Allograft Outcomes Research Articles

Butyryl chitosan: Synthesis, characterization and evaluation of the sustained release performance as tacrolimus carrier

Chitosan and its water-soluble derivatives have been widely used in biomaterials, but their disadvantages have hindered their widespread application. In this study, butyryl chitosan, a liposoluble chitosan derivative, was prepared by introducing butyryl groups into chitosan molecules through an acylation reaction. The synthesis conditions were optimised, the reaction was more efficient and simpler than previously reported strategies. Two butyryl chitosan with degrees of substitution greater than two were synthesised. Chemical characterisations confirmed that the hydroxyl and primary amine groups in the backbone of chitosan were converted into amide and ester groups, respectively. The butyryl chitosan films have advantages such as high mechanical properties, long biodegradation time, proper surface charge, good cytocompatibility, and histocompatibility. Butyryl chitosan was used as carrier to prepare an implantable tacrolimus sustained release film. Characterization results showed that tacrolimus existed in an amorphous state in the release film. This work embodies an innovative formulation using tacrolimus-loaded carboxymethyl chitosan amorphous solid dispersions embedded butyryl chitosan film with added advantage of sustained release, an effective blood concentration in vivo for 11 days and a systemic exposure but lower intrapatient variability in tacrolimus trough levels. This work merits sustainable tacrolimus release use by providing application-based proofs and qualifies as a potential formulation for sustainable tacrolimus release system. We expect an improvement in terms of therapeutic compliance with positive effects on allograft outcomes.

Donor-Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms.

Despite significant improvement in the rates of acute allograft rejection, proportionate improvements in kidney allograft longevity have not been realized, and are a source of intense research efforts. Emerging translational data and natural history studies suggest a role for anti-donor immune mechanisms in a majority of cases of allograft loss without patient death, even when overt evidence of acute rejection is not identified. At the level of the donor and recipient genome, differences in highly polymorphic HLA genes are routinely evaluated between donor and recipient pairs as part of organ allocation process, and utilized for patient-tailored induction and maintenance immunosuppression. However, a growing body of data have characterized specific variants in donor and recipient genes, outside of HLA loci, that induce phenotypic changes in donor organs or the recipient immune system, impacting transplant outcomes. Newer mechanisms for “mismatches” in these non-HLA loci have also been proposed during donor–recipient genome interactions with transplantation. Here, we review important recent data evaluating the role of non-HLA genetic loci and genome-wide donor-recipient mismatches in kidney allograft outcomes.

175 The Unfinished Journey towards Transplant Equity: an analysis of racial/ethnic disparities for children in the post-KAS era

OBJECTIVES/GOALS: Disparities in pediatric kidney transplantation (KT) result in reduced access and worse outcomes for minority children. We aimed to assess the impact of recent systemic changes on these disparities. METHODS/STUDY POPULATION: Retrospective cohort study of pediatric patients utilizing data from the United States Renal Data System (USRDS) and Scientific Registry of Transplant Recipients (SRTR). We compared access to transplantation, time to deceased donor kidney transplant (DDKT), and allograft failure (ACGF) using Cox proportional hazards in the 4 years preceding KAS to the 4 years post-KAS implementation. RESULTS/ANTICIPATED RESULTS: Compared to the pre-KAS era, patients post-KAS were more likely to be pre-emptively listed (26.8% vs 38.1%, p<0.001) and pre-emptively transplanted (23.8% vs 28.0%, p<0.001), however these benefits were not uniform across racial groups. Only 12.7% and 15.7% of Black and Hispanic children received a pre-emptive transplant compared to 29.6%, 49.8% and 54.4% of White, Asian and Other race children respectively. Compared to White children, Black and Hispanic children had a lower likelihood of transplant listing within 2 years of first dialysis service aHR 0.67 (0.59-0.76) and 0.82 (0.73-0.92), in the post-KAS era. Time to DDKT after listing was comparable across all racial groups in both eras. Black children have disproportionally worse 5-yr ACGF, aHR 1.50 (1.08-2.09), p=0.02. DISCUSSION/SIGNIFICANCE: After KAS implementation there remains equity in time to DDKT, however disparities persist in transplant listing and ACGF among Black children. Further studies are needed to identify granular SES factors impacting delayed referral and systemic barriers to transplant, as well as risk factors for poor allograft outcomes among minority children.

