Allograft Outcomes Research Articles

Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review.

Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.

Femoral head allograft for glenoid bone loss in primary reverse shoulder arthroplasty: functional and radiologic outcomes

Several techniques have been adopted during primary reverse shoulder arthroplasty (RSA) to manage glenoid bone defect. Among bone grafts, humeral head autograft is currently the mainstream option. However, autologous humeral heads may be unavailable or inadequate and allografts may be a viable alternative. The aim of the present study was to evaluate the functional and radiological outcomes of femoral head allografts for glenoid bone defects in primary RSA. We conducted a retrospective study with prospective data collection enrolling 20 consecutive patients who underwent RSA with femoral head allografts for glenoid bone defects. Indications for surgery were eccentric cuff tear arthropathy in 10 (50%) cases, concentric osteoarthritis in 9 (45%) cases, and fracture sequelae in one (5%) case. Each patient was evaluated preoperatively and at follow-up by X-ray and computed tomography (CT) and by assessing the range of motion (ROM) and the Constant-Murley score (CMS). A CT-based software, a patient-specific 3D model of the scapula, and patient specific instrumentation were used to shape the graft and to assess the position of K-wire for central peg. Postoperatively, CT scans were used to identify graft incorporation and resorption. After a median follow-up of 26.5 months (24-38), ROM and CMS showed a statistically significant improvement (all p=0.001). The median measures of the graft were as follows: 28 mm (28-29) for diameter, 22° (10°-31°) for angle, 4 mm (2-8 mm) for minimum thickness, and 15 mm (11-21 mm) for maximum thickness. Before the surgery, the median glenoid version was 21.8° (16.5°-33.5°) for the retroverted glenoids and -13.5° (-23° to -12°) for the anteverted glenoids. At the follow-up, the median postoperative baseplate retroversion was 5.7° (2.2°- 1.5°) (p=0.001), and this value was close to the 4° retroversion planned on the preoperative CT-based software. Postoperative major complications were noted in four patients: two dislocations, one baseplate failure following a high-energy trauma, and one septic baseplate failure. Partial graft resorption without glenoid component failure was observed in three cases that did not require revision surgery. The femoral head allograft for glenoid bone loss in primary RSA restores shoulder function with CMS values comparable to those of sex- and age-matched healthy individuals. A high rate of incorporation of the graft and satisfactory correction of the glenoid version can be expected after surgery. The management of glenoid bone defects remains a challenging procedure, and a 15% risk of major complication must be considered.

Urinary Tract Infection 1 Year After Kidney Transplant: Effect on Kidney Transplant Outcomes.

Transplant is the gold standard treatment for end-stage renal disease, and yet infectious complications frequently arise in kidney recipients in the context of immunosuppression therapy, with urinary tract infection being the most common. We aimed to assess the prevalence of posttransplant urinary tract infections in kidney transplant recipients and assess the effects on kidney allograft and overall patient outcomes. We performed a retrospective analysis of data from State University of New York Upstate University Hospital from January 2016 to November 2022 to assess transplant outcomes in patients who underwent a kidney transplant at our center and met the inclusion criteria. There were 507 renal allograft recipients who met our inclusion criteria and were assessed for the incidence of urinary tract infection within the first year after transplant. Urinary tract infection was recurrent in 113 transplant recipients (55.6%) within the first year, and 118 (58.1%) were on prophylactic antibiotics at urinary tract infection diagnosis. We observed no relation between recurrence of urinary tract infection and use of prophylactic antibiotics (P = .21). Overall allograft survival rate was 92.1% in the urinary tract infection group and 96.7% in the group without urinary tract infection, which was significantly different (P = .02). Urinary tract infection significantly affected allograft survival (hazard ratio, 3.51; 95% CI, 1.49-8.23; P = .004). Overall patient survival rates were 86.7% and 91.4% in the groups with and without urinary tract infection, respectively (P = .08). We determined that allograft survival was significantly greater in the group without urinary tract infection versus the urinary tract infection group. We found no relation between urinary tract infection recurrence and prophylactic antibiotics. We also found that overall patient survival was not significantly different in the group with urinary tract infection versus the group without urinary tract infection.

