Effect of pre-emptive rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients: A case series from the pediatric nephrology research consortium.

BACKGROUND: There are scant data on the effect of rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia. METHODS: Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab. RESULTS: Twenty-six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1-10.3). EBV DNA load monitoring by qPCR was performed at 1-3 month intervals. EBV DNAemia onset occurred at a median of 73 days post-transplant (IQR 52-307), followed by DNAemia peak at a median of 268 days (IQR 112-536). Rituximab was administered at a median of 9 days post peak (IQR 0-118). Rituximab regimens varied; median dose 375 mg/m2 (IQR 375-439) weekly for 1-4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow-up (median 2094 days post-transplant [IQR 1538-3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons. CONCLUSIONS: In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short-term reduction in DNA load; however, recurrent DNAemia is common.

Antibody-mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium.

BACKGROUND: Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. There is a paucity of large-scale pediatric-specific data regarding AMR treatment outcomes. METHODS: Data were obtained from 14 centers within the Pediatric Nephrology Research Consortium. Kidney transplant recipients aged 1-18 years at transplant with biopsy-proven AMR between 2009 and 2019 and at least 12 months of follow-up were included. The primary outcome was graft failure or an eGFR <20 mL/min/1.73 m2 at 12 months following AMR treatment. AMR treatment choice, histopathology, and DSA class were also examined. RESULTS: We reviewed 123 AMR episodes. Median age at diagnosis was 15 years at a median 22 months post-transplant. The primary outcome developed in 27.6%. eGFR <30 m/min/1.73 m2 at AMR diagnosis was associated with a 5.6-fold higher risk of reaching the composite outcome. There were no significant differences in outcome by treatment modality. Histopathology scores and DSA class at time of AMR diagnosis were not significantly associated with the primary outcome. CONCLUSIONS: In this large cohort of pediatric kidney transplant recipients with AMR, nearly one-third of patients experienced graft failure or significant graft dysfunction within 12 months of diagnosis. Poor graft function at time of diagnosis was associated with higher odds of graft failure.

Management of the sensitized pediatric renal transplant candidate.

Kidney transplantation is the treatment of choice for patients with ESRD as it is associated with improved patient survival and better quality of life, especially in children. There are several barriers to a successful transplant including organ shortage, anatomic barriers, and immunologic barriers. One of the biggest immunologic barriers that precludes transplantation is sensitization, when patients have antibodies prior to transplantation, resulting in positive crossmatches with donor. 30%-40% of adult patients on the wait list are sensitized. There is a growing number of pediatric patients on the wait list who are sensitized. This poses a unique challenge to the pediatric transplant community. Therefore, attempts to perform desensitization to remove or suppress pathogenic HLA antibodies resulting in acceptable crossmatches, and ultimately a successful transplant, while reducing the risk of acute rejection, are much needed in these children. This review article aims to address the management of such patients both prior to transplantation, with strategies to overcome sensitization, and after transplantation with monitoring for allograft rejection and other complications.

Children Are Not Small Adults: Similarities and Differences in Renal Transplantation Between Adults and Pediatrics.

Kidney transplantation is the treatment of choice for all patients with end-stage kidney disease, including pediatric patients. Graft survival in pediatrics was lagging behind adults, but now is comparable with the adult cohort. Although many of the protocols have been adopted from adults, there are issues unique to pediatrics that one should be aware of to take care of this population. These issues include recipient size consideration, increased incidence of viral infections, problems related to growth, common occurrence of underlying urological issues, and psychosocial issues. This article addresses the similarities and differences in renal transplantation, from preparing a patient for transplant, the transplant process, to post-transplant complications.

Utilization of SARS-CoV-2-Positive donors in pediatric renal transplantation.

