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Background: The study purpose was to add to limited literature assessing anti‐HLA donor‐specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring. Methods: This single‐center retrospective review included intestinal/MV recipients transplanted 1/1/15–9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post‐transplant. The primary outcome was biopsy‐proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed. Results: Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post‐transplant DSA. Fifteen patients in the DSA(+) group had T‐cell‐mediated BPAR versus five in the DSA(−) group (63% vs 45%, p =.47). Days to BPAR were 25 [IQR 19–165] (DSA(+) group) versus 232 [IQR 25.5–632.5] (DSA(−) group) (p =.066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow‐up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA‐ DQ (35%). Time to first DSA and to clearance did not differ between class I and II. Conclusion: Findings confirm previous data that suggest post‐transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In recent years, treatment‐adherence gained increasing attention in nearly every area of medicine including transplant medicine. Medication adherence following solid organ transplantation is known to be indispensable for a satisfactory allograft survival. Methods: We examined 60 patients between the ages of four months and 20 years who underwent kidney transplantation at Hannover Medical School between January 2011 and August 2017. Age at transplantation varied from 4 months to 20 years. 12 patients (20%) already underwent their second solid organ transplantation. 5 patients (8.3%) had a combined kidney‐liver‐transplantation. We used two different methods for rating adherence: An objective one based on the coefficient of variation (CoV%) of immunosuppressant trough levels, and a subjective questionnaire answered by the patients themselves, their parents or legal custodians, the treating pediatrician, as well as by the attending psychologist. Results: The CoV% in our study was by‐trend higher in those patients who suffered from a biopsy‐proven rejection (x̅CoV% = 35.7, σ CoV% = 30.1 in patients with rejection vs. x̅ CoV% = 26.0, σ CoV% = 10.5 in patients without rejection). Furthermore, the psychologist's assessment correlated significantly both with rejections as well as with the formation of de novo donor‐specific antibodies (dnDSA) while the pediatrician's rating showed no correlation (Prejections = 0.005 and PdnDSA = 0.03 for psychologist's rating vs. Prejections = 0.50 and PdnDSA = 0.50 for pediatrician). Conclusions: Apart from underlining the importance of medication adherence, the present research stresses the role of a multi‐disciplinary treatment approach to support pediatric renal transplant recipients and their families. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: HLA epitope‐based matching offers the potential to improve immunological risk prediction and management in children receiving renal allografts; however, studies demonstrating the association between systems for defining epitope mismatches and clinical end‐points are lacking in this population. Methods: We conducted a pragmatic, retrospective, registry‐based study of pediatric recipients of primary renal allografts in Victoria, Australia between 1990 and 2014 to determine the association between HLA EpMM and clinical outcomes including graft failure, re‐transplantation and dnDSA formation. Results: A total of 196 patients were included in the analysis with a median age of 11 years. Median follow‐up period was 15 years during which time 108 (55%) primary grafts failed and 72 patients were re‐transplanted. HLA class I but not class II EpMM was a significant predictor of graft failure on univariate analysis but not in adjusted models. EpMM was associated with reduced likelihood of re‐transplantation in univariate but not adjusted analysis. Within the limitations of the study, class‐specific EpMM was a strong predictor of dnDSA formation. Associations were stronger when considering only the subset of antibody‐verified EpMM. Conclusion: Associations between HLA EpMM and clinical outcomes in pediatric renal allograft recipients seen on univariate analysis were attenuated following adjustment for confounders. These findings are inconclusive but suggest that HLA EpMM may provide one tool for assessing long‐term risk in this population while highlighting the need for further clinical studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Preformed and de novo donor specific antibodies ( pDSA and dn DSA) are risk factors for ABMR. This study compares the effects of pDSA vs dn DSA 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 dn DSA. Patients with pDSA developed ABMR earlier (median = 63 vs 1344 days, P = .017), while patients with dn DSA 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 dn DSA (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 dn DSAs exhibited higher C4d+ ABMR ( P = .013). Patients developing dn DSAs showed ABMR later post-transplant with predominance of HLA-Class II iDSAs. Inadequate immunosuppression likely contributes to dn DSA formation. Patients with no DSA who have unprotocolized decreases in immunosuppression should be screened for dn DSA as it could lead to early intervention and potentially better outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Acute AMR is well reported following ABO-incompatible LTx. However, it remains uncommon in ABO-compatible LTx. It typically presents with graft dysfunction ≤2 weeks post- LTx and is often associated with graft loss. We report the clinical presentation, treatment regimen, and outcome of six pediatric LTx recipients diagnosed with early acute AMR based on (i) clinical signs of graft dysfunction, (ii) histopathology indicative of acute injury ± C4d staining, and (iii) presence of HLA DSA. All patients developed elevated ALT and GGT ≤ 45 days post- LTx. All showed HLA class I (n=4) and/or II (n=6) DSA (peak MFI 6153-11 910). Four had de novo DSA, and two had preformed DSA. Five were initially diagnosed with ACR refractory to steroid therapy. Four exhibited resolution of graft dysfunction with AMR therapy. Two had refractory AMR-one was re-transplanted; the other was treated with eculizumab and showed improvement in graft function but later died due to a tracheostomy complication. Our case series suggests that AMR following ABO-compatible LTx may be under-diagnosed. The presentation can be variable, and treatment should be individualized. Eculizumab may be an option for refractory AMR. Ultimately, future multicenter studies are needed to better define diagnostic criteria, characterize optimal treatment, and assess long-term outcomes following liver AMR. [ABSTRACT FROM AUTHOR]