Laparoscopic Toupet fundoplication: a safe and effective anti-reflux option in lung transplant recipients.

Fundoplication is known to improve allograft outcomes in lung transplant recipients by reducing retrograde aspiration secondary to gastroesophageal reflux disease, a modifiable risk factor for chronic allograft dysfunction. Laparoscopic Nissen fundoplication has historically been the anti-reflux procedure of choice, but the procedure is associated with discernable rates of postoperative dysphagia and gas-bloat syndrome. Laparoscopic Toupet fundoplication, an alternate anti-reflux surgery with lower rates of foregut complications in the general population, is the procedure of choice on our institution's lung transplant protocol. In this work, we evaluated the efficacy and safety of laparoscopic Toupet fundoplication in our lung transplant recipients. A prospective case series of 44 lung transplant recipients who underwent laparoscopic Toupet fundoplication by a single surgeon between September 2018 and November 2020 was performed. Preoperative and postoperative results from 24-h pH, esophageal manometry, gastric emptying, and pulmonary function studies were collected alongside severity of gastroesophageal reflux disease and other gastrointestinal symptoms. Median DeMeester score decreased from 25.9 to 5.4 after fundoplication (p < 0.0001), while percentage of time pH < 4 decreased from 7 to 1.1% (p < 0.0001). The severity of heartburn and regurgitation were also reduced (p < 0.0001 and p = 0.0029 respectively). Overall, pulmonary function, esophageal motility, gastric emptying, severity of bloating, and dysphagia were not significantly different post-fundoplication than pre-fundoplication. Patients with decreasing rates of FEV1 pre-fundoplication saw improvement in their rate of change of FEV1 post-fundoplication (p = 0.011). Median follow-up was 32.2months post-fundoplication. Laparoscopic Toupet fundoplication provides objective pathologic acid reflux control and symptomatic gastroesophageal reflux improvement in lung transplant recipients while preserving lung function and foregut motility. Thus, laparoscopic Toupet fundoplication is a safe and effective antireflux surgery alternative in lung transplant recipients.

Second Kidney Transplant Outcomes in Dialysis Dependent Recipients by Induction Type in the United States

We examined the association between induction type for a second kidney transplant in dialysis-dependent recipients and the long-term outcomes. Using the Scientific Registry of Transplant Recipients, we identified all second kidney transplant recipients who returned to dialysis before re-transplantation. Exclusion criteria included: missing, unusual, or no-induction regimens, maintenance regimens other than tacrolimus and mycophenolate, and positive crossmatch status. We grouped recipients by induction type into 3 groups: the anti-thymocyte group (N=9899), the alemtuzumab group (N=1982), and the interleukin 2 receptor antagonist group (N=1904). We analyzed recipient and death-censored graft survival (DCGS) using the Kaplan-Meier survival function with follow-up censored at 10 years post-transplant. We used Cox proportional hazard models to examine the association between induction and the outcomes of interest. To account for the center-specific effect, we included the center as a random effect. We adjusted the models for the pertinent recipient and organ variables. In the Kaplan-Meier analyses, induction type did not alter recipient survival (log-rank P=.419) or DCGS (log-rank P=.146). Similarly, in the adjusted models, induction type was not a predictor of recipient or graft survival. Live-donor kidneys were associated with better recipient survival (HR 0.73, 95% CI [0.65, 0.83], P < .001) and graft survival (HR 0.72, 95% CI [0.64, 0.82], P < .001). Publicly insured recipients had worse recipient and allograft outcomes. In this large cohort of average immunologic-risk dialysis-dependent second kidney transplant recipients, who were discharged on tacrolimus and mycophenolate maintenance, induction type did not influence the long-term outcomes of recipient or graft survival. Live-donor kidneys improved recipient and graft survival.

Reconstructing a Patellar Tendon Rupture Neglected for 14 Years When Anatomic Restoration Is Not Possible: A Case Report.

