Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM).

SIGNIFICANCE STATEMENT: Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study. BACKGROUND: Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited. METHODS: The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months. RESULTS: At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo. CONCLUSIONS: Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT02585622 .

Effects of HLA-matched blood transfusion for patients awaiting renal transplantation.

BACKGROUND: HLA sensitization in potential renal transplant recipients hinders opportunities of receiving suitable organs. To alleviate this, we sought to determine if supplying closely HLA Class I matched leukodepleted blood would minimize sensitization. METHODS: Patients received HLA selected or random units of packed red cells. Selected units were sourced from blood donors included in the British Bone Marrow Registry and had no HLA-A and HLA-B mismatches where available, or alternatively, no HLA antigens with more than five immunogenic triplet mismatches as determined by the HLA-Matchmaker algorithm. Posttransfusion antibody screening confirmed development of de novo Class I and Class II HLA-specific IgG antibody(s) or increases in preexisting antibody levels of at least 20%. RESULTS: Thirty-seven and 31 patients received HLA selected (mean, 2.5 units) and random (mean, 3.4 units) blood, respectively. A total of 20 of 37 (54.1%) patients receiving selected units and 10 of 31 (32.3%) patients receiving random units were previously sensitized. No patient receiving HLA selected units demonstrated any change in antibody levels. In patients who received random units, 7 of 31 demonstrated changes in antibody levels with three developing de novo HLA-specific antibodies and four an increase in panel reactive antibody (PRA) of at least 20% (P=0.002). CONCLUSIONS: The risk of developing HLA-specific antibody is significantly reduced in renal patients awaiting transplantation when transfused with HLA selected units of blood compared with random units. With planning, access to HLA typed blood is achievable as many blood transfusion centers recruit donors for stem cell donor registries.