Poor Allograft Research Articles

Abstract 003: Early and Late Post-Kidney Transplant Hypertension and Late Renal Allograft Outcome

Background: Association between pattern of blood pressure (BP) change at different period after kidney transplantation (KTx) and renal allograft function is unclear. We examine the association between changes in BP patterns and long-term allograft function. Methods: Kidney transplant recipients were stratified into 4 groups based on presence (+) or absence (-) of systolic hypertension (SHTN; SBP ≥130 mmHg) both at 1 and 6 mo post-KTx (Gr1 (-,-), Gr2 (-,+), Gr3 (+,-), Gr4 (+,+)). Declined allograft function defined by a decrease in eGFR from baseline eGFR at 1-mo post-KTx during 24 mo of follow-up among 4 different groups is examined by multivariable Cox regression analysis. Results: Of all 70 patients, mean±SD age was 52.7±12 yr and 41% was female. Mean SBP at 1- and 6-mo post-KTx were 130.9±18.3 and 136.2±18.2 mmHg, respectively. Baseline mean eGFR at 1-mo post-KTx was 50.86±18.89 ml/min/1.73 m 2 and were not different among all 4 groups. Among 70 patients, 57 patients (81%) had a decrease in eGFR between 1 and 24 mo post-KTx with a median time to outcome of 6.8 mo (IQR 2.8-19.6) and the incidence rate of 0.075 person-mo. The number of patients (% in each group) with declined eGFR in Gr1, 2, 3 and 4 were 15 (88%), 17 (89%), 7 (78%), and 18 (72%) patients, respectively (x 2 2.8830, p 0.410). Compared to Gr1, Gr2 had higher, but Gr 3 and 4 had lower the risk of declining eGFR but no statistical significance (HR(95% CI): Gr2 1.20 (0.60-2.40); Gr3 0.79 (0.32-1.95); Gr4 0.78 (0.39-1.55)). After adjusted for age, gender, race, types of induction immunosuppression, types of KTx, SBP, DBP, and BMI at the time of KTx, Gr3 became higher risk; otherwise, the direction of the association remains the same for Gr2 and Gr4. Conclusion: Changes in SBP from either normotension to HTN or vice versa between 1 and 6 mo post-KTx appears to be associated with poorer allograft function within 24 mo post-KTx; whereas, maintaining SBP pattern both normotension or HTN from 1 to 6 mo post-KTx may be protective for a decline in allograft function. Very early BP levels during 1 mo post-KTx may be the suitable target SBP for kidney transplant recipients and too liberal or tight BP control in normotensive or hypertensive patients after 1 mo post-KTx may associated with greater risk for worsening long-term allograft outcomes.

Antimicrobial stewardship in transplant patients

To provide an update on the current landscape of antimicrobial stewardship in solid organ transplant (SOT) recipients. Constructing personalized antimicrobial prescribing approaches to avoid untoward consequences of antimicrobials while improving outcomes is an emerging and critical aspect of transplant medicine. Stewardship activities encompassing the specialized interests of transplant patients and programs are evolving. New literature evaluating strategies to optimize antimicrobial agent selection, dosing, and duration have been published. Additionally, consensus guidance for certain infectious clinical syndromes is available and should inform institutional clinical practice guidelines. Novel metrics for stewardship-related outcomes in transplantation are desperately needed. Though exciting new molecular diagnostic technologies will likely be pivotal in the care of immunocompromised patients, optimal clinical adaptation and appropriate integration remains unclear. Important studies understanding the behaviors influencing antimicrobial prescribing in organizational transplant cultures are needed to optimize interventions. Consequences of antimicrobial use, such as Clostridiodes difficile and infections with multidrug-resistant organisms disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Application of ASP interventions tailored to SOT recipients is recommended though further studies are needed to provide guidance for best practice.