This case highlights the utility and outcomes of an Achilles tendon bone-block allograft in reconstructing the patellar tendon of a 44-year-old man in the setting of a high-riding, irreducible patella after a chronic patellar tendon rupture of 14 years. In cases of a neglected patellar tendon rupture with an irreducible high-riding patella, an Achilles tendon bone-block allograft can provide the length and tissue necessary to reconstruct the extensor mechanism. Although reconstruction may not be anatomic, patients can still experience great subjective and objective functional improvement with restoration of the extensor mechanism even after delayed reconstruction.

Association of Primary Kidney Disease Type and Donor Relatedness With Live Donor Kidney Transplant Outcomes: An Analysis of ANZDATA

There is limited information about the association between primary kidney disease and donor relatedness with transplant outcomes. This study addresses this gap by evaluating clinical outcomes after kidney transplantation in recipients of living donor kidneys as a function of primary kidney disease type and donor relatedness in Australia and New Zealand. Retrospective observational study. Kidney transplant recipients who received allografts from living donors between January 1, 1998, and December 31, 2018, as recorded in the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). Primary kidney disease type categorized as majority monogenic, minority monogenic, or other primary kidney disease based on disease heritability as well as donor relatedness. Primary kidney disease recurrence, graft failure. Kaplan-Meier analysis and Cox proportion hazards regression to generate hazard ratios for primary kidney disease recurrence, allograft failure, and mortality. Partial likelihood ratio test was used to examine possible interactions between primary kidney disease type and donor relatedness for both study outcomes. Among 5,500 live donor kidney transplant recipients, majority monogenic (adjusted HR, 0.58, P<0.001) and minority monogenic primary kidney diseases (adjusted HR, 0.64, P<0.001) were associated with reduced primary kidney disease recurrence compared with other primary kidney diseases. Majority monogenic primary kidney disease was also associated with reduced allograft failure (adjusted HR, 0.86, P=0.04) compared with other primary kidney diseases. Donor relatedness was not associated with primary kidney disease recurrence nor graft failure. No interaction was detected between primary kidney disease type and donor relatedness for either study outcome. Potential misclassification of primary kidney disease type, incomplete ascertainment of primary kidney disease recurrence, unmeasured confounding. Monogenic primary kidney disease is associated with lower rates of primary kidney disease recurrence and allograft failure. Donor relatedness was not associated with allograft outcomes. These results may inform pretransplant counseling and live donor selection. There are theoretical concerns that live-donor kidney transplants may be associated with increased risks of kidney disease recurrence and transplant failure due to unmeasurable shared genetic factors between the donor and the recipient. This study analyzed data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry and showed that, although disease type was associated with the risk of disease recurrence and transplant failure, donor relatedness did not impact transplant outcomes. These findings may inform pretransplant counseling and live donor selection.

#6395 TUBULORETICULAR INCLUSIONS: A NEW PROGNOSTIC BIOMARKER IN KIDNEY TRANSPLANTATION

Abstract Background and Aims Tubuloreticular inclusions (TRIs) seen on electron microscopy (EM) are classically associated with lupus nephritis (LN) and systemic viral infections in native biopsies. Traditionally a marker for enhanced type I interferon expression, little is known about their significance post-transplant. We aimed to look at a large cohort of transplant biopsies showing TRIs to investigate associations and outcomes. Method A retrospective analysis was performed on two prospective databases; an in-centre transplant registry and a histopathology database holding data on all kidney biopsies performed at our centre. All patients biopsied since 2015, who had EM examination were included. Where patients had more than one biopsy showing a TRI the earliest one was included. Demographic, clinical and transplant data was collected from the laboratory records. Results 2283 kidney transplant biopsies were performed between January 2015 and November 2022; 1898 (83.1%) had EM performed. Of 1898 with EM, 176 (10.8%) had evidence of TRIs. Of 176 patients, 34% were female, the median age was 52.2 (38.9-59.4) years, 32% had underlying glomerulonephritis as their cause of ESKD, 65% were deceased donors and 75% were of non-white ethnicity. TRIs were associated with serological evidence of autoimmunity (16%), viral infections (26%) and donor specific antibodies (28%), with no association found in 41%. Rejection occurred in 49%, including 31% of patients with no recognised association with TRIs. Allograft outcomes were poor, with all-cause allograft survival and death-censored allograft survival of 66% and 60%, after a follow up of 1.9 +/− 1.8 years post index biopsy. A comparison with a matched control group is planned Conclusion In extension to previous work, we show that TRIs appear to be associated with alloimmunity. In this regard they may be a useful biomarker especially in cases where the diagnosis is unclear or biopsy findings are ‘subthreshold’. Irrespective of aetiology, TRIs are associated with poor outcomes and warrant further consideration.

