Unmasking the Silent Threat: COVID-19's Pervasive Impact on Renal Allografts.

OBJECTIVES: Growing evidence has highlighted the substantial effects of COVID-19 on kidneys, ranging from mild proteinuria to severe acute kidney injury. However, comprehensive assessments of histopathological features in renal allograft biopsies are lacking. MATERIALS AND METHODS: Seventeen kidney transplant recipients with COVID-19 between March 2020 and November 2022 were evaluated. Clinical characteristics, pathological findings, and outcomes were studied. RESULTS: Six kidney transplant recipients (35.3%) developed acute kidney injury, leading to the requirement for hemodialysis. COVID-19 severity, as indicated by pneumonia (P = .028) and hospitalization (P = .002), was significantly associated with development of acute kidney injury. Most patients with COVID-19 (82.4%) showed considerably increased proteinuria levels (82.4%), along with presence of new-onset microscopic hematuria (35.3%) and nephrotic syndrome (58.8%). Tubular viral inclusionlike changes were detected in 47.1% of cases and were associated with a higher risk of graft loss (75%). Thrombotic microangiopathy and endothelial cell swelling in glomeruli were prevalent, highlighting extensive endothelial cell injury. Most recipients (88.2%) experienced rejection after COVID-19, with graft loss occurring in 46.7% of these cases. Biopsies revealed collapsing (n = 5), noncollapsing (n = 3), and recurrent (n = 2) focal segmental glomerulosclerosis, as well as acute tubulointerstitial nephritis (n = 3), crescentic glomerulonephritis with immunoglobulin A nephropathy (n = 1), and membranoproliferative glomerulonephritis (n = 1), in 129.7 ± 33 days. Eight patients experienced graft loss (8.2 ± 2 mo posttransplant). Hospitalization (P = .044) and viralinclusion-like nuclear changes in tubules (P = .044) significantly influenced graft survival. Collapsing (60%) and noncollapsing (66.7%) focal segmental glomerulosclerosis increased the risk of graft loss. CONCLUSIONS: COVID-19 has had a multifaceted and enduring effect on renal allografts, urging the need for meticulous monitoring and tailored management strategies to mitigate the risk of severe kidney-related complications and graft loss in this vulnerable population.

A Case of Primary Renal Allograft Dysfunction Caused by Missed Monoclonal Disease.

We present an unusual etiology of primary renal allograft dysfunction attributed to myeloma cast nephropathy in a patient with no history of multiple myeloma before kidney transplant. The patient, a 54-year-old woman, had been on hemodialysis for 6 months before transplant for presumed diabetic nephropathy; she developed graft dysfunction immediately after transplant. Graft biopsy specimens were consistent with myeloma cast nephropathy, and she was treated with bortezomib, cyclophosphamide, and dexamethasone. She achieved a complete hematological response and regained excellent graft function 3 months after transplant. The patient then received autologous stem cell transplant 8 months after kidney transplant. To our knowledge, this is the second report of a successful graft outcome after chemotherapy and the first report treated with autologous stem cell transplantation after remission of monoclonal disease.

Metastatic Calcification in Allograft Kidney Due to Persistent Secondary Hyperparathyroidism: A Rare Cause of Graft Dysfunction.

Successful kidney transplant corrects mineral and bone disorderto a large extent; however, disorders can persistin up to 80% ofrecipients.We describe a case of persistent hyperparathyroidism with graft dysfunction and metastatic calcification in graft biopsy. A 48-yearold renal transplant recipient developed graft dysfunction 3 weeks after kidney transplant. During pretransplant workup, the recipient was found to have severe secondary hyperparathyroidism (intact parathyroid hormone level of 2000 pg/mL), which was managed and well controlled before transplant. Graft dysfunction was evaluated using algorithmic approach. Prerenal causes, tacrolimus toxicity, and infections were ruled out. Graft biopsy revealed several foci of tubular and parenchyma calcific deposits (microcalcinosis) with tubular injury. The patient was restarted on medical management of hyperparathyroidism, and he showed improvement over 6 weeks, along with creatinine level returning to nadir value. Vascular and graft calcification is an independent predictor of long-term graftfunction and overall mortality. This report describes the challenges that we faced in diagnosis and management of persistent hyperparathyroidism, as no randomized controlled trials and guidelines are available.

Approach to Kidney Allograft Dysfunction: A Brief Review.

