Low-risk Kidney Transplant Recipients Research Articles

#2461 KIR-HLA-I genetic mismatch and the development of antibody-mediated rejection and microvascular inflammation after renal transplantation

Abstract Background and Aims Antibody-mediated rejection (ABMR) and microvascular inflammation (MVI) contribute to kidney transplant (KT) loss of function. The contribution of Natural Killer (NK) cells to the development of ABMR/MVI through inhibitory (iKIR) and activating (aKIR) HLA-I KIR (Killer-cell Immunoglobulin-like Receptors) has been proposed. The presence of an iKIR gene in the KT recipient (KTR) recognizing a self HLA-I ligand absent in the donor is defined as an iKIR-HLA-I mismatch (MM), and the presence of an aKIR gene in the KTR with HLA-I ligand in the graft absent in the KTR is defined as an aKIR-HLA-I MM. These MMs indicate the presence of potentially alloreactive NK cells that could contribute to the graft rejection, especially in the presence of NK receptor activating ligands or DSA. Our aim was to study the relationship between the number of KIR-HLA-I mismatches and ABMR/MVI. Method We selected 56 first KT, not treated with thymoglobulin or rituximab: 24 cases with ABMR/MVI and 32 controls without rejection in biopsies at 12-36 months. Donor and recipient HLA-I genotypes were determined by NGS, and recipient KIR genotypes by PCR-SSO (Luminex). The interactions considered were: KIR2DL1/HLA-C2, KIR2DL2&KIR2DL3/HLA-C1, KIR3DL1/HLA-Bw4, KIR3DL2/HLA-A*03, A*11, KIR2DS1/HLA-C2, KIR2DS2/HLA-C1, KIR3DS1/HLA-Bw4-I80 and KIR2DS4/HLA-A*11, C*02, C*04, C*05, C*16:01. Results KT recipients had a mean age of 54.55 years, 30.36% female and 8.92% living donor with no significant differences between ABMR/MVI and controls. The proportion of patients with ≥1 iKIR-HLA-I MM was higher in the ABMR/MVI group compared to controls (75% vs 56.25%, P = .1473), with a significant difference in the percentage of KIR3DL1 MM (29.17% vs 6.25%, P = .0296). The proportion of patients with at least one aKIR-HLA-I MM was non-significantly lower in ABMR/MVI compared to the control group (20.83% vs 28.13%, P = .5329). Overall, the proportion of KT recipients with ≥1 MM, either iKIR or aKIR, was 21% higher in the ABMR/MVI group (83.33% vs 68.75%, P = .2123). Conclusion In a population of immunologically low-risk KT recipients, we found a significantly greater proportion of patients with genetic iKIR-HLA-I MM in those with ABMR/MVI, but not of aKIR-HLA-I MM. NK cells with iKIR-HLA-I MM could contribute to antibody-mediated allograft damage together with other mechanisms.

Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Medical Aspects of mTOR Inhibition in Kidney Transplantation.

The advances in transplant immunosuppression have reduced substantially the incidence of kidney graft rejection. In recent years, the focus has moved from preventing rejection to preventing the long-term consequences of long-standing immunosuppression, including nephrotoxicity induced by calcineurin inhibitors (CNI), as well as infectious and neoplastic complications. Since the appearance in the late 1990s of mTOR inhibitors (mTORi), these unmet needs in immunosuppression management could be addressed thanks to their benefits (reduced rate of viral infections and cancer). However, management of side effects can be troublesome and hands-on experience is needed. Here, we review all the available information about them. Thanks to all the basic, translational and clinical research achieved in the last twenty years, we now use mTORi as de novo immunosuppression in association with CNI. Another possibility is represented by the conversion of either CNI or mycophenolate (MPA) to an mTORi later on after transplantation in low-risk kidney transplant recipients.

