Allograft Biopsies Research Articles

The appearance of C1q deposition in transplanted kidney allografts and its clinical and histopathologic features.

BackgroundC1q nephropathy is an uncommon type of glomerulonephritis characterized by extensive and dominant C1q mesangial deposition in the absence of systemic lupus erythematosus. However, there are limited studies about C1q deposition in renal allografts. This study aimed to report the prevalence of C1q deposition in transplanted kidney allograft biopsies and describe its clinical and histopathologic features.MethodsBetween January 2005 and December 2018, a total of 1,742 kidney transplantations were performed at Seoul National University Hospital. All renal allograft biopsies (n=10,217) of these patients were retrospectively screened for C1q deposition. C1q deposition was detected in the renal allograft biopsies of 104 patients (6.0%). Only 28 cases (1.6%) had intense (≥2+) C1q dominance and were reviewed in this study.ResultsAmong the 28 cases, only four (14.3%) had accompanying proliferative glomerulonephritis. Most did not have any other glomerular changes on light microscopy. No patients had nephrotic-range proteinuria at the time of biopsy. A follow-up biopsy was undertaken in 15 of the cases (53.6%). In these follow-up biopsies, C1q deposition either completely disappeared (n=13, 86.7%) or showed diminished staining (n=2, 13.3%).ConclusionsThe prevalence of dominant or codominant C1q deposition in transplanted renal allograft biopsies was 1.6%. Most cases did not have any other accompanying glomerular changes. The follow-up biopsies of these allografts showed spontaneous disappearance or diminished staining of C1q deposition. These findings suggest that C1q deposition found in renal allografts is most likely clinically benign, although this possibility should be confirmed in further large-scale studies.

A Review of Biomarkers of Cardiac Allograft Rejection: Toward an Integrated Diagnosis of Rejection.

Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, suffers from many limitations including the low prevalence of rejection, sample bias, high inter-observer variability, and international working formulations based on arbitrary cut-offs that simplify the landscape of rejection. The development of innovative diagnostic and prognostic strategies—integrating conventional histology, molecular profiling of allograft biopsy, and the discovery of new tissue or circulating biomarkers—is one of the major challenges of translational medicine in solid organ transplantation, and particularly in heart transplantation. Major advances in the field of biomarkers of rejection have paved the way for a paradigm shift in the monitoring and diagnosis of cardiac allograft rejection. We review the recent developments in the field, including non-invasive biomarkers to minimize the number of protocol endomyocardial biopsies and tissue biomarkers as companion tools of pathology to refine the diagnosis of cardiac rejection. Finally, we discuss the potential role of these biomarkers to provide an integrated bio-histomolecular diagnosis of cardiac allograft rejection.

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of the CYP3A5 and ABCB1 genes.

Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background. PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients. PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype. Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.

Donor-derived Cell-free DNA Measurement in Kidney Transplant Patients Without Allograft Dysfunction: More Evidence and More Questions.

Donor-derived Cell-free DNA Measurement in Kidney Transplant Patients Without Allograft Dysfunction: More Evidence and More Questions.

Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury

Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence-associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild-type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence-associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation-associated post-IRI chronic kidney dysfunction.

The Role of Early Sequential Biopsies in Delayed Renal Graft Function of Transplanted Kidney Is Reduced in Modern Immunosuppression Era

Background: Delayed graft function (DGF) immediately after kidney transplantation is considered a risk factor for acute rejection. According to clinical guidelines, a weekly allograft biopsy should be performed until DGF resolves. Based on clinical evidence, the first biopsy is considered appropriate. However, the recommendation for further biopsies is based on sparse evidence from era of earlier immunosuppression protocols, and the benefit of the second and further biopsies remains uncertain. The aim of this study was to reevaluate this policy. Methods: The database of a transplant medical center was retrospectively reviewed for all patients who underwent kidney transplantation in 2011–2020. Those with DGF who performed two or more graft biopsies within the first 60 days after transplantation were identified. Clinical data were collected from the medical files. The rates of diagnosis of acute rejection at the second and subsequent biopsies were analyzed relative to the previous ones. Results: Kidney transplantation was performed in 1,722 patients during the study period, of whom 225 (13.07%) underwent a total of 351 graft biopsies within 60 days after transplantation, mostly due to DGF. A second biopsy was performed in 32 patients (14.2%), and a third biopsy in 8, at weekly intervals. In 2 patients (6.25%), the diagnosis changed from the first biopsy (acute tubular necrosis or toxic damage) to acute rejection in the second biopsy. In both, the rejection was borderline. Third and fourth biopsies did not add information to the previous diagnosis. Conclusions: The common practice of performing sequential biopsies during a postoperative course of DGF seems to be of low benefit and should be considered on a case-by-case basis.