It is important for providers caring for kidney transplant recipients to be familiar with the common causes of allograft dysfunction. Early detection of allograft dysfunction leads to timely management, with the goal of preventing or delaying progression to allograft failure. Although transplant rejection is always a concern, the differential diagnoses for allograft dysfunction are broad and include perioperative complications, infections, recurrent disease, and calcineurin nephrotoxicity. In this review, we will go over early and late causes of allograft dysfunction and discuss the basic workup and principles of management for each condition.

Multicenter, prospective, observational study for urinary exosomal biomarkers of kidney allograft fibrosis.

Severity of deceased donor kidney fibrosis impacts graft survival in deceased-donor kidney transplantation. Our aim was to identify potential miRNA biomarkers in urinary exosomes that mirror interstitial fibrosis and tubular atrophy (IFTA) severity. Among 109 urine samples from deceased donors, 34 displayed no IFTA in the zero-day biopsy (No IFTA group), while the remaining 75 deceased donor kidneys exhibited an IFTA score ≥ 1 (IFTA group). After analyzing previous reports and electronic databases, six miRNAs (miR-19, miR-21, miR-29c, miR-150, miR-200b, and miR-205) were selected as potential IFTA biomarker candidates. MiR-21, miR-29c, miR-150, and miR-205 levels were significantly higher, while miR-19 expression was significantly lower in the IFTA group. MiR-21 (AUC = 0.762; P < 0.001) and miR-29c (AUC = 0.795; P < 0.001) showed good predictive accuracy for IFTA. In the No IFTA group, the eGFR level at 1 week after transplantation was significantly higher compared to the IFTA group (41.34 mL/min/1.73m2 vs. 28.65 mL/min/1.73m2, P = 0.012). These findings signify the potential of urinary exosomal miRNAs as valuable biomarker candidates for evaluating the severity of IFTA in deceased donor kidneys before they undergo recovery.

Gunshot-Induced Humeral Head Osteochondral Defect Treated with an Osteochondral Allograft: A Case Report.

CASE: A 25-year-old right-hand dominant male police officer presented to the emergency department with a gunshot wound to his left shoulder. Magnetic resonance imaging demonstrated an osteochondral defect overlying the humeral head along the mid to lower aspect of the glenohumeral joint. A staged operation with shoulder arthroscopy followed by an osteochondral allograft (OCA) of the humeral head was performed. During his 6-month postoperative visit, he had returned to full work duty with no restrictions and reported that his pain was well controlled. CONCLUSION: Humeral head OCA transplantation may be an effective treatment option for traumatic osteochondral lesions of the glenohumeral joint.

Donor Fractions of Cell-Free DNA Are Elevated During CLAD But Not During Infectious Complications After Lung Transplantation.

During the last few years, cell-free DNA (cfDNA) has emerged as a possible non-invasive biomarker for prediction of complications after lung transplantation. We previously published a proof-of-concept study using a digital droplet polymerase chain reaction (ddPCR)-based method for detection of cfDNA. In the current study, we aimed to further evaluate the potential clinical usefulness of detecting chronic lung allograft dysfunction (CLAD) using three different ddPCR applications measuring and calculating the donor fraction (DF) of cfDNA as well as one method using the absolute amount of donor-derived cfDNA. We analyzed 246 serum samples collected from 26 lung transplant recipients. Nine of the patients had ongoing CLAD at some point during follow-up. All four methods showed statistically significant elevation of the measured variable in the CLAD samples compared to the non-CLAD samples. The results support the use of ddPCR-detected cfDNA as a potential biomarker for prediction of CLAD. These findings need to be validated in a subsequent prospective study.

Comparative study of demineralized freeze-dried bone allograft and its combination with platelet-rich fibrin in the treatment of intrabony defects: A randomized clinical trial.

BACKGROUND: The clinical and radiographic efficacy of bone grafts and biomaterials, such as platelet-rich plasma and platelet-rich fibrin (PRF), for reconstructing lost periodontal structures has been well documented. However, there is limited data regarding the presence of demineralized freeze-dried bone allograft (DFDBA) in an environment with abundant growth factors provided by platelet concentrates. OBJECTIVES: The aim of the study was to compare the clinical and radiographic effectiveness of DFDBA with PRF versus DFDBA alone in the treatment of intrabony defects. MATERIAL AND METHODS: Twenty-four intrabony defects in contralateral sites were randomly assigned to either the DFDBA group or the DFDBA combined with PRF group. Clinical parameters, including the plaque index (PI), the gingival index (GI), probing pocket depth (PPD), relative attachment level (RAL), and radiographic bone fill (RBF), were measured at baseline, and at 6 and 9 months. Paired and unpaired t-tests were used for intraand intergroup comparisons. RESULTS: Both the PI and the GI showed statistically significant improvements from baseline to 9 months. However, the intergroup comparisons did not reveal any significant differences (p < 0.05) between the groups with regard to clinical and radiographic measurements from baseline to 9 months. CONCLUSIONS: Platelet-rich fibrin in combination with DFDBA did not show any additional benefit in terms of reconstructive output in the treatment of intrabony defects compared to the use of DFDBA alone.