Tumor Necrosis Factor-α Gene Polymorphism is Associated with Short- and Long-Term Kidney Allograft Outcomes.

IntroductionKidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved over the past two decades. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for kidney transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-α) gene (TNF) polymorphisms on kidney graft survival after transplantation.MethodsWe performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function and death-censored kidney allograft survival in 1271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.ResultsThe G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of immediate graft loss (odds ratio: 2.05; 95%-CI: 1.06–3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P < 0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05–2.19, P = 0.028).DiscussionIn conclusion, kidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF-α blockade in improving kidney transplantation outcomes.

Is Acute Rejection Truly Acute or an Exacerbation of an Underlying Disease?

<h3>Purpose</h3> The current paradigm defines acute rejection (AR), a composite of acute cellular rejection or antibody-mediated rejection, as distinct acute events. Yet, affected patients often progress to chronic lung allograft dysfunction despite initiation of targeted therapy at diagnosis of the acute process. We hypothesize that AR is not an acute event, but rather, an exacerbation of an on-going early post-transplant disease. Herein, we leverage donor-derived cell-free DNA, a sensitive marker, to define post-transplant allograft injury pattern associated with AR. <h3>Methods</h3> 141 prospectively enrolled lung transplant patients (NCT02423070) were grouped as acute rejection ("AR") or no rejection ("NR") as determined by adjudication. Allograft injury was measured by ddcfDNA via shotgun sequencing in 1557 prospectively collected plasma samples; medians and interquartile ranges (IQR) are reported <h3>Results</h3> Over the median 19.6 months follow-up, 87 episodes of AR were detected in 51 patients (34.7%) at a median 7.6 (IQR =2.4 - 12.7) months post-transplant. %ddcfDNA was high after transplant surgery and then decayed. "AR" showed slower decay. Their baseline ddcfDNA levels were higher than for "NR" well before AR diagnosis (<b>FigA</b>), starting from Day 7 post-transplant and reached 4X higher than for "NR" by 3 months post-transplant (0.88%, IQR=0.31% - 1.93% vs. 0.23%, IQR=0.13% - 1.59%). At AR diagnosis, ddcfDNA levels rose (1.95%, IQR=1.14% - 5.04%) and were ∼2 fold higher than the within subject high baseline levels (<b>FigB</b>), and ∼6X higher than for time-matched "NR". ddcfDNA reduced after AR treatment but remained higher than for time-matched "NR" (0.52%, IQR=0.22% - 1.59% vs. 0.25%, IQR=0.08% - 0.57%, <i>p<</i>0.01). <h3>Conclusion</h3> Early after transplant, "AR" patients show higher levels of baseline allograft injury that persist and then rise with diagnosis of AR. If ongoing studies confirm these findings and identify mechanisms that predict elevated baseline injury and AR phenotype, treatment paradigms could be revised to improve allograft outcomes.

Risk of New-Onset Diabetes after Transplantation among Kidney Transplant Recipients with Cytomegalovirus Infection: A Retrospective Analysis

Background: New-onset diabetes after transplantation (NODAT) is one of the common complications reported in patients with kidney transplant and is associated with risk of infection, poor allograft and patient survival. There is conflicting research literature regarding the role of cytomegalovirus (CMV) infection in increasing the risk of NODAT development. Objective: To assess the risk of development of NODAT in kidney transplant patients with CMV infection Methods: A total of 59 kidney transplant patients were studied from March 2017 to February 2019. NODAT was defined as two readings of fasting plasma glucose of ≥126 mg/dL at three months post-transplant. CMV viral load was also documented. The 12 months post-transplant allograft and patient survival outcomes were also measured. Results: Mean age was 43.4 ± 6.2 years. Nearly one-fourth, 14 (23.7%), of the patients had NODAT. CMV viral load and viremia were high in NODAT group; however, the result did not reach statistical significance. CMV DNA replication was statistically high during 1-6 months post-transplant for NODAT group (P&lt;0.001). Only 7 (11.9%) recipients advanced to symptomatic CMV infection. Also, we found that high CMV viremia load was associated with poor kidney allograft function at 12 months. Conclusions: In summary, this study showed that infection with CMV may not be a risk factor to develop NODAT in patients transplanted with kidney. An elevated CMV viral load may decrease the post-transplant allograft function at 12 months. The prompt diagnosis and timely management of CMV infection could substantially lessen the risk to develop NODAT subsequent worsening of allograft and patient survival. Keywords: Kidney; Transplant; NODAT; New-onset Diabetes; Cytomegalovirus

Early Assessment of National Kidney Allocation Policy Change.

