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The extent to which tissue-resident memory T (TRM) cells in transplanted organs possess alloreactivity is uncertain. This study investigates the alloreactive potential of TRM cells in kidney explants from 4 patients who experienced severe acute rejection leading to graft loss. Alloreactive T cell receptor (TCR) clones were identified in pretransplant blood samples through mixed lymphocyte reactions, followed by single-cell RNA and TCR sequencing of the proliferated recipient T cells. Subsequently, these TCR clones were traced in the TRM cells of kidney explants, which were also subjected to single-cell RNA and TCR sequencing. The proportion of recipient-derived TRM cells expressing an alloreactive TCR in the 4 kidney explants varied from 0% to 9%. Notably, these alloreactive TCRs were predominantly found among CD4+ and CD8+ TRM cells with an effector phenotype. Intriguingly, these clones were present not only in recipient-derived TRM cells but also in donor-derived TRM cells, constituting up to 4% of the donor population, suggesting the presence of self-reactive TRM cells. Overall, our study demonstrates that T cells with alloreactive potential present in the peripheral blood prior to transplantation can infiltrate the kidney transplant and adopt a TRM phenotype.

Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue–resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.

The use of mesenchymal stromal cells (MSCs) for clinical application is intensively investigated for a variety of areas, such as bone repair, haematological and autoimmune diseases, and solid organ transplantation. Moreover, increasing insights into their mechanism of actions revealed a lively (paracrine) interaction between MSCs and recipient (immune) cells and identified novel mediators such as extracellular vesicles (EVs). Both paracrine signals and EVs have been shown to play a role in the effects of MSCs and may potentially complement MSC-based therapies or represent therapeutic alternatives. This Special Issue of Cells is devoted to the many aspects of MSC-based therapy and includes original data papers and reviews on preclinical models, clinical studies, as well as MSC manufacturing protocols. [...]

——The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as mega-lin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/nepri-lysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. Significance Statement——Angiotensin formation in the kidney is widely accepted but little understood, and m

Background: Kidney transplantation is the optimal treatment of end-stage renal disease. Extracellular vesicles (EVs) have tremendous therapeutic potential, but their role in modulating immune responses in kidney transplantation remains unclear. Methods: We performed a systematic review and meta-analysis to investigate the therapeutic efficacy of EVs in preclinical kidney transplant models. Outcomes for meta-analysis were graft survival and renal function. Subgroup analysis was conducted between immune cell derived EVs (immune cell-EVs) and mesenchymal stromal cell derived EVs (MSC-EVs). Results: Seven studies published from 2013 to 2021 were included. The overall effects showed that EVs had a positive role in prolonging allograft survival (standardized mean difference (SMD) = 2.00; 95% confidence interval (CI), 0.79 to 3.21; P < 0.01; I2 = 94%), reducing serum creatinine (SCr) (SMD = -2.19; 95%CI, −3.35 to −1.04; P < 0.01; I2 = 93%) and blood urea nitrogen (BUN) concentrations (SMD = -1.69; 95%CI, −2.98 to −0.40; P = 0.01; I2 = 94%). Subgroup analyses indicated that only immune cell-EVs significantly prolonged graft survival and improve renal function but not MSC-EVs. Conclusions: EVs are promising candidates to suppress allograft rejection and improve kidney transplant outcome. Immune cell-EVs showed their superiority over MSC-EVs in prolonging graft survival and improving renal function. For interpretation of the outcomes, additional studies are needed to validate these findings.

Induced pluripotent stem cell (iPSC)-derived kidney organoids are a potential tool for the regeneration of kidney tissue. They represent an early stage of nephrogenesis and have been shown to successfsully vascularize and mature further in vivo. However, there are concerns regarding the long-term safety and stability of iPSC derivatives. Specifically, the potential for tumorigenesis may impede the road to clinical application. To study safety and stability of kidney organoids, we analyzed their potential for malignant transformation in a teratoma assay and following long-term subcutaneous implantation in an immune-deficient mouse model. We did not detect fully functional residual iPSCs in the kidney organoids as analyzed by gene expression analysis, single-cell sequencing and immunohistochemistry. Accordingly, kidney organoids failed to form teratoma. Upon long-term subcutaneous implantation of whole organoids in immunodeficient IL2Ry-/-RAG2-/- mice, we observed tumor formation in 5 out of 103 implanted kidney organoids. These tumors were composed of WT1+CD56+ immature blastemal cells and showed histological resemblance with Wilms tumor. No genetic changes were identified that contributed to the occurrence of tumorigenic cells within the kidney organoids. However, assessment of epigenetic changes revealed a unique cluster of differentially methylated genes that were also present in undifferentiated iPSCs. We discovered that kidney organoids have the capacity to form tumors upon long-term implantation. The presence of epigenetic modifications combined with the lack of environmental cues may have caused an arrest in terminal differentiation. Our results indicate that the safe implementation of kidney organoids should exclude the presence of pro-tumorigenic methylation in kidney organoids.

OBJECTIVE: Normothermic (37 C) machine perfusion (NMP) is a potential alternative to currently used hypothermic (4 C) machine perfusion (HMP) for donor kidney preservation before transplantation. NMP allows for metabolic activity and for functional assessment of donor kidneys. The kidneys are key producers of hormones and we investigated the release of prorenin/renin, erythropoietin (EPO), and vitamin D by kidneys on machine perfusion. DESIGN AND METHOD: Ten donor kidneys were subjected to HMP followed by 2 h of oxygenated NMP before transplantation. NMP perfusate was collected at three time points (0 h, 1 h, 2 h). Ten HMP perfusate samples were collected for the same measurements. RESULTS: Median release rates of prorenin (196 [i.q.r 28-266] ng/hour) and renin (228 [94-302] ng/hour) in the first hour of NMP were 83- and 37-fold higher than that in HMP perfusates respectively (p = 0.0009 and p < 0.0001). Median renin release rate showed a 3.2-fold downregulation during the second hour of NMP compared to the first hour. Median EPO release rate (14 [i.q.r 8-48] mIU/min) during the first hour of NMP was 2.9-fold higher than that in HMP perfusates (p = 0.035), while it remained stable in the second hour of NMP. Active vitamin D was undetectable in HMP perfusate samples, while there was a median vitamin D secretion of 56 (i.q.r 30-83) and 28 (8-50) pmol/hour in the first and second hour of NMP respectively (p = 0.0001 and p = 0.003). We then investigated whether there were correlations between the hormone releasing capacity and donor kidney status. Prorenin release rate in the second hour of NMP was lower as cold ischemia time (CIT) until NMP of donor kidneys increased (r = -0.605; p = 0.049). EPO release showed no correlation with donor age or CIT. Donor age and vitamin D release rate during two hours of NMP are highly correlated (r = 0.652; p = 0.034). Interestingly, donation after brain death (DBD) kidneys significantly released more vitamin D than donation afte