinical outcome during chronic small bowel allograft rejection, and this improvement was associated with reduced graft IL‐15 expression.     

De novo cholangiocarcinoma after liver transplantation in a pediatric patient

Channabasappa N, Johnson‐Welch S, Mittal N. De novo cholangiocarcinoma after liver transplantation in a pediatric patient
Pediatr Transplantation 2010: 14:E110–E114. © 2009 John Wiley & Sons A/S. Abstract: To date, no child has been reported to develop de novo CCA after liver transplantation although patients with transplants have a significantly higher risk of malignancy than the general population. CCA is extremely rare in the pediatric age group, seen mostly in patients with a history of choledochal cysts, Caroli’s disease, or PSC. We report the first case of pediatric de novo CCA in the liver allograft 12 yr after liver transplantation.     

Combined split liver and kidney transplantation in a three‐year‐old child with primary hyperoxaluria type 1 and complete thrombosis of the inferior vena cava

Khan Z, Sciveres M, Salis P, Minervini M, Maggione G, Cintorino D, Riva S, Gridelli B, Emma F, Spada M. Combined split liver and kidney transplantation in a three‐year‐old child with primary hyperoxaluria type 1 and complete thrombosis of the inferior vena cava.
Pediatr Transplantation 2011: 15: E64–E70. © 2009 John Wiley & Sons A/S. Abstract: PH1 is an inborn error of the metabolism in which a functional deficiency of the liver‐specific peroxisomal enzyme, AGT, causes hyperoxaluria and hyperglycolic aciduria. Infantile PH1 is the most aggressive form of this disease, leading to early nephrocalcinosis, systemic oxalosis, and end‐stage renal failure. Infantile PH1 is rapidly fatal in children unless timely liver‐kidney transplantation is performed to correct both the hepatic enzyme defect and the renal end‐organ damage. The surgical procedure can be further complicated in infants and young children, who are at higher risk for vascular anomalies, such as IVC thrombosis. Although recently a limited number of children with IVC thrombosis have underwent successful kidney transplantation, successful multi‐organ transplantation in a child with complete IVC thrombosis is quite rare. We report here the interesting and technically difficult case of a three‐yr‐old girl with a complete thrombosis of the IVC, who was the recipient of combined split liver and kidney transplantation for infantile PH1. Although initial delayed renal graft function with mild‐to‐moderate acute rejection was observed, the patient rapidly regained renal function after steroid boluses, and was soon hemodialysis‐independent, with good diuresis. Serum and plasma oxalate levels progressively decreased; although, to date they are still above normal. Hepatic and renal function indices were at, or approaching, normal values when the patient was discharged 15‐wk post‐transplant, and the patient continues to do well, with close and frequent follow‐up. This is the first report of a successful double‐organ transplant in a pediatric patient presenting with infantile PH1 complicated by complete IVC thrombosis.     

Relationship between cytotoxic T‐lymphocyte antigen 4 ‐318C/T (rs5742909) gene polymorphism and the risk of acute rejection in renal transplantation

Results on the relationship between CTLA4 ‐318C/T (rs5742909) gene polymorphism and risk of acute rejection in renal transplantation are still conflicting. This meta‐analysis was performed to update the association between CTLA4 ‐318C/T and risk of acute rejection in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta‐analysis method. Twelve reports were included in this meta‐analysis for the association of CTLA4 ‐318C/T gene polymorphism with acute rejection risk in renal transplantation, consisting of 728 acute rejection patients and 1628 non‐acute rejection controls. The association between CTLA4 ‐318C/T gene polymorphism and acute rejection risk in renal transplantation for overall populations was not found in this meta‐analysis (T allele: OR=0.96, 95% CI: 0.60‐1.54, P=.88; TT genotype: OR=0.90, 95% CI: 0.47‐1.71, P=.74; CC genotype: OR=1.00, 95% CI: 0.62‐1.59, P=.98). Interestingly, T allele was associated with the risk of acute rejection in renal transplantation in African population. In conclusion, CTLA4 ‐318C/T gene polymorphism is not associated with the risk of acute rejection in renal transplantation in overall populations.     

Successful adult‐to‐child renal transplantation utilizing the ovarian vein in children with inferior vena cava/iliac vein thrombosis

Tao R, Shapiro R. Successful adult‐to‐child renal transplantation utilizing the ovarian vein in children with inferior vena cava/iliac vein thrombosis.
Pediatr Transplantation 2010: 14:E70–E74. © 2009 John Wiley & Sons A/S. Abstract: IVC/iliac vein thrombosis has previously been considered to be a contraindication to renal transplantation because of the technical difficulties and the increased risk of graft thrombosis. We report two successful cases of adult‐to‐child kidney transplantation in which we anastomosed the graft renal vein to the recipient ovarian vein in the presence of IVC and/or iliac vein thrombosis, with no short or long term vascular complications. Our experience, which adds to the successful reports from several other centers, suggests that the inability to use the iliocaval axis should no longer be considered a contraindication to pediatric renal transplantation.     