Early and Late Post-Kidney Transplant Weight Changes and Renal Allograft Outcome (P21-036-19)

Abstract Objectives Post-Transplant weight gain is associated with poor renal allograft function. Association between pattern of weight gain at different period after kidney transplantation (KTx) especially during late transplantation and renal allograft function is unclear. We aim to address to potential effect of weight changes on renal allograft function. Methods Seventy kidney transplant recipients from a single center were stratified into 4 groups based on weight gain (+) and/or weight loss (−) compared to weight at the time of KTx both at 1 and 6 months post-KTx (Gr1 (−, −), Gr2 (−, +), Gr3 (+ , −), Gr4 (+, +)). Decline in renal allograft function defined by dropped in eGFR from baseline eGFR at 1-month post-KTx during 24 months of follow-up in different 4 groups is examined by multivariable Cox proportional hazard regression analysis. Results Mean ± SD age was 52.66 ± 11.97 years and 59% was male. Mean ± SD body mass index (BMI) at the time of KTx was 27.64 ± 5.64 kg/m2. Distribution of patients in 4 groups of Gr1, 2, 3, and 4 were 34, 36, 10, and 20%, respectively and mean BMI of all 4 groups at the time of KTx were not statistically significant (p 0.0981). Mean weight changes among 4 groups based on weight change both at 1- and 6-month post-KTx were summarized in the Table 1. Baseline renal allograft function with a mean eGFR of 50.86 ± 18.90 ml/min/1.73 m2 were not different among all 4 groups (Table 1). Among 70 patients, 43 patients (61%) had a decline in eGFR between 1 and 24 months post-KTx and contributed to the incidence rate of 0.056 person-months. The number of patients with dropped eGFR in Gr1, 2, 3 and 4 were 14 (58%), 14 (56%), 4 (57%), and 11 (79%) patients, respectively. Compared to Gr1, Gr2 had lower, but Gr 3 and 4 had higher the risk for declining eGFR but no statistical significance (HR(95% CI) :0.84 (0.40–1.76); 1.18 (0.39–3.60); 1.31 (0.60–2.90)). After adjusted for age, gender, race, types of KTx, systolic and diastolic blood pressure and BMI at the time of KTx, the association remains the same. (HR(95% CI) :0.78 (0.34–1.81); 1.66 (0.46–6.04); 1.32 (0.53–3.34)). Conclusions Weight loss at very early (1 month) post-KTx appears protective for a decline in renal allograft function during 24 months post-KTx; whereas, weight gain at later time post-KTx (6 months) after initial early weight loss was even associated with better renal allograft outcomes. Factors associated with early post-KTx weight gain may contribute to pathophysiology of poorer renal allograft function. Funding Sources None. Supporting Tables, Images and/or Graphs

Is anuria prior to pediatric renal transplantation associated with poor allograft outcomes?

Anuria from end-stage renal disease leads to a defunctionalized bladder and may pose technical challenges at the time of renal transplantation. Anuria's effect on bladder function after renal transplantation is considered to be minimal in adults, although a paucity of evidence is available in children. The purpose of this study was to examine the effects of anuria prior to pediatric renal transplantation for ESRD due to medical renal disease on allograft outcome. We performed a retrospective review of pediatric patients who underwent renal transplantation for medical renal disease at our institution between 2005 and 2016. Demographics and clinical data were assessed. We also compared GFR at 1year post-transplant for medical renal patients with history of anuria and those without. Twenty-one patients fulfilled our inclusion criteria with median duration of anuria was 10months. Preoperative VCUG was available in five patients and their bladder capacity was 29% of expected bladder capacity for age (range 8%-41%). Anticholinergic therapy was prescribed in six patients (28%) for a mean duration of 5months (range 1-16months). Comparison of GFR at 1year post-transplant in anuria group and those without anuria showed no difference (69 vs 75mL/min, P=0.37). No correlation was observed between duration of anuria and post-transplant GFR. The majority of children in our pretransplant anuria cohort did not develop bladder dysfunction after renal transplantation. No difference was observed between GFR at 1year when comparing anuric to non-anuric transplant recipients of medical renal disease etiology.

C-reactive protein at ICU admission as a marker of early graft dysfunction after liver transplant. A prospective, single-center cohort study.