#4769 EFFECT OF EXTREMELY LONG DIALYSIS VINTAGE ON RENAL ALLOGRAFT SURVIVAL: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Dialysis vintage is long in kidney transplant recipients (KTRs) due to the donor shortage in Turkey. We assessed the effect of pre-transplant dialysis duration (more than 10 years) on the outcomes of renal allografts. Method We retrospectively evaluated 480 KTRs who were grafted between January 2009 and October 2020 at Ankara University School of Medicine, Ibni Sina Hospital. KTRs were divided into two groups according to the duration of pre-transplant dialysis treatment: Group A, ≥10 years and Group B, &amp;lt;10 years. Data on demographics, comorbidities, immunologic properties and graft survivals were compared between the two groups. Results Group A included 60 patients and dialysis vintage was 288±60 months (Table 1). 420 patients in Group B had an average of 19 months period of dialysis treatment. While cadaveric transplantation was 78.3% in Group A, it was much lower in Group B (11.2%, p&amp;lt;0.001). Most of the patients were on hemodialysis treatment (95.0% vs. 58.3%, respectively, P = .001). Recipients’ age (P = .001), HLA mismatch number (P = .008) and PRA positivity (P = .001) were significantly higher in Group A. Although anti-human T-thymocyte globulin had been mostly chosen for induction therapy in Group A (p&amp;lt;0.001); almost all patients were under standard triple maintenance immunosuppression therapy. First year and late acute rejection rates were similar between two groups (p=1.000 and P = .407, respectively). Clinically important difference was demonstrated in graft loss, which was mostly seen in the ≥10 years dialysis group (Group A, 18.3% vs. Group B, 8.3%, P = .014). The 1-, and 5- years graft survival rates were 91.4%, and 81.3%, respectively, in Group A and 97.4%, and 93.4%, respectively, in Group B (P = .034 and P = .029, respectively). Patient loss was significantly higher in Group A (Group A, 28.3% vs. Group B, 14.3%, P = .018). Conclusion We demonstrated that pre-transplant dialysis duration for more than 10 years has adverse effects on post-transplant graft and patient outcomes, accompanied by high immunological risk. Updates of organ allocation system considering sensitized candidates and strategies to expand donor pool and donation rates are needed to reduce waiting times on dialysis.

#2970 CYTOMEGALOVIRUS INFECTION AND RISK OF NEW-ONSET DIABETES AFTER TRANSPLANTATION: A RETROSPECTIVE STUDY

Abstract Background and Aims 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. Aim To assess the risk of development of NODAT in kidney transplant patients with CMV infection Method 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&amp;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. Conclusion 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 2 management of CMV infection could substantially lessen the risk to develop NODAT subsequent worsening of allograft and patient survival.