The association of blood transfusions with GS after pediatric KTx is unclear. We retrospectively analyzed blood transfusions post- KTx and subsequent outcomes. Between 1984 and 2013, 482 children (<18 years of age) underwent KTx at our center. Recipient demographics, outcomes and transfusion data were collected. Cox regression with post- KTx blood transfusion as a time-dependent covariate was performed to model the impact of blood transfusion on outcomes. Of the 208 (44%) that were transfused, 39% had transfusion <1 month post- KTx; 48% >12 months. Transfused and non-transfused recipients were not significantly different. In univariate and multivariate analyses, there was no difference between transfused and non-transfused recipient patient survival, antibody-mediated and ACR, and DSA free survival. Transfusions <1 month post- KTx did not impact DCGS ( P= NS). Patients transfused >12 months post- KTx had significantly lower 12 month eGFR (compared to non-transfused) and worse subsequent DCGS. Post- KTx blood transfusions have increased in pediatric KTx over time but have no negative association with rejection or DSA production. DCGS is unaffected by transfusion within first month. Transfusions after the first year occur in patients with more advanced chronic kidney disease and are associated with significantly worse DCGS. [ABSTRACT FROM AUTHOR]

Although de novo DSA are associated with inferior graft survival, there are no effective strategies to prevent their formation. Underexposure to MPA (prodrug: MMF) also contributes to rejection rates early after transplantation, but the effect of this phenomenon on the formation of DSA long-term post-transplantation is unknown. Data are expressed as mean (standard deviation). All available data from 32 renal transplant recipients (age at transplantation 7.5 [4.5] yr) on tacrolimus and MPA immunosuppression with an average follow-up of 9.4 (s.d. 4.6) yr were analyzed. DSA were measured using the Luminex assay (>500 MFI was considered DSA-positive). Tacrolimus and MPA levels were measured with the Abbot Tacro II and EMIT assay, respectively. Among 1964 MPA and 3462 tacrolimus trough levels, the average MPA trough level was 3.2 (1.5) mg/L and the average tacrolimus level was 6.7 (2.8) ng/mL. At last follow-up, only 5/32 patients had undetectable DSA, with 5/32 having no class I antibodies and 6/32 having no class II antibodies. DSA formation was associated with a lower minimum MPA trough level (0.27 [0.23] vs. 0.47 [0.18] mg) and cystatin C eGFR (48 [21] vs. 70 [23] mL/min/1.73 m2) for class I DSA formers. The average eGFR of patients without class I DSA was 70 (23) mL/min/1.73 m2, whereas the average eGFR of patients with class I DSA was 48 (21) mL/min/1.73 m2 (p = 0.0071). MPA trough levels <1.3 mg/L long-term post-transplantation are associated with the formation of DSA. The association between the formation of DSA and minimum MPA exposure may support a strategy for preventing the formation of DSA. [ABSTRACT FROM AUTHOR]

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 u m 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. [ABSTRACT FROM AUTHOR]