The new kidney allocation changes with elimination of donor service areas (DSAs) and Organ Procurement and Transplantation Network regions were initiated to improve equity in organ allocation. The aim of this evaluation was to determine the operational, financial, and recipient-related effect of the new allocation system on a large rural transplantation program. A retrospective, cross-sectional analysis of organ offers, allograft outcomes, and attributed costs in a comparative time cohort, before (December 16, 2020 to March 14, 2021) and after (March 15, 2021 to June 13, 2021) the allocation change was performed. Outcomes were limited to adult, solitary, deceased donor kidney transplantations. We received 198,881 organ offers from 3,886 organ donors at our transplantation center from December 16, 2020 to June 31, 2021: 87,643 (1,792 organ donors) before the change and 111,238 (2094 organ donors) after the change, for a difference of +23,595 more offers (+302 organ donors). This resulted in 6.5 more organs transplanted vs a predicted loss of 4.9 per month. Local organ offers dropped from 70% to 23%. There was a statistically significantly increase in donor terminal serum creatinine (1.2 ± 0.86 mg/dL vs 2.2 ± 2.3 mg/dL, p < 0.001), kidney donor profile index (KDPI) (39 ± 20 vs 48 ± 22, p = 0.017), cold ischemia time (16 ± 7 hours vs 21 ± 6 hours, p < 0.001), and delayed graft function rates (23% vs 40%, p = 0.020). The new kidney allocation policy has led to an increase in KDPI of donors with longer cold ischemia time, leading to higher delayed graft function rates. This has resulted in increasing logistical and financial burdens on the system. Implementing large-scale changes in allocation based predominantly on predictive modeling needs to be intensely reassessed during a longer follow up.

No difference in postoperative efficacy and safety between autograft and allograft in anterior cruciate ligament reconstruction: a retrospective cohort study in 112 patients.

BackgroundArthroscopic anterior cruciate ligament reconstruction (ACLR) is the best treatment choice for returning to pre-injury activities following ACL rupture. Although allografts are considered an effective alternative to autografts, there is still controversy regarding the safety and effectiveness of this procedure, especially concerning the risk of postoperative infection and disease transmission. The purpose of this study was to compare the efficacy outcomes and safety between allografts and autografts in primary ACLR.MethodsThe retrospective analysis involved 112 patients (58 patients received allogeneic tendons and 54 patients received autologous hamstring tendons) who underwent primary ACLR. All patients were followed up and evaluated on admission and at 1 week, 3 months, 6 months, and 1 year postoperatively. The efficacy outcome of the ACLR was evaluated by International Knee Documentation Committee (IKDC) score and physical examinations (Lachman test, anterior drawer test, and pivot shift test). The safety outcome of allografts and autografts was compared by investigating the occurrence of postoperative complications, including postoperative inflammation and potential disease transmission. The benefits of each operation for surgeons and patients were also analyzed, including the length of surgical incision and operative time.ResultsThere was no significant difference in the demographic and clinical characteristics between the allograft and autograft groups. The two cohorts proved to be similar in terms of the acute or chronic nature of the cruciate ligament and the incidence of concomitant meniscal surgery. Arthroscopic ACLR was performed in all patients. The physical examinations were all positive before surgery and negative immediately after the operation. The KT-1000 and IKDC scores of two groups significantly decreased than pre-operative ones (P<0.05), but the difference between the two groups was not statistically significant (P>0.05). At final follow-up, all patients had returned to their pre-injury activities. Allografts showed no increased risk for postoperative infection or potential disease transmission relative to autografts.ConclusionsThe outcomes of reconstructed ACL with allografts were similar to those of autographs. Moreover, the safety of allografts showed to be comparable to that of autografts, especially concerning postoperative infection and disease transmission. Therefore, the surgical option should be chosen wisely according to the patient’s condition.

Sex and gender as predictors for allograft and patient-relevant outcomes after kidney transplantation

Sex and gender as predictors for allograft and patient-relevant outcomes after kidney transplantation

Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application.

Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia–reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.