Association of cytotoxic T‐lymphocyte antigen 4 +49A/G gene polymorphism with acute rejection risk in renal transplantation

The conclusions on the association between cytotoxic T‐lymphocyte antigen 4 (CTLA4) +49A/G gene polymorphism and acute rejection risk in renal transplantation are still debated. This meta‐analysis was performed to update the association between CTLA4 +49A/G and acute rejection risk in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta‐analysis method. Fourteen reports were included into this meta‐analysis for the association of CTLA4 A/G gene polymorphism and acute rejection risk in renal transplantation, consisting of 962 acute rejection patients and 2084 non‐acute rejection controls. The association between CTLA4 G allele/GG genotype and acute rejection risk in renal transplantation was found in this meta‐analysis (G allele: OR=1.21, 95% CI: 1.03‐1.44, P=.02; GG genotype: OR=1.37, 95% CI: 1.10‐1.69, P=.004). However, the AA genotype was not associated with acute rejection risk in renal transplantation. In conclusion, CTLA4 G allele/GG genotype is associated with the acute rejection risk in renal transplantation.     

Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation

Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopietic stem cell transplantation.
Pediatr Transplantation 2012: 16: E39–E42. © 2010 John Wiley & Sons A/S. Abstract: TA‐TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA‐TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA‐TMA after allogeneic HSCT.     

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.     

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.     

Upregulation of α‐enolase in acute rejection of cardiac transplant in rat model: Implications for the secretion of interleukin‐17

Acute allograft rejection remains a major problem in solid organ transplantation. The enzyme α‐enolase has been shown to induce an immune response in cardiac transplantation. In this study, we investigated the role of α‐enolase in acute allograft rejection in a rat model of heart transplantation. Hearts from either (WF: RT1^u) or (Lew: RT1¹) rats were transplanted into (Lew: RT1¹) rats. No rejection occurred in the isograft group, for which the median survival time was >168 days, whereas the median survival time of the allograft group was significantly less at 10 ± 2.1 days (n = 8 per group, p < 0.001). Increased inflammation was observed in allografts, including increased α‐enolase expression and increased numbers of infiltrating CD4⁺ T cells (p < 0.05). By immunohistochemical staining, we confirmed that α‐enolase was expressed not only in myocardial cells but also in the infiltrating lymphocytes. However, on the fifth day after transplantation, α‐enolase expression was no longer observed in the lymphocytes (n = 3, p < 0.001). In contrast, no lymphocytes were found in isografts after transplantation (n = 3, p < 0.001). α‐enolase expression was increased in lymphocytes, which are implicated in the acute rejection of cardiac transplants. Intragraft α‐enolase inhibition may be useful as an adjuvant therapy to systemic immunosuppression in heart transplantation.     

Long‐term outcomes of simultaneous heart and kidney transplantation in pediatric recipients

Pediatric sHKTx has become an effective therapy for patients with combined cardiac and renal failure. Often, these patients develop human leukocyte antigen antibodies from their previous allografts and are therefore more difficult to re‐transplant. We describe the largest case series of a predominantly sensitized pediatric sHKTx with emphasis on medical management and patient outcomes. Demographics, clinical characteristics, antibody, and biopsy data were retrospectively collected from University of California, Los Angeles database and correlated with short‐ and long‐term patient and allograft outcomes of all sHKTx performed between 2002 and 2015. We identified seven pediatric patients who underwent sHKTx at our center. Mean age at time of sHKTx was 13.7 years and 85.7% were re‐graft patients. 57.1% were sensitized with cPRA >50% and another 57.1% had preformed donor‐specific antibody. Five‐year renal allograft survival and patient survival was 85.7% for both end‐points. The remaining six patients are all alive (mean follow‐up 78.5 months) with good kidney and heart function. sHKTx in a population with increased immunological risk can be associated with good long‐term outcomes and offers potential guidance to the pediatric transplant community where data are limited.     