BACKGROUND: As COVID-19-positive donors are becoming more common, there is an increasing need for the transplant community to evaluate the safety and efficacy of organ transplant from a SARS-CoV-2-infected donor. METHODS: Here we describe outcomes of two pediatric kidney transplant recipients who were vaccinated against COVID-19 and received their allograft from a SARS-CoV-2-positive donor. RESULTS: Both donors did not die from a COVID-19-related illness; the first donor had 1 week of COVID-19 symptoms 4 weeks prior to donation and the second was asymptomatic. Donor 1 had a Ct of 33.4 at 3 days and Donor 2 with a Ct of 37.2 at 16 days prior to donation. The first recipient was positive for SARS-CoV-2 anti-spike IgG on the day of transplant, but the second patient was negative and both patients received IVIg perioperatively. There was no evidence of SARS-CoV-2 transmission or compromised renal function at 86- and 80-day post-transplant, respectively. CONCLUSIONS: This case series suggests favorable short-term outcomes with accepting SARS-CoV-2-positive donors for pediatric renal transplantation, after thorough evaluation of the donor's risk for transmission, assessing the recipient's serologic status to SARS-CoV-2, and considering pre-emptive measures to mitigate the risk for severe COVID-19 should the recipient acquire donor-derived SARS-CoV-2.

Pre-transplant angiotensin II receptor type I antibodies in pediatric renal transplant recipients: An observational cohort study.

BACKGROUND: The role of angiotensin II type 1 receptor antibodies (AT1R-Ab) in pediatric renal transplantation is unclear. Here, we evaluated pre-transplant AT1R-Ab on transplant outcomes in the first 5 years. Secondary analysis compared pre-transplant AT1R-Ab levels by age. METHODS: Thirty-six patients, 2-20 years old, were divided into two groups: pre-transplant AT1R-Ab- (<17 U/ml; n = 18) and pre-transplant AT1R-Ab+ (≥17 U/ml; n = 18). eGFR was determined at 6-month, 1-, 2-, and 4-year post-transplant. Allograft biopsies were performed in the setting of strong HLA-DSA (MFI > 10 000), AT1R-Ab ≥17 U/ml, and/or elevated creatinine. RESULTS: Mean age in pre-transplant AT1R-Ab- was 13.3 years vs. 11.0 in pre-transplant AT1R-Ab+ (p = 0.16). At 6 months, mean eGFR was 111.3 ml/min/1.73 m2 in pre-transplant AT1R-Ab- vs. 100.2 in pre-transplant AT1R-Ab + at 1 year, 103.6 ml/min/1.73 m2 vs. 100.5; at 2 years, 98.9 ml/min/1.73 m2 vs. and 93.7; at 4 years, 72.6 ml/min/1.73 m2 vs. 80.9. 11/36 patients had acute rejection (6 in pre-transplant AT1R-Ab-, 5 in pre-transplant AT1R-Ab + ). There was no difference in rejection rates. All 6 subjects with de novo HLA-DSA and AT1R-Ab ≥17 U/ml at the time of biopsy experienced rejection. Mean age in those with the AT1R-Ab ≥40 U/ml was 10.0 years vs. 13.2 in those <40 U/ml (p = 0.07). CONCLUSION: In our small cohort, pre-transplant AT1R-Ab ≥17 U/ml was not associated with reduced graft function or rejection. The pathogenicity of pre-transplant AT1R-Ab in pediatric kidney transplantation requires further investigation.

Long term tolerability and clinical outcomes associated with tocilizumab in the treatment of refractory antibody mediated rejection (AMR) in pediatric renal transplant recipients.

BACKGROUND: Treatment options for antibody-mediated rejection (AMR) are limited. Recent studies have shown that inhibition of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling can reduce inflammation and slow AMR progression. METHODS: We report our experience using monthly tocilizumab (anti-IL6R) in 25 pediatric renal transplant recipients with AMR, refractory to IVIg/Rituximab. From January 2013 to June 2019, a median (IQR) of 12 (6.019.0) doses of tocilizumab were given per patient. Serial assessments of renal function, biopsy findings, and HLA DSA (by immunodominant HLA DSA [iDSA] and relative intensity score [RIS]) were performed. RESULTS: Median (IQR) time from transplant to AMR was 41.4 (24.367.7) months, and time from AMR to first tocilizumab was 10.6 (8.317.6) months. At median (IQR) follow up of 15.8 (8.435.7) months post-tocilizumab initiation, renal function was stable except for 1 allograft loss. There was no significant decrease in iDSA or RIS. Follow up biopsies showed reduction in peritubular capillaritis (p = .015) and C4d scoring (p = .009). The most frequent adverse events were cytopenias. CONCLUSIONS: Tocilizumab in pediatric patients with refractory AMR was well tolerated and appeared to stabilize renal function. The utility of tocilizumab in the treatment of AMR in this population should be further explored.

