Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Abstract

Background and objectives Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy.Design, setting, participants, & measurements Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-a were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging.Results Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, . In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-a did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=20.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid-binding protein, whereas higher EGF excretion and TGF-a excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] mg/24 hours; P,0.001).1 ConclusionIn patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.

Parallel microarray profiling identifies ErbB4 as a determinant of cyst growth in ADPKD and a prognostic biomarker for disease progression

“…Pkd1 cystic kidneys and increased urinary HB-EGF has been detected in human ADPKD (10). Of interest, it was reported in the same study that treatment with the vasopressin V2 receptor antagonist (V2RA), tolvaptan, was associated with a significant increase in urinary HB-EGF (10).…”

The importance of total kidney volume in evaluating progression of polycystic kidney disease

“…Rapid cyst growth in utero could be caused, to some extent, by the high concentrations of growth factors that attend fetal development. Post-partum, cyst and kidney growth can be modified by growth factors, including epidermal growth factor 42 and insulin-like growth factor 43 , and by activators of adenylyl cyclase, such as arginine vasopressin, secretin, adenosine and adrenaline 8 . Of these, vasopressin has a powerful effect on the growth of cysts derived from the distal tubules and collecting ducts of patients 9 .…”

The epidermal growth factor receptor pathway in chronic kidney diseases

“…Interestingly, expression of HBEGF is also observed on the apical surface of cystic collecting tubules 78 . In human ADPKD, urinary HBEGF excre tion is increased and positively associated with disease severity, as assessed by measures of kidney function and total kidney volume 37 . These data support the hypothesis that HBEGF is produced abundantly in the kidneys of patients with ADPKD and can activate the apical EGFR by autocrine, paracrine or juxtacrine mechanisms to induce proliferation of tubular cells that express EGFR on the apical side and lead to cyst formation and growth.…”