Outcomes in Single versus Standard Dose Basiliximab After Lung Transplant

<h3>Purpose</h3> Basiliximab has become the most prevalent induction agent in lung transplant (LT). There are limited studies in low-risk kidney transplant recipients, but no studies in LT. Given it's half-life of 7 days, we hypothesize there is no significant difference in rejection outcomes with single compared to double doses in the setting of lung transplantation. <h3>Methods</h3> We reviewed 93 adult patients who received single or bilateral LTs from 1/2019 - 6/2021 at our institution. Primary outcomes were development of donor-specific antibodies (DSAs) and acute cellular rejection (ACR). Pathology for ACR was collected from surveillance biopsies or when otherwise clinically indicated. Therapeutic tacrolimus was defined as greater than 8 ng/mL with goal of 1 week. All patients received dose 1 intraoperatively. Dose 2 administration on post-operative day 4 was provider driven. SPSS v26 was used for analysis. <h3>Results</h3> Characteristics were similar between the single (n=25) and the standard dose group (n=68), except more post-operative ECMO patients were in the standard dose group (p=.006, Table 1). There was no difference in grade or time to development of ACR. The single dose group achieved therapeutic tacrolimus levels sooner (p=0.009) but there was no correlation between days to therapeutic level and ACR (r=-0.042). Differences in DSA development and CMV viremia within one year were not statistically significant. <h3>Conclusion</h3> There was no difference in DSA development, ACR, or CMV viremia. Patients with PGD requiring ECMO or with post-operative renal dysfunction were given a second dose of basiliximab. Time to therapeutic tacrolimus level did not correlate with ACR, but this may be confounded by basiliximab administration in cases when tacrolimus was delayed. This suggests renal dysfunction as a possible indication for multiple dosing of basiliximab. Otherwise, a single dose could be sufficient for induction and greatly cost-effective. Further investigation is needed with increased sample size and long-term chronic rejection outcomes.

Is the failure of recent trials on withdrawal of calcineurin inhibitors due to inadequate mycophenolic acid dosing?

Calcineurin inhibitors (CNIs) are the mainstay immunosuppressive therapy after kidney transplantation, despite their side effects. Recently, several randomized controlled trials attempting CNI withdrawal or minimization in stable, low-risk kidney transplant recipients led to an unacceptable risk of acute rejection and de novo HLA antibody formation. In the opinions of many, these trials definitively demonstrated that CNI-free regimens in the context of mycophenolate mofetil (MMF) maintenance are too risky. It can be argued, however, that the investigators failed to optimize the dose of the remaining immunosuppressive therapy. In particular, the potential benefit of MMF dosing based on the targeted mycophenolic acid (MPA) concentration was not taken into account. In this review, we present an overview of the studies on CNI withdrawal, both recent and older, paying specific attention to the MMF dose and elaborating on the possible benefit of MPA monitoring in this setting.

A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients

IntroductionSteroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF).MethodsIn this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]).ResultsAt 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3–4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years.ConclusionThe SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen.

1387. Impact of Cytomegalovirus Prophylaxis on Healthcare Resource Use and Costs among Kidney Transplant Recipients: A United States Renal Data System-Medicare Linked Database Study

BackgroundCytomegalovirus (CMV) management requires a balance between reducing the risk of CMV infection and avoiding anti-viral toxicities. Limited information is available on the impact of CMV prophylaxis on the healthcare resource use (HCRU) and costs among adult kidney transplant recipients (KTRs) in the United States. Therefore, we examined HCRU and cost associated with CMV prophylaxis stratified by the CMV risk categories among KTRs at 1-year post-KT. MethodsWe identified a cohort of 22,918 adults first-time KTRs during 2011–2017 using the US Renal Data System registry-linked Medicare data. Additional inclusion criteria were to have continuous coverage in Medicare Part A & B for ≥ 6-month pre- and ≥ 12-month post KT and Medicare Part D for ≥12-month post-KT. CMV prophylaxis was confirmed as ≥ 1 prescription fill for valacyclovir/(val)ganciclovir prophylaxis doses within 28 days post-KT. ResultsCMV prophylaxis was utilized in 86%, 82%, and 32% of high, intermediate, and low-risk KTRs with an average cost of prophylaxis per KTRs of &16,241, &9481, and &8,648, respectively. In no prophylaxis groups, valganciclovir was utilized in 52%, 34%, and 36% of KTRs (as either pre-emptive or deferred therapy) with an average cost of &6,719, &2,722, and &431 among high, intermediate, and low-risk KTRs, respectively. Among high-risk KTRs, CMV prophylaxis group had a significantly higher prescription drug cost (&26,060 vs. &13,433) but a lower average direct healthcare medical cost (&84,914 vs. &101,268), mainly due to lower all-cause hospitalization cost (&56,758 vs. &69,852) (Table 1). CMV prophylaxis group had lower rates of all-cause rehospitalization, and CMV-and opportunistic infection (OIs)-related hospitalization compared to no prophylaxis (Table 2). In high-risk KTRs, nearly 32% had myelosuppressive events-related hospitalization, and 15% filled granulocyte colony-stimulating factors with an average cost of &4,695 per treated KTR.ConclusionCMV prophylaxis had a higher cost of medications but had a lower medical cost with including all-cause and CMV-related hospitalizations. Myelosuppressive events were frequent and resource-intensive especially in high and intermediate-risk KTRs. Disclosures Amit D. Raval, PhD, Merck and Co., Inc. (Employee) Yuexin Tang, PhD, JnJ (Other Financial or Material Support, Spouse’s employment)Merck & Co., Inc. (Employee, Shareholder)