Clinical Impacts of Allograft Biopsy in Renal Transplant Recipients 10 Years or Longer After Transplantation.

We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.

The Collaborative Biobank (CoBi): Donor and recipient samples & data to facilitate future research on hematopoietic cell transplantation.

Biobanking provides benefit for future generations by facilitating medical research and subsequent translation and application of research findings. Long-term storage and research involving biological material and associated data necessitate the proper implementation of ethical and legal standards. A key principle includes recognizing informed consent as a crucial element for legitimizing the collection of biological material and data. Furthermore, any collected material and data must be employed exclusively for the research framework that aligns with the explicit consent provided by the participants. Last but not least, data privacy and security are essential in biobanking. This review elucidates chances and limitations of biobanking in the field of allogeneic hematopoietic cell transplantation. We discuss the practical implementation of the requirements, illustrated by the Collaborative Biobank, a collaborative research platform for research in blood cancer.

HLA-DM and HLA-DO interplay for the peptide editing of HLA class II in healthy tissues and leukemia.

HLA class II antigen presentation is modulated by the activity of the peptide editor HLA-DM and its antagonist HLA-DO, with their interplay controlling the peptide repertoires presented by normal and malignant cells. The role of these molecules in allogeneic hematopoietic cell transplantation (alloHCT) is poorly investigated. Balanced expression of HLA-DM and HLA-DO can influence the presentation of leukemia-associated antigens and peptides targeted by alloreactive T cells, therefore affecting both anti-leukemia immunity and the potential onset of Graft versus Host Disease. We leveraged on a large collection of bulk and single cell RNA sequencing data, available at different repositories, to comprehensively review the level and distribution of HLA-DM and HLA-DO in different cell types and tissues of the human body. The resulting expression atlas will help future investigations aiming to dissect the dual role of HLA class II peptide editing in alloHCT, and their potential impact on its clinical outcome.

Minor histocompatibility antigens to predict, monitor or manipulate GvL and GvHD after allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (alloHCT) provides a potential curative treatment for haematological malignancies. The therapeutic Graft-versus-Leukaemia (GvL) effect is induced by donor T cells attacking patient hematopoietic (malignant) cells. However, if healthy non-hematopoietic tissues are targeted, Graft-versus-Disease (GvHD) may develop. After HLA-matched alloHCT, GvL and GvHD are induced by donor T cells recognizing polymorphic peptides presented by HLA on patient cells, so-called minor histocompatibility antigens (MiHAs). The balance between GvL and GvHD depends on the tissue distribution of MiHAs and T-cell frequencies targeting these MiHAs. T cells against broadly expressed MiHAs induce GvL and GvHD, whereas those targeting MiHAs with hematopoietic-restricted expression induce GvL without GvHD. Recently, the MiHA repertoire identified in natural immune responses after alloHCT was expanded to 159 total HLA-I-restricted MiHAs, including 14 hematopoietic-restricted MiHAs. This review explores their potential relevance to predict, monitor, and manipulate GvL and GvHD for improving clinical outcome after HLA-matched alloHCT.

Shape of the art: TCR-repertoire after allogeneic hematopoietic cell transplantation.

The human adaptive immune repertoire is characterized by specificity and diversity to provide immunity against past and future tasks. Such tasks are mainly infections but also malignant transformations of cells. With its multiple lines of defense, the human immune system contains both, rapid reaction forces and the potential to capture, disassemble and analyze strange structures in order to teach the adaptive immune system and mount a specific immune response. Prevention and mitigation of autoimmunity is of equal importance. In the context of allogeneic hematopoietic cell transplantation (HCT) specific challenges exist with the transfer of cells from the adapted donor immune system to the immunosuppressed recipient. Those challenges are immunogenetic disparity between donor and host, reconstitution of immunity early after HCT by expansion of mature immune effector cells, and impaired thymic function, if the recipient is an adult (as it is the case in most HCTs). The possibility to characterize the adaptive immune repertoire by massively parallel sequencing of T-cell receptor gene rearrangements allows for a much more detailed characterization of the T-cell repertoire. In addition, high-dimensional characterization of immune effector cells based on their immunophenotype and single cell RNA sequencing allow for much deeper insights in adaptive immune responses. We here review, existing - still incomplete - information on immune reconstitution after allogeneic HCT. Building on the technological advances much deeper insights into immune recovery after HCT and adaptive immune responses and can be expected in the coming years.

