Mesenchymal Stem Cells in Organ Transplantation: Immunomodulatory properties of mesenchymal stem cells for application in organ transplantation

Kidney transplantation is the only effective treatment for patients with end-stage renal disease. Transplantation of a donor organ, however, leads to recognition of the foreign donor antigens by the recipient’s immune system, resulting in rejection of the graft. In addition, ischemia-reperfusion injury leads to the initiation of immune responses. To prevent graft rejection, transplant recipients need to use life-long immunosuppressive medication. These drugs, however, can lead to serious acute and chronic side effects, such as infections, nephrotoxicity, cardiovascular disease and malignancies 1. As an alternative, cellular therapies may be considered. One of the candidates is the mesenchymal stem cell (MSC). Mesenchymal stem cells have tissue regenerative and immunosuppressive properties 2-4. These properties make them promising as cellular therapy for tissue regeneration and treatment of immunological disease. In solid organ transplantation, MSC may repair graft injury and may reduce anti-donor reactivity, thereby improving graft function and alleviating the need for immunosuppressive drugs after transplantation. Despite recent clinical trials investigating the use of MSC in treating immune-mediated disease, such as therapy resistant graft-versus-host disease (GVHD) and inflammatory bowel disease, the applicability of MSC in solid organ transplantation is still unknown. The present thesis discusses the immunomodulatory properties of MSC and their potential to improve the outcome of solid organ transplantation

Diagnostic value of urinary dysmorphic erythrocytes in clinical practice

Background: In clinical practice, discriminating between glomerular and nonglomerular causes of hematuria is often difficult. Dysmorphic red blood cells (dRBC) in the urinary sediment are claimed to be effective, but the cutoff points in the literature vary. This follow-up study aimed to determine the diagnostic value of dRBC. Methods: We investigated 134 hematuria patients in the departments of nephrology and urology. To diagnose the origin of hematuria, urological and/or nephrological examination was performed and the %dRBC identified by microscopy. Follow-up was performed after 3.5 years. Results: The cause of hematuria was proven in 68 patients (35% glomerular; 65% nonglomerular). Patients with glomerular disease had significantly more albuminuria and dRBC than patients with nonglomerular disease, but the %dRBC ranged from 1 to 50% and no optimal cutoff could be identified. Logistic regression analysis showed that %dRBC had a predicted probability to diagnose glomerular disease of 77.9% (area under the curve, AUC, 0.85). When %dRBC was combined with other risk factors such as serum creatinine, sex, age, dipstick erythrocyte or proteinuria score and number of casts, the predictive probability increased to 90.6% (AUC 0.97). Follow-up of the included patients showed no benefit of dRBC to identify patients at risk for glomerular disease. Conclusions: The diagnostic value of routinely collected urinary dRBC to diagnose glomerular disease in patients presenting with hematuria is modest. However, including dRBC with other variables, such as age and erythrocyte score on dipstick testing may increase the sensitivity, but needs to be confirmed in another, preferably larger, population. Copyrigh

Development and external validation study combining existing models and recent data into an up-to-date prediction model for evaluating kidneys from older deceased donors for transplantation

With a rising demand for kidney transplantation, reliable pre-transplant assessment of organ quality becomes top priority. In clinical practice, physicians are regularly in doubt whether suboptimal kidney offers from older donors should be accepted. Here, we externally validate existing prediction models in a European population of older deceased donors, and subsequently developed and externally validated an adverse outcome prediction tool. Recipients of kidney grafts from deceased donors 50 years of age and older were included from the Netherlands Organ Transplant Registry (NOTR) and United States organ transplant registry from 2006-2018. The predicted adverse outcome was a composite of graft failure, death or chronic kidney disease stage 4 plus within one year after transplantation, modelled using logistic regression. Discrimination and calibration were assessed in internal, temporal and external validation. Seven existing models were validated with the same cohorts. The NOTR development cohort contained 2510 patients and 823 events. The temporal validation within NOTR had 837 patients and the external validation used 31987 patients in the United States organ transplant registry. Discrimination of our full adverse outcome model was moderate in external validation (C-statistic 0.63), though somewhat better than discrimination of the seven existing prediction models (average C-statistic 0.57). The model's calibration was highly accurate. Thus, since existing adverse outcome kidney graft survival models performed poorly in a population of older deceased donors, novel models were developed and externally validated, with maximum achievable performance in a population of older deceased kidney donors. These models could assist transplant clinicians in deciding whether to accept a kidney from an older donor

Considerable Variability Among Transplant Nephrologists in Judging Deceased Donor Kidney Offers

Introduction: Transplant clinicians may disagree on whether or not to accept a deceased donor kidney offer. We investigated the interobserver variability between transplant nephrologists regarding organ acceptance and whether the use of a prediction model impacted their decisions.Methods: We developed an observational online survey with 6 real-life cases of deceased donor kidneys offered to a waitlisted recipient. Per case, nephrologists were asked to estimate the risk of adverse outcome and whether they would accept the offer for this patient, or for a patient of their own choice, and how certain they felt. These questions were repeated after revealing the risk of adverse outcome, calculated by a validated prediction model. Results: Sixty Dutch nephrologists completed the survey. The intraclass correlation coefficient of their estimated risk of adverse outcome was poor (0.20, 95% confidence interval [CI] 0.08–0.62). Interobserver agreement of the decision on whether or not to accept the kidney offer was also poor (Fleiss kappa 0.13, 95% CI 0.129–0.130). The acceptance rate before and after providing the outcome of the prediction model was significantly influenced in 2 of 6 cases. Acceptance rates varied considerably among transplant centers. Conclusion: In this study, the estimated risk of adverse outcome and subsequent decision to accept a suboptimal donor kidney varied greatly among transplant nephrologists. The use of a prediction model could influence this decision and may enhance nephrologists’ certainty about their decision.</p

Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation

Over the last decade, there has been a rising interest in the use of mesenchymal stem cells (MSCs) for clinical applications. This interest stems from the beneficial properties of MSCs, which include multi-lineage differentiation and immunosuppressive ability, suggesting there is a role for MSC therapy for tissue regeneration and in immunologic disease. Despite recent clinical trials investigating the use of MSCs in treating immune-mediated disease, their applicability in solid-organ transplantation is still unknown. In this review, we identified topics that are important when considering MSC therapy in clinical organ transplantation. Whereas, from other clinical studies, it would appear that administration of MSCs is safe, issues like dosing, timing, route of administration, and in particular the use of autologous or donor-derived MSCs may be of crucial importance for the functional outcome of MSCs treatment in organ transplantation. We discuss these topics and assess the feasibility of MSCs therapy in organ transplantation