Cotransplantation of Adipose Tissue-Derived Insulin-Secreting Mesenchymal Stem Cells and Hematopoietic Stem Cells: A Novel Therapy for Insulin-Dependent Diabetes Mellitus

Aims. Insulin dependent diabetes mellitus (IDDM) is believed to be an autoimmune disorder with disturbed glucose/insulin metabolism, requiring life-long insulin replacement therapy (IRT), 30% of patients develop end-organ failure. We present our experience of cotransplantation of adipose tissue derived insulin-secreting mesenchymal stem cells (IS-AD-MSC) and cultured bone marrow (CBM) as IRT for these patients. Methods. This was a prospective open-labeled clinical trial to test efficacy and safety of IS-AD-MSC+CBM co-transplantation to treat IDDM, approved by the institutional review board after informed consent in 11 (males : females: 7 : 4) patients with 1–24-year disease duration, in age group: 13–43 years, on mean values of exogenous insulin requirement of 1.14 units/kg BW/day, glycosylated hemoglobin (Hb1Ac): 8.47%, and c-peptide levels: 0.1 ng/mL. Intraportal infusion of xenogeneic-free IS-AD-MSC from living donors, subjected to defined culture conditions and phenotypically differentiated to insulin-secreting cells, with mean quantum: 1.5 mL, expressing Pax-6, Isl-1, and pdx-1, cell counts: 2.1 × 103/μL, CD45−/90+/73+:40/30.1%, C-Peptide level:1.8 ng/mL, and insulin level: 339.3  IU/mL with CBM mean quantum: 96.3 mL and cell counts: 28.1 × 103/μL, CD45−/34+:0.62%, was carried out. Results. All were successfully transplanted without any untoward effect. Over mean followup of 23 months, they had a decreased mean exogenous insulin requirement to 0.63 units/kgBW/day, Hb1Ac to 7.39%, raised serum c-peptide levels to 0.38 ng/mL, and became free of diabetic ketoacidosis events with mean 2.5 Kg weight gain on normal vegetarian diet and physical activities. Conclusion. This is the first report of treating IDDM with insulin-secreting-AD-MSC+CBM safely and effectively with relatively simple techniques

Ahmedabad tolerance induction protocol and chronic renal allograft dysfunction: pathologic observations and clinical implications

<p>Abstract</p> <p>Background</p> <p>Chronic Renal Allograft Dysfunction (CRAD) is responsible for a large number of graft failures. We have abrogated acute T-cell rejections using Ahmedabad Tolerance Induction Protocol (ATIP) with hematopoietic stem cell transplantation (HSCT) under non-myeloablative conditioning pre-transplant. However B-cell mediated rejections and CRAD continue to haunt us. We carried out retrospective analysis of renal allograft biopsies performed in the last 4 years to evaluate the effect of ATIP on CRAD.</p> <p>Materials and methods</p> <p>Biopsies diagnosed as per modified Banff criteria belonged to 2 groups: ATIP under low dose immunosuppression of cyclosporine/Azathioprine/Mycofenolate mofetil+ Prednisolone, subjected to donor leucocyte transfusion, anti-T/B cell antibodies, low dose target specific irradiation, cyclophosphamide, cyclosporin followed by HSCT pre-transplant; controls who opted out of ATIP were transplanted under standard triple drug immunosuppression. Demographics of both groups were comparable.</p> <p>Results</p> <p>Incidence of chronic changes was higher in controls (17.5%) vs. 10.98% in ATIP over a mean follow up of 151.9 months in the former and 130.9 months in the latter. Proteinuria and hypertension were higher in controls (48.4%) vs. ATIP (32.7%) with chronic transplant glomerulopathy, focal global sclerosis in 67.7% in controls vs. 46.7% in ATIP, acute on chronic T/B cell rejection in 51.6% controls vs. 28.1% ATIP, with peritubular capillary C4d deposits in 19.4% controls vs. 1.9% ATIP biopsies. Acute on chronic calcineurin inhibitor toxicity was higher in ATIP (71.9%) vs. 48.4% in controls.</p> <p>Conclusion</p> <p>Chronic immune injury was less with ATIP vs controls as compared to a higher incidence of chronic calcineurin inhibitor toxicity in the former.</p

Renal Transplantation in Hepatitis C Positive Patients: A Single Centre Experience