Effect of donor-to-recipient HLA matching in low-immunological risk kidney transplant recipients without induction therapy on acute rejection, graft survival, infections, and surgical complications at 3 years: The road towards new recommendations

BackgroundDonor-to-recipient human leukocyte antigen mismatching is considered one of the strongest determinants for graft and patient survival in kidney transplant recipients (KTR). ObjectiveThis retrospective study discusses the impact of HLA matching as low immunological risk KTR without induction therapy. Material and methodsRecords of 80 adult kidney transplant patients were reviewed with three years of the follow-up. All patients had panel reactive antibodies (PRA) < 20%, absence of donor-specific antibodies (DSA) and did not receive the induction therapy. These patients were divided into two groups according to their HLA matching between donor and recipient: 55 patients with ≥ 3 HLA matches (Group I; low immunogenicity) were compared to 25 patients with <3 HLA matches (Group II; high immunogenicity). The primary endpoints included the rate and severity of acute rejection (AR) episodes, graft function (creatinine level), and survival at 1, 3, 6, 12, and 36 months. Secondary endpoints include the rate and type of infections at one-year, surgical complications at one-year, and patient survival at 1, 6, 12, and 36 months after kidney transplantation. Baseline demographic characteristics were comparable between the two groups except for recipient age, donor gender, and pre-transplant dialysis time. ResultsThere was no significant difference observed between two groups at one-year in infection rate, the length of hospital stay, AR severity, the rate of cytomegalovirus infection, and the occurrence of delayed graft function. However, the rate of AR, the graft function upon discharge, and the rate and type of surgical complications at one-year were significantly higher in Group II (high immunogenicity). The patient and graft survival at three years, the death-censored graft survival, and the serum creatinine levels at 1, 3, 6, 12, and 36 months were similar between two groups. Two deaths occurred in each group (NS). ConclusionIn our center, the donor-to-recipient HLA mismatch is not considered an immunological risk factor in low-risk kidney transplant recipients (PRA < 20% and absence of DSA).

Panel-reactive Antibody and the Association of Early Steroid Withdrawal With Kidney Transplant Outcomes.

