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Background: In kidney transplant recipients (KTR), BK polyomavirus-associated nephropathy (BKPyVAN) is a major cause of graft loss. To facilitate the clearance of BKPyV-DNAemia, reduction of immunosuppression is currently the treatment of choice but may increase the risk of graft rejection. Methods: This international CERTAIN study was designed to determine the risk of alloimmune response and graft dysfunction associated with immunosuppression reduction for BKPyV treatment in 195 pediatric KTR. Results: BKPyV-DNAemia was associated with a more than twofold increased risk of late T cell-mediated rejection (TCMR) (HR 2.22, p = 0.024), of de novo donor-specific HLA antibodies (dnDSA) and/or antibody-mediated rejection (ABMR) (HR 2.64, p = 0.002), and of graft function deterioration (HR 2.73, p = 0.001). Additional independent risk factors for dnDSA/ABMR development were a higher HLA mismatch (HR 2.72, p = 0.006) and re-transplantation (HR 6.40, p = 0.000). Other independent predictors of graft function deterioration were TCMR (HR 3.98, p = 0.003), higher donor age (HR 1.03, p = 0.020), and re-transplantation (HR 3.56, p = 0.013). Conclusions: These data indicate that reduction of immunosuppression for BKPyV-DNAemia management is associated with increased alloimmune response in pediatric KTR. Therefore, regular dnDSA screening and close monitoring of graft function in case of BKPyV-DNAemia followed by subsequent reduction of immunosuppressive therapy are recommended. Graphical sbstract: [ABSTRACT FROM AUTHOR]

Background: The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown. Methods: Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection. Results: The cohort comprised 59 children (aged 0–18 years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07–1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01–1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99–34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25–115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54–186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64–57.72, p = 0.01). Conclusions: Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA. [ABSTRACT FROM AUTHOR]

Introduction: Liver-kidney transplantation is a rare procedure in children, with just ten to 30 cases performed annually worldwide. The main indications are autosomal recessive polycystic liver-kidney disease and primary hyperoxaluria. This study aimed to report outcomes of liver-kidney transplantation in a cohort of pediatric patients. Methods: We retrospectively analyzed all pediatric liver-kidney transplantations performed in our center between September 2000 and August 2015. Patient data were obtained by reviewing inpatient and outpatient medical records and our transplant database. Results: A total of 14 liver-kidney transplants were performed during the study period, with a median patient age and weight at transplant of 144.4 months (131.0-147.7) and 27.3 kg (12.0-45.1), respectively. The indications for liver-kidney transplants were autosomal recessive polycystic liver-kidney disease (8/14), primary hyperoxaluria −1 (5/14), and idiopathic portal hypertension with end-stage renal disease (1/14). Median time on waiting list was 8.5 months (5.7-17.3). All but two liver-kidney transplants were performed simultaneously. Patients with primary hyperoxaluria-1 tended to present a delayed recovery of renal function compared with patients transplanted for other indications (62.5 vs 6.5 days, respectively, P 0.076). Patients with liver-kidney transplants tended to present a lower risk of acute kidney rejection than patients transplanted with an isolated kidney transplant (7.2% vs 32.7%, respectively; P < 0.07). Patient and graft survival at 1, 3, and 5 years were 100%, 91.7%, 91.7%, and 91.7%, 83.3%, 83.3%, respectively. No other grafts were lost. Conclusion: Long-term results of liver-kidney transplants in children are encouraging, being comparable with those obtained in isolated liver transplantation. [ABSTRACT FROM AUTHOR]

Introduction: We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. Methods: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan-Meier estimator. Results: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R 0.072; C3d: adjusted R 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q−) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q−) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30-1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d−); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d−) years; HR 0.38; 95% CI 0.15-0.97; p = 0.04]. Conclusion: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction. [ABSTRACT FROM AUTHOR]

