Risk Kidney Transplant Research Articles

Cardiovascular risk factors and kidney transplantation: a retrospective analysis

Abstract Introduction Cardiovascular disease (CVD) poses a significant risk to end-stage kidney disease (ESKD) patients and remains the leading cause of morbidity and mortality among kidney transplant (KT) recipients. With a global rise in ESKD patients dependent on dialysis, transplant programs face growing pressure to consider candidates with a greater burden of CVD for KT despite potential long-term risks. Enhancing pre-KT cardiac risk assessment is crucial to prevent cardiovascular complications post-transplant and meet the demand for KT globally. Purpose High-quality studies evaluating pre-KT cardiovascular risk factors in patients with ESKD are lacking. Our study aims to evaluate the association between pre-KT cardiovascular risk factors and the development of major adverse cardiac events (MACE) post-KT. Methods This retrospective cohort study of ESKD patients at a tertiary center consisted of consecutive patients referred for cardiovascular assessment prior to KT between January 2013 and January 2023. Clinical and demographic data prior to KT and outcomes 1-year post-KT were extracted. Patients who underwent multi-organ transplantation were excluded. The primary endpoint was MACE, defined as all-cause death, myocardial infarction (MI), ischemic stroke, coronary revascularization, heart failure requiring hospitalization, and cardiac resuscitation. Results A total of n=233 patients were referred for cardiac evaluation prior to KT. Of these, n=145 (62%) patients had a KT, n=69 (30%) patients died pre-KT, and n=19 (8%) patients were removed from the transplant program. Of the n=143 KT recipients that met our inclusion criteria, 122 (85%) were free of MACE, while 21 (15%) met the primary endpoint in the year following KT. Patients with MACE were significantly older (mean age = 65 vs. mean age = 59, p < 0.001), and more likely to have coronary artery disease (85.7% vs. 50.8%, p = 0.01), cardiomyopathy (42.9% vs. 17.2%, p = 0.04), smoking history (71.4% vs. 46.7%, p = 0.04), and diabetes (85.7% vs. 49.2%, p = 0.02). Furthermore, deceased donor KT was associated with a greater likelihood of MACE (85.0% vs. 57.5%, p = 0.02) compared to living donor recipients. There were no significant differences with respect to left ventricular ejection fraction, diagnosis of heart failure, or prior MI between MACE and non-MACE groups (p > 0.17 for all). Conclusion Among pre-KT patients with CVD, there is a high mortality rate (30%) prior to KT. Following a successful KT, 15% of patients experienced MACE within 1-year. Our findings underscore the urgency of developing strategies to facilitate timely kidney transplantation, particularly in light of the anticipated rise in demand for kidney transplants. The elevated incidence of major adverse events in the year following a successful KT emphasizes the necessity of collaborative care by cardiologists and nephrologists for these patients, and the need for further studies to improve long-term outcomes.

Antibody-mediated rejection diagnosed in early protocol biopsies in high immunological risk kidney transplant recipients.

Renal transplant recipients with donor-specific anti-HLA antibodies are at an increased risk of antibody-mediated rejection (AMR). Early protocolized renal biopsies may serve as a strategy to improve diagnosis in this patient population. We evaluated 155 highly sensitized renal transplant recipients with cPRA class I+II>90% pre-transplant from 2015 to 2022. Patients with protocol biopsies within the first two weeks post-transplant were included. A total of 122 patients were included in the study. Of these, 13 (10.6%) were diagnosed with very early antibody-mediated rejection (veABMR) within the first two weeks post-transplant. This corresponds to 52% (13/25 patients) of all ABMR cases reported during the follow-up of this population. The graft survival rates at one and three years were significantly lower in patients with veABMR (p<0.001) compared to patients without rejection in the early protocol biopsy. In terms of severity, the veABMR cohort exhibited a hazard ratio (HR) of 10.33 (95% CI 3.23-33.06; p<0.001) for graft failure. The presence of donor-specific antibodies (DSA) class II on the day of transplantation and a higher percentage of eplet mismatch (EpMM), particularly EpMM DQA1, correlated with the development of veABMR. Early protocol biopsies play a pivotal role in the early detection of veABMR in high-risk immunological patients. Patients with veABMR face significant risks of graft loss, despite early treatment of rejection.

