Rejection In Pediatric Patients Research Articles

Understanding Pediatric Kidney Transplant Rejection: Its Pathophysiology, Biomarkers, and Management Strategies.

End-stage kidney disease requires comprehensive management strategies to ensure patient survival and improve quality of life. Kidney transplantation remains the preferred treatment option, offering superior long-term outcomes. However, graft rejection remains a significant concern, and pediatric patients often require tailored immunosuppressive regimens due to differences in immune response compared to adults. Although the past decade has seen significant improvements in graft and patient survival among pediatric kidney transplant recipients, many questions remain unanswered. There is an ongoing search for non-invasive biomarkers capable of timely detecting graft rejection and novel treatment regimens, specifically tailored to pediatric practice. This review aims to discuss the current knowledge on kidney transplant rejection in pediatric patients, including epidemiology, pathophysiology, and risk factors. In addition, it seeks to explore the latest advancements in biomarkers for early detection of rejection and evaluate current and emerging immunosuppressive therapies. The possible outcomes of this review include identifying gaps in current research, providing recommendations for future studies, and suggesting strategies to enhance clinical practice. By synthesizing the latest evidence, this review aims to contribute to improved long-term outcomes and quality of life for pediatric kidney transplant recipients.

Relation between global longitudinal strain and acute rejection in pediatric patients within the first-year post heart transplant

BackgroundAcute rejection leading to graft dysfunction remains a major cause of morbidity and mortality. In adults, assessment of global longitudinal strain (GLS) using speckle tracking echocardiography (STE) has been used as an early marker for graft dysfunction. Studies evaluating GLS in a sizable pediatric transplant population are scarce. ObjectivesWe sought to determine association between GLS and acute rejection within first-year post-transplantation in pediatric patients. MethodsPatients 0 to 18 years old who received heart transplants (HT) at Cleveland Clinic Children's Hospital after April 2013 were identified. Clinical data was collected from pre-transplant evaluation and post-transplant surveillance endomyocardial biopsy (EMB) visit from time of transplantation to one-year post-transplantation. Left ventricular (LV) GLS was measured retrospectively using vendor independent software. Significant rejection was defined by escalation in immunosuppression therapy due to pathology or clinical diagnosis. Trends of GLS were compared between patients with (Group 1) and without (Group 2) rejection, controlled for age. At the visit of rejection diagnosis, GLS rejection measurements were compared to the range of “normal”, non-rejection measurements. ResultsTwenty-seven patients met inclusion criteria. Eight patients (29.6 %) had at least one clinically significant rejection episode. There was no significant difference in GLS at the first endomyocardial biopsy visit between groups. At last biopsy visit, subjects with rejection had significantly worse GLS (p ≤ 0.001). In a mixed effect model, average global, 3-chamber, and 4-chamber systolic strain had significant interaction of group and time (p = 0.016, 0.033, 0.003, respectively). Systolic strain in those views significantly worsened over time in rejection group while remaining stable in non-rejection group. GLS of subjects with rejection were worse and out of the range of “normal” by the time of the third EMB visit. ConclusionsThere was a trend toward worse GLS in those who developed acute rejection within first year post-transplant compared to those without rejection.

Short-Course Total Lymphoid Irradiation in Management of Pediatric Heart Transplant Rejection