To explore the behavior of C-reactive protein (CRP) after orthotopic liver transplantation (OLT) during the first postoperative days, and its usefulness as a marker of severe early allograft dysfunction (EAD). A prospective, single-center cohort study was carried out. The Intensive Care Unit (ICU) of a regional hospital with a liver transplant program since 1997. The study comprised a total of 183 patients admitted to our ICU immediately after liver transplantation between 2009 and 2015. C-reactive protein levels upon ICU admission and after 24 and 48h, severe EAD and hospital mortality. The CRP levels after OLT were: upon ICU admission 57.5 (51.6-63.3)mg/L, after 24h 80.1 (72.9-87.3)mg/L and after 48h 69.9 (62.5-77.4)mg/L. Severe EAD patients (14.2%) had higher mortality (23.1 vs 2.5; OR 11.48: 2.98-44.19) and lower CRP upon ICU admission (39.3 [29.8-48.7]mg/L) than the patients without EAD (0.5 [53.9-67.0]; p<0.05] - the best cut-off point being 68mg/L (sensitivity 92.3%; specificity 40.1%; Youden index 0.33). Lower CRP upon ICU admission was correlated to higher mortality (24.5 [9.2-39.7] vs 59.4 [53.4-65.4]; p<0.01, AUC 0.79 [0.65-0.92]). Liver transplant is a strong inflammatory stimulus accompanied by high levels of C-reactive protein. A blunted rise in CRP on the first postoperative day after OLT may be a marker of poor allograft function and is related to hospital mortality.

Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence

Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes. However, variable timing of DSA assessment and inclusion of patients who undergo desensitization treatments have hindered our understanding of its consequences and limited its predictive value. Here we prospectively studied non-desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post-transplant DSA. Using serial monitoring, 67 of 294 patients were found to develop DSA by one year. Compared to patients who do not develop DSA, those with DSA exhibit an increased incidence of both clinical and subclinical T-cell-mediated rejection (TCMR). The combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone. Moreover, DSA was associated with higher Banff grade TCMR and chronic changes at one year. Antibody-mediated rejection was uncommon and always associated with TCMR. Amongst factors independently associated with DSA plus TCMR; non-adherence is potentially modifiable. Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post-transplant year, further risk-stratified patients with DSA plus TCMR such that about 75% of these patients had impending graft loss by four years, whereas adherent patients with DSA plus TCMR had outcomes comparable to other patient groups. Thus, early post-transplant DSA, especially in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.

C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection.

C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9—indicative of complement-mediated injury—is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25–73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9– ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Clinical outcomes of kidney transplantation in older end-stage renal disease patients: A nationwide cohort study.

The aim of the present study was to investigate the clinical outcomes of kidney transplantation (KT) in elderly recipients compared with those in young recipients. We compared the incidence of biopsy-proven acute rejection, death-censored allograft survival and all-cause mortality, and also compared the impact of high sensitization or desensitization on the clinical outcomes of elderly and young recipients. A total of 4966 KT recipients from the Korean Organ Transplantation Registry were included. The definition of elderly recipients was based on age >60 years (n = 356), and recipients aged <60 years were defined as young recipients (n = 4610). The incidence of biopsy-proven acute rejection did not differ between the two groups irrespective of the donor type; however, the impact of high sensitization was significant only in young recipients. Being an elderly recipient was an independent risk factor for death-censored allograft failure in terms of overall and living donor KT, but not with deceased donor KT. In regard to patient death, being an elderly recipient was a significant predictor in general and in the two subgroups, and desensitization showed a significant interaction with death in the elderly recipients in the living donor KT group. In conclusion, KT in elderly recipients might be associated with poor allograft or patient survival in general, and especially, desensitization therapy carried out in these patients might increase the risk of patient mortality. Geriatr Gerontol Int 2019; 19: 392-398.

High Calcineurin Inhibitor Intrapatient Variability Is Associated With Renal Allograft Inflammation, Chronicity, and Graft Loss.