Isolated Osteochondral Autograft Versus Allograft Transplantation for the Treatment of Symptomatic Cartilage Lesions of the Knee: A Systematic Review and Meta-analysis

Background: Focal cartilage lesions of the knee remain a difficult entity to treat. Current treatment options include arthroscopic debridement, microfracture, autograft or allograft osteochondral transplantation, and cell-based therapies such as autologous chondrocyte transplantation. Osteochondral transplantation techniques restore the normal topography of the condyles and provide mature hyaline cartilage in a single-stage procedure. However, clinical outcomes comparing autograft versus allograft techniques are scarce. Purpose: To perform a comprehensive systematic review and meta-analysis of high-quality studies to evaluate the results of osteochondral autograft and allograft transplantation for the treatment of symptomatic cartilage defects of the knee. Study Design: Systematic review and meta-analysis; Level of evidence, 2. Methods: A comprehensive search of the literature was conducted using various databases. Inclusion criteria were level 1 or 2 original studies, studies with patients reporting knee cartilage injuries and chondral defects, mean follow-up ≥2 years, and studies focusing on osteochondral transplant techniques. Exclusion criteria were studies with nonknee chondral defects, studies reporting clinical outcomes of osteochondral autograft or allograft combined with other procedures, animal studies, cadaveric studies, non–English language studies, case reports, and reviews or editorials. Primary outcomes included patient-reported outcomes and failure rates associated with both techniques, and factors such as lesion size, age, sex, and the number of plugs transplanted were assessed. Metaregression using a mixed-effects model was utilized for meta-analyses. Results: The search resulted in 20 included studies with 364 cases of osteochondral autograft and 272 cases of osteochondral allograft. Mean postoperative survival was 88.2% in the osteochondral autograft cohort as compared with 87.2% in the osteochondral allograft cohort at 5.4 and 5.2 years, respectively (P = .6605). Patient-reported outcomes improved by an average of 65.1% and 81.1% after osteochondral autograft and allograft, respectively (P = .0001). However, meta-analysis revealed no significant difference in patient-reported outcome percentage change between osteochondral autograft and allograft (P = .97) and a coefficient of 0.033 (95% CI, –1.91 to 1.98). Meta-analysis of the relative risk of graft failure after osteochondral autograft versus allograft showed no significant differences (P = .66) and a coefficient of 0.114 (95% CI, –0.46 to 0.69). Furthermore, the regression did not find other predictors (mean age, percentage of female patients, lesion size, number of plugs/grafts used, and treatment location) that may have significantly affected patient-reported outcome percentage change or postoperative failure between osteochondral autograft versus allograft. Conclusion: Osteochondral autograft and allograft result in favorable patient-reported outcomes and graft survival rates at medium-term follow-up. While predictors for outcomes such as mean age, percentage of female patients, lesion size, number of plugs/grafts used, and treatment location did not affect the comparison of the 2 cohorts, proper patient selection for either procedure remains paramount to the success and potentially long-term viability of the graft.

Prevalence Rate of Proteinuria and Metabolic Acidosis Among Kidney Transplant Recipients in a Tertiary Teaching Hospital and Its Relationship to Dietary Intake

Proteinuria and metabolic acidosis adversely affect long term renal allograft outcome and are highly prevalent in reported studies. The role of dietary intake in influencing proteinuria and metabolic acidosis remained uncertain. This study aims to determine the prevalence rate of proteinuria and metabolic acidosis among kidney transplant recipients (KTRs) and to study their relationship with dietary intake. We performed a cross-sectional study on KTRs with functioning renal allograft and at least 3 months post transplant. Dietary protein, salt, and dietary acid load were estimated using 24-hour urine collection. Demographic characteristics, concomitant medications, medical history, and laboratory results were obtained from electronic medical records. A total of 204 KTRs were recruited with median age of 48 years (interquartile range [IQR], 18 years); male to female ratio was 61:39. A total of 79.9% (n=163) were living related kidney transplants. The median duration after transplant was 71 months (IQR, 131 months), and median eGFR was 65 mL/min/1.73 m2 (IQR, 25 mL/min/1.73 m2). The prevalence rates of proteinuria (defined as ≥ 0.5 g/d) and metabolic acidosis (defined as at least 2 readings of serum bicarbonate ≤ 22 mmol/L in the past 6 months) were 17.7 % and 6.2%, respectively. High dietary protein of > 1.2 g/kg ideal body weight (adjusted odds ratio, 3.13; 95% CI, 1.35-7.28; P=.008) was significantly associated with proteinuria. Dietary protein, salt, and acid load did not correlate with chronic metabolic acidosis. The prevalence rate of proteinuria is consistent with published literature, but metabolic acidosis rate is extremely low in our cohort. High protein intake (> 1.2 g/kg ideal body weight) is a risk factor of proteinuria and may have negative impact on KTR outcome.