Use of a donor-derived cell-free DNA assay to monitor treatment response in pediatric renal transplant recipients with allograft rejection.

BACKGROUND: Detection of donor-derived cell-free DNA (dd-cfDNA) reliably identifies allograft rejection in pediatric and adult kidney transplant (KT) recipients. Here, we evaluate the utility of dd-cfDNA for monitoring response to treatment among pediatric renal transplant recipients suffering graft rejection. METHODS: 58 pediatric transplant recipients were enrolled between April 2018 and March 2020 and underwent initial dd-cfDNA testing to monitor for rejection. Allograft biopsy was performed for dd-cfDNA scores >1.0%. Patients with histologically proven rejection formed the study cohort and underwent appropriate treatment. Results of dd-cfDNA, serum creatinine (SCr), biopsy findings, and treatment outcomes were evaluated. Standard statistical analyses were applied. RESULTS: Nineteen of 58 (31%) patients had dd-cfDNA score >1.0%, of which 18 (94.7%) had biopsy-proven rejection. Median dd-cfDNA value was 1.90% (interquartile range 1.43%-3.23%), and biopsy results showed 11 patients (61.1%) with antibody-mediated rejection (AMR), 2 patients (11.1%) with T-cell mediated rejection (TCMR), and 5 patients (27.7%) with mixed AMR/TCMR. SCr at time of biopsy was 1.28 ± 1.09 mg/dl. Following treatment, dd-cfDNA scores decreased for all types of rejection but still remained >1.0% in both AMR (1.50% [0.90%-3.10%]) and mixed (1.40% [0.95%-4.15%]) groups. Repeat dd-cfDNA values were <1.0% for patients with TCMR (0.20%-0.28%). SCr showed minimal change from pre-treatment levels regardless of rejection subtype. CONCLUSIONS: Patients with TCMR may be reliably followed by dd-cfDNA; however, it remains unclear whether persistently elevated dd-cfDNA levels in AMR is a reflection of ongoing subclinical rejection or an inherent limitation of the assay's utility.

Development of CMV-specific cytotoxic T cells (CMV-Tc) in pediatric renal transplant recipients with CMV viremia.

BACKGROUND: Viral infections are controlled primarily by viral-specific T cells, raising concern for adequate T-cell response to clear CMV infection in transplant recipients receiving lymphocyte-depleting agents (LDA). We examined the rates of CMV viremia and clearance, seroconversion, and CMV-specific CD8+ T cell (CMV-Tc) activity with class of induction agent received. METHODS: Retrospective review of 45 pediatric renal transplant recipients who received induction with LDA (n = 31) or non-LDA (NLDA; n = 14) received valganciclovir prophylaxis for 6 months post-transplant and CMV-PCR monitoring. CMV-Tc was measured by intracellular IFNγ flow cytometry, when possible, at baseline, 1 month after CMV viremia (>5 copies/PCR) and serially until CMV-Tc was positive (≥0.2%). RESULTS: Viremia rates at 1, 2, and 4 years post-transplant were higher in LDA vs. NLDA (46.3% vs. 7.2%, 64.2% vs. 7.2%, and 64.2% vs. 7.2%, respectively; p = .002). Viremia rates at these time points in seronegative LDA (50.3%, 71.6%, 71.6%) were significantly or near significantly higher than seronegative NLDA (9.1%, 9.1%, 9.1%; p = .004), seropositive-LDA (22.3%, 22.3%, 22.3%; p = .07), or seropositive NLDA (0%, 0%, 0%; p = .07). Eleven of 17 (64.7%) viremic subjects required valganciclovir dose reduction during the prophylaxis period for leukopenia. All viremic LDA patients developed CMV-Tc. One viremic NLDA patient did not develop CMV-Tc. No patients developed CMV disease. CONCLUSION: CMV seronegative pediatric renal transplant patients receiving LDA are more likely to have valganciclovir prophylaxis dose reduction and develop subclinical CMV viremia; however, all developed CMV-Tc. Larger prospective studies are needed to further understand the effects of induction agents on CMV-Tc and CMV-Tc's role post-transplant.