Early steroid withdrawal (ESW) is a viable maintenance immunosuppression strategy in low-risk kidney transplant recipients. A low panel-reactive antibody (PRA) may indicate low-risk condition amenable to ESW. We aimed to identify the threshold value of PRA above which ESW may pose additional risk and to compare the association of ESW with transplant outcomes across PRA strata. We studied 121 699 deceased-donor kidney-only recipients in 2002-2017 from Scientific Registry of Transplant Recipients. Using natural splines and ESW-PRA interaction terms, we explored how the associations of ESW with transplant outcomes change with increasing PRA values and identified a threshold value for PRA. Then, we assessed whether PRA exceeding the threshold modified the associations of ESW with 1-y acute rejection, death-censored graft failure, and death. The association of ESW with acute rejection exacerbated rapidly when PRA exceeded 60. Among PRA ≤60 recipients, ESW was associated with a minor increase in rejection (adjusted odds ratio [aOR], 1.001.051.10) and with a tendency of decreased graft failure (adjusted hazard ratio [aHR], 0.910.971.03). However, among PRA >60 recipients, ESW was associated with a substantial increase in rejection (aOR, 1.191.271.36; interaction P < 0.001) and with a tendency of increased graft failure (aHR, 0.981.081.20; interaction P = 0.028). The association of ESW with death was similar between PRA strata (PRA ≤60, aHR, 0.910.961.01; and PRA >60, aHR, 0.900.991.09; interaction P = 0.5). Our findings show that the association of ESW with transplant outcomes is less favorable in recipients with higher PRA, especially those with PRA >60, suggesting a possible role of PRA in the risk assessment for ESW.

Decreased incidence of acute rejection without increased incidence of cytomegalovirus (CMV) infection in kidney transplant recipients receiving rabbit anti-thymocyte globulin without CMV prophylaxis - a cohort single-center study.

Induction therapy with rabbit anti-thymocyte globulin (rATG) in low-risk kidney transplant recipients (KTR) remains controversial, given the associated increased risk of cytomegalovirus (CMV) infection. This natural experiment compared 12-month clinical outcomes in low-risk KTR without CMV prophylaxis (January/3/13-September/16/15) receiving no induction or a single 3mg/kg dose of rATG. We used logistic regression to characterize delayed graft function (DGF), negative binomial to characterize length of hospital stay (LOS), and Cox regression to characterize acute rejection (AR), CMV infection, graft loss, death, and hospital readmissions. Recipients receiving 3mg/kg rATG had an 81% lower risk of AR (aHR 0.14 0.190.25 , P<0.001) but no increased rate of hospital readmissions because of infections (0.68 0.911.21 , P=0.5). There was no association between 3mg/kg rATG and CMV infection/disease (aHR 0.86 1.101.40 , P=0.5), even when the analysis was stratified according to recipient CMV serostatus positive (aHR 0.94 1.251.65 , P=0.1) and negative (aHR 0.28 0.571.16 , P=0.1). There was no association between 3mg/kg rATG and mortality (aHR 0.51 1.253.08 , P=0.6), and graft loss (aHR 0.34 0.731.55 , P=0.4). Among low-risk KTR receiving no CMV pharmacological prophylaxis, 3mg/kg rATG induction was associated with a significant reduction in the incidence of AR without an increased risk of CMV infection, regardless of recipient pretransplant CMV serostatus.

PANEL REACTIVE ANTIBODY AND THE ASSOCIATION OF EARLY STEROID WITHDRAWAL WITH KIDNEY TRANSPLANT OUTCOMES

Introduction: Early steroid withdrawal (ESW) is a viable maintenance immunosuppression strategy in certain low-risk kidney transplant recipients. A low panel reactive antibody (PRA) may indicate low-risk condition amenable to ESW. We aimed to identify the threshold value of PRA above which ESW may pose additional risk, and to compare the association of ESW with transplant outcomes across PRA strata. Materials and Methods: Using the US national registry data, we studied 121,699 deceased-donor kidney-only recipients in 2002-2017. Using natural splines and ESW-PRA interaction terms, we explored how the associations of ESW with transplant outcomes change with increasing PRA values, and discovered rapid exacerbation in PRA>60 (Figure 1). Then, we assessed whether PRA>60 modifies the associations of ESW with 1-year acute rejection, death-censored graft failure, and death.Results: Among PRA≤60 recipients, ESW was associated with a minor increase in rejection (aOR=1.001.051.10) and with a tendency of decreased graft failure (aHR=0.910.971.03; Table 1). However, among PRA>60 recipients, ESW was associated with a substantial increase in rejection (aOR=1.191.271.36; interaction p<0.001) and with a tendency of increased graft failure (aHR=0.981.081.20; interaction p=0.028). The association of ESW with death was similar between PRA strata (PRA≤60, aHR=0.910.961.01; and PRA>60, aHR=0.900.991.09; interaction p=0.5).Conclusion: The associations of ESW with rejection and graft failure were significantly more adverse in recipients with high PRA, especially those above 60. PRA should be considered in the risk assessment for ESW tailoring. American Society of Nephrology. National Institutes of Health.