Long-term graft survival and function has not kept pace with short-term success in kidney transplant (Tx) recipients. LAR ≥6 months post-Tx may contribute to lack of improvement; risk factors for LAR are not well known. Of 64 Tx recipients followed over six yr, 23 (35.9%) had LAR ( LAR group) and 41 had no LAR (no LAR group). Of all variables, significant risk factors for LAR included DGF, (43.4% LAR vs. 14.6% in no LAR group, p = 0.0096); de novo DSA (65.2% vs. 26.8%, p = 0.003); mean COV% of TAC (41.8% vs. 34.6%, p = 0.03); and non-adherence (34.8% vs. 7.3%, p = 0.0043). DGF and DSA remained statistically significant (p = 0.002 and 0.003, respectively); COV% TAC had borderline significance (p = 0.057), and non-adherence was not significant on multivariate regression analysis. Patients with LAR had inferior graft survival and function, whereas graft function was stable in the no LAR group over a mean follow-up of 31.2 months. Patients with de novo DSA and DGF should be considered at risk of LAR; an early diagnosis and treatment of LAR may improve graft survival and function. [ABSTRACT FROM AUTHOR]

Butani L, Gallay BJ. Acute humoral rejection in pediatric renal transplant recipients receiving steroid minimization immunosuppression. Abstract: 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. [ABSTRACT FROM AUTHOR]

Gloor JM. The utility of comprehensive assessment of donor specific anti-HLA antibodies in the clinical management of pediatric kidney transplant recipients. Pediatr Transplantation 2011: 15: 557-563. © 2010 John Wiley & Sons A/S. Abstract: Advances in anti-HLA antibody characterization have had a major impact on kidney transplantation. Comprehensive characterization of DSA has improved protocols for allosensitized transplant candidates, increasing access to acceptable donors. Sensitive and specific solid phase antibody detection assays have given important insight into the clinical characteristics of antibody-mediated allograft injury, resulting in the development of a classification system for acute AMR. In addition, important insights into the nature of chronic antibody-mediated allograft rejection have been achieved as a result of improvements in DSA characterization. Finally, assays initially developed as tools to detect DSA in the clinical setting have been employed in innovative research protocols, allowing the investigation of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

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

Flow PRA and SAB are now routinely performed to identify HLA antibodies in the recipient sera. The presence of DSA is considered a risk factor for graft failure. However, this risk is not clearly defined. We reviewed all the pediatric recipients of living donor kidney transplants since Flow PRA and Flow SAB became routinely done at our institution. All children had negative CDC and Flow XMs. Comparison of clinical outcome was done between those with and without pretransplant DSA. Six children had positive DSA by Flow SAB. They received thymoglobulin, steroids, tacrolimus, and MMF. Five had anti-HLA class I antibodies and one anti-HLA class II. Only one child had an AR. Graft survival: 100% at last visit with GFR >70 mL/min/1.73 m2. A control group without DSA was used for comparison (n = 44). They received our standard protocol: basiliximab, tacrolimus, MMF, and steroids. AR rate was 9%. Both groups had similar follow-up time, and patient and graft survival rates. In our small series, we saw excellent outcome despite the presence of DSA pretransplant. No unequivocal ideal to establish the ideal immunosuppressive regimen for this cohort of patients has been established and the long-term outcome of these recipients has not been delineated. [ABSTRACT FROM AUTHOR]

BK DNAemia in renal transplant recipients is a significant cause of allograft dysfunction and can lead to graft loss due to BK polyomavirus–associated nephropathy or to graft rejection due to immunosuppression reduction. Currently, the first‐line treatment for BK DNAemia is immunosuppression reduction. Second‐line treatment for BK DNAemia has not been well‐established. In this report, we present a case of a highly sensitized second‐time pediatric renal transplant recipient with severe and persistent BK DNAemia and rising DSA, who was treated with IVIG and subsequently found to have clearance of BK viremia with concomitant reduction in DSA. [ABSTRACT FROM AUTHOR]

Trichodysplasia spinulosa (TS) is a rare cutaneous condition associated with the TSPyV and characterized by skin‐colored, folliculocentric papules with keratin spicule formation. TS is seen almost exclusively in immunosuppressed individuals, often presenting in patients with a history of solid organ transplantation or chemotherapy for a lymphoreticular malignancy. We report a case of widespread TS in a 9‐year‐old girl with a history of renal transplantation complicated by BK viremia, which is also caused by a polyomavirus, BKPyV. The clinical presentation of TS in this case morphologically resembled the more common, harmless skin condition known as "lichen nitidus," and was more extensive than expected for TS, creating a diagnostic challenge. This case illustrates an important presentation of severe TS of which transplant teams, oncologists, primary care providers, and dermatologists should be aware. [ABSTRACT FROM AUTHOR]