<h3>Purpose/Objective(s)</h3> To evaluate short-course total lymphoid irradiation (TLI) as treatment for refractory heart transplant rejection in pediatric patients. <h3>Materials/Methods</h3> Pediatric patients who received short-course TLI for treatment of recurrent heart transplant rejection at a single institution were retrospectively reviewed. Radiotherapy consisted of 448 cGy in 4 fractions delivered once daily consecutively. This regimen was previously reported in a small series of adults but has not been reported in children. Potential advantages of short-course TLI compared to a more standard 800 cGy in 10 fractions delivered twice weekly (over 5 weeks) include fewer anesthesia sessions, lower cumulative dose, and patient convenience. <h3>Results</h3> Between 2019-2021, 3 pediatric patients (ages 4, 15, 17; 1 girl, 2 boys) received short-course TLI for chronic or recurrent rejection after cardiac allograft transplant. TLI was delivered between 5-51 months after heart transplantation, and time from initial rejection to TLI was 4-30 months. All patients were critically ill with limited medical options to manage rejection at time of TLI. They all received TLI as planned without need for modification due to acute toxicity. Two patients achieved resolution of rejection after TLI. One of these patients was rejection free on endomyocardial biopsy 3 months later and was alive 6 months after TLI with no complications related to TLI. The other patient's endomyocardial biopsy at 3 months also demonstrated no evidence of rejection and was able to undergo a second heart transplant 8 months after TLI for heart failure that was present prior to TLI. This patient was alive 3 years after TLI with no complications related to TLI. One patient died within 1 month of TLI due to multi-organ failure and thus the effects of TLI were not able to be fully assessed. <h3>Conclusion</h3> Short-course TLI was well-tolerated and significantly reduced the duration of the radiation treatment course in comparison to standard course; this is particularly advantageous in young patients who require anesthesia as well as acutely ill patients with poor performance status. Fortunately, alternative anti-rejection therapies are often effective and TLI is rarely requested, but if required a short-course TLI regimen remains an option.

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.

Flow Cytometry Based Chimerism Analysis Can Predict Graft Rejection in Pediatric Patients Receiving HLA Mismatched Stem Cell Transplantation

AbstractAbstract 4156Graft failure is a life-threatening complication after allogeneic stem cell transplantation and its probability increases with the degree of HLA disparity between donor and recipient. In HLA-mismatched transplantation, specific T cells against mismatched HLA class I alleles were shown to be associated with rejection. Moreover, HLA mismatches allow to monitor the chimerism status of several cell populations by flow cytometry with specific monoclonal antibodies against HLA alleles with high sensitivity even in very low cell numbers. We report our experience with this method in a cohort of 90 pediatric patients who received T and B cell depleted haploidentical stem cells after myeloablative conditioning regimens. Diagnoses were: leukemias n=43, solid tumors n=28, non malignant diseases n=19. Graft manipulation was carried out by magnetic microbeads and the clinimacsÒ device with 4 to 5 log depletion efficacy. Conditioning regimens were TBI, Bu or Mel based and comprised ATG or OKT3. Immunosuppression with mycophenolate mofetil (MMF) was given in most patients (if donor T cells in the graft exceeded 25.000/kg body weight) Flow cytometry with HLA antibodies for detection of chimerism status of T and NK cell subsets in peripheral blood was started at day 0 and was repeated at least weekly. 14 out of 90 patients (15%) rejected the graft between day 19 and 86 (median day 33). Two different rejection patterns were observed: early rejections (diagnosis of rejection, day 19–40, median day 28) with cytokine release syndrome including high fever, massive elevation of CRP, ferritin, LDH and D-Dimers or late rejections without signs of inflammation (diagnosis of rejection, day 53–86). In all patients, residual T cells of recipient origin were still detectable after the conditioning procedure. The portion of residual recipient T cells within the first week (day 0–7) was predictive: Non-rejectors had a median percentage of 46+-5% recipient T cells detectable (n=42 analyses) whereas rejectors showed a significant higher percentage (85+-7%, n=13 analyses, p<0.001). In more than 90% of the rejectors, the portion of detectable autologous recipient T cells exceeded 60%. Thus, the risk of rejection for patients with >60% detectable recipient T cells was 41% (12 out of 29 rejected), whereas patients with <60% recipient T cells had a risk of 4% (only 1 out of 27 rejected; p=0.001). In non-rejectors, recipient T cells where detectable at a very low level (median 0,7/μl) up to day 60 without proliferation tendency, whereas strongly increasing and significantly higher numbers were observed in rejectors (from 3/μl at day 0–3 up to 617/μl at day 15–18; p< 0,05 for all data pairs). Based on these data, donor lymphocyte infusions (DLI) and cessation of MMF were performed in 12 patients with increasing residual recipient T cells to prevent imminent rejection (1–4 infusions, median number: 1; starting dose: 25.000 CD3+cells/kg bw). Recipient T cells were reduced/eradicated in 7/12 patients (60%) after DLIs and no rejection occurred. In 5 patients, DLIs had no impact on increasing recipient T cells, resulting in graft rejection in 4 out of these 5 patients. Conclusions:Flow cytometry with specific monoclonal antibodies against HLA alleles allows to analyze the origin of lymphocyte subsets and their kinetics after HLA mismatched transplantation with high sensitivity even in very low cell numbers. The percentage of residual recipient T cells in the first week posttransplant was predictive, since patients with >60% detectable recipient T cells had a significantly higher risk to experience graft rejection. In all cases, rejection was associated with increasing recipient T cells. Intervention with DLI and cessation of immune suppression may contribute to prevent rejection. Disclosures:No relevant conflicts of interest to declare.

