Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.

Eur J Clin Invest 2012; 42 (6): 649–656 Background  Recent studies show associations between inorganic phosphate and risk of heart failure in the general population as well as between fibroblast growth factor 23 (FGF‐23) and outcome in coronary heart disease. This study was carried out to assess whether circulating levels of inorganic phosphate and FGF‐23, a new central hormone in mineral bone metabolism, predict outcome in systolic heart failure.Materials and methods  Ninety‐nine consecutive outpatients with systolic heart failure were enrolled. Mean (SD) age was 61 years (11), mean left ventricular ejection fraction (LVEF) was 33% (10), 82 patients were men, median estimated creatinine clearance was 83 mL/min (Q₁–Q₃ 58–106), median NTproBNP level was 803 pg/mL (Q₁–Q₃ 404–2757), median inorganic phosphate was 1·12 mM (Q₁–Q₃ 1·02–1·22), median FGF‐23 was 39·02 pg/mL (Q₁–Q₃ 32·45–55·86) and median follow‐up was 35 months. Associations between inorganic phosphate, FGF‐23 and endpoints were assessed using Cox regression analyses.Results  Inorganic phosphate and FGF‐23 levels were significantly higher (P < 0·001 and P = 0·009) in patients reaching the combined endpoint of cardiac hospitalization or death. FGF‐23 (ln) predicted all‐cause mortality (hazard ratio (HR) 5·042, P = 0·032) in a model adjusted for age, gender, estimated creatinine clearance, LVEF, New York Heart Association (NYHA) stage and NTproBNP level. Inorganic phosphate predicted heart failure hospitalization (HR 26·944, P = 0·021), cardiac hospitalization (HR 16·016, P = 0·017) and the combined endpoint (HR 13·294, P = 0·015) in models adjusted for the same co‐variables.Conclusion  The results of this study demonstrate the independent prognostic value of inorganic phosphate and FGF‐23 in heart failure even in the context of established risk markers.

The plasma soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker for focal segmental glomerulosclerosis (FSGS), but its value is under discussion because of ambiguous results arising from different ELISA methods in previous studies. The aim of this study was to compare diagnostic performance of two leading suPAR ELISA kits and examine four objectives in 146 subjects: (1) plasma suPAR levels according to glomerular disease (primary, secondary and recurrent FSGS after kidney transplantation, other glomerulonephritis) and in healthy controls; (2) suPAR levels based on glomerular filtration rate; (3) sensitivity and specificity of suPAR for FSGS diagnosis and determination of optimal cut-offs; (4) suPAR as prognostic tool. Patients with FSGS showed significant higher suPAR values than patients with other glomerulonephritis and healthy individuals. This applied to subjects with and without chronic kidney disease. Although both suPARnostic™ assay and Quantikine Human uPAR ELISA Kit exerted high sensitivity and specificity for FSGS diagnosis, their cut-off values of 4.644 ng/mL and 2.789 ng/mL were significantly different. Higher suPAR was furthermore predictive for progression to end-stage renal disease. In summary, suPAR values must be interpreted in the context of population and test methods used. Knowing test specific cut-offs makes suPAR a valuable biomarker for FSGS.