Background: We investigated the prognostic value of overall and complement-binding donor-specific HLA antibodies (DSA) in pediatric patients undergoing clinically indicated graft biopsies and their association with graft outcome and specific histological lesions. Methods: Sera of 62 patients at time of indication biopsy ≥1 year posttransplant were assessed for DSA and C1q-fixing DSA by single-antigen bead (SAB) technology. Results: Twenty-six patients (42 %) were DSA-positive at time of indication biopsy and nine (15 %) were C1q-positive. At 4 years postbiopsy, patients with C1q-positivity had a low graft survival (11 %) compared to DSA-positive, C1q-negative patients (82 %, p = 0.001) and to DSA-negative patients (88 %, p < 0.001). The majority (89 %) of C1q-positive patients were diagnosed with active chronic antibody-mediated rejection (ABMR). C1q DSA-positivity [adjusted hazard ratio (HR) 6.35], presence of transplant glomerulopathy (HR 9.54), and estimated glomerular filtration rate (eGFR) at the time of indication biopsy (HR 0.91) were risk factors for subsequent graft loss. Conclusions: The presence of C1q-positive DSA in the context of an indication biopsy identifies a subgroup of pediatric renal transplant recipients with a markedly increased risk of subsequent graft loss. Because a fraction of DSA-positive patients escape rejection or graft dysfunction, the C1q assay increases the specificity of a positive DSA result regarding unfavorable transplant outcome. [ABSTRACT FROM AUTHOR]

Acute antibody-mediated rejection is a diagnostic challenge in renal transplantation medicine. However, it is an important diagnosis to make, since chronic antibody-mediated rejection (CAMR) is the main cause of long-term graft loss. Antibody-mediated rejection is diagnosed by detecting donor-specific antibodies (DSAs) in the blood in combination with observing typical histomorphological signs in kidney biopsy, as described in the Banff classification. Therapy is based on the removal of DSAs by administering intravenous immunoglobulins (IVIGs), plasmapheresis, or immunoadsorption. Reoccurrence of antibodies is diminished by the use of rituximab, increased immunosuppression, and in some cases additional experimental substances. A combination of these techniques has been shown to be successful in the majority of cases of acute and chronic antibody-mediated rejection. Routine DSA monitoring is warranted for early detection of antibody-mediated rejection. [ABSTRACT FROM AUTHOR]

ABO-compatible as well as ABO-incompatible kidney transplantation are well established in the pediatric population. There are particularities in the histopathological evaluation of pediatric kidney transplant biopsies as for example the recurrence of certain diseases different from the adult population. Furthermore, the challenging transition of pediatric renal transplant recipients to adulthood is associated with an increased rate of non-adherence triggered rejection episodes. With modern immunosuppressive drugs, T-cell-mediated rejection of renal allografts is well controlled. In contrast, antibody-mediated rejection (AMR) is increasingly recognized as one of the major reasons for allograft loss. However, the 2001 diagnostic Banff criteria for antibody-mediated rejection require further refinement, as the morphological spectrum of AMR expands while effective therapeutic strategies are lacking. For example, endarteritis, which traditionally has been attributed to T-cell-mediated rejection, has recently been shown to be part of the AMR spectrum in some cases. Many findings in transplant renal biopsies are not specific for a certain disease but need consideration of differential diagnoses. To use the term 'chronic allograft nephropathy' as a diagnostic entity is no longer appropriate. Therefore, the precise identification of specific diseases is paramount in the assessment of transplant renal biopsies in order to enable tailored therapeutic management. [ABSTRACT FROM AUTHOR]