High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes. However, the relationship between early allograft histological changes, their progression, and CNI-IPV is less well studied. Hence, we evaluated effect of CNI-IPV defined by the degree of fluctuation of CNI levels in all kidney transplant patients over 2 to 12 months posttransplant on early allograft inflammation, subsequent chronicity, and later clinical outcomes. Two hundred eighty-six patients transplanted from January 2013 to November 2014 were enrolled with protocol and indication biopsies. The mean CNI-IPV was 28.5% and a quarter of our cohort had IPV of 35% or greater (high CNI IPV). Baseline demographic differences were similar between high and low CNI IPV groups. High CNI-IPV was associated with a higher incidence of acute rejection (AR) within 1 year (52% vs 31% P < 0.001), more persistent/recurrent AR by 1 year (18.2% vs 6.2%, P = 0.002), higher-grade AR (≥Banff 1B, 27.5% vs 7.3%, P < 0.001), and worse interstitial fibrosis/tubular atrophy (P = 0.005). High CNI-IPV was associated with increased graft loss (GL) and impending graft loss (iGL, defined as eGFR<30 ml/min and >30% decline in eGFR from baseline), regardless of donor-specific antibody, delayed graft function, rejection, or race. In a multivariate Cox Proportional Hazards Model, high CNI-IPV was independently associated with GL + iGL (hazard ratio, 3.1; 95% confidence interval, 1.6-5.9, P < 0.001). High CNI-IPV within 1 year posttransplant is associated with higher incidence of AR, severe AR, allograft chronicity, GL, and iGL. This represents a subset of patients who are at risk for poor kidney transplant outcomes and potentially a modifiable risk factor for late allograft loss.

Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values.

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies

IntroductionAngiotensin II type 1 receptor antibody (AT1R-Ab), is a non–human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients.MethodsBlood samples from 65 pediatric renal transplant recipients drawn during the first 3 months posttransplant, at 6, 12, and 24 months posttransplant, and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated.ResultsAT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even after controlling for relevant clinical factors and was consistent across all time points. In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years posttransplant.ConclusionsThis profile of vascular cytokines may be informative for clinical monitoring and designing future studies to delineate the distinct pathophysiology of AT1R-Ab–mediated allograft injury in kidney transplantation.

Abstract 16779: Mitochondrial Related Intragraft Gene Expression During Acute Rejection After Heart Transplantation

Introduction: Endomyocardial biopsies (EMB) for the surveillance of acute cellular rejection (ACR) after heart transplant (HT) is inconsistent and provides limited information. Mitochondrial dysfunction is associated with poor allograft prognosis and can overstimulate the inflammatory response. Mitochondrial related gene expression (GE) in EMB may be useful as a functional surrogate for EMB. Hypothesis: We hypothesize that down-regulated mitochondrial associated GE in EMB correlates with ACR. Methods: We collected 64 EMB from 47 post HT patients (mean age 50 ± 14.7 years). Purified mRNA was subjected to whole-genome next-generation sequencing. Weighted gene co-expression network analysis was applied to construct functional gene modules. Module derived eigengenes were correlated with ISHLT EMB criteria or using an unsupervised classification method we previously developed and B-type natriuretic peptide (BNP) levels. Biological significance and function of each module were assessed by gene ontology (GO) and pathway analyses. Highly relevant genes were identified by Hub gene analysis. Results: The reconstructed network resulted in 16 modules including two mitochondria-related modules (MRM) and one immune response module (IRM). Compared to 0R (n= 30/46.9%) samples, 2R (n= 11/17.2%) EMB showed enrichment of IRM and decreased expression of MRM. ISHLT 1R (n= 23/35.9%) samples did not show a significant correlation with IRM or MRM. Following the unsupervised classification method, findings were concordant, with higher phenotype-module eigengene correlation and significance level. MRM Hub genes included ATP5B, ATP5O, ACO2, COX14, COX4I1 , FH, NDUFV1, PDK2, SDHA and UQCR11 among others. GO categories enriched by these genes included oxidative phosphorylation, beta-oxidation, tricarboxylic acid cycle, glycolysis and gluconeogenesis. There was an inverse correlation between MRM and BNP level and positive correlation between IRM and BNP (Figure). Conclusions: EMB of patients with ISHLT 2R ACR show decrease activity of MRM, increased activity of IRM and elevated BNP suggesting an inverse functional relationship between immune activation, mitochondrial activity and cardiac allograft function.

Association Between Delayed Graft Function (DGF) Biomarkers and Long-term Outcomes After Living Donor Kidney Transplantation.