Introduction. Hepatitis C virus (HCV) infection is an independent risk factor for renal transplantation (RTx). Immunosuppression minimization can render better quality of life to these patients. Methods. We analyzed 132 HCV-positive RTx patients (group A) transplanted under tolerance induction protocol (TIP) and compared them with 79 controls (group B) transplanted using standard triple drugs. TIP consisted of 1 donor-specific transfusion, peripheral blood stem cell infusion, portal infusion of bone marrow, and target-specific irradiation. Their immunosuppression was cyclosporin, 2 ± 1 mg/kg BW/day + prednisone, 10 mg/day. Results. TIP had no side effects. Although unequal in size, the groups were well balanced. Group A patient survival at 1, 5, and 10 years was 92.4%, 70.4%, and 63.7%, respectively, versus 75.6%, 71.7%, and 55.7% in later, and graft survival was 92.9%, 81.5%, and 79.1% versus 91.7%, 75.7%, and 67.7%, respectively. Mean serum creatinine (mg/dL) at these time periods in former was 1.38, 1.72, and 1.87, versus 1.3, 1.75, and 2.1 in later. Altered liver functions were noted in 22% patients in former versus 31% in later. Group A had lesser rejection episodes. Conclusion. RTx using TIP in HCV-positive patients is a viable option with acceptable outcome

Modifying cyclosporine associated renal allograft dysfunction

Transplantation is accepted therapy for chronic kidney disease. However the essential immuno-suppressive agents for graft survival have their own side-effects. Renal biopsy is a reliable tool for diagnosing cyclosporine (CsA) nephrotoxicity. To present our observations on CsA toxicity in renal allograft biopsies, we studied prospectively 207 renal allograft biopsies performed for graft dysfunction as per Ahmedabad Tole-rance Induction Protocol (ATIP) and compared them to 50 controls from January to October 2007. The ATIP comprised donor specific leucocyte infusions, low dose target specific irradiation; non-myeloablative condi-tioning with Anti-T &#177; B cell antibodies followed by intraportal administration of cultured donor bone marrow (BM) &#177; adipose tissue derived mesenchymal stem cells. Renal transplantation was performed following nega-tive lymphocytotoxicity cross-matching. The post-transplant immunosuppressive agents included CsA 2.5 &#177; 0.5 mg/kg BW/day and prednisone 0.2 mg/kg BW/day. The controls were transplanted using standard triple immunosuppressive agents including CsA 5 &#177; 1 mg/Kg BW/day, prednisone 0.6 mg/kg BW/day, and MMF/ Azathioprine. The Institutional Review Board approved the ATIP. The biopsies were categorized into 2 groups; group A (N=97): performed &lt; 6 months, group B (N= 160), &gt; 6 months posttransplant. Acute CsA toxicity was observed in group A: 2.5&#x0025; ATIP and 11.1&#x0025; controls; group B: 16.2&#x0025; ATIP and 8.8&#x0025; controls. Chronic CsA toxicity was observed in group B: 10.8 &#x0025; ATIP and 17.6 &#x0025; controls. Acute toxicity was more in the ATIP, while chronic toxicity was more in the controls. CsA doses were reduced post-biopsy and resulted in improved graft function evaluated by serum creatinine. We conclude that CsA nephrotoxicity evaluated by allograft biopsy resulted in allograft function recovery by decreasing the cyclosporine dose, and the ATIP decreased the incidence of CsA nephrotoxicity

Malaria induced acute renal failure: A single center experience

Malaria has protean clinical manifestations and renal complications, particularly acute renal failure that could be life threatening. To evaluate the incidence, clinical profile, out-come and predictors of mortality in patients with malarial acute renal failure, we retrospectively studied the last two years records of malaria induced acute renal failure in patients with peripheral smear positive for malarial parasites. One hundred (10.4&#x0025;) (63 males, 37 females) malaria induced acute renal failure amongst 958 cases of acute renal failure were evaluated. <i>Plasmodium (P). falciparum</i> was reported in 85&#x0025;, <i>P. vivax</i> in 2&#x0025;, and both in 13&#x0025; patients. The mean serum creatinine was 9.2 &#177; 4.2 mg&#x0025;, and oligo/anuria was present in 82&#x0025;; 78&#x0025; of the patients required hemodialysis. Sixty four percent of the patients recovered completely, 10&#x0025; incompletely, and 5&#x0025; developed chronic kidney failure; mortality occurred in 21&#x0025; of the patients. Low hemoglobin, oligo/anuria on admission, hyperbilirubinemia, cerebral malaria, disseminated intravascular coa-gulation, and high serum creatinine were the main predictors of mortality. We conclude that ma-laria is associated with acute renal failure, which occurs most commonly in plasmodium falci-parum infected patients. Early diagnosis and prompt dialysis with supportive management can reduce morality and enhance recovery of renal function