Diabetic nephropathy remains the most common cause of end-stage renal disease worldwide. The current standard of therapy for diabetic nephropathy involves stringent blood pressure control via blockade of the renin-angiotensin system and control of hyperglycemia. Despite these strategies, diabetic nephropathy is still seen to progress relentlessly. A pressing need for novel therapeutic agents has fueled endless basic science research projects and clinical trials in the quest for a more specific therapy. Throughout the process, only a handful of ancillary agents have shown experimental promise and even fewer have demonstrated an impact in human trials. This review article aims to summarize the available data from landmark studies for the main therapeutic approaches investigated.

Background:Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib.Methods: HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models.Results: Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5. 38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4. 25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions:In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202,

African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)-ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.

BackgroundCoronary artery calcified atherosclerotic plaque (CAC) predicts cardiovascular disease (CVD). Despite exposure to more severe conventional CVD risk factors, African Americans (AAs) are less likely to develop CAC, and when they do, have markedly lower levels than European Americans. Genetic factors likely contribute to the observed ethnic differences. To identify genes associated with CAC in AAs with type 2 diabetes (T2D), a genome-wide association study (GWAS) was performed using the Illumina 5 M chip in 691 African American-Diabetes Heart Study participants (AA-DHS), with replication in 205 Jackson Heart Study (JHS) participants with T2D. Genetic association tests were performed on the genotyped and 1000 Genomes-imputed markers separately for each study, and combined in a meta-analysis.ResultsSingle nucleotide polymorphisms (SNPs), rs11353135 (2q22.1), rs16879003 (6p22.3), rs5014012, rs58071836 and rs10244825 (all on chromosome 7), rs10918777 (9q31.2), rs13331874 (16p13.3) and rs4459623 (18q12.1) were associated with presence and/or quantity of CAC in the AA-DHS and JHS, with meta-analysis p-values ≤8.0 × 10−7. The strongest result in AA-DHS alone was rs6491315 in the 13q32.1 region (parameter estimate (SE) = −1.14 (0.20); p-value = 9.1 × 10−9). This GWAS peak replicated a previously reported AA-DHS CAC admixture signal (rs7492028, LOD score 2.8).ConclusionsGenetic association between SNPs on chromosomes 2, 6, 7, 9, 16 and 18 and CAC were detected in AAs with T2D from AA-DHS and replicated in the JHS. These data support a role for genetic variation on these chromosomes as contributors to CAC in AAs with T2D, as well as to variation in CAC between populations of African and European ancestry.Electronic supplementary materialThe online version of this article (10.1186/s12863-017-0572-9) contains supplementary material, which is available to authorized users.