Search

In this article the author talks about clinical safety and benefits of antiretroviral therapy (ART) use in HIV-infected children and adolescents. Topes discussed include HIV-associated nephropathy tends to improve following ART initiation; dramatic decrease in glomerular filtration rate (GFR); and using iohexol is the gold standard for measuring GFR in children and adults.

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/m 2 (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., (© 2024 Wiley Periodicals LLC.)

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 m 2 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 m 2 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., (© 2024 Wiley Periodicals LLC.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2021 Wiley Periodicals LLC.)

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., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

Background: Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti-IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy., Methods: From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months., Results: No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 +/- 10.5 months but after TCZ was 8.1 +/- 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor-specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 +/- 25 mL/min., Conclusions: Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy

Background: Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR., Methods: Twenty highly sensitized patients desensitized with IVIG+rituximab±plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed., Results: One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups., Conclusions: The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted.

Background: Tuberous sclerosis complex (TSC) predisposes to the development of benign lesions within multiple organ systems, including the brain, kidneys, heart, lungs, and skin. Disease mortality is due to space-occupying subependymal giant cell astrocytomas and hemorrhage-prone renal angiomyolipomas. The recent use of mTORC1 inhibitors, such as everolimus, has allowed for direct targeting of TSC-associated mass lesions without apparent effect on surrounding tissues. Because of the mechanism of these drugs, there is reason to believe that these effects are not durable and that there may be need for continued long-term maintenance therapy., Case-Diagnosis/treatment: We present a case of TSC-associated mass lesions that were ill-suited for definitive surgical therapy. The patient was started on everolimus, however due to a complex social situation treatment was discontinued and ultimately resumed many months later. Radiologic studies acquired before and after each period of therapeutic onset/cessation reveal the dramatic but impermanent effects of mTORC1 inhibition., Conclusions: While everolimus provides a non-invasive way to treat TSC-associated lesions, patients may require lifelong therapy. When termination of therapy is considered, the patient should be made aware of the expectation of potentially dramatic increases in lesion size. If consideration is to be given to definitive surgical therapy, it should be pursued while the patient is still on the medication, or at least soon after treatment is halted.

Background: Desensitization with intravenous immune globulin (IVIG) and rituximab improves transplantation rates. It is unclear if desensitization increases the risk of polyomavirus BK (BKV) viremia. Here, BKV viremia in HLA-sensitized patients after desensitization with IVIG and rituximab was analyzed., Methods: Baseline characteristics and outcomes were compared in the desensitized group (N=187) and the non-desensitized group (N=284). Surveillance for BKV viremia was done at 1, 2, 3, 6, 9, and 12 months posttransplant. Univariable and multivariable analyses were performed., Results: BKV viremia was observed in 20% of the desensitized and 10% of the non-desensitized (P<0.001) groups by 2 years posttransplant. The desensitized group had more lymphocyte depleting induction and more rejection. They also had a greater degree of viremia with more patients having a peak viral load greater than 10,000 copies per milliliter (P<0.001). However, there was no significant difference in BKV-associated nephropathy or graft loss in the two groups. There was an association of BKV viremia with desensitization and lymphocyte induction. Only desensitization remained a significant predictor in the multivariable model with an adjusted HR of 2.13 (95% CI 1.21-3.77, P=0.009)., Conclusions: Desensitization with IVIG and rituximab is associated with a higher incidence of BKV viremia with high viral copies and was the major predictor of BKV viremia in the multivariable model. More frequent surveillance for BKV viremia and an early, aggressive treatment strategy are essential for preventing high BKV viral loads in this patient population.

