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BackgroundKidney transplantation has improved survival and quality of life for patients with end-stage renal disease. Despite excellent short-term results due to better and more potent immunosuppressive drugs, long-term survival of transplanted kidneys has not improved accordingly in the last decades. Consequently there is a strong interest in immunosuppressive regimens that maintain efficacy for the prevention of rejection, whilst preserving renal structure and function. In this respect the infusion of mesenchymal stromal cells (MSCs) may be an interesting immune suppressive strategy. MSCs have immune suppressive properties and actively contribute to tissue repair. In experimental animal studies the combination of mammalian target of rapamycin (mTOR) inhibitor and MSCs was shown to attenuate allo immune responses and to promote allograft tolerance. The current study will test the hypothesis that MSC treatment, in combination with the mTOR inhibitor everolimus, facilitates tacrolimus withdrawal, reduces fibrosis and decreases the incidence of opportunistic infections compared to standard tacrolimus dose.Methods/design70 renal allograft recipients, 18–75 years old, will be included in this Phase II, open label, randomized, non-blinded, prospective, single centre clinical study. Patients in the MSC treated group will receive two doses of autologous bone marrow derived MSCs IV (target 1,5x106, Range 1-2x106 million MSCs per/kg body weight), 7 days apart, 6 and 7 weeks transplantation in combination with everolimus and prednisolone. At the time of the second MSC infusion tacrolimus will be reduced to 50% and completely withdrawn 1 week later. Patients in the control group will receive everolimus, prednisolone and standard dose tacrolimus. The primary end point is to compare fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups at 6 months compared to 4 weeks post-transplant. Secondary end points include: composite end point efficacy failure (Biopsy Proven Acute Rejection, graft loss or death); renal function and proteinuria; opportunistic infections; immune monitoring and “subclinical” cardiovascular disease groups by assessing echocardiography in the different treatment groups.DiscussionThis study will provide information whether MSCs in combination with everolimus can be used for tacrolimus withdrawal, and whether this strategy leads to preservation of renal structure and function in renal recipients.Trial registrationNCT02057965.

BackgroundMesenchymal stromal cells (MSC) may serve as an attractive therapy in renal transplantation due to their immunosuppressive and reparative properties. While most studies have used autologous MSCs, allogeneic MSCs offer the advantage of immediate availability for clinical use. This is of major importance for indications where instant treatment is needed, for example allograft rejection or calcineurin inhibitor toxicity. Clinical studies using allogeneic MSCs are limited in number. Although these studies showed no adverse reactions, allogeneic MSCs could possibly elicit an anti-donor immune response, which may increase the incidence of rejection and impact the allograft survival in the long term. These safety issues should be addressed before further studies are planned with allogeneic MSCs in the solid organ transplant setting.Methods/design10 renal allograft recipients, 18–75 years old, will be included in this clinical phase Ib, open label, single center study. Patients will receive two doses of 1.5 × 106 per/kg body weight allogeneic bone marrow derived MSCs intravenously, at 25 and 26 weeks after transplantation, when immune suppression levels are reduced. The primary end point of this study is safety by assessing biopsy proven acute rejection (BPAR)/graft loss after MSC treatment. Secondary end points, all measured before and after MSC infusions, include: comparison of fibrosis in renal biopsy by quantitative Sirius Red scoring; de novo HLA antibody development and extensive immune monitoring; renal function measured by cGFR and iohexol clearance; CMV and BK infection and other opportunistic infections.DiscussionThis study will provide information on the safety of allogeneic MSC infusion and its effect on the incidence of BPAR/graft loss.Trial registration: NCT02387151

BackgroundEssential information regarding efficacy and safety of vitamin K-antagonists (VKA) treatment for atrial fibrillation (AF) in non-dialysis dependent chronic kidney disease (CKD) is still lacking in current literature. The aim of our study was to compare the risks of stroke or transient ischemic attack (TIA) and major bleeds between patients without CKD (eGFR >60 ml/min), and those with moderate (eGFR 30–60 ml/min), or severe non-dialysis dependent CKD (eGFR <30 ml/min).MethodsWe included 300 patients without CKD, 294 with moderate, and 130 with severe non-dialysis dependent CKD, who were matched for age and sex. Uni- and multivariate Cox regression analyses were performed reporting hazard ratios (HRs) for the endpoint of stroke or TIA and the endpoint of major bleeds as crude values and adjusted for comorbidity and platelet-inhibitor use.ResultsOverall, 6.2% (45/724, 1.7/100 patient years) of patients developed stroke or TIA and 15.6% (113/724, 4.8/100 patient years) a major bleeding event. Patients with severe CKD were at high risk of stroke or TIA and major bleeds during VKA treatment compared with those without renal impairment, HR 2.75 (95%CI 1.25–6.05) and 1.66 (95%CI 0.97–2.86), or with moderate CKD, HR 3.93(1.71–9.00) and 1.86 (95%CI 1.08–3.21), respectively. These risks were similar for patients without and with moderate CKD. Importantly, both less time spent within therapeutic range and high INR-variability were associated with increased risks of stroke or TIA and major bleeds in severe CKD patients.ConclusionsVKA treatment for AF in patients with severe CKD has a poor safety and efficacy profile, likely related to suboptimal anticoagulation control. Our study findings stress the need for better tailored individualised anticoagulant treatment approaches for patients with AF and severe CKD.

Background. Urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) have been validated as biomarkers for acute kidney injury. We investigated the performance of both markers in predicting the occurrence and duration of functionally defined delayed graft function (fDGF) in donation after circulatory death (DCD) kidney transplant recipients. Methods. Urine samples of 74 DCD recipients were analyzed. TIMP-2 and IGFBP7 were measured with ELISA on postoperative days 1 to 7, day 10, week 6, and month 6, and values were corrected for osmolality (mOsm). Immunosuppression consisted of anti-CD25 antibody induction and triple maintenance therapy (steroids, mycophenolate mofetil, and calcineurin inhibitor). Statistical analysis included receiver operating characteristic curves and multivariate logistic regression. Results. Fifty-one (69%) renal transplant recipients had fDGF, of which 14 experienced prolonged fDGF (≥21 days). TIMP-2/mOsm on day-1 and day-10 adequately identified patients with fDGF (area under the curve [AUC], 0.91) and prolonged fDGF (AUC, 0.80), respectively, whereas IGFBP7/mOsm did not (AUC, 0.63 and 0.60). Multivariate analysis on day 1 identified 24-hour urinary creatinine excretion and TIMP-2/mOsm as significant predictors of fDGF (AUC, 0.90, 95% confidence interval, 0.80-0.98). The best predictors of prolonged fDGF on day 10 were 24-hour urinary creatinine excretion, TIMP-2/mOsm, and total warm ischemia time with an AUC of 0.85 (95% confidence interval, 0.72-0.95). Consecutive TIMP-2/mOsm values showed a decrease in TIMP-2/mOsm before an increase in estimated glomerular filtration rate, enabling us to monitor fDGF and predict resolution of fDGF. Conclusions. Urinary TIMP-2, but not IGFBP7, is a promising biomarker to predict the occurrence and duration of fDGF in DCD kidney transplant recipients.