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

Sickle cell nephropathy with diffuse proliferative lupus nephritis: a case report

<p/> <p>Background</p> <p>Sickle cell nephropathy (SCN) is an important cause of mortality in patients with sickle cell disease. SCA with systemic lupus erythematosus (SLE) is known in children and less common in adults, however diffuse proliferative lupus nephritis (DPLN) with SCN has rarely been reported in adults. It requires early diagnosis and aggressive management.</p> <p>Case presentation</p> <p>We present here a 35 years old lady with sickle cell disease who presented with edema, dyspnoea on exertion, pyuria and had raised s. creatinine of 7 mg%. Her biopsy revealed SCN with DPLN. She is on maintenance hemodialysis after 2 months of diagnosis.</p> <p>Conclusion</p> <p>DPLN with SCN is a rare entity with poor prognosis, which may be overlooked and needs aggressive management.</p

Pathology Associated with Hormones of Adrenal Cortex

Adrenal gland is an endocrine organ comprising of an outer cortex and inner medulla. These secrete various hormones that have a vital role in maintaining the normal homeostasis of the body. Lesions of adrenal cortex are quite common to encounter and most of these are related to the hormones secreted by three layers of adrenal cortex: the zona glomerulosa, the zona fasciculata, and the zona reticularis. Also it is very infrequent to encounter metastatic lesions in the adrenal glands too. So it is very important as a part of a clinician as well as a pathologist to know the pattern in which these hormones are secreted along with their physiological roles. Thus this chapter includes the disease that are related to excess as well as deficiencies of the hormones secreted by adrenal cortex. The chapter also includes various genetic syndromes that are associated with the disorders associated with hormones of adrenal cortex. The last part of the chapter includes a brief description of various benign as well as malignant lesions, the pathological as well as the etiological aspects and the hormonal abnormalities associated. This chapter thus mainly focuses on the pathology associated with the adrenal cortex and hormones secreted by the various layers of adrenal cortex

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

Urinary Tract Infection in Renal Allograft Recipents

Renal replacement therapy in the form of renal transplantation (RT) is the treatment of choice in these patients. Various factors influence the graft survival, infections being most common. Infections account for 16% of patient deaths and 7.7% of death censored graft failure in renal transplant patients. Urinary tract infection (UTI) is the most common infectious complication accounting for 45–72% of all infections. According to few studies UTI may have a negative impact over the long term survival of renal allograft. There are multiple factors that predispose these patients to UTI. Elderly age group, female gender, increased duration of catheterization and anatomical abnormalities of the urinary tract are most common predisposing factors. E. coli is the most frequently isolated organisms from the urine of these patients. We would proceed further with two cases which presented as UTI in post-transplant period. The first patient transplanted (living donor related) for diabetes induced end stage renal disease had developed UTI 4 years post-transplant. The other patient underwent deceased donor renal transplant for adult polycystic disease related chronic kidney disease, presented 2 years post-transplant with UTI

Mitochondrial Cytopathies of the Renal System

Mitochondria are major intracellular organelles with a variety of critical roles like adenosine triphosphate production, metabolic modulation, generation of reactive oxygen species, maintenance of intracellular calcium homeostasis, and the regulation of apoptosis. Mitochondria often undergo transformation in both physiological and pathological conditions. New concepts point that mitochondrial shape and structure are intimately linked with their function in the kidneys and diseases related to mitochondrial dysfunction have been identified. Diseases associated with mitochondrial dysfunction are termed as “mitochondrial cytopathies”. Evidence support that there is a role of mitochondrial dysfunction in the pathogenesis of two common pathways of end-stage kidney disease, namely, chronic kidney disease (CKD) and acute kidney injury (AKI). Mitochondrial cytopathies in kidneys mainly manifest as focal segmental glomerular sclerosis, tubular defects, and as cystic kidney diseases. The defects implicated are mutations in mtDNA and nDNA. The proximal tubular cells are relatively vulnerable to oxidative stress and are therefore apt to suffer from respiratory chain defects and manifest as either loss of electrolyte or low-molecular-weight proteins. Patients with mitochondrial tubulopathy are usually accompanied by myoclonic epilepsy and ragged red muscle fibers (MERRF), and Pearson’s, Kearns-Sayre, and Leigh syndromes. The majority of genetic mutations detected in these diseases are fragment deletions of mtDNA. Studies have shown significantly increased ROS production, upregulation of COX I and IV expressions, and inactivation of complex IV in peripheral blood mononuclear cells of patients with stage IV–V CKD, thereby demonstrating the close association between mitochondrial dysfunction and progression to CKD. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and lncRNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases

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

Late Plasma Cell Depletion After Thymoglobulin Induction in Kidney Transplant Recipients

Objectives: Induction therapy with rabbit antithymocyte globulin is frequently used in kidney transplant recipients and contributes to regulating the humoral alloantibody response. However, the effect of rabbit antithymocyte globulin on B-cell subpopulations, including plasma cells, has not been previously studied in humans in vivo. Materials and methods: We prospectively studied a cohort of 39 adult kidney transplant recipients. Twenty patients received rabbit antithymocyte globulin as induction therapy. Peripheral blood samples were obtained pretransplant and at 6 and 12 months posttransplant. T and B cells were acquired by flow cytometry. Results: Total lymphocytes and CD3 and CD4 cells significantly decreased at 6 and 12 months only in patients who received rabbit antithymocyte globulin. In contrast, the CD19 population did not change after rabbit antithymocyte globulin induction. One-year circulating plasma cells remained significantly lower than pretransplant levels in patients who received rabbit antithymocyte globulin. We observed sig-nificant differences in plasma cell numbers at 12 months after transplant between patients who received rabbit antithymocyte globulin and those patients who did not receive it (median of 5 and interquartile range of 3-17 vs median of 25 and interquartile range of 12-35; P = .001). Conclusions: Rabbit antithymocyte globulin induction leads to a late reduction in the number of circulating plasma cells at 1 year after kidney transplant. This effect can contribute to down-regulation of the humoral alloantibody response