Risk Factor For Allograft Dysfunction Research Articles

Incidence, risk factors, management strategies, and outcomes of antibody-mediated rejection in pediatric kidney transplant recipients-a multicenter analysis of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN).

This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5years post-transplant. The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5; the corresponding data for de novo class II HLA-DSA were 10%, 22.5%, and 30.6%, respectively. For 5years post-transplant, the cumulative incidence of acute ABMR was 10% and that of chronic active ABMR was 5.9%. HLA-DR mismatch and de novo HLA-DSA, especially double positivity for class I and class II HLA-DSA, were significant risk factors for ABMR, whereas cytomegalovirus (CMV) IgG negative recipient and CMV IgG negative donor were associated with a lower risk. BKPyV nephropathy was associated with the highest risk of graft dysfunction, followed by ABMR, T-cell mediated rejection, and older donor age. This study provides an estimate of the incidence of de novo HLA-DSA and ABMR in pKTR and highlights the importance of BKPyV nephropathy as a strong risk factor for allograft dysfunction.

Bortezomib for antibody-mediated rejection of kidney transplant in youth: Associations with donor-specific antibody.

Antibody-mediated rejection is one of the most significant risk factors for allograft dysfunction and failure in children and adolescents with kidney transplants, yet optimal treatment remains unidentified. To date, there are mixed findings regarding the use of Bortezomib, a plasma cell apoptosis inducer, as an adjunct therapy in the treatment of antibody-mediated rejection. In a retrospective single center study, we reviewed the efficacy and tolerability of bortezomib as adjunct therapy for treatment-refractory antibody-mediated rejection. Six patients with a median age of 14.6 years (range 6.9-20.1 years) received bortezomib at a mean of 71 months (range 15-83 months) post-kidney transplant. Four patients experienced decline in estimated glomerular filtration rate (eGFR) from 4% to 42%. One patient started bortezomib while on hemodialysis and did not recover graft function, and another patient progressed to hemodialysis 6 months after receiving bortezomib. Although DSA did not completely resolve, there was a statistically significant decline in DSA MFI pre and 12-months post-BZ (p = .012, paired t-test) for the subjects who were not on dialysis at the time of bortezomib. Chronic Allograft Damage Index (CADI) score of ≥3 was seen in all six subjects at their biopsy prior to therapy. No adverse effects were reported. Bortezomib was well tolerated and resulted in improvements in MFI of DSA among four pediatric subjects without allograft failure, although no effects were observed on eGFR trajectory. Further studies are needed to clarify whether earlier intervention with bortezomib could prevent renal failure progression.

Hyperparathyroidism Is an Independent Risk Factor for Allograft Dysfunction in Pediatric Kidney Transplantation

Little is known about the consequences of deranged chronic kidney disease-mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. This registry study from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) collected data at baseline, months 1, 3, 6, 9, and 12 after transplant; and every 6 months thereafter up to 5 years. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR)≤30 ml/min per 1.73 m2 or a≥50% decline from eGFR at month 1 posttransplant was performed. Associations of parathyroid hormone (PTH), calcium, phosphate, and 25-hydroxyvitamin D (25(OH)D) with allograft outcome were investigated using conventional stratified Cox proportional hazards models and further verified with marginal structural models with time-varying covariates. We report on 1210 patients (61% boys) from 16 European countries. The composite end point was reached in 250 grafts (21%), of which 11 (4%) were allograft losses. In the conventional Cox proportional hazards models adjusted for potential confounders, only hyperparathyroidism (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.74) and hyperphosphatemia (HR, 1.94; 95% CI, 1.28-2.92) were associated with the composite end point. Marginal structural models showed similar results for hyperparathyroidism (HR, 2.74; 95% CI, 1.71-4.38), whereas hyperphosphatemia was no longer significant (HR, 1.35; 95% CI, 0.87-2.09), suggesting that its association with graft dysfunction can be ascribed to a decline in eGFR. Hyperparathyroidism is a potential independent risk factor for allograft dysfunction in children.

Anemia after kidney transplantation.

Anemia is a frequent complication in pediatric kidney transplant recipients (KTR) with a variable reported prevalence estimated between 20 and 80% depending on how defined. Causes of and risk factors for post-transplantation anemia (PTA) are multifactorial with iron deficiency being the primary cause of early PTA (within the first 6months after transplantation) and impaired glomerular filtration rate (GFR) commonly responsible for late PTA (after 6months). Medications, viral infections, chronic inflammation, and comorbidities also play a role. PTA has relevant long-term consequences and is a potential risk factor for allograft dysfunction, cardiovascular morbidity, and mortality. Thus, an anemia evaluation, approximately 3months post-transplantation, is recommended in order to start early treatment and improve prognosis. Iron status, vitamin B12, folate, markers of hemolysis, and viral PCR should be checked, and medications, in particular combinations of medications, should be carefully evaluated. PTA treatment may be challenging and should be directed to the underlying causes. Iron supplementation and erythropoietin therapy, not extensively used in KTR, may be indicated. Every effort should be made to avoid blood transfusions in the pre-transplant period to avoid allosensitization. Anemia should be corrected to prepare candidates for kidney transplantation in order to reduce the need for perioperative blood transfusions as well.