220.3: Outcomes of high immunological risk kidney transplantation in an Asian tertiary academic transplant centre.

220.3: Outcomes of high immunological risk kidney transplantation in an Asian tertiary academic transplant centre.

Pre-Transplant Frequencies of FoxP3+CD25+ in CD3+CD8+ T Cells as Potential Predictors for CMV in CMV-Intermediate Risk Kidney Transplant Recipients.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience

Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P &amp;lt; 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.

Very Low Frequency of Pathological Findings in One-year Protocol Biopsies of Uneventful Standard Risk Kidney Transplant Recipients: Results From the Nordic Protocol Biopsy Study.

The clinical significance of kidney transplant protocol biopsies has been debated. We studied the frequency of borderline changes and T cell-mediated rejection (TCMR) in 1-y protocol biopsies in standard risk kidney transplant recipients. Consecutive non-HLA-sensitized recipients of kidney transplants between 2006 and 2017, who underwent a protocol biopsy at 1 y in 2 national transplant centers were studied retrospectively (N = 1546). Donor-specific HLA antibodies (DSAs), graft function (plasma creatinine), and proteinuria were measured at the time of 1-y protocol biopsy. The occurrence of subclinical acute TCMR (i2t2v0 or higher) or borderline changes suspicious of TCMR (i1t1v0 or higher) in the protocol biopsy was studied, together with frequency of findings causing changes in the composite score iBox. Subclinical acute TCMR was detected in 30 of 1546 (1.9%) of the protocol biopsies, and borderline or TCMR in 179 of 1546 (12%). Among patients with no history of acute rejection, and no proteinuria or DSA, TCMR was detected in only 1 of 974 (0.1%) and borderline or TCMR in only 48 of 974 (4.9%) patients at 1 y. In the absence of proteinuria (<30 mg/g, or equivalent as measured with a negative dipstick proteinuria) or DSA, or history of acute rejection, only 50 of 974 (5.1%) biopsies showed any lesions significant for the iBox score. The likelihood of pathological findings in 1-y protocol biopsies in non-HLA-sensitized patients without previous immunological events is low. Clinical usefulness of protocol biopsies seems limited in these patients.

Mycophenolate mofetil hampers antibody responses to a broad range of vaccinations in kidney transplant recipients: Results from a randomized controlled study

To study the effect of mycophenolate mofetil (MMF) on various vaccination responses in kidney transplant recipients. In a randomized controlled trial (EudraCT nr.: 2014-001372-66), low immunologically risk kidney transplant recipients were randomized to TAC/MMF or TAC-monotherapy (TACmono), six months post-transplantation. One year after transplantation, in a pre-specified sub-study, recipients were vaccinated against pneumococcus, tetanus and influenza. Blood was sampled before and 21 days after vaccination. Adequate vaccination responses were defined by international criteria. A post-hoc analysis was conducted on SARS-CoV-2 vaccination responses within the same cohort. Seventy-one recipients received pneumococcal and tetanus vaccines (TAC/MMF: n=37, TACmono: n=34), with 29 also vaccinated against influenza. When vaccinated, recipients were 60 (54-66) years old, with median eGFR of 54 (44-67) ml/min, tacrolimus trough levels 6.1 (5.4-7.0) ug/L in both groups and TAC/MMF daily MMF dose of 1000 (500-2000) mg. Adequate vaccination responses were: pneumococcal (TAC/MMF 43%, TACmono 74%, p=0.016), tetanus (TAC/MMF 35%, TACmono 82%, p<0.0001) and influenza (TAC/MMF 20%, TACmono 71%, p=0.0092). Only 7% of TAC/MMF responded adequately to all three compared to 36% of TACmono (p=0.080). Additionally, 40% of TAC/MMF responded inadequately to all three, whereas all TACmono patients responded adequately to at least one vaccination (p=0.041). Lower SARS-CoV-2 vaccination antibody responses correlated with lower pneumococcal antibody vaccination responses (correlation coefficient: 0.41, p=0.040). MMF on top of tacrolimus severely hampers antibody responses to a broad range of vaccinations.