Early recipient chimerism testing in the T- and NK-cell lineages for risk assessment of graft rejection in pediatric patients undergoing allogeneic stem cell transplantation

Timely diagnosis of impending graft rejection is crucial for effective therapeutic intervention after allogeneic hematopoietic stem cell transplantation (SCT). We have investigated the predictive potential of early leukocyte subset-specific chimerism for graft loss in children undergoing SCT. In total, 192 pediatric patients transplanted for the treatment of malignant and non-malignant diseases after reduced-intensity or myeloablative conditioning were investigated. Surveillance of lineage-specific chimerism was initiated upon first appearance of leukocyte counts amenable to cell sorting. Graft rejection occurred in 23 patients between 24 and 492 days post-transplant (median 63 days). The first chimerism analysis of T and NK cells performed at a median of 20 days after SCT identified three different risk groups that were independent from the conditioning regimen: recipient chimerism (RC) levels in T cells below 50% indicated a very low risk of rejection (1.4%), whereas high levels of RC (>90%) both in T and NK cells heralded graft loss in the majority of patients (90%) despite therapeutic interventions. RC >50% in T cells and ≤90% in NK cells defined an intermediate-risk group in which timely immunotherapy frequently prevented rejection. Early assessment of T- and NK-cell chimerism can therefore be instrumental in the risk assessment and therapeutic management of imminent graft rejection.

Impact of acute cellular rejection on coagulation and fibrinolysis biomarkers within the immediate post-operative period in pediatric liver transplantation

We studied restoration of the coagulation and fibrinolysis system in pediatric patients following liver transplantation and biomarkers of blood coagulation and fibrinolysis for suspecting the occurrence of acute cellular rejection. Coagulation activity recovered rapidly within two days following transplantation, but it took approximately 21-28 days for full recovery of the coagulation and fibrinolysis factors synthesized in the liver. PAI-1 levels were significantly higher in patients at the time of acute cellular rejection compared with levels after control of AR, and levels on days 14 and 28 in patients without AR. Plasma protein C and plasminogen levels at the time of rejection were significantly lower than those on day 14 in patients without AR. Statistical analysis suggested that an increase in plasma PAI-1 at a single time point in the post-operative period is a reliable marker among the coagulation and fibrinolysis factors for suspecting the occurrence of acute cellular rejection. These data suggested that appropriate anticoagulation may be required for 14 days after liver transplantation in order to avoid vascular complications and measurement of plasma PAI-1 levels may be useful for suspecting the occurrence of acute cellular rejection in pediatric patients following liver transplantation.

Retransplantation with stem cells from mismatched related donors after graft rejection in pediatric patients