#4364 LEUCOPENIA AFTER KIDNEY TRANSPLANTATION: SWITCHING MYCOPHENOLATE TO MTOR INHIBITOR APPEARS SAFE AND FEASIBLE TO REDUCE THE RISK OF ALLOSENSITIZATION

Abstract Background and Aims Mycophenolate acid (MPA) is a standard component of maintenance immunosuppression after kidney transplantation. MPA, however, increases the risk of leucopenia. In the past, mTOR inhibitors (mTOR-I) in combination with calcineurin inhibitors (CNI), were considered immunologically safe but showed higher mortality in the long term. Method We conducted a retrospective single-center study analyzing 98 kidney transplant recipients (KTRs) under standard triple maintenance immunosuppression between 2020 and 2022 who developed leucopenia. We compared patient and kidney allograft outcomes between 31 KTRs who were temporarily switched from MPA to mTOR-I and 67 KTRs who underwent a reduction of MPA dose. Results A switch to mTOR-I was performed more often in case of a CMV high-risk status (50% vs. 21%, p = 0.009), CMV primary infection (68.2% vs. 22%, p&amp;lt;0.001), and more severe leucopenia (median nadir of neutropenia: 0.52 G/L vs. 0.86 G/L, p = 0.023). The median duration of leucopenia was comparable between the two groups (69 vs. 80 days). 9 of 67 KTRs (13%) developed de novo donor-specific antibodies (dnDSA) under reduced MPA compared to 1 of 31 KTRs (3%) under mTOR-I (p = 0.17). Biopsy-proven rejections were comparable between the two groups (1 in each). There was a slight but insignificant improvement of eGFR under mTOR-I compared to MPA (ΔeGFR +17 vs. +7 ml/min/1.73m2, p = 0.13) and no difference in proteinuria. Conclusion A temporary switch from MPA to mTOR-I is a feasible and safe strategy to overcome leucopenia, especially in cases of CMV high-risk status and CMV primary infection. No significant adverse effects on kidney allograft outcomes were observed. Development of dnDSA tended to be lower in the mTOR-I group, suggesting that this strategy may have the potential to reduce the risk of allosensitization.

#5108 SUSTAINED IL-6 SECRETION CAN LEAD TO AN AMPLIFIED INFLAMMATORY RESPONSE, MEDIATED BY THE ACTIVATION OF STAT3 AND NFKB VIA THE IL-6 AMPLIFIER LOOP

Abstract Background and Aims Organ transplants are the preferred treatment for end-stage organ failure. Potent and specific immunosuppressive agents have significantly decreased acute allograft rejection following renal transplantation. A significant barrier to long-term kidney allograft outcomes is chronic antibody-mediated rejection (CABMR). Chronic inflammation is a major cause of late graft loss that is mediated by soluble mediators released by immune and non-immune cells. IL-6 is a crucial cytokine that plays a central role in developing chronic inflammation. Non-immune cells, such as fibroblasts, have recently been identified as mediating chronic allograft rejection by activating the IL-6 amplifier loop (IL-6+IL-17). Our Aim of the study: -to study the effect of IL-6+IL-17 on secretion of IL-6 in the culture supernatant of fibroblasts derived from renal biopsy of chronic antibody mediated rejection (CABMR) patients; -to see the effect of anti-IL-6 (Tocilizumab)and anti-IL-17 on the secretion of IL-6 from the fibroblasts derived from kidney tissue of chronic antibody mediated rejection (CABMR) patients; and -to elucidate the pro-inflammatory pathway leading to increased IL-6 secretion by induction of Amplifier loop. Method Fibroblasts from grafted kidney from CABMR patients (n = 6) were cultured and stimulated with IL-6 (20ng/ µl), IL-17(50ng/ µl), IL-6 plus IL-17 for 24 hours. Levels of IL-6, MCP-1 and CCL20 were estimated in culture supernatants by ELISA as marker of IL-6 amplifier loop activation. mRNA expression of IL-6, MCP1, CCL20, and SOCS3 genes were measured in the stimulated fibroblasts. Stimulated Renal fibroblast cells from CABMR patients were lysed with Lysis buffer and subjected to SDS–PAGE and western blotting with anti-phospho-STAT3 and anti-phospho-NFκB p65. Additionally, IL-6, MCP1, and CCL20 levels were measured in Healthy control (n = 10), CABMR (n = 20), and non-CABMR (n = 30) patients. Results IL-6 and IL-17 synergistically induced more IL-6, CCL-20 &amp; MCP-1 production from fibroblasts in culture supernatant. Gene expression analysis of IL-6, MCP1, and CCL20 was significantly higher with synergistic activation of IL-6 and IL-17 as compared to either IL-6 or IL-17 alone, while SOCS3 gene expression was downregulated. Our results also suggested that IL-6 Amplifier loop activation induces the NFκB and STAT3 signalling pathway activation in the non-immune cells like fibroblast derived from CABMR patients. Additionally, concentrations of IL-6, CCL-20 &amp; MCP-1 in sera were significantly higher in CABMR patients compared to non-CABMR patients (p&amp;lt;0.001). There was a significant reduction in IL-6 concentration in culture supernatant with IL-6 and IL-17 inhibitor together and mRNA expression of IL-6, CCL20 and MCP-1 was significantly reduced while SOCS3 gene expression was upregulated. Conclusion In humans after kidney transplantation, IL-6 amplifier activation plays an active role in chronic rejection responses. Inhibition of IL-6 with Anti-IL-6 (Tocilizumab) and inhibition of IL-17 with Anti-IL-17 together reduces markers of tissue injury (IL-6, MCP1, CCL20) and rejection of allografts. so, IL-6 amplifier may be a therapeutic target for Chronic transplant rejection.