DIFFERENTIAL IMPACT OF ALLOGRAFT REJECTION ON KIDNEY TRANSPLANT PATIENTS WITH BKV INFECTION

Background: BK virus-associated nephropathy (BKVAN) is a known risk factor for allograft dysfunction and graft failure in kidney transplant recipients. The mainstay of treatment for BKVAN is reduction of immunosuppression and this may increase risk for acute rejection. We proposed to observe the effects of acute rejection on patients with BKVAN. Methods: Using data from the Korean Organ Transplantation Registry, a nationwide organ transplantation database, we com pared graft function, and allograft survival in BKVAN patients with or without biopsy proven acute rejection (BPAR). Results: Among the 5,403 patients who received kidney transplantation between 2014 and June 2019, a total of 97 patients were diagnosed with BKVAN. Twenty-six patients (27%) developed BPAR within 6 months of BKVAN diagnosis, 71 patients did not. There were no differences in baseline characteristics, immunosuppression or BKVAN treatment methods between the BPAR and no BPAR groups. There was a significant decrease in allograft function in the BPAR group compared to the no BPAR group in both the 1-year (BPAR creatinine [Cr], 2.5±1.9 mg/dL vs. no BPAR Cr, 1.9±0.9 mg/dL; P=0.044) and 2-year follow-up period (BPAR Cr, 3.8±3.6 mg/dL vs. no BPAR Cr, 2.2±1.0 mg/dL; P=0.015). The BPAR group had lower allograft survival rates compared to the no BPAR group, although not statistically significant (P=0.474). On multivariate Cox regression analysis, MMF discontinuation was observed as a significant risk factor for rejection in BKVAN patients (hazard ratio, 4.000; 95% confidence interval [CI], 1.014- 15.775; P=0.048). Conclusions: Acute rejection with BKVAN is associated with poorer allograft function and survival. Also, discontinuation of MMF as treatment for BKVAN increases risk for acute rejection.

P1743IMPORTANCE OF KIDNEY ALLOGRAFT REJECTİON IN BK VIRUS NEPHROPATHY

Abstract Background and Aims Allograft rejection following BK virus nephropathy (BKVN) is an important cause of allograft loss in kidney transplant recipients. However, the effect of rejection type on allograft survival in patients with BKVN has not been described previously. This study aimed to investigate the relationship between allograft rejection type and graft survival in patients with BKVN. Method We retrospectively analyzed the data of 159 kidney transplant recipients diagnosed BKVN and followed-up in our center between January 2009 and December 2019. BKVN was diagnosed by persistent viremia of more than 10000 copies/mL for four weeks or allograft biopsy. Vascular, obstructive or other non-parenchymal etiologies for allograft dysfunction were excluded. All patients were investigated for the presence of anti-HLA antibody at 6 and 12 months after BKVN diagnosis. Luminex solid-phase assay was used to investigate Class I and Class II PRA and MFI values greater than 1000 were accepted as positive. Allograft biopsy was performed in patients with progressive graft dysfunction or the presence of donor-specific antibodies (DSA) and analyzed according to the Banff Classification. The primary outcomes were defined as allograft loss or the allograft dysfunction which defined as was doubling serum creatinine levels. Results Patients were followed-up median 70 (IQR 13-198) months after kidney transplantation. Demographic data and clinical characteristics are provided in the table. 28 kidney transplant recipients suffered from allograft rejection after BKVN. Median rejection time to rejection after BKVN was 9 (IQR 5-164) months. 3 patients (18,8%) in the AMR group and 1 patient (8,3%) in the TCMR group experienced graft loss during follow-up. The mean serum creatinine levels at the last clinical visit were significantly higher in the AMR group compared to the TCMR group (1,9±0,8 vs 1,3±1,2 mg/dl; p=0,002). In multivariate analysis, AMR was an independent risk factor for allograft dysfunction (HR, 1,735; 95% CI 1,060 to 2,839; p=0,028). Conclusion The occurrence of AMR after BKVN is an important indicator of allograft dysfunction compared to TCMR. DSA screening should be routinely used in this group for early diagnosis and treatment of AMR.