Outgrowing skin involvement in malakoplakia after kidney transplantation: A case report

IntroductionMalakoplakia is a rare pseudotumor that arises in the context of recurrent infections, particularly in immunocompromised states. We report a case of renal allograft parenchymal malakoplakia. Case reportA 59-year-old woman successfully received a cadaveric renal transplant in June 2018. Two months after transplantation, she was treated for a urinary tract infection (UTI). In March 2019, she underwent allograft biopsy for increasing creatinine. The biopsy identified T cell mediated rejection and steroid pulse therapy was performed. In December 2019, she was hospitalized for right flank pain and pyuria, and her creatinine level was 1.9 mg/dL. Radiographic findings were suggestive of a hematoma or abscess in the perirenal area, and septated fluid collection was suspected. Biopsy results suggested malakoplakia, and von Kossa stain was positive for Michaelis- Gutmann bodies. Tissue culture demonstrated Escherichia coli, and this was treated with antibiotics. The dose of tacrolimus was reduced. The patient was discharged after 1 month of hospitalization and was maintained on oral antibiotics. Follow-up imaging revealed an increase in the extent of lesion into the adjacent abdominal wall. Assuming the case to be refractory, we performed surgical resection and abscess drainage. Although the renal parenchymal involvement persisted, the size showed a decreasing trend over 2 months of serial observation with ultrasonography. ConclusionsMalakoplakia should be considered as a differential diagnosis for recurrent UTI with graft dysfunction. Malakoplakia can be successfully treated with reduction in immunosuppression and medical therapy using long-term antibiotic treatment in most cases. However, early surgical treatment must be considered for refractory cases.

Acute Antibody-mediated rejection in liver transplantation: Impact and applicability of the Banff working group on liver allograft pathology 2016 criteria

This study was aimed to examine the clinical utility and impact of the 2016 Banff criteria for acute antibody-mediated rejection (acute AMR) in patients with liver transplantation. Among adult patients with donor-specific antibody (DSA) assays performed between 2015 and 2020, cases with proved DSA (mean fluorescent index >2000) and matched liver biopsy available were reviewed. Among 55 patients identified, 28 (51%) had class I DSA, 45 (82%) had class II DSA and 18 (33%) had both. Mild, moderate and severe microvasculitis were observed in 11 (20%), 2 (4%) and 1 (2%) case, respectively. Diffuse immunoreactivity to C4d on portal microvascular endothelia was confirmed in 5 cases (9%), which met the criteria of definite (n=2) or suspicious for acute AMR (n=3). Cases of acute AMR more commonly had class I DSA (100% vs. 46%; p=0.027) or both class I and II DSA (80% vs. 28%; p=0.018) than cases of non-acute AMR. One case of pure acute AMR with veno-occlusion was successfully treated with plasma exchange. The remaining 4 cases had features of combined acute AMR/T cell-mediated rejection (TCMR), and two progressed to ductopenic rejection within 3 weeks. In conclusion, only 9% of DSA-positive patients met the Banff criteria for acute AMR, necessitating careful morphological and immunohistochemical assessments of the allograft biopsies according to the proposed standards. Combined acute AMR/TCMR was more common than isolated acute AMR, and additional AMR in TCMR cases may be associated with rapid progression to ductopenic rejection.

Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients.

