Co-infusion of insulin secreting and hematopoietic stem cells with renal transplantation offers better glycemic control and protection of the renal allograft from immune injury in diabetes mellitus with end stage renal disease- an initial experience

Vivek Kute¹, Hargovind L Trivedi¹, Shruti S Dave¹, Aruna V Vanikar¹, Umang G Thakkar¹, Himanshu V Patel¹

¹Department of Nephrology and Transplantation Medicine, IKDRCITS, Ahmedabad, India

Introduction: Diabetes mellitus (DM) is a common cause of end stage renal disease (ESRD). Various factors contribute to wide fluctuations in blood glucose levels and exogenous insulin requirement in these patients even after renal transplantation (RT). Therapeutic options for such patients are simultaneous kidney-pancreas transplants or stem cell therapy (SCT) with RT. We present an initial experience of SCT preceding RT in diabetic nephropathy leading to ESRD.

Material and methods: Five patients (4 males, 1 female, mean age 39±11 years) suffering from DM since 12.4 ± 4.7 years and ESRD since 7.8 ±1.64 months, underwent living donor RT (LDRT) following co-infusion of in vitro generated insulin-secreting cells differentiated from donor adipose tissue derived mesenchymal stem cells (ADMSC) and bone marrow (BM)-derived hematopoietic SC (HSC) into subcutaneous tissue, portal and thymic circulation. Pre-infusion conditioning was done with Bortezomib, 1.3 mg/m²body surface area with methylprednisone 125 mg, on day 1, 4, 8 and 11, and rabbit anti-thymocyte globulin, 1.5 mg/kg BW on day 12. SC were infused on 14^th day and RT was performed on any day from 16^th to19^th day after favourable immune response (lymphocyte cross match).

Results: Total quantum infused was 86 ±16 ml, out of which 2 ml were infused in thymus, 54 ml in portal and 30 ml subcutaneously. Total nucleated cell count was 5.05 ±0.83 x 10⁶/kgBW, HSC CD34+, 2.85± 1.43x 10⁴ /kgBW, ADMSC CD 90+/73+, 0.82 ±0.26 x 10⁴ /kgBW and insulin-making cells 1.48±0.28 x 10⁴/kgBW. SC infusion was uneventful.

Over a follow-up of 7.97± 4.91 months, their pre-transplant weight of 56 ±16 kg is sustained at 59.6 ±15.2 kg, fasting and post-prandial blood sugar of 213± 26mg/dL and 295± 30mg/dL respectively sustained at 94± 5.2mg/dL and 145±21 mg/dL respectively, and HbA1c of 9.1±0.54 % is reduced to 6.7 ± 0.40% with sustained insulin requirement of 25±10 IU/day which was 75±29 IU/day before ESRD and 32±12 IU/day pre-transplant. They all have stable graft function with serum creatinine, 0.96 ± 0.05 mg/dL and zero rejection on Tacrolimus, 0.05 mg /kg and prednisone, 10 mg /day.

Conclusion: This initial single centre experience of co-infusion of insulin secreting and hematopoietic stem cells subcutaneously and in portal and thymic circulation followed by renal transplantation shows better glycemic control and protection of the renal allograft from immune injury in diabetes mellitus with end stage renal disease. SCT with RT will open up safe and effective avenues for diabetic nephropathy patients.