Obliterative portal venopathy: A histopathologic finding associated with chronic antibody‐mediated rejection in pediatric liver allografts

The significance of post‐transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA‐positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non‐HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non‐HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy.     

Clinical and histopathologic features of antibody‐mediated rejection among pediatric renal transplant recipients with preformed vs de novo donor‐specific antibodies

Preformed and de novo donor specific antibodies (pDSA and dnDSA) are risk factors for ABMR. This study compares the effects of pDSA vs dnDSA in pediatric kidney transplant recipients. Sixteen pediatric patients with biopsy‐proven ABMR were evaluated. Strong DSA (MFI >10 000) was recorded at transplant, rejection, and follow‐up. DSAs with the highest MFI were termed iDSAs. Allograft biopsies were scored according to Banff 2013 criteria. Seven of 16 (44%) patients had pDSA at transplant; 9 (56%) developed dnDSA. Patients with pDSA developed ABMR earlier (median = 63 vs 1344 days, P = .017), while patients with dnDSA were more likely to have strong Class II iDSA (100% vs 28%, P = .009). Viral infection or non‐adherence was more common in patients developing dnDSA (88.8% vs 28.6%, P < .01). Pathology in those with pDSAs demonstrated worse transplant glomerulitis (g score 1.57 ± 0.98 vs 0.56 ± 0.73, P = .031); however, those with dnDSAs exhibited higher C4d+ ABMR (P = .013). Patients developing dnDSAs showed ABMR later post‐transplant with predominance of HLA‐Class II iDSAs. Inadequate immunosuppression likely contributes to dnDSA formation. Patients with no DSA who have unprotocolized decreases in immunosuppression should be screened for dnDSA as it could lead to early intervention and potentially better outcomes.     

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.     

IGG3 anti‐HLA donor‐specific antibodies and graft function in pediatric kidney transplant recipients

Anti‐HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single‐center retrospective chart review of pediatric KT recipients with anti‐HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty‐six patients (mean age 15.4y) with DSAs initially detected 1 month‐14.3 years post‐transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty‐two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3‐ patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97‐55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA‐positive pediatric KT recipients.     

Antibody‐mediated rejection with the presence of glomerular crescents in a pediatric kidney transplant recipient: A case report

Glomerular crescents in kidney transplantation are indicative of severe glomerular injury and constitute a hallmark of RPGN. Their concurrence with ABMR has been rarely described only in adult patients. We report a case of 10‐year‐old boy with compound heterozygous Fin‐major Finnish‐type congenital nephrotic syndrome, who had received a deceased‐donor kidney transplant 5 years before onset of acute kidney injury and nephrotic range proteinuria without hematuria. Kidney allograft biopsy illustrated 6 glomeruli with global sclerosis and 6 with remarkable circumferential or segmental cellular crescents. Negative glomerular immunofluorescence for immune‐complex deposits and the absence of serum ANCA eliminated the presence of immune‐mediated and ANCA‐positive pauci‐immune crescentic glomerulonephritis. Diagnosis of ABMR was based on the high levels of HLA class II DSA and the histological evidence of glomerulitis, peritubular capillaritis, and acute tubular injury with positive linear peritubular capillary C4d staining. The patient despite plasmapheresis and enhanced immunosuppressive treatment progressed to end‐stage renal disease. We conclude that glomerular crescents may represent a finding of AMBR and possibly a marker of poor allograft prognosis in pediatric patients.     

Impacts of donor‐specific anti‐HLA antibodies and antibody‐mediated rejection on outcomes after intestinal transplantation in children

AMR is a risk factor for graft failure after SBTx. We studied impact of DSAs and AMR in 22 children transplanted between 2008 and 2012 (11 isolated SBTx, 10 liver inclusive Tx, and one modified multivisceral Tx). Three patients never developed DSA, but DSAs were found in seven in the pre‐Tx period and de novo post‐Tx in 19 children. Pathology revealed cellular rejection (15/19), with vascular changes and C4d+. Patients were treated with IV immunoglobulins, plasmapheresis, and steroids. Rescue therapy included antithymocyte globulins, rituximab, eculizumab, and bortezomib. Pathology and graft function normalized in 13 patients, graft loss occurred in two, and death in seven. At the end of the follow‐up, 15 children were alive (68%), 13 with functioning graft (59%). Prognosis factors for poor outcome after Tx were the presence of symptoms at AMR suspicion (P +.033). DSAs were often found following SBTx, mostly de novo. Resistant ACR or severe AMR is still difficult to differentiate, with a high need for immunosuppression in both. DSAs may precede development of severe disease and pathology features on the graft: relationship and correlation need to be better investigated with larger groups before and after Tx.     