Intravenous immunoglobulin, HLA allele typing and HLAMatchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients

The use of intravenous immunoglobulin (IVIG) in sensitized transplant candidates has resulted in reduced HLA antibody levels and shorter transplant wait times. In addition, the HLAMatchmaker program has been used to identify acceptable mismatches to permit transplantation in highly sensitized patients. We used IVIG desensitization in conjunction with high resolution HLA allele typing and HLAMatchmaker grading of donor offers to facilitate successful transplantation in two highly sensitized children who were awaiting second renal transplants. Both patients lost their initial transplant in <10 days to accelerated acute rejection, and were on dialysis for an average of 50 months with high panel reactive antibody (PRA) levels. They were started on monthly IVIG infusions (2 g/kg/dose). Within one wk following their third and fifth IVIG doses, both patients received a crossmatch compatible, deceased donor renal transplant selected by HLAMatchmaker as a suitable donor offer. Both patients remain rejection free with excellent renal function 19 and 15 months post-transplant, respectively. In conclusion, combining IVIG therapy and donor selection by HLA humoral epitope matching permitted successful transplantation of two highly sensitized children. Further studies in larger numbers of patients with longer follow-up are needed to determine the individual role played by, and relative importance of each component of this combined strategy.     

Pretransplant IgG antibodies to polyoma BK virus in pediatric renal transplants

Bijol V, Cimic A, Viscidi RP, Hymes LC. Pretransplant IgG antibodies to polyoma BK virus in pediatric renal transplants.
Pediatr Transplantation 2010:14:224–227. © 2009 John Wiley & Sons A/S. Abstract: We retrospectively measured IgG antibody levels to BKV in pretransplant sera and compared levels in children who developed BK viremia to a control group who remained free of infection after transplantation. Sera from 45 renal transplant patients were available for analysis (BK viremia = 23, controls = 22). Serum BKV PCR levels ranged from 3400 to 6.5 million DNA copies/mL (mean ± s.d.: 978K ± 1.77 million) and were highest in patients with BK nephritis (p = 0.007). Overall, 35% of children with BK viremia were BKV‐seronegative vs. 9% of children in control group (p = 0.04), but mean antibody levels were similar between viremic and control patients (p = 0.15). However, children who developed viremia later than six months post‐transplantation had significantly lower antibody levels compared with controls (p = 0.004) and patients with early viremia (p = 0.007), and may represent de novo infection or reinfection, rather than recurrence of latent infection. Pretransplant antibody status was significantly associated with subsequent development of BK viremia. Although our findings identified possible factors for developing BK viremia, there was sufficient overlap of both seropositive status and antibody levels among viremic patients and the control group to question the clinical utility of pretransplant IgG antibodies.     

Long‐term experience of steroid‐free pediatric renal transplantation: Effects on graft function,body mass index,and longitudinal growth

Increased focus on the potential negative side effects of steroid usage in pediatric transplantation has led to steroid minimization or steroid‐free transplantation. In this study, we report results after complete steroid avoidance in renal transplantation in the period 1994–2009. We evaluate the effects of complete steroid avoidance on allograft function, BMI, and linear growth. The majority of transplanted children were induced with antithymocyte globulin and immunosuppressed with a calcineurin inhibitor and mycophenolate mofetil. Steroids were given only when rejection occurred or due to comorbidities. Anthropometric data were collected from 65 transplantations in 60 children. Patient survival was 93%; graft survival was 81% after five yr (N = 42) and 63% after 10 yr (N = 16). Acute rejection within the first year of transplantation was 9%. The distribution of the children's BMI before transplantation was normal; the mean BMI‐SDS was 0.21 before transplantation, and this value remained stable during the next five yr. Post‐transplantation the children demonstrated significant improved growth as the mean height‐SDS increased significantly from ?1.7 to ?1.1. Catch‐up growth was most pronounced in the youngest (< six yr). Steroid‐free immunosuppression in pediatric renal transplantation is safe and protects against steroid‐induced obesity and short stature.     

Acute rejection associated with donor-specific anti-MICA antibody in a highly sensitized pediatric renal transplant recipient

Allograft rejection in HLA identical transplant recipients and in patients without detectable donor-specific anti-HLA antibodies has lead to the identification of non-HLA antigens as targets of the alloimmune response. MICA antigen has been recognized as an important non-HLA target in renal transplantation. Recent studies have shown that anti-MICA antibodies are associated with acute renal allograft rejection and failure. Current cross match procedures using donor lymphocytes fail to detect MICA antibodies. Transplant candidates are not routinely tested for pre-sensitization to MICA antigens nor are transplant donors typed for MICA alleles. Optimal classification and treatment of acute rejection associated with MICA antibody remains unknown. In this case report, we are the first to describe the clinical course and treatment of donor-specific MICA antibody associated with both Banff type II A ACR and AMR in a highly sensitized pediatric renal re-transplant recipient. This case also emphasizes the importance of pre-transplant screening for donor-specific MICA antibody especially in highly sensitized renal transplant patients.