Use of Rituximab for persistent EBV DNAemia, and Its effect on donor-specific antibody development in pediatric renal transplant recipients: A case series.

INTRODUCTION: Persistent EBV DNAemia (PEBV) is associated with late-onset PTLD. The efficacy of rituximab in PEBV is not conclusive. We monitored PEBV and DSA in pediatric kidney transplant patients with or without rituximab. METHODS: 13 PEBV patients received standard treatment with immunosuppression reduction and valganciclovir, with or without IVIG; 5/13 were further treated with rituximab. RESULTS: All Rituximab-treated and 6/7 No-Rituximab patients were EBV seronegative at transplant and seroconverted post-transplant. Peak EBV PCR levels were lower in No-Rituximab than Rituximab patients and all No-Rituximab patients cleared PEBV after standard treatment. Additional 1-2 doses of rituximab reduced EBV PCR levels in all 5 Rituximab patients, 3 cleared PEBV. One No-Rituximab patient developed localized PLTD. None of Rituximab patients developed de novo DSA, while 4/8 No-Rituximab patients did: 2/4 had ABMR. 1/5 Rituximab and 5/8 No-Rituximab patients had acute rejection. There was no change in eGFR between pre-EBV DNAemia and follow-up in Rituximab patients, while reduction in No-Rituximab patients was found. There was no difference in graft and patient survival. CONCLUSIONS: While early intervention with rituximab in pediatric patients with PEBV may reduce viral load and PTLD, we observed a slower development of de novo DSA, and rejection and maintenance of eGFR.

Donor-derived cell-free DNA (dd-cfDNA) for detection of allograft rejection in pediatric kidney transplants.

In pediatric transplantation, acute rejection is a major contributor of graft failure. Current approaches include kidney biopsy in response to graft dysfunction and/or the emergence of donor-specific HLA antibodies (DSA). However, biopsy is associated with potential complications. Thus, there is a need for non-invasive diagnostics. Detection of donor-derived cell-free DNA (dd-cfDNA, AlloSure) > 1% is associated with rejection in adult kidney transplants. Here, we evaluate the utility of dd-cfDNA for identifying allograft rejection in pediatric patients. Between 10/2017 and 10/2019, 67 patients, who underwent initial testing with dd-cfDNA as part of routine monitoring or in response to clinical suspicion for rejection, were included. Biopsies were performed when dd-cfDNA > 1.0% or where clinical suspicion was high. Demographics, dd-cfDNA, antibody status, and biopsies were collected prospectively. Data were analyzed to determine predictive value of dd-cfDNA for identifying grafts at risk for rejection. 19 of 67 patients had dd-cfDNA testing as part of routine monitoring with a median dd-cfDNA score of 0.37 (IQR: 0.19-1.10). 48 of 67 patients who had clinical suspicion of rejection had median dd-cfDNA score of 0.47 (0.24-2.15). DSA-positive recipients had higher dd-cfDNA scores than those who were negative or had AT1R positivity alone (P = .003). There was no association between dd-cfDNA score and strength of DSA positivity. 7 of 48 recipients had a biopsy with a dd-cfDNA score <1%; two showed evidence of rejection. Neither DSA nor AT1R positivity was statistically associated with biopsy-proven rejection. However, dd-cfDNA >1% was diagnostic of rejection with sensitivity of 86% and specificity of 100% (AUC: 0.996, 0.98-1.00; P = .002). dd-cfDNA represents a non-invasive method for early detection of rejection in pediatric renal transplants. Our study shows dd-cfDNA to be highly predictive of histological rejection and superior to other indicators such as graft dysfunction or antibody positivity alone. Further studies are necessary to refine these initial observations.