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.     

Failure of bortezomib to cure acute antibody‐mediated rejection in a non‐compliant renal transplant patient

Bortezomib has appeared recently as a potential active treatment for acute AMR for few years. We reported a patient who received two courses of bortezomib for the treatment of an acute AMR associated with de novo HLA DSA that occurred 18 months after renal transplantation because of non‐compliance. Graft biopsy revealed features of acute humoral rejection with plasmocyte infiltration and C4d staining. Bortezomib was associated with corticosteroid pulses, IVIgs, and PP. Despite this rapid management, the patient lost his graft and carried on dialysis. Bortezomib therapy in addition to current therapy of AMR is not always effective in the treatment for late acute AMR in renal transplantation. We discuss on the place of such a treatment and other therapeutic strategies in this indication.     

Persistent C4d and antibody‐mediated rejection in pediatric renal transplant patients

Pediatric renal transplant recipient survival continues to improve, but ABMR remains a significant contributor to graft loss. ABMR prognostic factors to guide treatment are lacking. C4d staining on biopsies, diagnostic of ABMR, is associated with graft failure. Persistent C4d+ on follow‐up biopsies has unknown significance, but could be associated with worse outcomes. We evaluated a retrospective cohort of 17 pediatric renal transplant patients diagnosed with ABMR. Primary outcome at 12 months was a composite of ≥50% reduction in eGFR, transplant glomerulopathy, or graft failure. Secondary outcome was the UPCR at 12 months. We used logistic and linear regression modeling to determine whether persistent C4d+ on follow‐up biopsy was associated with the outcomes. Forty‐one percent reached the primary outcome at 12 months. Persistent C4d+ on follow‐up biopsy occurred in 41% and was not significantly associated with the primary outcome, but was significantly associated with the secondary outcome (estimate 0.22, 95% CI 0.19‐0.25, P < .001), after controlling for confounding factors. Persistent C4d+ on follow‐up biopsies was associated with a higher UPCR at 12 months. Patients who remain C4d+ on follow‐up biopsy may benefit from more aggressive or prolonged ABMR treatment.     

Preformed and de novo DSA are associated with T‐cell–mediated rejection in pediatric liver transplant recipients requiring clinically indicated liver biopsy

Despite growing interest about the impact of donor‐specific HLA antibodies (DSA) in LT limited data are available for pediatric recipients. Our aim was to perform a retrospective single‐center chart review of children (0‐16 years) having undergone LT between January 1, 2005 and December 31, 2017, to characterize DSA, to identify factors associated with the development of de novo DSA, and to analyze potential associations with the diagnosis of TCMR. Information on patient‐ and donor‐characteristics and LB reports were analyzed retrospectively. Serum obtained before LT and at LB was analyzed for presence of recipient HLA antibody using Luminex^® technology. MFI > 1000 was considered positive. In 63 pediatric LT recipients with a median follow‐up of 72 months, the overall prevalence of de novo DSA was 60.3%. Most were directed against class II antigens (33/38, 86.8%). Preformed DSA were present in 30% of patients. Twenty‐eight (28/63) patients (44.4%) presented at least one episode of TCMR, mostly (12/28, 43%) moderate (Banff 6‐7). De novo DSA were significantly more frequent in patients with TCMR than in patients without (75% vs 48.6%, P = .03), and patients with preformed and de novo DSA had a significantly higher rate of TCMR than patients without any DSA (66.7% vs 20%, P = .02). Neither preformed DSA nor de novo DSA were associated with frequency or severity of TCMR. Recipients with lower weight at LT developed de novo DSA more frequently (P = .04). De novo DSA were highly prevalent in pediatric LT recipients. Although associated with the development of TCMR, they did not appear to impact the frequency or severity of TCMR or graft survival. Instead, de novo DSA may suggest a state of insufficient IS.     