Lymphocytes B Development After Kidney Transplantation

Introduction Alloantibodies are commonly used in kidney transplantation for donor/recipient immune matching as well as a marker of organ rejection after transplantation. In a broader context, anti-HLA antibodies development is associated with humoral response and B cells differentiation to long-lived memory cells. Recently studies on operational tolerance pointed to characteristic B cell phenotype and molecular signature. Thus, immune markers of anti-HLA antibodies development could point to early humoral immunity activation and may be beneficial for personalized risk stratification. Materials and Methods Low-risk kidney transplant recipients (n=53) were followed-up to 24 months after transplantation for alloantibodies development and organ rejection. Every three months anti-HLA antibodies, lymphocytes B phenotype, and cytokines were assessed. Memory B lymphocytes phenotype was recognized as CD27+ cells, both IgM positive and negative. In contrary naïve B cells were identified as CD27- and CD5+ B lymphocytes. Th1/Th2 and BAFF serum levels were measured with Luminex solid phase assay. Results and Discussion For the 34 recipients, alloantibodies were not present after transplantation, while for 19 others DSA antibodies were confirmed. The higher rate was observed 20 months after transplantation. Anti-HLA antibodies development was proceeded by increased in BAFF and INFgamma levels, as well as memory B lymphocytes numbers. It was found, that alloantibodies development was correlated with a number of memory B cells, Rs=0,96 (Spearman rank correlation). Conclusion Lymphocytes B phenotype monitoring after kidney transplantation is useful for alloantibodies development and may serve as an additional marker of humoral immunity activation. These could be also beneficial for individual risk stratification and tailored immunosuppression protocol development after kidney transplantation. National Centre for Research and Development, Poland (No. STRATEGMED1/233368/1/NCBR/2014). National Science Centre, Poland (No. NN402420738 and NN402 562440).

Similar Microvascular Inflammation and Tubulointerstitial Injury in ABO-Incompatible and Matched ABO-Compatible Kidney Allografts

ABO-incompatible (ABOi) kidney transplantation represents a viable tool to increase the donor pool for kidney transplantation, however, increased alloimmune response has been debated. The early outcomes of 25 low-risk ABOi kidney transplant recipients were compared with thoroughly matched 50 ABO-compatible (ABOc) ones. The matching process was based on gender and age of recipients and immunologic parameters, such as panel reactive antibodies, number of human leukocyte antigen mismatches, and transplantation era. Three-month protocol kidney graft biopsy Banff scores and 1-year clinical outcomes were compared. Apart from C4d positivity, no statistically significant differences were found regarding the Banff scores between the two groups. Similarly, microvascular inflammation and tubulointerstitial injury revealed no differences either. The eGFR at 3 months and 1 year was similar in both groups. In conclusion, blood group incompatibility yields no additional microvascular and tubulointerstitial graft injury if desensitization protocol was applied to low-risk kidney transplant recipients.

Steroid free immunosuppression is associated with enhanced Th1 transcripts in kidney transplantation

BackgroundSteroid avoidance in immunosuppression in kidney transplantation offers several metabolic advantages, however it is associated with higher early acute rejection rate. Cellular and molecular mechanisms of this phenomenon remain poorly understood. MethodsIn this single center observational study, low-risk kidney transplant recipients randomized into large multicenter prospective ADVANCE trial with steroid avoidance/early withdrawal and center standard of care treated patients were monitored for 12months. The expressions of 28 transcripts, associated with alloimmune response and operational tolerance, were evaluated in the peripheral blood using RT-qPCR at 0, 7, 14, 90 and 365 postoperative days (POD) and in the protocol graft biopsy at 3months while lymphocyte subpopulations were analyzed by flow-cytometry within the follow-up. ResultsBoth steroid avoidance and withdrawal regimens were associated with significantly higher granzyme B (GZMB) transcript at POD 14 and perforin 1 (PRF1) transcript at POD 7. The higher interleukin 2 (IL-2) expression at POD 7 was detected only in the steroid avoidance group. Initial steroids decreased the expression SH2D1B transcript at POD14 and there were no further differences in other operational tolerance transcripts among groups. The statistically significant decrease in absolute numbers of peripheral NK cells in the first 14days was observed in the standard of care group only. There were no differences in analyzed intrarenal transcripts in 3-month biopsies among groups. ConclusionsThe enhanced expression of some of Th1 associated transcripts and limited effects on NK cells of steroid avoidance immunosuppression suggest higher susceptibility for early acute rejection.