BackgroundClotrimazole troches are used as prophylaxis against oropharyngeal candidiasis post‐transplant and have limited systemic absorption. Following several occurrences of tacrolimus concentration fluctuations after clotrimazole discontinuation, its use as prophylaxis was discontinued post‐kidney transplant.MethodsWe conducted a retrospective cohort study to evaluate the effect of clotrimazole prophylaxis on tacrolimus trough concentrations post‐kidney transplant. The study included adult patients who received a kidney transplant at Cleveland Clinic Main Campus from August 1, 2019 to July 1, 2020 and were maintained on per‐protocol, standard‐dose tacrolimus through 90 days post‐transplant. Patients were excluded if they received cyclosporine, systemic antifungals, strong CYP3A4 inhibitors or inducers, or a simultaneous multiorgan transplant. The primary objective was to compare tacrolimus trough concentrations before and after completion of clotrimazole prophylaxis. Secondary objectives were to compare the time to first post‐transplant goal tacrolimus trough concentration, the rate of for‐cause allograft biopsies within 90 days after transplant, and the incidence and type of candidiasis within 30 days after transplant, pre‐ and post‐protocol change.ResultsFollowing clotrimazole discontinuation, the median tacrolimus trough concentration decreased from 10.5 ng/ml (IQR 8.4–12.2) to 6.6 ng/ml (IQR 5–8.7, p < 0.0001). No statistically significant differences in the rate of for‐cause allograft biopsies (4.9% vs. 9.7%, p = 0.264) or incidence of candidiasis (1.2% vs. 5.4%, p = 0.217) were observed between those who received clotrimazole and those who did not receive clotrimazole.ConclusionsOur study provides further evidence of a significant drug–drug interaction between tacrolimus and clotrimazole among kidney transplant recipients that can potentially lead to negative allograft outcomes.

Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts.

We tested the hypothesis that single-cell RNA-sequencing (scRNA-seq) analysis of human kidney allograft biopsies will reveal distinct cell types and states and yield insights to decipher the complex heterogeneity of alloimmune injury. We selected 3 biopsies of kidney cortex from 3 individuals for scRNA-seq and processed them fresh using an identical protocol on the 10x Chromium platform; (i) HK: native kidney biopsy from a living donor, (ii) AK1: allograft kidney with transplant glomerulopathy, tubulointerstitial fibrosis, and worsening graft function, and (iii) AK2: allograft kidney after successful treatment of active antibody-mediated rejection. We did not study T-cell-mediated rejections. We generated 7217 high-quality single cell transcriptomes. Taking advantage of the recipient-donor sex mismatches revealed by X and Y chromosome autosomal gene expression, we determined that in AK1 with fibrosis, 42 months after transplantation, more than half of the kidney allograft fibroblasts were recipient-derived and therefore likely migratory and graft infiltrative, whereas in AK2 without fibrosis, 84 months after transplantation, most fibroblasts were donor-organ-derived. Furthermore, AK1 was enriched for tubular progenitor cells overexpressing profibrotic extracellular matrix genes. AK2, eight months after successful treatment of rejection, contained plasmablast cells with high expression of immunoglobulins, endothelial cell elaboration of T cell chemoattractant cytokines, and persistent presence of cytotoxic T cells. In addition to these key findings, our analysis revealed unique cell types and states in the kidney. Altogether, single-cell transcriptomics yielded novel mechanistic insights, which could pave the way for individualizing the care of transplant recipients.

Donor Derived Cell Free DNA in Kidney Transplantation: The Circa 2020-2021 Update.

The routine surveillance of kidney transplant allografts has relied on imperfect non-invasive biomarkers such as creatinine and urinary indices, while the gold standard allograft biopsy is associated with risk of bleeding, organ injury and sampling errors. Donor derived cell free DNA (dd-cfDNA) is being employed as a biomarker that addresses limitations of these surveillance methods, albeit has inherent drawbacks. This review provides an update on the enhanced understanding of dd-cfDNA and its expanded use beyond the conventional indication of detecting allograft rejection.

POS-047 PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF PEGCETACOPLAN IN THE TREATMENT OF PATIENTS WITH POSTTRANSPLANT RECURRENCE OF C3G OR IC MPGN

POS-047 PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF PEGCETACOPLAN IN THE TREATMENT OF PATIENTS WITH POSTTRANSPLANT RECURRENCE OF C3G OR IC MPGN

The Case | Late allograft dysfunction with unexpected biopsy findings

A 63-year-old man with end-stage kidney disease secondary to atrophic right kidney and type 2 diabetes mellitus received a living-related kidney allograft from his sister. Induction therapy included thymoglobulin, and maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil. The early post-transplant course was complicated by 2 episodes of acute kidney injury, occurring at 2 and 8 months after transplantation, where allograft biopsies showed tubular degenerative changes consistent with acute tubular injury.

Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology

Kidney transplant injury processes are associated with molecular changes in kidney tissue, primarily related to immune cell activation and infiltration. How these processes are reflected in the circulating immune cells, whose activation is targeted by strong immunosuppressants, is poorly understood. To study this, we analyzed the molecular alterations in 384 peripheral blood samples from four European transplant centers, taken at the time of a kidney allograft biopsy, selected for their phenotype, using RNA-sequencing. In peripheral blood, differentially expressed genes in 136 rejection and 248 no rejection samples demonstrated upregulation of glucocorticoid receptor and nucleotide oligomerization domain-like receptor signaling pathways. Pathways enriched in antibody-mediated rejection (ABMR) were strongly immune-specific, whereas pathways enriched in T cell-mediated rejection were less immune related. In polyomavirus infection, upregulation of mitochondrial dysfunction and interferon signaling pathways was seen. Next, we integrated the blood results with transcriptomics of 224 kidney allograft biopsies which showed consistently upregulated genes per phenotype in both blood and biopsy. In single-cell RNASeq (scRNASeq) analysis of seven kidney allograft biopsies, the consistently overexpressed genes in ABMR were mostly expressed by infiltrating leukocytes in the allograft. Similarly, in peripheral blood scRNASeq analysis, these genes were overexpressed in ABMR in immune cell subtypes. Furthermore, overexpression of these genes in ABMR was confirmed in independent cohorts in blood and biopsy. Thus, our results highlight the immune activation pathways in peripheral blood leukocytes at the time of kidney allograft pathology, despite the use of current strong immunosuppressants, and provide a framework for future therapeutic interventions.

FC 118: The Effect of Spironolactone on Calcineurin Inhibitor Induced Nephrotoxicity—The Spiren Trial

Abstract BACKGROUND AND AIMS Improving long-term allograft survival has been a challenge for nephrologists for decades. A common feature in late allograft failure is progressive interstitial fibrosis and tubular atrophy.[1] Increasing evidence points towards the mineralocorticoid hormone aldosterone to contribute to renal fibrosis.[2] The SPIREN trial was designed to test the hypothesis that the mineralocorticoid receptor antagonist spironolactone attenuates renal injury in kidney transplant patients treated with calcineurin inhibitors evaluated as measured glomerular filtration rate, proteinuria and renal fibrosis.[3] METHOD The SPIREN trial was a randomized, placebo-controlled, double-blind clinical trial including 188 prevalent renal transplant patients from four Danish sites. Patients were randomized 1:1 to spironolactone 25–50 mg daily or placebo for 3 years. At baseline and yearly hereafter, we performed chrome-EDTA clearance, 24-h urine samples, ambulatory blood pressure measurements, and blood and urine samples. In a subgroup, an allograft biopsy was made at baseline and after 2 years (n = 48). Numeric data were analysed using mixed-effects linear regressions. Biopsies were scored according to the Banff classification and the extent of fibrosis was additionally evaluated using point counting. All analyses were performed as intention to treat. RESULTS In total, 180 patients were randomized to spironolactone (n = 90) or placebo (n = 90). The groups were comparable at baseline (Table 1) except a difference in the age of the allograft [median 4.4 (IQR 1.1–10.0) versus 2.0 (0.7–6.6) years]. There was a significant reduction in chrome-EDTA clearance in the spironolactone group after 1 year independently of time since transplantation and blood pressure. This persisted throughout the trial. This reduction corresponded to a reduction of eGFR after 1 week of treatment as evaluated by the CKD-EPI formula. The renal function of the placebo group remained stable. Twenty-four-hour proteinuria was reduced significantly after 1 year in the spironolactone group, but this difference was not significant after 2 and 3 years. Ambulatory systolic blood pressure was reduced to 1–2 mmHg in the spironolactone group and increased to 1–4 mmHg in the placebo group (P &amp;lt; 0.05). Data regarding urine albumin/creatinine ratio and quantitative biopsy data are pending. CONCLUSION Spironolactone added to standard therapy for three years in renal transplant patients did not improve renal function or long-term proteinuria. The reduction of chrome-EDTA clearance in the spironolactone group occurred within the first year of treatment and was most likely due to the well-known, reversible and presumed hemodynamic adverse effect of spironolactone on renal function. Whether spironolactone reduced progression of interstitial fibrosis remains to be analysed.