#6352 CLINICAL AND MOLECULAR SPECTRUM OF V-LESION

Abstract Background and Aims Isolated v-lesion is an increasingly recognized but clinically challenging entity. Some studies suggest that isolated v+ early post-transplant may be caused by non-alloimmune etiologies such as ischemic injury. We aimed to characterize the allograft outcomes of isolated v-lesions according to post-transplant time (early: ≤1 month vs. late: &amp;gt;1 month) and further understand the significance of this lesion by characterizing its molecular phenotype in comparison with other forms of rejection v+. Method The NanoString B-HOT panel (770 genes) was used to measure the expression of six literature-derived gene sets in 92 archival FFPE kidney biopsies from two centers, including transplant biopsies with isolated v-lesion (n = 23), antibody-mediated rejection (ABMR) with v+ (n = 26), pure T-cell mediated rejection (TCMR) with v+ (n = 10), mixed rejection v+ (n = 23), and normal implant biopsies (Normal, n = 10). The evaluated gene sets included transcripts previously associated with ABMR, DSA (DSAST), endothelial injury (ENDAT), TCMR, early injury, and late injury. Gene expression was compared between groups using principal component and class comparison analyses. Death-censored graft survival according to diagnosis and time after KT was assessed. Results Isolated v+ early conferred the worst death-censored graft survival one year after the biopsy (40%) when compared to isolated v+ late (100%) or other forms of rejection (≥82%, p = 0.034). The principal component analysis demonstrated significant molecular overlap between sample groups (PC1: 29.4%, PC2: 8.1%). However, gene set analysis showed lower expression of TCMR-related genes in isolated v+ groups compared to TCMR and mixed rejection (p&amp;lt;0.001). Both Isolated v+ early and late had lower ABMR-related genes than ABMR, mixed rejection, and TCMR groups (p ≤ 0.022). Moreover, isolated v+ late showed lower DSAST and ENDAT gene set expression than ABMR (p ≤ 0.046); and lower early injury gene set expression than isolated v+ early, ABMR, TCMR, and mixed rejection (p ≤ 0.026). Late injury gene set expression was highest in TCMR and mixed rejection compared to the other groups (p ≥ 0.034). Conclusion These results suggest that early and late isolated v+ lesions display lower expression of TCMR-related genes than TCMR and mixed rejection and lower expression of ABMR-related genes than ABMR. Isolated v+ early confers a bad prognosis and is associated with higher expression of early injury genes compared to isolated v+ late, suggesting a different ethology.

Complement activation and kidney transplantation; a complex relationship

Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement’s role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.

Outcomes of Femoral Head Allograft for the Management of Glenoid Bone Defects in Revision Reverse Shoulder Arthroplasty: A Case-Controlled Study.