Is HLA-E with its receptors an immune checkpoint or an antigenic determinant in allo-HCT?

Hematopoietic cell transplantation (HCT) represents a potentially curative therapeutic approach for various hematologic and non-hematologic malignancies. Human leukocyte antigen (HLA) matching is still the central selection criterion for HCT donors. Nevertheless, post-transplant complications, in particular graft-versus-host disease (GvHD), relapse of disease and infectious complications, represent a major challenge and contribute significantly to morbidity and mortality. Recently, non-classical HLA class I molecules, especially HLA-E, have gained increasing attention in the context of allogeneic HCT. This review aims to summarize the latest findings on the immunomodulatory role of HLA-E, which serves as a ligand for receptors of the innate and adaptive immune system. In particular, we aim to elucidate how (i) polymorphisms within HLA-E, (ii) the NKG2A/C axis and (iii) the repertoire of peptides presented by HLA-E jointly influence the functionality of immune effector cells. Understanding this intricate network of interactions is crucial as it significantly affects NK and T cell responses and thus clinical outcomes after HCT.

Patient-Specific Distal Femoral Guides Optimize Cartilage Topography Matching in Osteochondral Allograft Transplantations.

BACKGROUND: Osteochondral allograft (OCA) transplantation is an important surgical technique for full-thickness chondral defects in the knee. For patients undergoing this procedure, topography matching between the donor and recipient sites is essential to limit premature wear of the OCA. Currently, there is no standardized process of donor and recipient graft matching. PURPOSE: To evaluate a novel topography matching technique for distal femoral condyle OCA transplantation using 3-dimensional (3D) laser scanning to create 3D-printed patient-specific instrumentation in a human cadaveric model. STUDY DESIGN: Descriptive laboratory study. METHODS: Human cadaveric distal femoral condyles (n = 12) underwent 3D laser scanning. An 18-mm circular osteochondral recipient defect was virtually created on the medial femoral condyle (MFC), and the position and orientation of the best topography-matched osteochondral graft from a paired donor lateral femoral condyle (LFC) were determined using an in silico analysis algorithm minimizing articular step-off distances between the edges of the graft and recipient defect. Distances between the entire surface of the OCA graft and the underneath surface of the MFC were evaluated as surface mismatch. Donor (LFC) and recipient (MFC) 3D-printed patient-specific guides were created based on 3D reconstructions of the scanned condyles. Through use of the guides, OCAs were harvested from the LFC and transplanted to the reamed recipient defect site (MFC). The post-OCA recipient condyles were laser scanned. The 360° articular step-off and cartilage topography mismatch were measured. RESULTS: The mean cartilage step-off and graft surface mismatch for the in silico OCA transplant were 0.073 ± 0.029 mm (range, 0.005-0.113 mm) and 0.166 ± 0.039 mm (range, 0.120-0.243 mm), respectively. Comparatively, the cadaveric specimens postimplant had significantly larger step-off differences (0.173 ± 0.085 mm; range, 0.082-0.399 mm; P = .001) but equivalent graft surface topography matching (0.181 ± 0.080 mm; range, 0.087-0.396 mm; P = .678). All 12 OCA transplants had mean circumferential step-off differences less than a clinically significant cutoff of 0.5 mm. CONCLUSION: These findings suggest that the use of 3D-printed patient-specific guides for OCA transplantation has the ability to reliably optimize cartilage topography matching for LFC to MFC transplantation. This study demonstrated substantially lower step-off values compared with previous orthopaedic literature when also evaluating LFC to MFC transplantation. Using this novel technique in a model performing MFC to MFC transplantation has the potential to yield further enhanced results due to improved radii of curvature matching. CLINICAL RELEVANCE: Topography-matched graft implantation for focal chondral defects of the knee in patients improves surface matching and has the potential to improve long-term outcomes. Efficient selection of the allograft also allows improved availability of the limited allograft sources.

Fresh Osteochondral Allograft Transplantation of the Capitellum for the Treatment of Osteochondritis Dissecans.