The association between preoperative Urine Neutrophil Gelatinase-associated Lipocalin (uNGAL) and interleukin-18 (uIL-18) with poor 1-year allograft function has been shown in deceased-donor kidney transplant recipients previously, and also these markers could predict 3-month allograft function. However, it is unknown whether there is an association between these postoperative biomarkers with important recipient outcomes beyond this time in livedonor transplants. NGAL and IL-18 four and 24 hours were measured in live-donor kidney transplant recipients after transplantation. The relationships between changes in these markers with clinical outcomes as well as kidney function were examined at 1 month and 2 years. Moreover, the association between delayed graft function with clinical outcome and Serum Creatinine (SrCr) was evaluated during this period. The Mean age for kidney recipients was 23.9 years. Significant interaction was observed between uNGAL 24 hr (pvalue=0.01) and uIL-18 four and 24 hr after transplantation (pvalue=0.04, 0.03; respectively) with patients' outcome after 1 month and changes in uNGAL with outcomes after 2 years (pvalue= 0.04). Changes in urine NGAL postoperative are associated with worst outcomes, 2 years after kidney transplantation, suggesting its potential role in identifying patients that are at high risk for diminished allograft function, outcome and survival.

Abstract P122: Early Renal Allograft Function and Hypertension after Kidney Transplantation

Background: Poor renal allograft function is associated with post-transplant hypertension (HTN). The association between allograft function at an early post-transplant period and HTN is unclear. Method: Of 70 transplant recipients, the difference between serum creatinine (SCr) at the discharge date from kidney transplantation (KT) and those at pre-transplantation (ΔCr) divides the study population into Group 1 (ΔCr ≥80%) and Group 2 (ΔCr &lt;80%). Cox proportional hazard regression is performed to find the association between different ΔCr and post-transplant systolic HTN (SHTN) and diastolic HTN (DHTN) defined by SBP ≥130 and DBP ≥80 mmHg, respectively during a 96-week follow-up period. Results: Mean age±SEM is 52.66±1.43 years and 58.6% is male. Mean length of stay is 8.50±1.35 days. Thirty patients (43%) are in the Groups 1. Mean absolute ΔCr is greater in the Group 1 (ΔCr -7.41±0.43 vs. -3.49±0.42, p &lt;0.001). Compared to Group 1, Group 2 has a 17.1% increased risk of SHTN (HR 1.171, 95%CI 0.715 to 1.918, p 0.530, Fig1A), but has a 24.5% decreased risk of DHTN (HR 0.755, 95%CI 0.417 to 1.367, p 0.353, Fig1B). After adjusting for age, gender, type of induction immunosuppressants, type of KT, and BMI, Group 2 has an 80.2% greater risk for SHTN (HR 1.802, 95%CI 0.976 to 3.325, p 0.060, Fig2A), but has a 6.8% lowered risk of DHTN (HR 0.932, 95%CI 0.467 to 1.857, p 0.840, Fig2B). Conclusions: The degree of change in SCr during immediate post-KT does not predict post-transplant SHTN and DHTN. However, patients with better renal allograft function appear to become less SHTN but more DHTN. The pattern of association between long-term allograft function and SHTN and DHTN needs further studies.

Intragraft vasculitis and gene expression analysis: Association with acute rejection and prediction of mortality in long-term heart transplantation.

Vasculitis entails heterogeneous origins; it starts with an inflammatory process that leads to small vessels' necrosis, hemorrhage, and ischemic lesion, and may further result in occlusion of the vascular lumen. Vasculitis' contribution to allograft rejection is still unclear. This study aims to investigate the incidence of vasculitis in the early stages of heart transplantation as well as to assess the intragraft genes' expression associated with vascular function and subsequently to verify the way in which it affects the outcome of the allograft. In this retrospective study, 300 archive paraffin-embedded endomyocardial biopsies from 63 heart allograft recipients were assessed. Cellular rejection and vasculitis were diagnosed through histological analysis, and antibody-mediated rejection was performed with immunohistochemical C4d staining. The transcripts of ICAM, VCAM, VEGF, CCL2, IFNG, TGFB, TNF, ADIPOR1, and ADIPOR2 genes were examined through quantitative polymerase chain reaction using B2M for normalization. We observed a higher prevalence of severe vasculitis in the early period of post-transplant, and recovery was observed to take place around 1year post-transplant. Additionally, vasculitis was found to be directly associated with acute cellular rejection and antibody-mediated rejection. The intense C4d capillary positivity predicts higher long-term cardiovascular disease mortality. In comparison with the vasculitis-free group, the group with severe vasculitis displayed reduced left ventricular ejection fraction and an upregulation of VCAM and IFNG associated with the downregulation of VEGF, ADIPOR1, and ADIPOR2. The vasculitis associated with the presence of C4d and the change in intragraft gene expression profile may contribute to poor allograft outcomes.

