Aims/hypothesis
The sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of ...the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD).
Methods
A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride.
Results
Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%;
p
< 0.001), IL-6 (26.6%;
p
= 0.010), matrix metalloproteinase 7 (MMP7; 24.9%;
p
= 0.011) and fibronectin 1 (FN1; 14.9%;
p
= 0.055) during 2 years of follow-up.
Conclusions/interpretation
The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis.
Trial registration ClinicalTrials.gov NCT00968812
In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular ...pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.
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The aim of this study was to investigate 28-day mortality after COVID-19 diagnosis in the European kidney replacement therapy population. In addition, we determined the role of patient ...characteristics, treatment factors, and country on mortality risk with the use of ERA-EDTA Registry data on patients receiving kidney replacement therapy in Europe from February 1, 2020, to April 30, 2020. Additional data on all patients with a diagnosis of COVID-19 were collected from 7 European countries encompassing 4298 patients. COVID-19–attributable mortality was calculated using propensity score–matched historic control data and after 28 days of follow-up was 20.0% (95% confidence interval 18.7%–21.4%) in 3285 patients receiving dialysis and 19.9% (17.5%–22.5%) in 1013 recipients of a transplant. We identified differences in COVID-19 mortality across countries, and an increased mortality risk in older patients receiving kidney replacement therapy and male patients receiving dialysis. In recipients of kidney transplants ≥75 years of age, 44.3% (35.7%–53.9%) did not survive COVID-19. Mortality risk was 1.28 (1.02–1.60) times higher in transplant recipients compared with matched dialysis patients. Thus, the pandemic has had a substantial effect on mortality in patients receiving kidney replacement therapy, a highly vulnerable population due to underlying chronic kidney disease and a high prevalence of multimorbidity.
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In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the ...contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRNAs, tRNA fragments (tRFs), mitochondrial tRNAs, or lincRNAs. For their computational identification from RNA-seq data, we developed a novel computational pipeline, designated as ncRNASeqScan. By these analyses, in CKD patients we identified 30 differentially expressed ncRNAs, derived from urinary exosomes, as suitable biomarkers for early diagnosis. Thereby, miRNA-181a appeared as the most robust and stable potential biomarker, being significantly decreased by about 200-fold in exosomes of CKD patients compared to healthy controls. Using a cell culture system for CKD indicated that urinary exosomes might indeed originate from renal proximal tubular epithelial cells.
PurposePatients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright ...position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure.MethodsAs a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension.ResultsIn patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management.ConclusionsThe establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.
Large clinical trials demonstrated that SGLT2 inhibitors (SGLT2i) slow the progression of kidney function decline in type 2 diabetes. Because the underlying molecular mechanisms are largely unknown, ...we studied the effects of SGLT2i on gene expression in two human proximal tubular (PT) cell lines under normoglycemic conditions, utilizing two SGLT2i, namely empagliflocin and canagliflocin. Genome-wide expression analysis did not reveal substantial differences between these two SGLT2i. Microarray hybridization analysis identified 94 genes that were both upregulated by TGF-β1 and downregulated by either of the two SGLT2i in HK-2 and RPTEC/TERT1 (renal proximal tubular epithelial cells/telomerase reverse transcriptase 1) cells. Extracellular matrix organization showed the highest significance in pathway enrichment analysis. Differential gene expression of three annotated genes of interest within this pathway was verified on mRNA level in both cell lines. Whereas TGF-β1 induced mRNA expression of thrombospondin 1 (THBS1; 4.3-fold), tenascin C (TNC; 8-fold), and platelet-derived growth factor subunit B (PDGF-B; 4.2-fold), SGLT2i downregulated basal mRNA expression of THBS1 (0.2-fold), TNC (0.5 fold), and PDGF-B (0.6-fold). Administration of SGLT2i in the presence of TGF-β1 resulted in a significant inhibition of TGF-β1-induced THBS1 and TNC mRNA expression and TGF-β1-induced THBS1, TNC, and PDGF-BB protein expression. We conclude that SGLT2i block basal and TGF-β1-induced expression of key mediators of renal fibrosis and kidney disease progression in two independent human PT cell lines.
SGLT2 inhibitor-related nephroprotection is—at least partially—mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic ...cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i.
Adult primary focal segmental glomerulosclerosis (FSGS) remains a therapeutic challenge for the treating physician. With the advent of novel immunosuppressive measures, our arsenal of therapeutic ...options increased considerably. The aim of this review was to summarize reports published over the last two decades which reported on treatment outcome. Most reports included patients with a steroid-resistant (SR) disease course, yet the cohort with the highest unmet need, since persistent nephrotic range proteinuria is associated with a poor renal prognosis and portends a high risk of developing end-stage renal disease. While in first-line treatment, steroid treatment remains the recommended standard with an overall remission rate of 50% and higher, optimal treatment strategies for steroid-dependent/multirelapsing (SD/MR) and SR patients have to be defined. In both entities, calcineurin inhibitors showed good efficacy, while mycophenolate mofetil was less effective in SR cases compared to those with SD/MR. The same was true for rituximab, a monoclonal antibody targeting B-cells. In resistant cases, addition of extracorporeal treatment options or treatment with alkylating agents may be considered. To shape the future for treatment of FSGS, international collaborations to conduct larger clinical trials are needed to identify potential novel efficacious immunosuppressive or immunomodulatory therapies.
SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential ...gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1β as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1β (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (
= 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1β upregulated basal MCP-1/CCL2 (15- and 19-fold) and ET-1 (3- and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6- and 0.5-fold) and ET-1 (0.3- and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1β-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1β-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection.
Type II diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes mellitus cases in the world. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased ...capability to target directly or indirectly six core defects associated with T2DM, while the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients. Urine samples of thirty-two T2DM patients from the PROVALID study (“A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers”) collected pre- and post-treatment with GLP-1R agonist drugs were analyzed by CE-MS. In total, 70 urinary peptides were significantly affected by GLP-1R agonist treatment, generated from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides, was highlighted. Treatment also resulted in the downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR, and TTR, many of which were previously found to be associated with increased insulin resistance and inflammation. The findings indicate potential molecular mechanisms of GLP-1R agonists in the context of the management of T2DM and the prevention or delaying of the progression of its associated diseases.
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