BACKGROUND: Osteochondritis dissecans (OCD) of the humeral capitellum is a rare and challenging condition to treat. Several surgical options exist, but in the last few years, the pendulum has swung from debridement and microfracture to restoration of the articular surface. Osteochondral autografts from the rib and knee have been described, but donor-site morbidity is a concern. PURPOSE: To expand the results of fresh osteochondral allograft transplantation (FOCAT) in a previously published report with inclusion of additional patients and a longer follow-up period. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: After institutional review board approval, the charts of patients who underwent FOCAT for OCD of the capitellum between 2006 and 2022 by a single surgeon were reviewed. The majority of cases (94%) had unstable lesions (Minami grades 2 and 3). A trial of nonoperative treatment had failed in all. All patients underwent diagnostic arthroscopy, followed by a mini-open, ligament-sparing approach with grafting using commercially available guides and instruments. RESULTS: A total of 35 patients were identified, of whom 25 were male. The mean age was 16 ± 3.9 years (range, 11-32 years). There were 24 baseball players (19 pitchers and 5 position players), 5 gymnasts, 3 cheerleaders/tumblers, 1 tennis player, 1 student (who did not participate in athletics), and 1 patient with avascular necrosis from chemotherapy. Eighteen patients had a mean flexion contracture of 14.1°± 11.9°. A single osteochondral allograft plug was used in 23 patients (mean diameter, 11.3 ± 2.8 mm), and 12 patients required 2 plugs (Mastercard technique). The mean follow-up was 92.6 ± 54.5 months (range, 24-204 months). There was significant improvement in Oxford (from 25.5 ± 4.9 to 46.7 ± 3.5; P < .00001) and visual analog scale for pain (from 7.5 ± 2 to 0.3 ± 1.0; P < .0001) scores. The mean Single Assessment Numeric Evaluation score at the time of follow-up was 90.6 ± 10.8 (range, 60-100). In overhead athletes, there was significant improvement in the Kerlan-Jobe Orthopaedic Clinic score (from 40.8 ± 11.8 to 90.6 ± 10.8; P < .00001). A postoperative magnetic resonance imaging scan was obtained in 16 (46%) patients at a mean of 32.6 months. In all cases, the graft was incorporated. All overhead athletes were able to return to their sport and perform at the same level or higher for >2 years. Two elbows required a subsequent arthroscopy for loose-body removal; otherwise, there were no other complications. CONCLUSION: FOCAT is an excellent option for treating OCD lesions of the humeral capitellum. Excellent outcomes and high return-to-sport rates were observed, with midterm follow-up showing no graft failures. FOCAT eliminates donor-site morbidity.

What makes the kidney so tolerant?

Various organ allografts differ in their propensity to be spontaneously accepted without any immunosuppressive treatment. Understanding the mechanisms behind these differences can aid in managing alloimmune responses in general. C57BL/6 mice naturally accept DBA/2J kidney allografts, forming tertiary lymphoid organs containing regulatory T cells (rTLOs), crucial for graft acceptance. In this issue of the JCI, Yokose and colleagues revealed that rTLOs promote conversion of cytotoxic alloreactive CD8+ T cells into exhausted/regulatory ones, through an IFN-γ-mediated mechanism. Their study provides insights into tolerance development that could help promote the acceptance of grafts at higher risk of rejection.

Unique Lessons From the Natural Progression of Rejection in Human Uterine Allografts.

INTRODUCTION: Uterus transplantation (UTx) is a novel treatment for absolute uterine infertility. Acute T cell-mediated rejection (TCMR) can be monitored only through serial cervical biopsies. METHODS: This study, the first of its kind in human transplantation, evaluated clinical, serological, and pathophysiological manifestations of allograft rejection from immunosuppression withdrawal (ISW) to graft hysterectomy (Hx). RESULTS: Following live birth, immunosuppression was abruptly withdrawn from six living-donor UTx recipients. ISW occurred at a median of 7.4 weeks before graft Hx. Post-ISW signs of rejection included: (1) discoloration of the cervix; (2) increased uterine size compared to day of ISW; (3) serological evidence of eosinophilia and progressive development of donor-specific antibodies (DSA) or child-specific antibodies (CSA); (4) histopathological evidence of TCMR in cervical biopsies preceding the development of antibodies in serum; and (5) C4d deposition in tissue before formation of DSA or CSA in all but two recipients. At graft Hx, endometrial glands were preferentially targeted for destruction over stroma while parametrial arteries displayed variable arteritis and fibrointimal hyperplasia. CONCLUSION: Recognition of the progression of uterine allograft rejection may be important for other human organ recipients and drive research on modulation of immunosuppression and the paradoxical relationship between adaptive cellular and humoral immunity in natural pregnancies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02656550.