The Efficacy of Rabbit Anti-Thymocyte Globulin for Acute Kidney Transplant Rejection in Patients Using Calcineurin Inhibitor and Mycophenolate Mofetil-Based Immunosuppressive Therapy.

BackgroundT cell depleting antibody therapy with rabbit anti-thymocyte globulin (rATG) is the treatment of choice for glucocorticoid-resistant acute kidney allograft rejection (AR) and is used as first-line therapy in severe AR. Almost all studies investigating the effectiveness of rATG for this indication were conducted at the time when cyclosporine A and azathioprine were the standard of care. Here, the long-term outcome of rATG for AR in patients using the current standard immunosuppressive therapy (i.e., tacrolimus and mycophenolate mofetil) is described.Material/MethodsBetween 2002 to 2012, 108 patients were treated with rATG for AR. Data on kidney function in the year following rATG and long-term outcomes were collected.ResultsOverall survival after rATG was comparable to overall survival of all kidney transplantation patients (P=0.10). Serum creatinine 1 year after rATG was 179 μmol/L (interquartile range (IQR) 136–234 μmol/L) and was comparable to baseline serum creatinine (P=0.22). Early AR showed better allograft survival than late AR (P=0.0007). In addition, 1 year after AR, serum creatinine was lower in early AR (157 mol/L; IQR 131–203) compared to late AR (216 mol/L; IQR 165–269; P<0.05). The Banff grade of rejection, kidney function at the moment of rejection, and reason for rATG (severe or glucocorticoid resistant AR) did not influence the allograft survival.ConclusionsTreatment of AR with rATG is effective in patients using current standard immunosuppressive therapy, even in patients with poor allograft function. Early identification of AR followed by T cell depleting treatment leads to better allograft outcomes.

P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes.

Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.

Inflammation in Fibrotic Areas (i-IF/TA) Identifies a T cell-mediated Rejection Component of IF/TA with Poor Kidney Allograft Outcome

Addressing the etiological heterogeneity of interstitial fibrosis in kidney allografts represents an important challenge to improve long-term transplant outcomes. We investigated the determinants, clinical and histological phenotype, and outcome of i-IF/TA in a prospective cohort of kidney recipients. We prospectively enrolled 1539 kidney recipients transplanted between 2004 and 2010, with systematic assessment of i-IF/TA using the i-IF/TA Banff score and of tubulitis in atrophic tubules (t-IF/TA), on allograft biopsies performed at 1 year post-transplantation. We considered donor, recipient and transplant baseline characteristics, immunosuppression, infectious diseases (CMV, pyelonephritis, BK virus), presence of donor-specific anti-HLA antibodies (DSAs) and all the biopsy-proven diagnoses (T cell-mediated rejection [TCMR], antibody-mediated rejection [ABMR], recurrence, BK virus-associated nephropathy [BKVAN], calcineurin inhibithor [CNI] toxicity, acute tubular necrosis) recorded within the first year after transplantation. We identified 946 (61%) patients with IF/TA at one year post-transplant, among whom 394 (42%) patients showed i-IFTA, which was associated with t-IF/TA in 309 (78%) patients. Patients with i-IF/TA at 1 year post-transplant had significantly decreased allograft survival at 8 years compared with patients with non-inflammatory IF/TA (81% vs 87%, P=0.002). Independent risk factors for i-IF/TA included: TCMR (OR=2.7, p<0.001), BKVAN (OR=3.3, p=0.007) and HLA B (OR=1.3, p=0.012) and DR (OR=1.2, p=0.044) mismatching, while steroid therapy (OR=0.6, p=0.039), CNI therapy (OR=0.5, p=0.011) and inosine-5'-monophosphate dehydrogenase inhibitor therapy (OR=0.5, p=0.011) had protective effects on i-IF/TA occurrence. Unsupervised hierarchical clustering based on the whole spectrum of Banff elementary lesions assessed at 1 year post-transplant showed that i-IF/TA aggregated in the TCMR cluster (i, t, ti, t-IF/TA and i-IF/TA) and not in the ABMR (g, ptc, C4d, cg) and chronicity clusters (cv, ci, ct, ah). We observed a positive gradient between increasing level of i-IF/TA and t-IF/TA Banff scores and the risk of allograft loss (p<0.001). i-IFTA may reflect a TCMR subcomponent of IF/TA related to under-immunosuppression and is associated with poor kidney transplant outcome compared to non-inflammatory IF/TA.