Revision shoulder arthroplasty often requires management of glenoid bone defects. Options include using allograft, harvesting iliac crest autograft, or using augmented metal components. The purpose of this study is to report outcomes of revision shoulder arthroplasty requiring management of glenoid bone defects with femoral head allograft in a large cohort of patients using a single reverse shoulder implant system and compare them to a matched cohort based on the indication for surgery. Outcomes of patients who had successful glenoid reconstruction were compared to those that required a re-revision, and to a control group that was revised without the need for bone graft. This was a retrospective review of data collected from 2009 to 2018. There were 36 patients in the bone graft group and 52 in the control group. All patients underwent revision to a reverse shoulder arthroplasty to manage a failed total shoulder arthroplasty (n = 29 and 11), hemiarthroplasty (n = 1 and 24), or reverse shoulder arthroplasty (n = 6 and 17). All patients had a minimum of 2 years of clinical follow-up. The primary endpoint was survival of baseplate fixation. Secondary outcomes included range of motion and functional outcome scores. Patients that had recurrent baseplate failure and were re-revised were compared to patients with bone graft that did not require additional surgery, and to patients who were revised without the need for bone graft. Patients who required revisions for reasons other than recurrent baseplate failure were also recorded. Five of 36 (14%) patients had recurrent baseplate failure. Mean time to failure was 12 months. Three of 5 had successful re-implantation of another baseplate. Two of 5 were revised to a hemi arthroplasty after failure of their revisions. Preoperative ASES scores were 31 in the grafted patients that did not require re-revision, 39 in the grafted patients that required re-revision, and 33 in the control group. Final ASES scores were 64, 36, and 56, respectively. One patient required revision surgery not related to baseplate failure. There were no baseplate failures in the control group. The use of femoral head allograft to manage glenoid bone defects in the revision setting produces predictable improvement in functional outcomes that is not inferior to those in patients revised without bone graft. However, there is a 14% rate of baseplate failure.

The effect of late-onset CMV infection on the outcome of renal allograft considering initial graft function.

Delayed graft function (DGF) increases the renal allograft failure risk. Late-onset Cytomegalovirus (CMV) infection's effect on the association between DGF and allograft failure has not been determined. In this retrospective cohort, we included all renal allograft recipients at London Health Sciences Centre from January 1, 2014 to December 30, 2017, and continued clinical follow-up until February 28, 2020. We determined whether late-onset CMV infection affects the association between DGF and allograft failure in stratified and Cox proportional hazard analyses. Of 384 patients (median age [interquartile range]: 55 [43.3-63]; 38.7% female), 57 recipients (14.8%) were diagnosed with DGF. Patients with DGF were at a greater risk of CMV infection than patients without DGF (22.8% vs. 11.3%, p = .017). Late-onset CMV infection (odds ratio [OR]: 4.7, 95% CI: 2.07-10.68) and rejection (OR: 9.59, 95% CI: 4.15-22.16) significantly increased the risk of allograft failure in recipients with DGF. Patients with DGF had a significantly greater risk of graft failure than those without DGF (17.5% vs. 6.1%, p = .007). In the adjusted Cox hazard model, CMV infection significantly increased the risk of allograft failure (aHR: 3.19, 95% CI: 1.49-6.84). Late-onset CMV infection considerably increased the risk of graft failure in patients with DGF. A hybrid preventive model including prophylaxis followed by CMV-specific cell-mediated immunity monitoring may decrease the risk of allograft failure in recipients with DGF.

The Best Method for CMV Prevention in High-risk Kidney Transplant Recipients? Either, per National Norwegian Transplant Database: Commentary on Blom et al, Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

The Best Method for CMV Prevention in High-risk Kidney Transplant Recipients? Either, per National Norwegian Transplant Database: Commentary on Blom et al, Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

Impact of Resolved Preformed, Persistent Preformed, and De Novo Anti-HLA Donor-Specific Antibodies in Kidney Transplant Recipients on Long-Term Renal Graft Outcomes.