Utility of Routine Post Kidney Transplant Anti-HLA Antibody Screening

IntroductionDe novo DSA (dnDSA) is a strong biomarker associated with the development of antibody mediated rejection and graft loss after kidney transplantation. Although this procedure is expensive, systematic annual screening was recommended by some national organ transplant agencies or societies though its clinical utility was not clearly established. MethodsTo address this question, we retrospectively assessed the incidence of dnDSA according to the test justification (clinically indicated or systematic) in a cohort of low-immunological risk patients, defined by being non-HLA sensitized and having no prior kidney transplants. ResultsA total of 1072 patients, for whom 4611 anti-HLA tests were performed, were included in the study. During follow-up period of 8 IQR (5 ; 11) years, seventy-seven recipients developed dnDSA (prevalence of 7.2%) . Thirty-five (45.5%) of these dnDSA were detected during the first year posttransplantation. In 95% of patients with dnDSA, an immunizing event was identified in their medical records. De novo DSA was detected in 46 out of 4267 systematic screening tests performed (1.08%). Active and chronic antibody mediated rejection were frequently observed in biopsies performed after systematic DSA testing (17.9% and 15.4% respectively). ConclusionOur results suggest that the detection by systematic screening of dnDSA in low immunological risk kidney transplant patients without sensitizing events is a rare event, especially after one year. Moreover, in real life, systematic annual screening for dnDSA, seems having a limited impact to detect AMR at an earlier stage compared to patients in whom dnDSA was detected after a clinically indicated test.

Outcomes of immunological high risk kidney transplantation

Outcomes of immunological high risk kidney transplantation

Single-dose antithymocyte globulin in standard immunological risk kidney transplant recipients: efficacy and kinetics of peripheral blood CD3+ T lymphocyte modulation.

Polyclonal anti-T cell antibodies (ATG or thymoglobulin®) are used as induction therapy in kidney transplant recipients. This study evaluates the safety, efficacy, and CD3+T lymphocyte modulation of two ATG regimens. The trial included two cohorts of kidney transplant recipients that were followed for one year. The study group, including standard immunological risk recipients, received one 3mg/kg dose of ATG. The comparator group, including standard and high immunological risk kidney transplant recipients, received a fractionated dose regimen (up to four 1.5mg/kg doses). Patient and graft outcomes and the kinetics of CD3+T lymphocyte modulation in the peripheral blood were evaluated. One hundred kidney transplant recipients were included in each group. The one-year incidence of treated acute rejection, and patient and graft survival did not differ between groups. Bacterial infections were significantly more frequent in fractionated-dose group patients (66%versus 5%; P = 0.0001). At one-year follow-up, there was no difference in the incidence of cytomegalovirus infection (P = 0.152) or malignancies (P = 0.312). CD3+T lymphocyte immunomodulation in the single-dose group was more effective in the first two days after transplantation. After the third post-transplant day, CD3+T lymphocyte modulation was more efficient in the fractionated dose group. Both regimens resulted in low rejection rates and equivalent survival. The single and reduced dose regimen protects from the occurrence of bacterial infections. CD3+T lymphocyte modulation occurred with different kinetics, although it did not result in distinct outcomes.

Profilaksis vs. Terapi Preemtif Penyakit Cytomegalovirus (CMV) pada Pasien Transplantasi Ginjal Risiko Tinggi: Suatu Laporan Kasus Berbasis Bukti

Kidney transplant recipients require the use of immunosuppressive agents to prevent multiple organ rejection. Administration of immunosuppressive agents triggers an increased risk of impaired immunity and microbial infections, one of which is cytomegalovirus (CMV). Prevention of cytomegalovirus infection can be given as a prophylaxis or preemptive therapy. However, the efficacy of choosing prophylaxis or preemptive therapy is still under debate, thus we conducted this study to identify current approach in preventing CMV disease in clinical practice. A literature search was carried out using the PubMed, Cochrane Library, Embase and Scopus databases with the keywords “high risk kidney transplant”, “prophylaxis”, “preemptive” and “CMV infection disease”. Inclusion criteria were only studies in adult kidney transplant patients as a population. , prophylaxis as intervention, preemptive therapy as comparison, and cytomegalovirus infection as outcome. The exclusion criteria of this study were the study articles that were not in Bahasa Indonesia or English, case reports and studies with subjects &lt;18 years old. Critical review using Oxford Center for Evidence Based Medicine (CEBM) Critical Appraisal Tools for Prognostic Study And Systematic Review. The total number of articles identified based on the keywords used is 115 articles. Eliminating duplication with EndNote resulted in 92 articles. Furthermore, exclusion was carried out based on title and abstract so that 29 articles were filtered for which the full text was available. Of these, 23 articles did not have appropriate research questions, 3 studies did not have appropriate patient populations, and 3 articles with types that did not meet the inclusion criteria of this study. As a result, there were 4 articles that can be used in this report. Based on those four articles, it can be concluded that prophylaxis is more effective in preventing CMV disease but had more side effects, when compared to preemptive therapy. However, there was no difference in long term outcome between kidney transplant patients with CMV prophylactic or preemptive therapy.