Early outcomes comparing induction with antithymocyte globulin vs alemtuzumab in two steroid-avoidance protocols in pediatric renal transplantation.

Steroid avoidance in pediatric kidney transplants was found effective with extended daclizumab induction. Upon discontinuation of daclizumab, lymphocyte-depleting agents became used, with little comparative data. We assessed outcomes in children undergoing low immunologic-risk deceased donor (DD) kidney transplants using induction with antithymocyte globulin (ATG) compared to alemtuzumab. We reviewed consecutive DD kidney transplants from January 2015 to September 2017 at two pediatric centers that used different lymphocyte-depleting agents in steroid-avoidance protocols: ATG (Center A) and alemtuzumab (Center B), with tacrolimus and MMF as maintenance immunosuppression. Anti-infective prophylaxis was based on center protocol. Over the first year post-tx, there were similar rates of infections. EBV and BK viremia were comparable though Center A manifested more low-grade CMV viremia (A 46% vs B 0%; P = .0009) at median onset 1.8 months, followed by early seroconversion. Reduction of immunosuppression did not differ between groups. DSA at 1 year was similar (A 8% vs 13%) with low rates of BPAR. Need for steroid-based conversion was low. There were no graft losses and no differences in median eGFR at 30, 90, 180, and 365 days. (a) 1-year graft outcomes are excellent in steroid-avoidance regimens using ATG or alemtuzumab induction; (b) conversion to steroid-based therapy is low; (c) alemtuzumab/high-dose MMF is associated with lower WBC and more GCSF use; (d) alemtuzumab/higher dose MMF results in more diarrhea and azathioprine conversion than ATG/lower dose MMF; (e) CMV viremia is seen more often with ATG use with infection prophylaxis reduction; however, seroconversion occurs promptly.

A phase I/II, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients.

Delayed graft function (DGF) is defined as need for dialysis early posttransplant. DGF is related to ischemia-reperfusion injury (IRI) that diminishes allograft function and may be complement dependent. Here, we investigate the ability of C1 esterase inhibitor (C1INH) to prevent IRI/DGF in kidney transplant recipients. Seventy patients receiving deceased donor kidney transplants at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours. The primary end point was need for hemodialysis during the first week posttransplant. Assessments of glomerular filtration rate and dialysis dependence were accomplished. Complications and safety of therapy were recorded. Similar characteristics with no significant differences in cold-ischemia time or risk factors for DGF were seen. C1INH did not result in reduction of dialysis sessions at 1 week posttransplant, but significantly fewer dialysis sessions (P = .0232) were required 2 to 4 weeks posttransplant. Patients at highest risk for DGF (Kidney Donor Profile Index ≥85) benefited most from C1INH therapy. Significantly better renal function was seen at 1 year in C1INH patients (P = .006). No significant adverse events were noted with C1INH. Although the primary end point was not met, significant reductions in need for dialysis and improvements in long-term allograft function were seen with C1INH treatment.

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.

Risk factors for the development of antibody-mediated rejection in highly sensitized pediatric kidney transplant recipients.

ABMR remains a significant concern for early graft loss, especially for those who are HS against HLA antigens. We sought to determine the risk factors leading to ABMR in HS pediatric kidney transplant recipients. From January 2009 to December 2015, 16 HS pediatric kidney transplant patients at our center (age range 2-21) were retrospectively reviewed for outcomes and risk factors for ABMR. All HS patients received desensitization with high-dose IVIG/rituximab prior to transplant. Two groups were examined: ABMR+ (n = 7) and ABMR- (n = 9). Patient survival was 100%; however, one patient in the ABMR+ group suffered graft loss from ABMR 16 months post-transplant. ABMR+ patients had higher Class I PRA at the time of transplant (Class I: 73.1 ± 19.1 vs 49.1 ± 28.3, P = .075), although not statistically significant. ABMR+ patients were more likely to have a history of transplant nephrectomy (P = .013). The characteristic that most strongly correlated with ABMR was the DSA-RIS (P = .045), a scoring system used to quantify cumulative intensity of all DSA. In conclusion, DSA, as quantified by the RIS at the time of transplant, should be considered as part of the initial allocation strategy and patients with high RIS monitored closely for ABMR post-transplant.