FC 109: Microvascular Inflammation in Kidney Transplant Biopsies in the Absence of HLA-DSA Displays Intense Cytotoxic T-Cell and NK Cell but not Plasma Cell Infiltration

Abstract BACKGROUND AND AIMS Microvascular inflammation (MVI) without evidence of HLA-donor-specific antibodies (HLA-DSA) or C4d+ deposition remains an enigmatic phenotype, which cannot be classified as antibody-mediated rejection (ABMR) according to recent Banff classifications. We aimed to compare peripheral blood lymphocyte (PBL) distribution and infiltrating immune cells in kidney transplant (KT) biopsies presenting MVI (g + ptc ≥ 2) without C4d+ and HLA-DSA, ABMR and normal histology to explore the role of immune cells in these entities. METHODS A total of 221 allograft biopsies with ABMR (n = 73), MVI (n = 32) and normal (n = 116) diagnoses were analysed. RESULTS MVI patients showed a decrease in the absolute number of T-cells compared with ABMR and normal cases (P = 0.020 and P = 0.006) due to a significant decrease of CD4+ T-cells compared to normal cases (P = 0.013) and a reduction of CD8+ T-cells compared with ABMR (P = 0.029). ABMR and MVI presented a lower absolute number of circulating Natural Killer (NK) cells than normal cases. Immunohistochemistry assessment was performed in 22 ABMR, 13 MVI and 16 normal cases. Glomeruli in ABMR and MVI had more T-cells and CD68+ infiltration than normal biopsies, although TIA1+ was only increased in MVI (P &amp;lt; 0.001), suggesting increased T-cell cytotoxic capacity. Peritubular capillaries displayed more circulating T-cells, CD56+ TIA1+ and CD68+ in ABMR and MVI groups. Contrarily, MVI cases showed mild circulating plasma cell infiltration (CD138+) in peritubular capillaries (P = 0.059) and interstitial aggregates (P = 0.024) compared with ABMR (Figure 1). CONCLUSION In conclusion, MVI without HLA-DSA and C4d+ displays decreased circulating T-cell and NK cells, and intense T-cell and NK cell cytotoxic infiltration in the allograft, similar to ABMR. However, the deficiency of plasma cell infiltration in MVI suggests a different underlying stimulus from ABMR.

Screening for Polyomavirus Viruria Like Early Detection of Human Polyomavirus Infection and Replication: The Results of a Single-Center Observation

Polyomavirus (PV) infection and PV-associated nephropathy (PVAN) are some of the most important problems in kidney transplantation. Our objective was to determine the incidence of PV viruria and PV replication in single-center Polish kidney transplant recipients (KTR). Urine samples from 155 cadaveric KTR were analyzed for PV viruria using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The PV replication was recognized when the urine level was >107 PV DNA copies/mL of urine. Based on the PV DNA analysis, the patients were divided into 3 groups: Group 1 (n = 87; 56.1%) without viruria, Group 2 (n=44; 28.4%) with viruria but without PV replication, and Group 3 (n =24; 15.5%) with PV replication. The presence of PV viruria was correlated with the type of immunosuppressive regimen, strongly associated with tacrolimus intake. There was no correlation between viruria and mycophenolate daily dose in the study population. In Group 3 there were 6 patients (3.9%) with high viruria (>1010 copies/mL), and 5 patients from this group had confirmed PVAN in allograft biopsy. The prevalence of BK virus infection in KTR is similar to that reported in studies from other countries. We confirmed that PV viruria can be both a good screening for PV infection and a good predictor of PVAN. Tacrolimus was the most important predictor of PV viruria and PV replication in KTR.

Omics-based biomarkers for diagnosis and prediction of kidney allograft rejection.

Kidney transplantation is the preferred treatment for patients with end-stage kidney disease, because it prolongs survival and improves quality of life. Allograft biopsy is the gold standard for diagnosing allograft rejection. However, it is invasive and reactive, and continuous monitoring is unrealistic. Various biomarkers for diagnosing allograft rejection have been developed over the last two decades based on omics technologies to overcome these limitations. Omics technologies are based on a holistic view of the molecules that constitute an individual. They include genomics, transcriptomics, proteomics, and metabolomics. The omics approach has dramatically accelerated biomarker discovery and enhanced our understanding of multifactorial biological processes in the field of transplantation. However, clinical application of omics-based biomarkers is limited by several issues. First, no large-scale prospective randomized controlled trial has been conducted to compare omics-based biomarkers with traditional biomarkers for rejection. Second, given the variety and complexity of injuries that a kidney allograft may experience, it is likely that no single omics approach will suffice to predict rejection or outcome. Therefore, integrated methods using multiomics technologies are needed. Herein, we introduce omics technologies and review the latest literature on omics biomarkers predictive of allograft rejection in kidney transplant recipients.