Three-year Outcomes After Conversion From Monthly to Every 2-month Belatacept Maintenance Therapy in Kidney Transplant Recipients: Results From a Randomized Controlled Trial.

To determine whether every 2-mo (q2m) belatacept is noninferior to standard q1m maintenance, we conducted a prospective, single-center randomized trial in low-immunologic-risk, stable renal transplant recipients. Here, post hoc analysis of 3-y outcomes, including renal function and adverse events, are reported. One hundred sixty-three patients received treatment in the q1m control group (n = 82) or q2m study group (n = 81). Renal allograft function as measured by baseline-adjusted estimated glomerular filtration rate was not significantly different between groups (time-averaged mean difference of 0.2 mL/min/1.73 m2; 95% confidence interval: -2.5, 2.9). There were no statistically significant differences in time to death or graft loss, freedom from rejection, or freedom from donor-specific antibodies (DSAs). During the extended 12- to 36-mo follow-up, 3 deaths, 1 graft loss occurred in the q1m group, compared with 2 deaths, and 2 graft losses in the q2m group. In the q1m group, 1 patient developed DSAs and acute rejection. In the q2m group, 3 patients developed DSAs and 2 associated with acute rejection. Based on the similar renal function and survival at 36 mo compared with q1m, q2m belatacept is a potentially viable maintenance immunosuppressive strategy in low immunologic risk kidney transplant recipients that may facilitate increased clinical utilization of costimulation blockade-based immunosuppression.

210. Neutropenia and Associated Infectious Complications Among Kidney Transplant Recipients Receiving Valganciclovir Prophylaxis in the United States: An Administrative Claims Database Study

Abstract Background Valganciclovir (VGCV) prophylaxis is commonly utilized to prevent cytomegalovirus (CMV) infection among high (D+/R-) and intermediate (R+) risk kidney transplant recipients (KTRs). Due to the myelosuppressive effects of VGCV, KTRs may be at an increased risk of opportunistic infections (OIs) resulting in interruptions to VGCV therapy. Therefore, we aimed to quantify the clinical burden of neutropenia among adult KTRs receiving VGCV prophylaxis. Methods A retrospective cohort design was utilized to identify adult KTRs who received VGCV prophylaxis using the IBM MarketScan Commercial and Medicare Supplemental claims databases. First-time KTRs between 1/1/2012 - 12/31/2018 with 1 year of continuous pharmacy and medical coverage before (baseline period) and after (follow-up period) were included. KTRs with a History of other solid organ transplantation were excluded. Fills of ≥ 1 prescription of VGCV (either 450 mg or 900 mg/day) within 30 days of the kidney transplant (KT). Neutropenia events were identified as either ≥ 1 inpatient, or ≥ 2 outpatient ICD-9/ICD-10 diagnoses codes within 14 days. Results Of the 4,965 adults KTRs with baseline and follow-up enrollment, 3,258 (66%) used VGCV prophylaxis. 311/3256 (9.5%) developed neutropenia within 1-year post KT. Baseline characteristics were similar between those with and without neutropenia (table 1). The majority received the following pre-transplant immunosuppression: tacrolimus (78.9%), mycophenolate mofetil (62.8%) and steroids (prednisone, 79.3%, methylprednisolone 10.6%). KTRs with neutropenia had a nearly two-fold increase in the development of CMV infection compared to those without neutropenia. In addition, KTRs with neutropenia had significantly higher rate of bacterial or fungal infections compared to those without neutropenia (Table 2). Interruptions in VGCV prophylaxis (gap &amp;gt;15 days) were more common in KTRs with neutropenia (P&amp;lt; 0.001). Conclusion Our findings showed that neutropenia was associated viral, bacterial, and fungal OIs among adults KT receiving VGCV prophylaxis. The findings highlight the needs for interventions to reduce neutropenia and its associated OIs. These results suggest that clinical management steps to reduce rates of neutropenia among KT recipients may warrant further study. Disclosures Vladimir Turzhitsky, PhD, Merck &amp; Co., Inc.,: Employee|Merck &amp; Co., Inc.,: Stocks/Bonds Amit D. Raval, PhD, Merck and Co., Inc.: Employee of Merck|Merck and Co., Inc.: Stocks/Bonds Pamela Moise, PharmD, Merck &amp; Co., Inc: Employee &amp; Shareholder Sanjay Merchant, PhD, Merck &amp; Co., Inc.: Stocks/Bonds.