Cell mediated rejection revisited: Past, current, and future directions.

The Banff histopathology classification system is the gold standard for assessing the causes of kidney allograft dysfunction triggered by antibody-mediated and T-cell-mediated immune reactions, thereby providing mechanistic insight and guiding therapeutic decisions. The original Banff classification (1993) consisted of four histological categories representing cell-mediated rejection: interstitial inflammation (i), tubulitis (t), endoarteritis (v), and transplant glomerulitis (g). The revised Banff 2007 classification added total inflammation score (ti) from both scarred and unscarred areas based on evolving interpretations of interstitial infiltrates. Further reappraisal of cell-mediated interstitial inflammation led to the introduction of a new inflammation score specific for areas of interstitial fibrosis and tubular atrophy, termed i-IF/TA, in the Banff 2015 scheme, establishment of a new Banff working group on T-cell-mediated rejection (TCMR), and revised criteria of chronic active TCMR in Banff 2017 classification. These Banff scheme updates reflect the general recognition that chronic interstitial inflammation is a common denominator of poor kidney allograft outcome. However, revised theories on the pathogenic importance of interstitial infiltrates have created difficulties in interpretation of chronic tubulointerstitial inflammation, as there are currently no histological criteria to discriminate immune-mediated tissue injury from 'non-specific' injury. Evolving theories on vascular lesions, both active and chronic, have also complicated histological assessment by obscuring the distinction between antibody-mediated and T-cell-mediated tissue injury. This review provides an overview of recent ideas on interstitial inflammation and vascular lesions based on emerging concepts of T-cell-mediated rejection.

Angioplasty Versus Medical Treatment of Transplant Renal Artery Stenosis

Background Transplant renal artery stenosis (TRAS) is a recognized vascular complication after kidney transplantation and is associated with hypertension and poor allograft survival. Treatment of TRAS is primarily percutaneous intraluminal angioplasty with or without stent. Objective To compare outcomes of angioplasty versus medical treatment for the treatment of TRAS from 2000 to 2017. Methods We retrospectively reviewed transplant patients whom diagnosed TRAS by Duplex ultrasound. The clinical diagnosis of TRAS was based on uncontrolled hypertension and/or unexplained allograft dysfunction. Patients were divided into two groups: angioplasty group (percutaneous intraluminal angioplasty and surgical angioplasty) and medical treatment group. Results Of 166 patients screened for TRAS, 45 patients were diagnosed TRAS from Duplex ultrasound. Two patients were excluded from the analysis due to inadequate information. The median time of follow-up was 49.47 months (range, 3-140 months). Nineteen patients received angioplasty (17 patients with percutaneous intraluminal angioplasty and 2 patients with surgical angioplasty) and 23 patients receive medical treatment. Estimated glomerular filtration rate (eGFR) was significantly improved during the first 6 months after intervention in angioplasty group compared to medical treatment group (+2.68 ml/min/1.73 m2/month vs +0.17 ml/min/1.73 m2/month, p=0.006). However, change of eGFR after 6 months were not different between groups. The time to 30% increase of serum creatinine from baseline and allograft survival were not different between groups. Conclusion Angioplasty improved allograft function during the first 6 months after an intervention. However, long-term graft function and allograft survival were not different between treatment with angioplasty and medical treatment.