POS-769 ALLOGRAFT OUTCOMES, SAFETY AND EFFICACY OF QUINOLONE BASED AND RIFAMPIN BASED REGIMENS FOR THE TREATMENT OF TUBERCULOSIS IN KIDNEY TRANSPLANT RECIPIENTS

Among patients with kidney transplant receiving rifampicin-based anti-tuberculosis treatment regimen, the need for increased dose of immunosuppressants along with frequent drug level monitoring, imposes significant financial and economic burden in this disadvantaged population, more so in the middle- or low-income countries. However, as yet there are no prospective randomised studies comparing the efficacy of levofloxacin-based anti-tuberculosis treatment with rifampicin-based anti-tuberculosis treatment in kidney transplant recipients. The present study was designed to study the efficacy, safety and effect on allograft function in levofloxacin- versus rifampicin-based anti-tuberculosis treatment regimen. We conducted a prospective randomized study at the Post Graduate Institute of Medical Education and Research, Chandigarh between the period January 2020 to June 2021. The study included 20 kidney transplant recipients who developed TB post-kidney transplant and were randomized to receive 12 months of anti-tuberculosis treatment with either a rifampicin-based anti- tuberculosis treatment or levofloxacin-based anti-tuberculosis treatment regimen and were followed up for the duration of their treatment. All patients were on a calcineurin inhibitor based maintenance immunosuppression regimen, with 90% receiving tacrolimus and 10% on cyclosporine. Out of total 20 patients,40% had pulmonary TB, 50% had extra-pulmonary TB and 10% had pulmonary and extra-pulmonary TB. Tuberculosis was diagnosed by histopathology in 15%, microbiological in 40% and clinical-radiological in 45%. Anti-tuberculosis treatment was commenced within 4 weeks of onset of symptoms in 55% of the patients and, within 6 weeks in all patients. In the rifampicin-based anti-tuberculosis treatment group, 40% had to discontinue treatment and switch to levofloxacin-based anti-tuberculosis treatment, in view of drug related adverse effects or difficulty in maintaining immunosuppressant levels. All patients in the levofloxacin-based anti-tuberculosis treatment group remained on levofloxacin for the duration of treatment. All patients responded to anti- tuberculosis treatment and there was no mortality observed in the cohort during the period of follow- up. In our study levofloxacin-based anti-tuberculosis treatment had similar allograft outcomes as rifampicin-based anti-tuberculosis treatment and appeared to be associated with less adverse drug effects, lesser chance of discontinuation of drug therapy and more stable calcineurin inhibitor drug levels. Given these attributes, the study findings lend support to the use of Levofloxacin-based anti-tuberculosis treatment as the first line therapy regimen for kidney transplant recipients with TB who are on calcineurin inhibitor based maintenance immunosuppression regimen. The findings of this study serve as pilot towards future larger randomized trial to prospectively compare the two treatment regimens.

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

Study ObjectiveThis study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients.Design and SettingA cross‐sectional, open‐label, single center, 12‐h pharmacokinetic‐pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration‐time curve (AUC0–12), AUC0–4, 12‐h troughs (C 12 h), maximum concentrations (C max), oral clearance (Cl), with dose‐normalized AUC0–12, troughs, and C max with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate‐adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms.Patients65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post‐transplant were evaluated.Measurements and Main ResultsBlack recipients exhibited higher tacrolimus AUC0–12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0–12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0–12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%–19% of tacrolimus variability in dose (p = 0.002); AUC0–12 h* (p < 0.001), and Cl (p < 0.001).ConclusionsTacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0–12 h.

