Renin–angiotensin–aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

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.

Significant deviations of serum potassium and sodium levels are frequently observed in hospitalized patients and are both associated with increased all‐cause and cardiovascular mortality. The presence of acute or chronic renal failure facilitates the pathogenesis and complicates the clinical management. In the absence of reliable outcome data in the context of dialysis prescription, requirement of renal replacement therapy in patients with severe electrolyte disturbances constitutes a therapeutic challenge. Recommendations for intradialytic management are based on pathophysiologic reasoning and clinical observations only, and as such, heterogeneous and limited to expert opinion level. This article reviews current strategies for the management of severe hyperkalemia and hyponatremia in hemodialysis patients.

Background: Arteriovenous (AV) fistulas are considered the gold standard for ensuring safe and long-term vascular access in patients with haemodialysis-dependent end-stage renal disease. However, previous studies demonstrated that high-flow AV fistulas might add additional cardiovascular burden in the post-transplant setting, leading to frequent fistula closure in this population. Currently, there is no consensus regarding management of high-flow fistulas in post-transplant patients with stable kidney function. The present randomized controlled trial examines the effect of prophylactic AV fistula closure on high-output heart failure. Methods: Twenty-eight kidney transplant patients with stable graft function, absence of pre-existing severe cardiac failure, and brachial arterial flow rate of at least 1,500 mL/min were recruited and randomized in a 1:1 ratio to an intervention and control group, respectively. The intervention group was subject to immediate fistula ligature. Patients within the control group were referred to fistula ligature only if the main study endpoint high-output heart failure was reached. The latter was defined by the presence of at least 1 clinical sign (i.e., worsening NYHA score) and at least 2 of the following echocardiographic parameters: diameter of right atrium (major) >53 mm, right atrium (minor) >44 mm, inferior vena cava ≥21 mm, right pulmonary artery >20 mm, TAPSE 40 mm Hg, and/or left ventricular eccentricity index <1. During a 24-month follow-up period, quarterly measurements of kidney function, NT-proBNP, and lactate dehydrogenase as well as a biannual echocardiographic check-up were performed. Results: High-output heart failure attributable to high-flow fistula was reported in 5 of 13 control patients (38.5%), whereas no patient in the intervention group presented with clinical and echocardiographic signs of high-output heart failure during the follow-up period. Thus, prophylactic ligature of high-flow fistulas avoided high-output heart failure in our patient population (p = 0.013). Three patients in the control group, however, had to undergo fistula ligature due to aneurysm formation (n = 2) and steal phenomenon (n = 1). Median NT-proBNP levels decreased from 317 ng/L pre-ligature to 223 ng/L post-ligature (p = 0.003). Serum creatinine levels did not significantly differ before and after AV fistula ligature (1.69 vs. 1.60 mg/dL, respectively, p = 0.059). Improvement of echocardiographic findings (e.g., a decrease in systolic pulmonary arterial pressure) was found in 7 of 8 ligature patients but did not reach statistical significance. Conclusion: Prophylactic ligature of high-flow AV fistulas after kidney transplantation can avoid high-output heart failure, and a more liberal approach to close AV fistulas might be justified.

Sarkozi R, Hauser C, Noppert SJ, Kronbichler A, Pirklbauer M, Haller VM, Grillari J, Grillari-Voglauer R, Mayer G, Schramek H. Oncostatin M is a novel inhibitor of TGF-beta 1-induced matricellular protein expression. Am J Physiol Renal Physiol 301: F1014-F1025, 2011. First published August 3, 2011; doi:10.1152/ajprenal.00123.2011.-Matricellular proteins in the kidney have been associated with the development of tubulointerstitial fibrogenesis and the progression of renal disease. This study investigated potential antifibrotic effects of the cytokine oncostatin M (OSM) in human proximal tubule cells (PTC), particularly with regard to inhibition of profibrotic events initiated by TGF-beta 1. In human PTC, OSM diminished transforming growth factor (TGF)-beta 1-induced expression of the transcriptional epithelial-mesenchymal transition mediator FoxC2. Furthermore, exposure to OSM attenuated basal and TGF-beta 1-induced expression of the matricellular proteins SPARC, TSP-1, TNC, and CTGF regardless of the sequence of ligand administration. OSM was shown to result in rapid and sustained phosphorylation of both Stat1 and Stat3 and also in transient phosphorylation of Smad2/3 in contrast to TGF-beta 1, which demonstrated a gradually building phosphorylation of Smad2/3 and a brief phosphorylation of Smad1/5/8. Utilizing receptor-blocking molecules, we found the inhibitory effect of OSM on TGF-beta 1-induced CTGF mRNA expression occurs independently of Smad2/3 signaling and present evidence that this effect may be partially driven by OSM receptor-mediated Stat1 and/or Stat3 signaling pathways, thereby providing a mechanism whereby OSM can contribute to tubulointerstitial protection.