The impact of induction therapy in low-immunological risk kidney transplant recipients regardless of HLA matching

BackgroundInduction agents have proved to reduce the rate of acute rejection (AR) in kidney transplant recipients (KTRs) without improving long-term graft and patient survival (PS). ObjectiveThis study evaluates the utility of induction therapy in low immunological risk KTRs regardless of donor-to-recipient HLA matching. MethodsWe retrospectively reviewed the records of 218 patients undergoing kidney transplantation (KT). These patients were divided into two groups according to the usage of induction therapy: 82 did not receive any induction therapy (Group I), and 136 patients received either Anti-IL2 receptor antibodies or anti-thymocyte globulin (Group II). All patients had panel reactive antibody (PRA) < 20% and absence of donor-specific antibodies (DSA). The difference in outcomes were assessed at different intervals following KT. ResultsThe rate of bacterial infections at one year (p-value = 0.032) and the frequency of CMV disease (p-value = 0.044) were significantly higher in Group II (with induction therapy). The duration of hospital stay, the rate and severity of acute rejection, the occurrence of delayed graft function, the rate and type of surgical complications at one year, and the graft function and survival at one and three years were similar between the two groups (p-value = NS). In addition, the financial burden is much less in Group I (without induction therapy), reducing the total cost of the transplant procedure. ConclusionWe conclude that induction therapy in low-immunological risk kidney transplant patients is not a must regardless of donor-to-recipient HLA matching. Therefore, induction therapy did not yield significant health results, but had negative financial consequences.

Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study

BackgroundSubclinical inflammation, including borderline lesions (BL), is very common (30–40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function.MethodsThe TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression.DiscussionThis phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL.Trial registrationclinicaltrials.gov: NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1. Protocol Version 2 of 21 January 2022. Sponsor: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org.

Association of Maternal and Neonatal Birth Outcomes With Subsequent Pediatric Transplants.

We identified maternal and neonatal birth characteristics that were associated with organ or tissue transplants during childhood. We designed a retrospective cohort study of the population of children born between 2006 and 2019 in Quebec, Canada. The exposure included birth complications such as congenital anomaly, neonatal blood transfusion, and oligohydramnios. The main outcome measure was organ or tissue transplantation before 14 y of age. We categorized transplants according to type (major organs versus superficial tissues). To determine the association of birth characteristics with risk of pediatric transplant, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards models adjusted for potential confounders. The cohort comprised 1 038 375 children with 7 712 678 person-years of follow-up, including 436 children who had transplants before 14 y of age. Birth complications were predominantly associated with major organ transplants. Congenital anomaly was associated with heart or lung (HR, 10.41; 95% CI, 5.33-20.33) and kidney transplants (HR, 13.69; 95% CI, 7.48-25.06), compared with no anomaly. Neonatal blood transfusion was associated with all major organ transplants, compared with no transfusion. Maternal complications were not as strongly associated with the risk of childhood transplant, although oligohydramnios was associated with 16.84 times (95% CI, 8.09-35.02) the risk of kidney transplant, compared with no oligohydramnios. Adverse birth outcomes such as congenital anomaly, neonatal blood transfusion, and maternal oligohydramnios are associated with a greater risk of transplantation before 14 y of age. Maternal and neonatal birth outcomes may be useful predictors of transplantation.