Prevalence and Impact of Reformed and De Novo Anti-HLA Donor-Specific Antibodies in Liver Transplantation

IntroductionThe prevalence and impact of pre-existing and de novo anti-HLA donor-specific antibodies (DSAs) after orthotopic liver transplantation (OLT) is still controversial. We investigated the prevalence of DSAs and their implication in the development of allograft dysfunction after OLT. Patients and MethodsA total of 65 liver transplant patients were tested for anti-HLA antibodies, with single antigen bead technology, before, 1, 3, 6, and 12 months after transplantation, and thereafter annually, along with other risk factors. Sixteen out of 65 patients (24.6%) had circulating pre-existing anti-HLA antibodies, and 4 of them (25%) had DSAs. All patients positive for anti-HLA antibodies (100%) presented allograft dysfunction. Fourteen out of 65 patients (21.5%) had circulating de novo DSAs, and 12 out of 14 (85.7%) presented allograft dysfunction. The investigated risk factors for allograft dysfunction were: recipient and donor age, time on the waiting list, cold ischemia time, cytomegalovirus infection, immunosuppression regimen, de novo DSAs, Model for End-Stage Liver Disease, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (GGT), direct bilirubin and total bilirubin peak post-transplant, and alkaline phosphatase. The multivariate analysis showed that de novo DSAs and time on the waiting list were independent risk factors for allograft dysfunction. ConclusionOur results show that de novo DSAs are an independent risk factor for allograft dysfunction, along with time on the waiting list.

Perillyl alcohol protects human renal tubular epithelial cells from hypoxia/reoxygenation injury via inhibition of ROS, endoplasmic reticulum stress and activation of PI3K/Akt/eNOS pathway

Ischemia/reperfusion (I/R) injury plays an essential role in renal transplantation, and represents a crucial risk factor for allograft dysfunction and acute renal failure. Modulation of oxidative stress is an effective therapeutic strategy for I/R injury. Perillyl alcohol (POH), a dietary monoterpene with antioxidant activity is found in a variety of plants. The study was carried out to investigate whether treatment of POH could reduce hypoxia/reoxygenation (H/R)-induced injury. H/R induced significant injury in HK-2 cells. H/R caused an increase in ROS level, apoptosis and ER stress. Meanwhile H/R also inhibited the cell viability and PI3K/Akt/eNOS signaling pathway. Pretreatment with POH prior to H/R improved cell viability, reduce ROS level, ER stress and apoptosis. Moreover, POH could also activate the PI3K/Akt/eNOS pathway. Therefore, POH may possess protective effects in H/R-induced cellular damage.

(315) - CMV-Specific CD8+ T Cells Persist During Early Chronic Infection With Impaired Function and an EomeshiPD-1hi Exhausted Phenotype in Lung Transplant Recipients With Relapsing Viremia

CMV reactivation remains a risk factor for allograft dysfunction and reduced survival in lung transplantation. The factors required for high-risk lung transplant recipients (LTRs) to establish durable immune control of CMV remain incompletely understood. Understanding CMV immunity may facilitate risk stratification of LTRs and an individualized approach to CMV therapy.

CYP2C8*3 Polymorphism and Donor Age are Associated With Allograft Dysfunction in Kidney Transplant Recipients Treated With Calcineurin Inhibitors

Epoxieicosatrienoic acids (EETs) play a protective role against damaging processes in the kidney. We have assessed the effect of polymorphisms in EETs-producing enzymes (CYP2C8 and CYP2J2) and other proteins involved in calcineurin inhibitors (CNIs) disposition (CYP3A4, CYP3A5, and ABCB1) on graft function and clinical outcome in 166 renal transplant recipients treated with CNIs. Both CYP2C8*3 and donor age greater than 48 years were associated to a higher incidence of delayed graft function (DGF) [OR = 2.01 (1.1-4.1), P = .04 and 5.14 (2.4-10.9), P < .0001; respectively] and worse creatinine clearance 1 year after grafting (P < .05 and P < .001, respectively). In addition, carrying 4-6 variants in the 3 ABCB1 loci and older donor age were individually associated to higher incidence of calcineurin-inhibitor-induced nephrotoxicity [OR = 2.38 (1.1-5.4), P = .03 and OR = 1.03 (1.01-1.06), P = .038]. Regression analyses confirmed the relevant effect of both CYP2C8*3 and donor age on graft dysfunction. Carrying the 2C8*3 allele and having a donor older than 48 years was defined as a high-risk status and observed to be highly related to DGF [OR = 3.91 (1.46-10.48), P < .01] and worse creatinine clearance (P = .033). Our results show that genetic and clinical parameters can be combined to identify risk factors for allograft dysfunction in renal transplant recipients.

Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation

Lung transplantation is limited by chronic lung allograft dysfunction. Acute cellular rejection (ACR) is a risk factor for allograft dysfunction; however, the role of antibody-mediated rejection (AMR) is not well characterized. This was a retrospective review from 2007 to 2011 of lung transplant recipients with human leukocyte antigen (HLA) antibody testing using Luminex (Luminex Corp, Austin, TX) single-antigen beads. Statistics included Fisher's exact test for significance. Donor-specific antibodies (DSA) developed in 13 of 44 patients. Of the 13 with DSA, 12 had cystic fibrosis compared with 18 of 31 in the non-DSA group (p = 0.035). Of those with DSAs, 23.1% occurred within the first year, and 69.2% occurred between 1 and 3 years. Twelve of 13 DSA patients had anti-HLA DQ specificity compared with 2 of 31 non-DSA patients (p = 0.0007). AMR developed in 10 of the 13 DSA patients compared with 1 of 31 non-DSA patients (p = 0.0001). The DSA group experienced 2.6 episodes/patient of cellular rejection vs 1.7 episodes/patient in the non-DSA group (p = 0.059). Bronchiolitis obliterans syndrome developed in 11 of 13 in the DSA group vs 10 of 31 in the non-DSA group (p = 0.0024). In the DSA group, 11.5% HLAs matched compared with 20.4% in the non-DSA group (p = 0.093). AMR developed in 11 of 22 patients in the non-DSA HLA group compared with 0 of 22 in the group without non-DSA HLA antibodies (p = 0.002). Survival at 1 and 3 years was 92% and 36% in the DSA group, respectively, and 97% and 65% in the non-DSA group. DSAs and non-DSAs occur frequently after lung transplantation. DSAs are prevalent in the cystic fibrosis population and are associated with AMR, bronchiolitis obliterans syndrome, and possibly, ACR.

Two-Year Results of Renal Transplantation in Kidney Recipients From ≥65-Year-Old Deceased Donors: A French Region Experience

The use of elderly deceased donors requires refining criteria for both the donor and the recipient. This report attempted to identify parameters susceptible to further improvement. This retrospective multicenter study analyzed the outcomes of kidney recipients from 15 consecutive elderly deceased donors in the south French region (IR9). Donors were 65 to 74 years old. Mean creatinine clearance was 80 mL/min/1.73 m 2. The donor risk factors for allograft dysfunction were stroke, hypertension, cardiovascular disease, cardiac death, smoking, arrhythmia, and diabetes. The recipients were 35 to 70 years old. The median cold ischemia time was 24 hours. Four patients (16%) suffered delayed graft function (DGF). Three recipients (12%) died within the first 2 months after transplantation. The postoperative complications (29%) were 2 renal artery thromboses, 4 renal artery stenoses, and 1 toe ischemia. Two years after transplantation, their mean serum creatinine was 157 μmol/L. The patient and graft survivals were 88% and 70%, respectively. These results seemed worse than those reported in the literature, but it was a small cohort and a new experience. DGF is probably linked to improvable management to reduce cold ischemia time. The elevated rate of surgical complications might be related to a lack of experience in donor and recipient evaluations. Kidney transplantation from elderly donors requires an efficient organization and an accurate evaluation of both donor renal function and recipient cardiovascular state.

Optimal Management Strategies for Patients With Complex Congenital Heart Disease

The combination of critical pulmonary outflow obstruction with a large ventricular septal defect is symbolized by the diagnosis of tetralogy of Fallot, the most common form of cyanotic congenital heart disease. In many ways, the history of management for patients with tetralogy is representative of the evolution of management for all children with complex congenital cardiac diagnoses. Tetralogy was the first complex lesion addressed surgically with the palliative Blalock-Taussig shunt in 1945 and the first repaired completely with patients’ mothers serving as the bypass machine in 1954.1,2 The introduction of valved conduits in 1964 allowed repair of lesions not previously considered amenable to correction.3 The next 3 decades were marked by improved survival at open heart repair, recognition of the progressive deterioration of valved conduits necessitating early and repeated reoperation, and a progressive decrease in the age of primary repair to now the first few months of life.4,5 In the late 1970s, reports of arrhythmia and late sudden death among tetralogy survivors led to evaluation of tetralogy cohorts with residual right ventricular (RV) volume and/or pressure overload identified as predictors of late complications.6,7 Recognition of this problem heightened appreciation of the importance of arrhythmias in postoperative congenital heart disease patients and identified the need for informed long-term care and attention to residua of earlier procedures for all patients with congenital heart disease.8 Finally, the last 20 years have witnessed the dramatic rise in interventional procedures to address both correction of simple lesions and palliation/management of complex diagnoses.9 Article p 2598 The remarkable progress in care of children with tetralogy exemplifies the collaboration between pediatric cardiologists and congenital cardiac surgeons, the development of new techniques to address problems as they emerge, and the continuous evolution of management that have characterized care of all patients with …