Liver allograft findings of donation after cardiac death versus brain death in recipients with hepatitis C related cirrhosis: a matched histologic comparison

As the demand for organ transplantation increases, utilization of liver allografts of donation after cardiac death (DCD) is becoming increasingly necessary. Althoughthe clinical outcomes of DCD allografts have been well described, the histologic features are not well characterized. Liver biopsies (n=131) from age-matched DCD (n=60) and donation after brain death (DBD; n=71) recipients with hepatitis C virus were compared. Histologic features were studied in a blinded fashion, subgrouped into time 0, 0-6 months, and >6 months. In time 0 biopsies, more DCD cases had zone 3 (43.8 vs 29%) and bridging necrosis (19 vs 0%), albeit not statistically significant. At 0-6 months, more DCD cases had portal edema (p=0.01). Pericholangitis (30.4% vs 18.8%) and acute cholestasis (21.7% vs 12.5%) were more common in DCD, but not statistically significant. At >6 months, pericholangitis (19% vs 4.5%) persisted in DCD, although not statistically significant. Overall, both groups had similar bile duct injury, portal inflammation, and fibrosis. Postoperative biliary complications were more common in DCD (19% vs 0%). Three-year and 10-year graft survival and patient outcomes were similar in both cohorts. Biliary alterations were more prevalent in the 0-6 month time period DCD biopsies, reflecting increased vulnerability of this group to biliary complications in the early post-orthotopic liver transplant (OLT) period. This finding may suggest poor graft perfusion despite comparable cold ischemia times. However, these features improved and DCD recipients have similar graft and overall survival compared to DBD recipients, indicating that carefully selected DCD liver allografts are a viable option for transplantation.

Clinical Significance of C3d Assay in Kidney Transplant Recipients With Donor-Specific Anti–Human Leukocyte Antigen Antibodies

Antibody-mediated rejection (AMR) is a major cause of allograft loss in kidney transplant. Although donor-specific anti-human leukocyte antigen antibody (DSA) is a key cause of AMR, not all patients with DSA are diagnosed as having AMR and show poor allograft outcomes. This study aimed to evaluate clinical significance of C3d-binding activity in patients with DSA identified by single-antigen bead (SAB) assay. A total of 168 recipients screened for DSA from 2015 to 2018 were enrolled. Among them, 52 patients had DSA confirmed by SAB assay. Sera were tested using the C3d assay on Luminex platform. AMR was defined by kidney allograft biopsy results using Banff 2015 criteria. Of 52 patients, C3d-binding DSAs were detected in 22 patients (42.3%). Indication allograft biopsy was performed in 35 patients, with 31 (88.6%) diagnosed as having AMR. Patients with C3d-binding DSA had more class II SAB-DSA (73.3% vs 100%, P=.015) and showed significantly higher mean (SD) fluorescence intensity of class II SAB-DSA than the C3d-binding DSA(-) group (9606.7 [6096.6] vs 1921.0 [1483.8], P < .001). There was a positive correlation in the highest mean fluorescence intensity between class II SAB-DSA and class II C3d-binding DSA (r=0.70, P < .001). Patients with C3d-binding DSA showed worse death-censored graft survival than those with non-C3d-binding DSA (P=.023). This study showed that presence of C3d-binding DSA was significantly associated with allograft loss in SAB-DSA-positive patients. Further trials are warranted.

Impact of Post-Transplantation Hypomagnesemia on Long-Term Graft and Patient Survival after Transplantation

Background: Post-transplant hypomagnesemia is commonly observed among patients prescribed calcineurin inhibitor (CNIs). Methods: We conducted a retrospective single-center analysis (2000–2013, N = 726) to examine the association of hypomagnesemia with long-term patient and allograft outcomes in kidney transplant recipients. A median serum magnesium (Mg) level of all measured Mg levels from 1 month to 1 year posttransplant was calculated. Results: For every increase in Mg of 0.1 mg/dL, the risk for either graft loss or death, overall mortality, and death with a functioning graft increased by 11%, 14%, and 12%, respectively (p < 0.01). In a multivariate model, patients with median Mg level ≥1.7 mg/dL had a reduced overall survival rate (HR 1.57, 95% CI: 1.04–2.38, p = 0.033) compared to those with median Mg level <1.7 mg/dL. This association was observed in subgroups of patients above 60 years old, in those who had a slow graft function (SGF) and in females. Conclusions: Posttransplant hypomagnesemia is associated with better patient and allograft survival up to 10 years posttransplant. This relationship remained significant after accounting for baseline allograft function, presence of SGF and CNI trough levels.