The Presence of Donor-specific Antibodies Around the Time of Pancreas Graft Biopsy With Rejection Is Associated With an Increased Risk of Graft Failure.

Donor-specific antibodies (DSA) against HLA are an important biomarker predicting graft injury, rejection (Rej), and failure in various solid-organ transplant recipients. However, the impact of DSA with or without histopathological evidence of rejection among pancreas transplant recipients (PTRs) is unknown. In this study, we included all PTRs at our center between 2005 and 2020, with pancreas allograft biopsy before March 31, 2021, and with DSA checked within 15 d of the biopsy. PTRs were divided into 4 groups based on the biopsy findings on the index biopsy and DSA status as Rej-/DSA-, Rej+/DSA-, Rej-/DSA+, and Rej+/DSA+. Two hundred two PTRs had a pancreas allograft biopsy during the study period. Thirty-nine were in Rej-/DSA-, 84 Rej+/DSA-, 24 Rej-/DSA+, and 55 Rej+/DSA+. The mean interval from transplant to index biopsy was not statistically different between the 4 groups. The most common type of rejection was T cell-mediated rejection; however, antibody-mediated rejection was more prevalent in the Rej+/DSA+ group. At 5 y postbiopsy, the rate of death-censored graft failure (DCGF) for Rej-/DSA- was 18%, 24% in Rej+/DSA-; 17% in Rej-/DSA+ and 36% in Rej+/DSA+ (P = 0.14). In univariate analysis, mixed rejection (hazard ratio [HR], 3.0; 95% confidence intervals [CI], 1.22-7.39; P = 0.02) along with solitary pancreas transplantation and Rej+/DSA+ were associated with DCGF. In multivariate analysis, compared with Rej-/DSA-, Rej+/DSA+ was significantly associated with DCGF (HR, 2.32; 95% CI, 1.03-5.20; P = 0.04); however, Rej+/DSA- was not (HR, 1.06; 95% CI, 0.32-3.56; P = 0.92). PTRs with pancreas allograft rejection and concomitant DSA have an increased risk of DCGF.

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

BackgroundAntibody-mediated rejection (ABMR) is a cardinal cause of renal allograft loss. This rejection type, which may occur at any time after transplantation, commonly presents as a continuum of microvascular inflammation (MVI) culminating in chronic tissue injury. While the clinical relevance of ABMR is well recognized, its treatment, particularly a long time after transplantation, has remained a big challenge. A promising strategy to counteract ABMR may be the use of CD38-directed treatment to deplete alloantibody-producing plasma cells (PC) and natural killer (NK) cells.MethodsThis investigator-initiated trial is planned as a randomized, placebo-controlled, double-blind, parallel-group, multi-center phase 2 trial designed to assess the safety and tolerability (primary endpoint), pharmacokinetics, immunogenicity, and efficacy of the fully human CD38 monoclonal antibody felzartamab (MOR202) in late ABMR. The trial will include 20 anti-HLA donor-specific antibody (DSA)-positive renal allograft recipients diagnosed with active or chronic active ABMR ≥ 180 days post-transplantation. Subjects will be randomized 1:1 to receive felzartamab (16 mg/kg per infusion) or placebo for a period of 6 months (intravenous administration on day 0, and after 1, 2, 3, 4, 8, 12, 16, and 20 weeks). Two follow-up allograft biopsies will be performed at weeks 24 and 52. Secondary endpoints (preliminary assessment) will include morphologic and molecular rejection activity in renal biopsies, immunologic biomarkers in the blood and urine, and surrogate parameters predicting the progression to allograft failure (slope of renal function; iBOX prediction score).DiscussionBased on the hypothesis that felzartamab is able to halt the progression of ABMR via targeting antibody-producing PC and NK cells, we believe that our trial could potentially provide the first proof of concept of a new treatment in ABMR based on a prospective randomized clinical trial.Trial registrationEU Clinical Trials Register (EudraCT) 2021-000545-40. Registered on 23 June 2021. ClinicalTrials.gov NCT05021484. Registered on 25 August 2021