The post-transplant evolution of antihuman leukocyte antigen donor-specific antibodies (anti-HLA DSAs) includes three clinical patterns: resolved preformed DSAs, persistent preformed DSAs, and de novo DSAs. The aim of this retrospective study was to analyze the impact of resolved preformed, persistent preformed, and de novo anti-HLA-A, -B, and -DR DSAs in kidney transplant recipients on long-term renal allograft outcomes. This is a post hoc analysis of the study conducted in our transplant center. One hundred eight kidney transplant recipients were included in the study. Patients were followed for a minimum of 24 months after allograft biopsy, which was performed 3 to 24 months after kidney transplantation. The identification of persistent preformed DSAs at the time of biopsy was the most significant predictor of the combined endpoint of the study (>30% decline in estimated glomerular filtration rate or death-censored graft loss; HR = 5.96, 95% CI 2.041-17.431, p = 0.0011), followed by the occurrence of de novo DSAs (HR = 4.48, 95% CI 1.483-13.520, p = 0.0079). No increased risk was observed in patients with resolved preformed DSAs (HR = 1.10, 95% CI 0.139-8.676, p = 0.9305). Patients with resolved preformed DSAs have similar graft prognoses as patients without DSAs, therefore, the persistence of preformed DSAs and development of de novo DSAs are associated with inferior long-term allograft outcomes.

Endotrophin Levels Are Associated with Allograft Outcomes in Kidney Transplant Recipients.

Early prediction of kidney graft function may assist clinical management, and for this, reliable non-invasive biomarkers are needed. We evaluated endotrophin (ETP), a novel non-invasive biomarker of collagen type VI formation, as a prognostic marker in kidney transplant recipients. ETP levels were measured with the PRO-C6 ELISA in the plasma (P-ETP) of 218 and urine (U-ETP/Cr) of 172 kidney transplant recipients, one (D1) and five (D5) days, as well as three (M3) and twelve (M12) months, after transplantation. P-ETP and U-ETP/Cr at D1 (P-ETP AUC = 0.86, p < 0.0001; U-ETP/Cr AUC = 0.70, p = 0.0002) were independent markers of delayed graft function (DGF) and P-ETP at D1 had an odds ratio of 6.3 (p < 0.0001) for DGF when adjusted for plasma creatinine. The results for P-ETP at D1 were confirmed in a validation cohort of 146 transplant recipients (AUC = 0.92, p < 0.0001). U-ETP/Cr at M3 was negatively associated with kidney graft function at M12 (p = 0.007). This study suggests that ETP at D1 can identify patients at risk of delayed graft function and that U-ETP/Cr at M3 can predict the future status of the allograft. Thus, measuring collagen type VI formation could aid in predicting graft function in kidney transplant recipients.

Living Donor Kidney Transplant in Recipients With Glomerulonephritis: Donor Recipient Biologic Relationship and Allograft Outcomes.

Using the Scientific Registry of Transplant Recipients, we examined the association between donor-recipient biologic relationship and long-term recipient and allograft survival among glomerulonephritis (GN) patients. Four GN types were studied: membranous nephropathy, IgA, lupus-associated nephritis, and focal segmental glomerulosclerosis (FSGS). We identified all adult primary living-donor recipients between 2000 and 2018 (n = 19,668): related (n = 10,437); unrelated (n = 9,231). Kaplan-Meier curves were generated for the recipient, death-censored graft survival and death with functioning graft through ten years post-transplant. Multivariable Cox proportional hazard models were used to examine the association between the donor-recipient relationship and outcomes of interest. There was an increased risk for acute rejection by 12months post-transplant among the unrelated compared to the related group in IgA (10.1% vs. 6.5%, p<0.001), FSGS (12.1% vs. 10%, p-0.016), and lupus nephritis (11.8% vs. 9.2%; p-0.049). The biological donor-recipient relationship was not associated with a worse recipient or graft survival or death with functioning graft in the multivariable models. These findings are consistent with the known benefits of living-related-donor kidney transplants and counter the reports of the potential adverse impact of the donor-recipient biologic relationship on allograft outcomes.