Safety and Efficacy of Alemtuzumab Induction in Highly Sensitized Pediatric Renal Transplant Recipients.

BACKGROUND: Studies show that alemtuzumab, a potent lymphocyte-depleting agent, is well tolerated in pediatric renal transplantation. We report on the use of alemtuzumab induction in highly HLA sensitized (HS) pediatric kidney transplant patients. METHODS: Fifty pediatric renal transplants were performed from 1/2009-12/2014. 15 HS patients received IVIG (2 g/kg ×2 doses)/rituximab (375 mg/m ×1) for desensitization with alemtuzumab induction (15-30 mg, 1 dose, subcutaneous), whereas 35 nonsensitized patients received anti-IL-2R. Graft survival and infections were compared between 2 groups. RESULTS: All HS patients had received a prior transplant and were older with lower risk for viral infections due to serostatus. Patient survival was 100%, and graft outcomes were similar with mean 1-year creatinine of 1.03 ± 0.45 versus 0.99 ± 0.6 (P = 0.48). Although a higher incidence of acute cellular rejection was seen in HS patients receiving alemtuzumab (P = 0.001), there was a nonsignificant difference in antibody-mediated rejection. White blood cell and absolute lymphocyte count were significantly lower in alemtuzumab group at 30 days (P < 0.0001) and at 1 year (P = 0.026 and P = 0.001), respectively. There was no significant difference in bacterial, viral, or fungal infections after transplant. CONCLUSIONS: Alemtuzumab induction with desensitization led to nearly equivalent graft survival and functional outcomes in HS pediatric patients as nonsensitized patients receiving anti-IL-2R induction. With this small sample size, we observed significant reduction of white blood cell and absolute lymphocyte count up to 1 year posttransplant. The risk of infection was comparable between the 2 groups; however, patients who received alemtuzumab were older and at lower risk of viral infection due to serostatus.

Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection.

BACKGROUND: Current therapeutic strategies to effectively treat antibody-mediated rejection (AMR) are insufficient. Thus, we aimed to determine the benefit of a therapeutic protocol using bortezomib for refractory C4d + AMR in pediatric kidney transplant patients. METHODS: We examined seven patients with treatment-refractory C4d + AMR. Immunosuppression included antithymocyte globulin or anti-CD25 monoclonal antibody for induction therapy with maintenance corticosteroids, calcineurin inhibitor, and anti-metabolite. Estimated glomerular filtration rate (eGFR) calculated by the Schwartz equation, biopsy findings assessed by 2013 Banff criteria, and human leukocyte antigen (HLA) donor-specific antibodies (DSA) performed using the Luminex single antigen bead assay were monitored pre- and post- bortezomib therapy. RESULTS: Seven patients (86 % male, 86 % with ≥6/8 HLA mismatch, and 14 % with pre-formed DSA) age 5 to 19 (median 15) years developed refractory C4d + AMR between 1 and 145 (median 65) months post-transplantation. All patients tolerated bortezomib. One patient had allograft loss. Of the six patients with surviving grafts (86 %), mean pre-bortezomib eGFR was 42 ml/min/1.73 m(2) and the mean 1 year post-bortezomib eGFR was 53 ml/min/1.73 m(2). Five of seven (71 %) had improvement of histological findings of AMR, C4d staining, and/or acute cellular rejection. Reduction in HLA DSAs was more effective for class I than class II. CONCLUSIONS: Bortezomib appears safe and may correlate with stabilization of eGFR in pediatric kidney transplant patients with refractory C4d + AMR.