J. Clin. Med., Volume 4, Issue 6 (June 2015) – 11 articles , Pages 1171-1347

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. Full article

The objective of the study was to identify all parallel design randomised controlled trials (RCTs) comparing treatments for eczema in recent dermatology literature that have failed to report a between-group analysis. The GREAT database (www.greatdatabase.org.uk) was searched to identify parallel group RCTs comparing two or more interventions published in the English language in the last decade, 2004 to 2013. The primary outcome was the number of studies that had not reported a between-group analysis for any of the outcomes. Where possible we re-analysed the data to determine whether a between-group analysis would have given a different conclusion to that reported. Out of a total of 304 RCTs in the study period, 173 (56.9%) met the inclusion criteria. Of the 173 eligible studies, 12 (6.9%) had not conducted a between-group analysis for any of the reported outcomes. There was no clear improvement over time. Five of the eight studies that were re-analysed yielded non-significant between-group differences yet reported significant within-group comparisons. All but one of the 12 studies implied that the experimental intervention was successful despite not undertaking any between-group comparisons. Although the proportion of all RCTs that fail to report an appropriate between-group analysis is small, the fact that any scientist who purports to compare one treatment against another then chooses to omit the key comparison statistic is worrying. Full article

Diabetic nephropathy (DN) often develops in patients suffering from type 1 or type 2 diabetes mellitus. DN is characterized by renal injury resulting in proteinuria. Neuropilin-1 (NRP-1) is a single-pass transmembrane receptor protein devoid of enzymatic activity. Its large extracellular tail is structured in several domains, thereby allowing the molecule to interact with multiple ligands linking NRP-1 to different pathways through its signaling co-receptors. NRP-1’s role in nervous system development, immunity, and more recently in cancer, has been extensively investigated. Although its relation to regulation of apoptosis and cytoskeleton organization of glomerular vascular endothelial cells was reported, its function in diabetes mellitus and the development of DN is less clear. Several lines of evidence demonstrate a reduced NRP-1 expression in glycated-BSA cultured differentiated podocytes as well as in glomeruli from db/db mice (a model of type 2 Diabetes) and in diabetic patients diagnosed with DN. In vitro studies of podocytes implicated NRP-1 in the regulation of podocytes’ adhesion to extracellular matrix proteins, cytoskeleton reorganization, and apoptosis via not completely understood mechanisms. However, the exact role of NRP-1 during the onset of DN is not yet understood. This review intends to shed more light on NRP-1 and to present a link between NRP-1 and its signaling complexes in the development of DN. Full article

Background: Osteopontin (OPN) C-443T promoter polymorphism has been shown as a genetic risk factor for diabetic nephropathy (DN) in type 2 diabetic patients (T2D). Methods: In the present study we investigated the association of three functional promoter gene polymorphisms C-443T, delG-156G, and G-66T and their haplotypes with the risk of DN and estimated Glomerular Filtration Rate (eGFR) in Asian Indians T2D patients using Real time PCR based Taqman assay. A total of 1165 T2D patients, belonging to two independently ascertained Indian Asian cohorts, were genotyped for three OPN promoter polymorphisms C-443T (rs11730582), delG-156G (rs17524488) and G-66T (rs28357094). Results: -156G allele and GG genotypes (delG-156G) and haplotypes G-C-G and T-C-G (G-66T, C-443T, delG-156G) were associated with decreased risk of DN and higher eGFR. Haplotype G-T-delG and T-T-delG (G-66T, C-443T, delG-156G) were identified as risk haplotypes, as shown by lower eGFR. Conclusion: This is the first study to report an association of OPN promoter gene polymorphisms; G-66T and delG-156G and their haplotypes with DN in T2D. Our results suggest an association between OPN promoter gene polymorphisms and their haplotypes with DN. Full article

Diabetes mellitus is one of the most important causes of chronic kidney disease (CKD). In patients with advanced diabetic kidney disease, kidney transplantation (KT) with or without a pancreas transplant is the treatment of choice. We aimed to review current data regarding kidney and pancreas transplant options in patients with both type 1 and 2 diabetes and the outcomes of different treatment modalities. In general, pancreas transplantation is associated with long-term survival advantages despite an increased short-term morbidity and mortality risk. This applies to simultaneous pancreas kidney transplantation or pancreas after KT compared to KT alone (either living donor or deceased). Other factors as living donor availability, comorbidities, and expected waiting time have to be considered whens electing one transplant modality, rather than a clear benefit in survival of one strategy vs. others. In selected type 2 diabetic patients, data support cautious utilization of simultaneous pancreas kidney transplantation when a living kidney donor is not an option. Pancreas and kidney transplantation seems to be the treatment of choice for most type 1 diabetic and selected type 2 diabetic patients. Full article