Outcome of antibody‐mediated rejection compared to acute cellular rejection after pediatric heart transplantation

Outcomes of ACR after pediatric HTx have been well described, but less has been reported on outcomes of AMR. We compared the clinical characteristics and cardiovascular outcomes (composite end‐point of death, retransplantation, or allograft vasculopathy) of pediatric HTx recipients with AMR, ACR, and no rejection in a retrospective single‐center study of 104 recipients. Twenty were treated for AMR; 15 were treated for ACR. Recipients with AMR had an increased frequency of congenital heart disease (90% vs ACR 67% vs no rejection 59%, P = .03), homograft (68% vs 7% vs 18%, P < .001), HLA sensitization (45% vs 13% vs 13%, P = .008), and positive cross‐match (30% vs 7% vs 9%, P = .046). AMR caused hemodynamic compromise more often than ACR (39% vs 4%, P = .02). AMR recipients had worse cardiovascular outcome than recipients with ACR or no rejection (40% vs 20% vs 8.6%, P = .003). In bivariate Cox analysis, AMR (HR 4.1, CI 1.4‐12.0, P = .009) and ischemic time (HR 1.6, CI 1.1‐2.3, P = .02) were associated with worse cardiovascular outcome; ACR was not. In summary, pediatric HTx recipients who develop AMR have worse cardiovascular outcome than recipients who develop only ACR or experience no rejection at all.     

Acute humoral rejection in pediatric renal transplant recipients receiving steroid minimization immunosuppression

SM protocols have increasingly gained acceptance owing to their favorable side effect profile with comparable cellular rejection rates. After encountering SM patients with AHR, we performed a case-control study to identify predictors associated with AHR in this cohort. Patients with (n = 4) and without (n = 19) biopsy proven AHR on a SM regimen were compared using the Student's t-tests. The median age at transplant was 13.8 yr. Compared to controls, the AHR cohort was older (15.9 vs. 12.1 yr, p = 0.01). Children with AHR had a lower mean tacrolimus trough level and were more likely to have a sub-therapeutic trough at six months (3.5 vs. 5.5 ng/mL, p = 0.05); mean MMF doses were lower at all times points except three months in the AHR group (not statistically significant). This occurred in spite of higher MPA trough levels at all study points in the AHR group (significant at 3 [p = 0.019] and 6 [p = 0.03] months). Children receiving a SM regimen have a lower safety net and may benefit from more intensive monitoring of tacrolimus exposure. MMF dose modifications based on MPA trough determinations should be resisted in the setting of SM.     

Protective immunity and use of bortezomib for antibody‐mediated rejection in a pediatric kidney transplant recipient

Standard treatments for AMR—rituximab, intravenous immunoglobulin, and/or plasmapheresis—aim to suppress the production and modulate the effect of donor‐specific antibodies and remove them, respectively. Proteasome inhibitors such as bortezomib are potent therapeutic agents that target plasma cells more effectively than rituximab to reduce measurable donor‐specific antibody production. Little is known in adults, and no data exist in children about effects of proteasome inhibition to treat AMR on protective antibody titers. We present a pediatric renal transplant recipient who received bortezomib for relatively early AMR and whose antibody titers to measles and tetanus were tracked. The AMR was treated successfully, and we noted no clinical decrease in the overall level of protective immunity from pretransplant baseline levels at almost one yr after AMR treatment cessation. Larger studies will elucidate more clearly how proteasome inhibition to treat AMR affects protective immunity in pediatric transplant recipients.     

Antibody‐mediated rejection after ABO‐incompatible pediatric living donor liver transplantation for propionic acidemia: A case report

We herein present the case of a four‐yr‐old boy with PA who developed AMR after ABO‐incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO‐incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor‐type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re‐administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO‐incompatible LDLT if B cell reactivation is suspected.     

