J. Clin. Med.2015, 4(7), 1348-1368; doi:10.3390/jcm4071348 - published 26 June 2015 Show/Hide Abstract
Abstract: Creatinine is produced in muscle metabolism as the end-product of creatine phosphate and is subsequently excreted principally by way of the kidneys, predominantly by glomerular filtration. Blood creatinine assays constitute the most common clinically relevant measure of renal function. The use of individual patient-level real-time serum creatinine trajectories provides a very attractive and tantalizing methodology in nephrology practice. Topics covered in this review include acute kidney injury (AKI) with its multifarious rainbow spectrum of renal outcomes; the stimulating vicissitudes of the diverse patterns of chronic kidney disease (CKD) to end-stage renal disease (ESRD) progression, including the syndrome of rapid onset end stage renal disease (SORO-ESRD); the syndrome of late onset renal failure from angiotensin blockade (LORFFAB); and post-operative AKI linked with the role of intra-operative hypotension in patients with diabetes mellitus and suspected diabetic nephropathy with CKD. We conclude that the study of individual patient-level serum creatinine trajectories, albeit a neglected and forgotten diagnostic methodology for diabetic CKD prognostication and prediction, is a most useful diagnostic tool, both in the short-term and in the long-term practice of nephrology. The analysis of serum creatinine trajectories, both in real time and retrospectively, indeed provides supplementary superior diagnostic and prognostic insights in the management of the nephrology patient.
J. Clin. Med.2015, 4(6), 1325-1347; doi:10.3390/jcm4061325 - published 18 June 2015 Show/Hide Abstract
Abstract: 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.
J. Clin. Med.2015, 4(6), 1312-1324; doi:10.3390/jcm4061312 - published 17 June 2015 Show/Hide Abstract
Abstract: 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.
J. Clin. Med.2015, 4(6), 1293-1311; doi:10.3390/jcm4061293 - published 17 June 2015 Show/Hide Abstract
Abstract: 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.
J. Clin. Med.2015, 4(6), 1281-1292; doi:10.3390/jcm4061281 - published 10 June 2015 Show/Hide Abstract
Abstract: 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.
J. Clin. Med.2015, 4(6), 1269-1280; doi:10.3390/jcm4061269 - published 9 June 2015 Show/Hide Abstract
Abstract: 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.