Single-Dose Basiliximab Induction in Low-Risk Renal Transplant Recipients.

To compare the efficacy of a single dose of basiliximab with two doses in preventing acute rejection in selected low-risk renal transplant recipients. This observational study of 760 kidney transplant recipients considered to be at low immunologic risk (peak panel reactive antibody less than 10%) compared patient and graft outcomes following a single-dose versus a two-dose regimen of basiliximab. No differences were found in patient survival (92% vs 92%, p=0.6), graft survival (86% vs 83%, p=0.2), acute rejection (cellular [4% vs 7%, p=0.2], antibody-mediated rejection [19% vs 19%, p=0.9]), or opportunistic infections (34% vs 30%, p=0.3) between the single versus two-dose regimens, respectively. In multivariate analyses, the number of doses of basiliximab was not associated with acute rejection or patient/graft survival despite adjustment with Cox regression and propensity scores. However, delayed graft function (DGF), donor age older than 65 years, and human leukocyte antigen mismatch of 3 or higher were associated with acute rejection (hazard ratio [HR] 2.64, 1.91, and 1.57, respectively, p≤0.04), and DGF and diabetes were associated with death/graft loss (HR 2.56 and 1.63, respectively, p≤0.009). A single dose of basiliximab is safe and effective for induction in low-risk kidney transplant recipients.

Posttransplant soluble B-cell activating factor kinetics in pediatric recipients of first kidney allograft.

Development of de novo donor-specific antibodies (dnDSA) is associated with late or chronic antibody-mediated rejection (CAMR) and poor graft outcome in low-risk kidney transplant recipients. High-level soluble B-cell activating factor (sBAFF) was observed in kidney recipients at higher risk of developing dnDSA. We longitudinally analyzed sBAFF levels in 81 consecutive primary pediatric kidney recipients monitored for de novo human leukocyte antigen (HLA) antibody (Ab) occurrence to gain insight into the events conditioning B-cell activation posttransplant and to analyze the usefulness of paired DSA-sBAFF monitoring in this clinical setting. At a median follow-up of 65 months, 23 patients (28%) developed dnDSA, with 13 of 23 developing CAMR. Irrespective of HLA Ab status, sBAFF levels progressively increased in all patients in the first posttransplant year, thereafter reaching a plateau. sBAFF levels were influenced by the degree of HLA class I antigen match and donor age. Despite higher levels of sBAFF in HLA Ab-positive patients (median and 95% confidence interval sBAFF in DSA+non-DSA patients: 568, 534-608 pg/mL vs. 502, 422-548 pg/mL in Ab-negative patients; P<0.05), we found that sBAFF monitoring could not predict DSA development by a time to event longitudinal analysis. Moreover, sBAFF kinetics up to CAMR onset could not anticipate CAMR development in the DSA cohort. Our findings provide evidence of early posttransplant B-cell activation even in unsensitized recipients of first kidney allograft. The significance of this activation, likely induced by exposition to the allograft, is yet unclear.

0% PRA Kidney Transplant Recipients Induced With Thymoglobulin: Is a Dual Maintenance Regimen More Effecitve Than Triple?