Background: There are no guidelines for the removal of a failed renal allograft, and its impact on subsequent dialysis and retransplantation has not yet been described. Methods: We performed a 10-year review of allograft failure to study the factors that determined an outcome of transplant nephrectomy and choice of subsequent renal replacement therapy in children with or without nephrectomy. Results: A total of 34 children developed graft failure over the 10-year study period, of whom 18 (53 %) required transplant nephrectomy. The median graft survival was 1.1 (range 0.2-10.6) versus 7.5 (1.5-15.0) years in the nephrectomy and non-nephrectomy groups, respectively ( p = 0.011). Children with graft failure within 1 year of transplantation were four-fold more likely to require transplant nephrectomy than those with graft failure after 1 year ( p = 0.04). Renal biopsy performed at ≤8 weeks prior to graft loss showed Banff grade II acute rejection in 13 of the 18 children who required subsequent nephrectomy versus three of the 13 children who did not need nephrectomy ( p = 0.01). Inflammation (fever, graft tenderness and raised C-reactive protein (CRP) in the 2 weeks preceding graft failure) was seen in 66 % of nephrectomized children, but not in any in the non-nephrectomy group ( p = 0.0003 for CRP between groups). Banff II rejection, an inflammatory response and the time post-transplantation significantly and independently predicted the outcome of nephrectomy ( p = 0.008, R = 67 %). Human leukocyte antigen (HLA) antibody levels after graft failure were higher in the nephrectomy group ( p = 0.0003), but there was no difference between groups in terms of the presence or class of donor-specific antibodies. Of the children with graft failure, 82 % required dialysis (61 % hemodialysis) and 35 % have to date been successfully retransplanted. Conclusions: Children with Banff II rejection, an inflammatory response and early graft loss are more likely to require transplant nephrectomy. Nephrectomy may be associated with higher circulating HLA antibody levels. [ABSTRACT FROM AUTHOR]

ntibody-mediated rejection (AMR) is a unique, significant, and often severe form of allograft rejection that is not amenable to treatment with standard immunosuppressive medications. Significant advances have occurred in our ability to predict patients at risk for, and to diagnose, AMR. These advances include the development of newer anti-human leukocyte antigen (HLA)-antibody detection techniques and assays for non-HLA antibodies associated with AMR. The pathophysiology of AMR suggests a prime role for antibodies, B cells and plasma cells, but other effector molecules, especially the complement system, point to potential targets that could modify the AMR process. An emerging and potentially larger problem is the development of chronic AMR (CAMR) resulting from de novo donor-specific anti-HLA antibodies (DSA) that emerge more than 100 days posttransplantation. Therapeutic options include: (1) High-dose intravenously administered immunoglobulin (IVIG), which has many potential benefits. (2) The use of IVIG + rituximab (anti-CD20, anti-B cell). (3) The combination of plasmapheresis (PP) + low-dose IVIG with or without rituximab. Data support the efficacy of all of the above approaches. Newer approaches to treating AMR include using the proteosome inhibitor (bortezomib), which induces apoptosis in plasma cells, and eculizumab (anti-C5, anticomplement monoclonal antibody). [ABSTRACT FROM AUTHOR]

There have been marked improvements in the short- and long-term outcomes for children after renal transplantation over the past two decades with superior quality and quantity of life. It is encouraging to see increased patient and renal allograft survival rates with initially lower acute renal allograft rejection rates due to improved matching and immunosuppressive regimens. Unfortunately, longer-term renal allograft survival remains unchanged with chronic allograft injury from both immune and non-immune causes, resulting in chronic allograft dysfunction, morbidity from chronic kidney disease, and eventual renal allograft loss. Acute and chronic antibody-mediated rejection remains a clinical dilemma with a growing evidence base of its treatment, including proteasome inhibition using intravenous bortezomib. The future goal is to reduce chronic allograft dysfunction and make renal transplants last longer for pediatric renal transplant recipients who may require retransplantation during their childhood and adult lives, which can become successively more difficult due to sensitization. [ABSTRACT FROM AUTHOR]

Steroid-resistant rejection after pediatric renal transplantation forms a rare but severe complication with a guarded prognosis particularly if this occurs late after transplantation. There is a paucity of data on how to manage these challenging rejection episodes, particularly in the pediatric literature. Mohan Shenoy et al. published a case series of 15 patients who were treated with anti-thymocyte globulin for steroid-resistant acute allograft rejection over a 15-year period in a single center in this issue of Pediatric Nephrology. While the results for the early rejection group were encouraging, the results in the eight patients with late rejection episodes after transplantation were unfavorable and afflicted with a high incidence of side-effects. Important diagnostic tools such as C4d staining of the renal transplant biopsy and the measurement of donor-specific antibodies were underutilized. The editorial reviews the importance of the differentiation between humoral and cellular rejection and the challenges of treating late antibody-mediated acute rejection in these patients. A multi-center approach is required to establish a registry of these events and ideally prospective randomized interventions should be designed to provide some evidence base for the management of this challenging complication after pediatric renal transplantation. [ABSTRACT FROM AUTHOR]