311.4: Every 2-Month Belatacept Maintenance Therapy in Kidney Transplant Recipients: 3-Year Follow-up of a Randomized, Non-inferiority Trial

Introduction: Maintenance immunosuppression with belatacept following kidney transplantation results in improved long-term graft function as compared to calcineurin inhibitors. However, broad application of belatacept has been limited, in part related to logistical barriers surrounding a monthly (q1m) IV infusion requirement. Our center conducted a randomized, non-inferiority trial comparing every 2-month (q2m) dosing to standard q1m maintenance. At twelve month follow up, q2m dosing was noninferior to standard q1m dosing as determined by renal function (eGFR). Two-month dosing was safe and well tolerated without a significant incidence of immunologic events in subjects adherent to the study protocol, but longer term follow-up is of interest to better elucidate patient and graft outcomes. Here, we present the 3-year outcomes from this study. Methods: Low immunologic risk, stable renal transplant recipients a minimum of 1 year post-transplant were randomized to q1m or q2m belatacept maintenance therapy. 36-month follow-up was conducted as intention-to-treat on the population that initiated the study protocol. An autoregressive model using baseline-adjusted means with a random effect for subject was used to compare renal function between groups. Kaplan Meier survival analysis was performed for analysis of adverse and immunologic events. Results: 163 patients initiated the study protocol and received treatment in the q1m control group (n=82) or q2m study group (n=81). Renal allograft function as measured by baseline adjusted eGFR was not significantly different between groups at 36 months (mean [95% CI], q1m: 73.43[70.37, 76.49] vs. q2m: 72.46[69.08, 75.84].There were no statistically significant differences in time to death or graft loss (cumulative survival at 36 months, q1m: 92.6%, q2m: 95.0%, p=0.49; freedom from rejection (q1m: 98.7%, q2m: 92.4%, p=0.06), or freedom from DSA (q1m: 98.7%, q2m: 92.4%, p=0.06). During the extended 12-36 month follow-up period, 3 deaths, 1 graft loss occurred in the q1m group, compared to 2 deaths, 2 graft losses in the q2m group. In the q1m group, one patient developed DSA and acute rejection. In the q2m group, 3 patients developed DSA, 2 associated with acute rejection. All acute rejections in both groups were associated with documented medication nonadherence.Conclusions: Based on similar renal function and adverse event rates at 36 months compared to q1m, q2m belatacept is a viable and safe maintenance immunosuppressive strategy in low immunologic risk kidney transplant recipients with potential to facilitate increased clinical utilization of costimulation blockade-based immunosuppression. (ClinicalTrials.gov NCT02560558) James O. Robbins Foundation. James M. Cox Foundation. Carlos and Marguerite Mason Trust.

Steroidresistant nephrotic syndrome in a child associated with a mutation in the INF2 gene

Introduction. Nephrotic syndrome (NS) is a disease of the glomeruli that occurs in childhood with a frequency of 12–16 per 100,000. More than 85 % children with NS respond to corticosteroid therapy, approximately 10–15 % remain refractory or later become resistant to them. In 10–30 % of patients with steroid-resistant nephrotic syndrome (SRNS), mutations in the structural genes of podocytes, modifier genes were found, there is also evidence of the formation of circulating antibodies to the structure of podocytes, the influence of environmental factors. Difficulties in the diagnosis and treatment of SRNS are determined by its heterogeneous etiology, the frequent absence of remission with the development of multidrug resistance and the progression of the disease with the formation of end-stage chronic renal failure and the return of NS after kidney transplantation. The aim of the study is to present a clinical case of steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis associated with the c.1280_1285delCACCCC mutation in the INF2 gene, localized on chromosome 14 in a 15-year-old child. Materials and methods. An analysis of clinical and anamnestic data was used - primary medical documentation (medical history), the results of an objective examination with examination, analysis of laboratory, instrumental diagnostic and molecular genetic methods for studying a child with steroid-resistant nephrotic syndrome. Results and Discussion. The presented clinical case demonstrates the development in a child of SRNS with FSGS associated with a mutation in the structural podocyte gene INF2, which was also detected in a close relative. The course of the disease was characterized by multiple drug resistance. Conclusion. The presented clinical case of the development of FSGS in a child with SRNS demonstrates the importance of morphological verification of the disease in a child, conducting a molecular genetic study not only of the patient himself, but also of his parents to predict the risks of kidney transplantation, the return of NS in the recipient and donor.