ABO‐incompatible liver transplantation for children under 2 years of age: A case report and a single‐center review

Desensitization with RTX has been broadly introduced in adult LT across the ABO blood type barrier. For pediatric LT, the prophylactic use of RTX has not been standardized, especially for children under 2 years of age. A 20‐month‐old girl with BA underwent living donor LT from her ABO‐I mother. On POD 6, she developed combined T cell‐mediated and AMRs. Steroid bolus injection was immediately introduced, followed by antibody‐depleting therapy with PE and IVIG. Based on a peripheral blood lymphocyte analysis by fluorescence‐activated cell sorting, ATG and RTX were introduced for refractory rejection. Although she recovered from the combined rejections, IHBCs were inevitable as a consequence. We recommend extending the desensitization protocol to cover children under 2 years of age in order to prevent life‐threatening complications.     

Donor‐specific antibodies in a pediatric kidney transplant population—Prevalence and association with antiproliferative drug dosing

Prevalence and implications of anti‐HLA class I and class II antibodies are beginning to be better characterized in pediatric kidney transplant recipients. dnDSA formation is predictive of AMR and downstream diminished graft function and survival. However, risk factors for the development of dnDSA are not well defined in this patient population. After introducing DSA surveillance into our pediatric kidney transplant program, we are reporting the prevalence of class I and class II DSA in 67 otherwise stable recipients. Secondary end‐points included risk factors for DSA development and assessment of graft function. Significantly, lower median daily MMF doses were observed in patients with DSAs compared to patients without DSAs (371 vs 617 mg/m²/d, respectively; P = 0.035). Class II DSA formation was more common, with a prevalence of 17.9%, as compared to 10.4% for class I DSA. Estimated glomerular filtration rate was also decreased in patients with positive DSA vs those with negative titers (71, SD 25 vs 78, SD 29 mL/min/1.73 m², respectively; P = 0.034). We conclude that reduced‐dose MMF is associated with dnDSA and DSA is associated with diminished graft function in stable pediatric kidney transplant recipients.     

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.     

Using individual DSA titers to assess for accommodation after late humoral rejection

Management of late humoral rejection remains challenging, and DSA may persist. A case report illustrates how individual DSA titers using solid‐phase‐based assays may help to assess for accommodation. A male cystinosis patient received a cadaveric renal transplant at the age of 12 yr with a daclizumab, tacrolimus, MMF, and steroids‐based immunosuppression. After three acute rejection episodes over the first eight months, interstitial fibrosis/tubular atrophy (IF/TA) was diagnosed on biopsy, while the immunosuppression was left unchanged with a high target exposure for both tacrolimus and MPA. One yr later, AMR type III (C4d and DSA positive) was treated with daily plasmapheresis, IVIG 100 mg/kg and pulse steroids 5 mg/kg. DSA (DR 53, DQ4, and DQ 2) were not responding until the plasma volume was increased to 2.5 plasma volumes. A second rise of creatinine confirmed worse humoral rejection; daily plasma exchange was resumed, and two doses of rituximab (375 mg/m²) were given. Subsequently, all DSA dropped, but only DR53 DSA remained unchanged, whereas the DQ antibodies rebounded to very strong titers. With a follow‐up of over 120 days after recovery of the CD19 count, off all additional treatment and on identical immunosuppression with tacrolimus and MMF and prednisone, the patient's creatinine remained stable between 45 and 50 um while DQ DSA remain strong to very strong. We conclude that the patient is in a state of accommodation. DSA titers should be monitored when managing late humoral rejection.     

Pathological antibody‐mediated rejection in pediatric heart transplant recipients: Immunologic risk factors,hemodynamic significance,and outcomes

Biopsy‐diagnosed pAMR has been observed in over half of pediatric HT recipients within 6 years of transplantation. We report the incidence and outcomes of pAMR at our center. All endomyocardial biopsies for all HT recipients transplanted between 2010 and 2015 were reviewed and classified using contemporary ISHLT guidelines. Graft dysfunction was defined as a qualitative decrement in systolic function by echocardiogram or an increase of ≥3 mm Hg in atrial filling pressure by direct measurement. Among 96 patients, pAMR2 occurred in 7 (7%) over a median follow‐up period of 3.1 years, while no cases of pAMR3 occurred. A history of CHD, DSA at transplant, and elevated filling pressures were associated with pAMR2. Five‐sixths (83%) of patients developed new C1q+ DSA at the time of pAMR diagnosis. There was a trend toward reduced survival, with 43% of patients dying within 2.3 years of pAMR diagnosis.