Graft failure is a life-threatening complication after transplantation of hematopoietic stem cells. We report a cohort of 11 pediatric patients with leukemias ( n = 8) and severe aplastic anemia ( n = 3) who experienced graft rejection after myeloablative transplantation from mismatched related donors ( n = 6) or after cord blood or matched unrelated donor transplantation ( n = 5). In the latter, the original donor was not available anymore. All patients were re-transplanted with CD34 + selected or CD3/CD19 depleted stem cells from a second, haploidentical donor. Median time span from diagnosis of rejection to second transplant was 9 days. Reconditioning regimens comprised total lymphoid irradiation, thiotepa, fludarabine, ATG/OKT3 and were well tolerated. A median number of 23.5 × 10 6/kg stem cells with 95,000/kg residual T-cells were infused. Sustained engraftment of neutrophiles/platelets and complete donor chimerism was achieved in all patients (ANC > 500/μl: 9 (11–32) days). No GvHD > grade II was observed. 8/11 patients are disease free (median follow up 1.9 years; 1 year-EFS = 72%). Causes of death were: pneumonitis, infection, relapse. Thus, haploidentical transplantation represents a realistic option to rescue patients with graft failure within a short time span, for whom a second donation from the original donor is not available. The use of different donors may contribute to avoid a second rejection.

Retransplantation with Stem Cells from Mismatched Related Donors after Graft Rejection in Pediatric Patients.

Graft failure is a rare but life-threatening complication after transplantation of hematopoietic stem cells. Treatment comprises immunoablative reconditioning regimens and a second stem cell donation from the same or from a different donor as soon as possible to minimize the time of pancytopenia and its sequelae.We report a cohort of 11 pediatric patients with leukemias (acute lymphatic n=4, acute or chronic myeloic/MDS n=4) and severe aplastic anemia (n=3) who experienced graft rejection after TBI, busulphan or melphalan based myeloablative transplantation from mismatched related donors (MMRD) (n=6) or after cord blood/matched unrelated donor (MUD) transplantation (n=5) between 2000 and 2006. In the latter the original donor was not available a second time. Thus, all patients were re-transplanted with CD34+ positive selected or CD3/CD19 depleted stem cells from a second, haploidentical parental donor (MACS method, Miltenyi Biotec). Median time span from diagnosis of graft rejection to second donation was 16 days. The reconditioning regimens consisted of total lymphoid irradiation or cyclophosphamide, thiotepa (5mg/kg), fludarabine (120 mg/m2) and ATG/OKT3. A median number of 25×106/kg of body weight stem cells with 60.000/kg residual T cells were infused. Mofetilmycophenolat was given as GvHD prophylaxis, if residual T cells exceeded 25 000/kg bw. Sustained engraftment was achieved in all patients (ANC>500/μl: 9 (11–32) days). No GvHD > grade II was observed. T cell recovery was delayed, however no lethal viral infection occurred. Severe organ toxicity was observed in 2 patients (BOOP, hemorrhagic cystits) and moderate mucositis in 11 patients. 8/11 patients are disease free (median follow up 1.5 (0.3–6.6) years; 1 year EFS=73%). Causes of death were: BOOP (n=1), infection (n=1); only one patient with refractory AML relapsed. Thus, transplantation of stem cells from haploidentical donors represents a realistic option to rescue patients with graft failure within a short time span and for whom a second donation of the original donor is not available. The use of a different donor may help to avoid a second rejection.

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

Long-term follow-up after total lymphoid irradiation in pediatric heart transplant recipients

Background Total lymphoid irradiation (TLI) is used to treat recurrent allograft rejection. Short-term success and complication rates have been reported in pediatric and adult cardiac transplant populations. We report the long-term efficacy and safety of TLI in treating intractable rejection in pediatric patients. Methods Eight pediatric patients were treated with TLI (7 for recurrent rejection, 1 for risk of medication non-compliance). Therapy consisted of a mid-plane dose of 8 Gy administered with a 6-MeV linear accelerator using an anterior–posterior opposed technique. We reviewed outcomes for a total of 40 patient-years of follow-up. Results We encountered rejection (>Grade 2 by International Society for Heart and Lung Transplantation criteria) in 56.7% ± 34.7% of biopsies performed within 90 days before TLI. Rejection rates dropped to 3.1% ± 8.8% within the first 90 days ( p < 0.005) after therapy and remained low at 5.6% ± 1.3% ( p < 0.05) during the first year after completion of TLI. Median time from TLI to the first subsequent rejection episode was 305 days (range, 77–1,920 days). Long-term follow-up (>3 years) of 5 patients demonstrated a continuing low incidence of rejection. Non-Hodgkin’s lymphoma was diagnosed in 1 of 8 patients, graft coronary artery disease in 4 of 8 patients, and restrictive cardiomyopathy in 1 of 8 patients after TLI. Conclusions Total lymphoid irradiation is an effective treatment for recurrent rejection and has short- and long-term efficacy. Morbid events may include cancer, graft coronary artery disease, and restrictive cardiomyopathy.