Association of Vascular Endothelial Growth Factor 936 C/T Gene Polymorphism with Renal Allograft Outcome: A Study from North India.

The significance of vascular endothelial growth factor (VEGF) and its polymorphisms in renal allograft rejection has recently become the subject of extensive research. Recently, some studies have shown some role of VEGF in rejection episodes and graft survival. VEGF +936 C>T polymorphism is significant in the transcription regulation of VEGF. Herein, we report the results of a prospective, single-center study seeking an association of VEGF +936 C/T gene polymorphism and allograft rejection. One hundred and forty-seven kidney transplant recipients with age-and sex-matched controls were included in this study. VEGF 936 C/T genes were studied using restriction fragment length polymorphism analysis of the blood specimen of these patients. All patients were studied for allograft rejection, response to treatment, and overall graft survival. We found that CT genotype and T allele carrier state were associated with good graft outcomes (P = 0.008 and 0.002, respectively). There was a lower number of rejection episodes with T allele, although it was not a significant finding (P = 0.880). Our findings suggest that good graft outcome in kidney transplant recipients is associated with an increased frequency of the VEGF 936 CT genotype and T allele, and that determination of the T allele might be helpful for the identification of recipients with overall good graft survival.

Kidney transplantation in pediatric patients with rheumatologic disorders.

Providers caring for children with end-stage kidney disease from rheumatologic conditions face questions such as when to proceed with kidney transplantation, how common is disease recurrence posttransplant, how does recurrent disease impact patient and allograft outcomes, and what approaches are available to prevent and treat recurrent disease. We discuss recent developments and relevant literature that address these questions for the most common rheumatologic disorders that lead to end-stage kidney disease in childhood namely, systemic lupus erythematosus, IgA nephropathy, IgA Vasculitis/Henoch Schoenlein Purpura, and Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis. Recent data suggest that children with IgA nephropathy, IgA vasculitis, and ANCA-associated vasculitis have similar patient and allograft survival to other conditions despite the risk of recurrent disease, yet those with lupus have worse posttransplant patient and allograft outcomes. A period of disease quiescence may be prudent prior to transplantation to decrease the risk of recurrence, which is associated with decreased allograft survival. Data on preventive strategies and treatment options are limited. It is recommended that patients with systemic rheumatologic conditions not be excluded from kidney transplantation but that patients be counseled on the risk of potential recurrent disease with its impact on transplant outcomes.

Effect of anti-angiotensin II type 1 receptor antibodies on the outcomes of kidney transplantation: a systematic review and meta-analysis

Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been recognized as non-human leukocyte antigen antibodies associated with allograft rejection and poor allograft outcomes after kidney transplantation. The aim of this study was to assess the risk anti-AT1R-Abs pose for rejection and graft loss among kidney transplant (KT) populations. We systematically searched PubMed, Embase and the Cochrane Library databases for relevant articles published from inception until June 2021 to identify all studies concerning the role AT1R-Abs play in the clinical outcome after kidney transplantation. Two reviewers independently identified studies, abstracted outcome data and assessed the quality of the studies. The meta-analysis was summarized using fixed-effects or random-effects models, according to heterogeneity. The major outcomes included delayed graft function, acute rejection, graft loss or patient death after transplantation. Twenty-one eligible studies involving a total of 4023 KT recipients were included in the evaluation. Meta-analysis results showed that the AT1R-Ab-positive KT group had a greater incidence of antibody-mediated rejection {relative risk [RR]1.94 [95% confidence interval (CI) 1.61-2.33]; P <0.00001} and graft loss [RR 2.37 (95% CI 1.50-3.75); P=0.0002] than did the AT1R-Abs-negative KT group. There was no significant statistical difference in delayed graft function rate, T-cell-mediated rejection, mixed rejection, acute cellular rejection, acute rejection and patient death rate between the AT1R-Ab-positive KT and AT1R-Ab-negative KT groups. Our study shows that the presence of anti-AT1R-Abs was associated with a significantly higher risk of antibody-mediated rejection and graft loss in kidney transplantation. Future studies are still needed to evaluate the importance of routine anti-AT1R monitoring and therapeutic targeting. These results show that assessment of anti-AT1R-Abs would be helpful in determining immunologic risk and susceptibility to immunologic events for recipients.