INTRODUCTION:Optimal maintenance immunosuppression in low risk kidney transplant recipients (KTR), specifically those with 0% PRA, has yet to be determined. Our institution uses reduced-dose Thymoglobulin (rATG) induction at 4.5 mg/kg of actual body weight with either maintenance FK/MPA (DUAL) or FK/MPA/Pred (TRIPLE) in these pts. We aimed to assess safety/efficacy of our immunosuppressive regimens in 0% PRA KTR. METHODS:This was a retrospective study of adult KTR transplanted 10/07-6/10 with 0% PRA at time of tx who received rATG 4.5 mg/kg. We excluded KTR with graft loss/death within 30 d of tx. We assessed CMV ifxn and other opportunistic ifxn (OI) at 1 yr; rejection, pt/graft survival, malignancy at 2 yr; Neupogen use during viral ppx; mean FK levels at pre-specified time points. RESULTS:163 KTR were included (77.9% DUAL vs 22.1% TRIPLE). Demographics and immunologic risks were mostly similar although TRIPLE had more DCD/ECD donors. CMV, other OI and rejection occurred at a greater incidence in TRIPLE compared to DUAL. There were no differences in pt/graft survival, malignancy and Neupogen use. Mean FK levels were slightly less at most time points in TRIPLE.Table: No Caption available.CONCLUSION:In 0% PRA KTR induced with rATG 4.5 mg/kg, those receiving TRIPLE appear to have more rejection and ifxn with comparable pt/graft survival vs DUAL.

Epitope Mismatch Predicts De Novo DSA After CNI Withdrawal in Low-Risk Kidney Transplant Recipients.

De novo donor specific antibody (dnDSA) correlates with kidney transplant (KTx) loss, and is predicted by early acute rejection (AR) and non-adherence. CTOT-09, a multi-centre randomized prospective trial, hypothesized that immune quiescence at 6 months (mo) in “low risk” patients (pts) treated with rabbit-ATG, tacrolimus (Tac), mycophenolate mofetil and prednisone can identify pts who may be safely withdrawn from Tac with careful immunologic monitoring. We further hypothesized that Class II epitope mismatch (mm) load in CTOT-09 would predict dnDSA development after Tac withdrawal. Enrollees were adult recipients of primary live donor KTx with peak flow PRA<30%, no DSA and a negative flow crossmatch prior to KTx. Pts free of AR in the first 6 mo, no AR on a 6 mo protocol biopsy, and no dnDSA at 6 mo were randomized 1:2 to Tac maintenance (TM) or withdrawal (TW). DSA testing by flow beads was performed every 3 mo post-KTx. Donor-recipient HLA epitope mm was determined using HLA Matchmaker (V3.0). 21 of 47 enrollees qualified for randomization (7 TM, 14 TW). DQ dnDSA developed in 1/7 TM pts (at 24 mo). In contrast, DQ dnDSA developed in 5/14 TW pts and were detected earlier (at 10.4±1.5 mo). DQ epitope mm loads were not significantly different but trended higher in the TM pts (28±20 vs 19±16, p=0.13). A predefined and published threshold of >16 DQ epitope mm load was significantly associated with the development of DQ dnDSA in the TW pts (all 5 who developed DQ dnDSA had epitope mm loads >16 as compared to only 3/9 in those who did not, p=0.03). 2 of 14 TW pts with DQ dnDSA also developed DR dnDSA. There were no Class I dnDSA in any pts. In summary, Tac withdrawal is associated with a high rate of DQ dnDSA that occurs early and cannot be predicted by immune quiescence at 6 mo, even in low risk pts. Rather, high levels of HLA DQ epitope mm is significantly associated with DQ dnDSA development supporting the concept that minimizing/withdrawing Tac should be restricted to KTx pts with low epitope mm loads.

Tolerance and Rejection Associated Transcripts in Low-Risk Kidney Transplant Recipients: Prospective Study.

Tolerance and Rejection Associated Transcripts in Low-Risk Kidney Transplant Recipients: Prospective Study.

Modulating kidney transplant interstitial fibrosis and tubular atrophy: is the RAAS an important target?

In follow-up to a recently published randomized controlled clinical trial, Issa et al. provide evidence that systemic activity and physiological responsiveness of the renin aldosterone angiotensin system (RAAS) are well within normal limits in most kidney recipients during the first 5 years post-transplant. Implications of the results include the need to better understand intra-renal RAAS activity in transplanted kidneys and to identify patients in which the graft-protective effects of RAAS blockade are most relevant.