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for adult patients with acute myeloid leukemia (AML), but its use for consolidation therapy after first remission with induction chemotherapy used to be limited to younger patients and those with suitable donors. The median age of AML diagnosis is in the late 60s. With the introduction of reduced-intensity conditioning (RIC), many older adults are now eligible to receive allo-HCT, including those who are medically less fit to receive myeloablative conditioning. Furthermore, AML patients commonly have no human leukocyte antigen (HLA)-identical or medically suitable sibling donor available to proceed with allo-HCT. Technical advances in donor matching, suppression of alloreactivity, and supportive care have made it possible to use alternative donors, such as unrelated umbilical cord blood (UCB) and partially HLA-matched related (haploidentical) donors. Outcomes after alternative donor allo-HCT are now approaching the outcomes observed for conventional allo-HCT with matched related and unrelated donors. Thus, with both UCB and haploidentical donors available, lack of donor should rarely be a limiting factor in offering an allo-HCT to adults with AML. Full article

Non-melanoma skin cancers represent a major cause of morbidity after organ transplantation. Squamous cell carcinomas (SCC) are the most common cutaneous malignancies seen in this population, with a 65–100 fold greater incidence in organ transplant recipients compared to the general population. In recent years, human papillomaviruses (HPV) of the beta genus have been implicated in the pathogenesis of post-transplant SCCs. The underlying mechanism of carcinogenesis has been attributed to the E6 and E7 proteins of HPV. Specific immunosuppressive medications, such as the calcineurin inhibitors and azathioprine, are associated with a higher incidence of post-transplant SCCs compared to other immunosuppressive agents. Compared to other immunosuppressives, mTOR inhibitors and mycophenolate mofetil have been associated with a decreased risk of developing post-transplant non-melanoma skin cancers. As a result, they may represent ideal immunosuppressive medications in organ transplant recipients. Treatment options for post-transplant SCCs include surgical excision, Mohs micrographic surgery, systemic retinoid therapy, adjunct topical therapy, electrodessication and curettage, and radiation therapy. This review will discuss the epidemiology, risk factors, and management options of post-transplant SCCs. In addition, the underlying mechanisms of beta-HPV mediated carcinogenesis will be discussed. Full article

Malassezia spp. is a genus of lipophilic yeasts and comprises the most common fungi on healthy human skin. Despite its role as a commensal on healthy human skin, Malassezia spp. is attributed a pathogenic role in atopic dermatitis. The mechanisms by which Malassezia spp. may contribute to the pathogenesis of atopic dermatitis are not fully understood. Here, we review the latest findings on the pathogenetic role of Malassezia spp. in atopic dermatitis (AD). For example, Malassezia spp. produces a variety of immunogenic proteins that elicit the production of specific IgE antibodies and may induce the release of pro-inflammatory cytokines. In addition, Malassezia spp. induces auto-reactive T cells that cross-react between fungal proteins and their human counterparts. These mechanisms contribute to skin inflammation in atopic dermatitis and therefore influence the course of this disorder. Finally, we discuss the possible benefit of an anti-Malassezia spp. treatment in patients with atopic dermatitis. Full article

Diabetes Mellitus (DM) is a growing worldwide epidemic. It was estimated that more than 366 million people would be affected. DM has spread its presence over the world due to lifestyle changes, increasing obesity and ethnicities, among others. Diabetic nephropathy (DN) is one of the most important DM complications. A changing concept has been introduced from the classical DN to diabetic chronic kidney disease (DCKD), taking into account that histological kidney lesions may vary from the nodular or diffuse glomerulosclerosis to tubulointerstitial and/or vascular lesions. Recent data showed how primary and secondary prevention were the key to reduce cardiovascular episodes and improve life expectancy in diabetic patients. A stabilization in the rate of end stage kidney disease has been observed in some countries, probably due to the increased awareness by primary care physicians about the prognostic importance of chronic kidney disease (CKD), better control of blood pressure and glycaemia and the implementation of protocols and clinical practice recommendations about the detection, prevention and treatment of CKD in a coordinated and multidisciplinary management of the DM patient. Early detection of DM and DCKD is crucial to reduce morbidity, mortality and the social and economic impact of DM burden in this population. Full article

The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and iPSC technology. IPSCs provide three potential ways of treating autoimmune disease; (i) providing pure replacement of lost cells (immuno-reconstitution); (ii) through immune-modulation of the disease process in vivo; and (iii) for the purposes of disease modeling in vitro. In this review, we will use examples of systemic, system-specific and organ-specific autoimmunity to explore the potential applications of iPSCs for treatment of autoimmune diseases and review the evidence of iPSC technology in auto-immunity to date. Full article

Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ET_A) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ET_A and ET_B) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described. Full article