Tolerance protocol of living kidney transplant for developing countries through basic strategy of lymphocyte depletion.

End-stage kidney failure (ESKD) is a global issue where kidney replacement therapy imposes enormous economic burden to people of developing countries, in addition to the severe limitations to the availability of hemodialysis and peritoneal dialysis technique. The best option of kidney transplantation also requires lifelong combination immunosuppressive medicines, the cost of which is equally comparable to lifelong dialysis. A strategy of achieving transplant tolerance that requires minimum immunosuppressive medicines, although in experimental stage, also requires state-of-art technology with costly medicines and interventions. This is evidently beyond the reach of ESKD patients of developing countries. Hence, globally in developing countries, a need for an innovative but cost-effective tolerance protocol is a burning need for a successful transplant program. In brief, transplant tolerance is defined as a state of donor-specific unresponsiveness to the allograft antigens without the need for ongoing pharmacologic immunosuppression or with a minimal need. Current state-of-art techniques involves: (1) A state of hematological chimera, for complete tolerance; (2) Prope or partial tolerance where immune-reactive T-lymphocytes are inhibited using monoclonal antibodies; and (3) Chimeric antigen receptor for T-regulatory (T-reg) cell therapy using genetically engineered T-reg cells targeting specific T-lymphocyte receptors for inducing anergy. From our real-world experience in transplant management in post-transplant lympho-proliferative disorders (PTLD), we noticed frequently a drastic reduction in the need of immunosuppressive medicines following lympho-ablative therapy for PTLD. We recently published a case study on a real-world experience transplant case where we explained a partial or prope tolerance that developed after lymphocyte ablation therapy, following which the allograft was maintained with low dose dual standard immunosuppressive medicines. Based on this publication, we propose here an innovative tolerance protocol for living related low risk kidney transplantation for developing countries, in this opinion review.

The prognostic and diagnostic implications of surveillance serial myocardial perfusion imaging in asymptomatic renal transplant candidates

BackgroundThe utility of serial SPECT myocardial perfusion imaging (MPI) for CAD surveillance in asymptomatic ESRD patients awaiting kidney transplantation (KT) is uncertain. Methods and ResultsWe retrospectively investigated 700 asymptomatic KT candidates with ≥ 2 pre-transplant SPECT-MPIs (mean interval, 20 ± 13 months). Worsening MPI was defined as total perfusion deficit increase (ΔTPD) > 5%. High clinical risk was defined as ≥ 3 AHA/ACC KT risk factors. The primary outcome was major adverse cardiac events (MACE) of cardiac death or myocardial infarction. The initial MPI was normal in 462 (66%) subjects. On repeat MPI, ΔTPD > 5% was observed in 82 (12%) subjects, and the incidence increased with increasing time gap between MPIs (P = .006). During a mean follow-up of 16 ± 8 months, there were 119 (17%) MACEs. In the entire cohort, ΔTPD > 5% was not significantly associated with MACE (HR = 1.38; P = .210). ΔTPD > 5% was associated with increased MACE rate among patients with normal initial MPI (HR = 2.30; P = .005), but not among those with abnormal initial MPI (P = .260). There was a significant interaction between ΔTPD > 5% and initial MPI normalcy status in predicting MACE (interaction P = .018), such that the predictive value of ΔTPD is dependent on the initial MPI normalcy. Among subjects with normal initial MPI, ΔTPD > 5% was significantly associated with MACE only if the sum of KT risk factors was ≥ 3 (HR = 2.26; P = .016). Among 123 patients who underwent coronary angiography, ΔTPD > 5% was associated with a higher prevalence of obstructive CAD when the initial MPI was normal and the sum of KT risk factors was ≥ 3. ConclusionAmong patients with ESRD waitlisted for KT, new/worsening MPI abnormalities are expected. On serial surveillance, ΔTPD > 5% is associated with MACE and obstructive CAD among those with a normal initial MPI and ≥ 3 AHA/ACC KT risk factors.