Comparison of Quantitative Echocardiography With Endomyocardial Biopsy to Define Myocardial Rejection in Pediatric Patients After Cardiac Transplantation

Endomyocardial biopsy is the gold standard for determining rejection; however, no echocardiographic indexes have been widely accepted as indicators of rejection. The stress-velocity relation of corrected velocity of circumferential fiber shortening to wall stress is a preload independent index of contractility that incorporates afterload and has been shown to distinguish a decreased velocity caused by excess afterload from that caused by decreased contractility. Wall stress has not been previously reported as a determinant of rejection. We report a prospective double-blind study of pediatric cardiac transplant patients comparing biopsy and quantitative systolic echocardiographic data. Thirty-two pediatric patients underwent 67 biopsies. At the time of catheterization, an echocardiographic evaluation was performed. Standard measurements of systolic function were collected and left ventricular (LV) fractional shortening, LV volume, LV mass, velocity of circumferential fiber shortening, and estimated end-systolic wall stress were calculated. In evaluating echocardiographic data of patients with and without biopsy-proven rejection, we were unable to identify any significant correlation between any systolic echocardiographic parameter and rejection. We conclude that: (1) the stress-velocity relation does not detect myocardial rejection; and (2) neither LV fractional shortening, LV volume, nor LV mass detect rejection; and (3) central venous pressure influence wall stress values significantly.

Decreased urinary excretion of nitric oxide in acute rejection episodes in pediatric renal allograft recipients.

Acute renal allograft rejection continues to have a negative effect on graft survival despite a better understanding of the molecular basis of renal allograft rejection. Nitric oxide (NO) has important biological functions in cell defense and injury and some evidence exists that it may act as an immunomodulator in allograft transplantation. To determine if NO has any role in acute renal allograft rejection in pediatric patients, acute rejection episodes in pediatric renal transplant recipients were evaluated. Four out of eleven patients who received a renal allograft in 1995 at Children's Kidney Center at The Children's Hospital of Buffalo had eight episodes of acute rejection. One patient received a living-related and three received cadaveric grafts. Stable metabolites of NO (NO-2 + NO-3 = NOx) were measured in the serum and urine samples of the patients daily. Serum levels of NO did not change significantly during acute rejection episodes. Urinary NOx levels decreased by 73+/-9% of the baseline values during episodes of acute rejection: mean +/-SE urinary nitric oxide/creatinine ratio (NOx/Cr) of 0.17+/-0.05 at baseline vs. 0.05+/-0.01 during rejection (P=0.02). Successful treatment of acute rejection by administration of high dose i.v. steroids or OKT-3 induced acute rises in the urinary NO levels to baseline values: NO/Cr = 0.17+/-0.04 (mean +/-SE). We conclude that urinary NO excretion decreases significantly during acute renal allograft rejection and that NOx concentration in the urine increases in response to successful antirejection therapy.

Incidence of rejection in pediatric patients following living-related orthotopic liver transplantation (OLT)

Incidence of rejection in pediatric patients following living-related orthotopic liver transplantation (OLT)

OKT3 monoclonal antibody reversal of renal and hepatic rejection in pediatric patients

The monoclonal antibody OKT3 was previously shown to be superior to conventional high-dose steroid therapy for reversal of acute rejection of renal allografts. Furthermore, OKT3 was effective in reversing acute renal or hepatic allograft rejection that was resistant to treatment with steroids, anti-thymocyte globulin, or both. Our analysis demonstrates that OKT3 is also effective in pediatric patients in reversing acute rejection of renal allografts (rescue treatment) or hepatic allografts (primary or rescue treatment).