Induction therapy to prevent the acute rejection of mismatched allografts with the ultimate aim of prolonging the life of the allograft has been the cornerstone of immunosuppression since the introduction of renal transplantation. Agents used for induction therapy have changed over time. Their role in transplantation is expanding to include corticosteroid avoidance and immunosuppression minimization. This review provides an overview of induction therapies for renal transplantation including historic therapies such as total lymphoid irradiation and Minnesota antilymphocyte globulin, and current therapies with polyclonal and monoclonal antibodies and chemical agents, with special emphasis on children. Data from adult studies, and pediatric studies whenever available, are summarized. A brief summary of experimental therapies with fingolimod and belatacept is provided. Historically, induction therapies were targeted at T cells. The role of induction therapies targeted at B cells is emerging in select groups of patients that include highly sensitized recipients and those receiving transplants from blood group incompatible donors. With the advent of newer maintenance immunosuppressive medications and with very low rates of acute rejection, induction protocols for renal transplantation need to be targeted so that excessive immunosuppression and infections are avoided. Several single-center and registry data analyses in children suggest that the addition of an interleukin (IL)-2 receptor antagonist may improve graft survival compared with no induction. The safety profile of IL-2 receptor antagonists is indistinguishable from that of placebo, with no apparent difference in the incidence of infection or post-transplant lymphoproliferative disease. IL-2 receptor antagonists and polyclonal lymphocyte-depleting antibodies offer equivalent efficacy in standard-risk populations. However, in high-risk patients, acute rejection rates and graft outcomes may be improved with the use of lymphocyte-depleting agents such as Thymoglobulin. However, cytomegalovirus infection and other infections may be more common with this therapy. Therefore, in patients at high risk of graft loss, Thymoglobulin may be the preferred choice for induction therapy, while for all other patients, IL-2 receptor antagonists should be considered the first-line choice for induction therapy. Newer lymphocyte-depleting agents such as alemtuzumab may be better utilized in minimization regimens involving one or two oral maintenance immunosuppressive agents.

Control of CMV replication depends primarily on anti-CMV T lymphocyte activity. However, the functional T-cell responses to CMV in immunosuppressed solid organ transplant recipients are not well understood. In this study we employed cytokine flowcytometry (CFC) using pooled CMV peptides and viral lysates to detect CMV-specific T-cell responses in 17 healthy controls, 33 stable renal transplant recipients (Tx recipients) and 6 transplant recipients with active CMV infection (CMV(+)). We found that pooled peptides and lysates provide optimal detection of IFN gamma production in anti-CMV CD8(+) and CD4(+) T cells, respectively. In both healthy controls and Tx recipients, CMV-specific T-cell levels strongly correlated with serostatus. Seropositive Tx recipients have significantly higher levels of CMV-specific CD8(+) T-cell responses compared to healthy controls, which may signify an effort to control enhanced viral replication in immunosuppressed Tx recipients. In some individuals, absence of anti-CMV T-cell response may correlate with lack of viral clearance by ganciclovir therapy, even when CMV isolates are not ganciclovir resistant. Thus, monitoring cellular immunity with CFC along with viral load by PCR merits further exploration for identification of patients at the risk of developing CMV disease, tailoring prophylactic and therapeutic decisions and preventing complications.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder is a well-known complication of solid organ transplantation. The risk factors include type and degree of immunosuppression and EBV status of the donor and recipient before transplantation. The manifestations of posttransplantation lymphoproliferative disorders are myriad, from subtle findings such as tonsillar hypertrophy to fulminant manifestations such as hepatocellular failure and death. Here we report an unusual presentation of posttransplantation lymphoproliferative disorder as unilateral leg swelling in a 68-year-old man 10 years after kidney transplantation. The patient had detectable EBV-DNA by polymerase chain reaction in the peripheral blood and EBV messenger RNA by in situ hybridization in biopsy tissue. The patient's tumor did not respond to reductions in immunosuppressive medication, intravenous immunoglobulin, ganciclovir, and rituximab. Eventually the patient responded to CHOP (cyclophosphamide, Oncovin [vincristine, Eli Lilly, Indianapolis, IN], prednisone, and doxorubicin) therapy. He is currently 2 years posttreatment, with a serum creatinine of 0.8 mg/dL, on no immunosuppression.