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Background Various properties of mesenchymal stromal cells (MSCs) might be particularly of interest after liver transplantation (LT). In this paper, we report the long-term results of their prospective, controlled and first-in-human phase-1 study evaluating the safety of a single MSC infusion after LT. Methods Ten LT recipients under standard immunosuppression received 1.5-3x106 /kg third-party unrelated MSCs on post-operative day 3±2 and were prospectively compared to a control group of 10 LT recipients. Primary endpoints were set to prospectively detect potential delayed side effects of MSC infusion, and particularly occurrence of infections and cancers. Secondary endpoints of liver graft and patient survival, graft rejection and function, occurrence of bile duct complications, and development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) against liver or MSC donors, were studied. Median follow-up was 85 months. Results There was no difference in overall rates of infection or cancer at 5 years of follow-up between the two groups. There was also no difference in secondary endpoints. The prevalence of de novo liver DSAs related to HLA-mismatches was twice as high in the MSC group compared to the control group. All the de novo class II HLA antibodies against MSCs were linked to a shared HLA mismatch between the liver and MSCs. Conclusions This study confirms the safety of a single MSC infusion after LT. The potential benefits of MSC injections in the context of organ transplantation have still to be demonstrated by larger prospective studies. The development of anti-HLA antibodies against MSC donor should be further evaluated especially in cases of shared HLA mismatches between graft and MSC donors, despite the fact that no deleterious effect has been detected.

Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs (∼2 × 106/kg) on day 3 ± 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m2, compared to 32.5 ml/min/1.73m2 in controls and 29.3 ml/min/1.73m2 in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied.

Background and Aims Proteinuria, hematuria and acute kidney injury (AKI) are frequently observed in hospitalized patients with COVID-19. However, few data are available on these parameters after hospital discharge. Method This retrospective, observational and monocentric study included 153 hospitalized patients, in whom urine total proteinuria and α1-microglobulin (a marker of tubular injury) were measured. Thirty patients died. Among the 123 survivors, follow-up urine and creatinine analyses were available for 72 patients (after a median of 51 [19;93] days following hospital discharge). Results The median proteinuria at hospitalization and follow-up (n=72) was 419 [239; 748] and 79 [47; 129] mg/g, respectively (p15 mg/g (%) 88 29 Urine β2-microglobulin (n=60) (mg/L) 0.92 [0.41;4.52] 0.00 [0.00;0.00] 0.19 mg/L (%) 82 13 Hematuria (>10 per field) (%) (n=51) 19 12 ns

Over the past decade, the clinical application of mesenchymal stromal cells (MSCs) has generated growing enthusiasm as an innovative cell-based approach in solid organ transplantation (SOT). These expectations arise from a significant number of both transplant- and non-transplant-related experimental studies investigating the complex anti-inflammatory, immunomodulatory, and tissue-repair properties of MSCs. Promising preclinical results have prompted clinical trials using MSC-based therapy in SOT. In the present review, the general properties of MSCs are summarized, with a particular emphasis on MSC-mediated impact on the immune system and in the ischemic conditioning strategy. Next, we chronologically detail all clinical trials using MSCs in the field of SOT. Finally, we envision the challenges and perspectives of MSC-based cell therapy in SOT.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis is an autosomal-recessive disease caused by mutations in the CLDN16 or CLDN19 genes, which encode tight junction-associated proteins, claudin-16 and -19. The resultant tubulopathy leads to urinary loss of Mg(2+) and Ca(2+), with subsequent nephrocalcinosis and end-stage renal disease (ESRD). An 18-year-old boy presented with chronic kidney disease and proteinuria, as well as hypomagnesaemia, hypercalciuria and nephrocalcinosis. A kidney biopsy revealed tubular atrophy, interstitial fibrosis and segmental sclerosis of some glomeruli. Two novel mutations in the CLDN16 gene were identified: c.340C>T (nonsense) and c.427+5G>A (splice site). The patient reached ESRD at 23 and benefited from kidney transplantation.

Kidney transplantation represents the best treatment of end-stage renal disease. In addition to the degree of human leukocyte antigen matching, long-term graft survival is influenced by the quality of the graft before its transplantation. Quality criteria include the level of ischemic damage caused by the transplantation per se. Renal ischemic preconditioning (IP) consists of different approaches to prevent ischemia/reperfusion (I/R) damage induced by the interruption and recovery of renal circulation, as observed during transplantation. Distinct animal models show promising results regarding the efficiency of PCI to preserve kidney structure and function in I/R conditions. Characterizing the cellular cascades involved in I/R led to the identification of putative targets of renal IP, including the adenosine monophosphate-activated protein kinase (AMPK). AMPK is a ubiquitous energy sensor, which has been implicated in the maintenance of epithelial cell polarization under energy deprivation. Among others, the anti-diabetic drug, metformin, is a potent activator of AMPK. Here, we summarize the in vitro and in vivo data about the role of AMPK in renal IP. Defining the pharmacological conditions of IP would help to improve the quality of the renal graft before its transplantation, thereby increasing its long-term survival.

Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbimortality. AKI treatment mostly relies on supportive manoeuvres in the absence of specific target-oriented therapy. The pathophysiology of AKI commonly involves ischaemia/reperfusion (I/R) events, which cause both immune and metabolic consequences in renal tissue. Similarly, at the time of kidney transplantation (KT), I/R is an unavoidable event which contributes to early graft dysfunction and enhanced graft immunogenicity. Mesenchymal stromal cells (MSCs) represent a heterogeneous population of adult, fibroblast-like multi-potent cells characterized by their ability to differentiate into tissues of mesodermal lineages. Because MSC have demonstrated immunomodulatory, anti-inflammatory and tissue repair properties, MSC administration at the time of I/R and/ or at later times has been hypothesized to attenuate AKI severity and to accelerate the regeneration process. Furthermore, MSC in KT could help prevent both I/R injury and acute rejection, thereby increasing graft function and survival. In this review, summarizing the encouraging observations in animal models and in pilot clinical trials, we outline the benefi to f MSC therapy in AKI and KT, and envisage their putative role in renal ischaemic conditioning.

The diagnosis of acute rejection still relies on renal allograft biopsy. In fact, histological features including C4d staining can be useful to differentiate cellular and antibody-mediated acute rejection. However, the pathogenic mechanism to define the type of rejection is usually assessed by anti-HLA donor specific antibodies (DSA) monitoring. Suspicion of acute rejection is usually based on renal function deterioration. This method has low sensitivity. Moreover, creatinine increase follows graft injury and therefore the diagnosis is performed when there is an ongoing acute rejection. One strategy to overcome the limitation of serum creatinine as predictor of acute rejection is to perform surveillance protocol biopsies. However, the low incidence of subclinical acute rejection among patients treated with tacrolimus-based immunosuppression makes this procedure questionable in terms of cost-effectiveness. In this scenario new biomarkers predicting acute rejection are urgently needed. Ideally, such biomarkers should anticipate acute rejection, thus allowing preventive actions such as maintenance immunosupression intensification and/or modification. Alternatively, these new biomarkers should at least improve the predictive value of serum creatinine monitoring. Although many of the new biomarkers are promising, none have been translated to the clinic to date because of a lack of validation studies and the existence of major methodological concerns.

Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene expression profiling and omics analyses of blood and urine samples. Most imaging techniques, like contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leukocytes may be detectable by 18F-fluoro-deoxy-glucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3e, IP-10 and 18S RNA levels, have been identified. None of these approaches has been adopted yet in the clinical follow-up of KTRs, but standardization of procedures may help assess reproducibility and compare diagnostic yields in large prospective multicentric trials.