Urinary Epidermal Growth Factors and Decline in Kidney Function in ADPKD

As patients with autosomal dominant polycystic kidney disease (ADPKD) age, renal cysts develop and grow, gradually replacing health kidney tissue, resulting in impaired kidney function. Gaining a clear understanding of the molecular pathways underlying formation of cysts may result in the development of novel therapeutic interventions and biomarkers to predict disease progression in patients with ADPKD.

A pathway of particular interest is the one mediated by the epidermal growth factor receptor (EGFR) family. Laura R. Harskamp, MD, and colleagues conducted a study to test the hypothesis that there is an association between urinary EGFR ligands, as a reflection of EGFR activity, and decline in kidney function in patients with ADPKD, and, as the disease progresses, an indication of insufficient repair. Results of the study were reported in Nephrology Dialysis Transplantation [doi.org/10.1093/ndt/gfad050].

Activation of the EGFR pathway was measured via analysis of urinary excretion of two ligands of the EGFR family (EGF and heparin-binding EGF-like growth factor [HB-EGF]) and by expression of three receptors of the EGFR family (the EGFR [ErbB1/HER1], ErbB2 [HER2/neu], and ErbB4 [HER4]).

The study population included patients who participated in the DIPKA-1 (Developing Intervention Strategies to Halt Progression of Autosomal Dominant Polycystic Disease) trial. In DIPKA-1, patients were randomized to receive the somatostatin analogue lanreotide in addition to standard of care or standard of care alone. The primary outcome of interest was the change in slope of estimated glomerular filtration rate (eGFR) during a treatment period of 2.5 years.

The overall cohort in the current study included 301 patients with ADPKD who were age- and sex-matched with 72 healthy controls. The two groups were similar in baseline characteristics, with the exception of blood pressure: those in the patient group had higher systolic and diastolic blood pressure and were more likely to use blood-pressure-lowering medication, compared with the control group. Patients were also more likely to have lower baseline eGFR (51.7 mL/min/1.73 m² vs 94.5 mL/min/1.73 m²).

In the group with ADPKD, excretion of urinary EGF was lower compared with healthy controls (18.6 µg/24 hours vs 51.0 µg/24 hours; P<.0010). The groups were similar in urinary HB-EGF excretion (176 ng/24 hours vs 170 ng/24 hours; P=.64). Following correction of urinary excretion of those markers for creatinine excretion, results were essentially similar (EGF 1.4 µg/mmol vs 3.8 µg/mmol, respectively, P<.001; and HB-EGF 14.1 ng/mmol vs 13.9 ng/mmol, respectively, P=.87).

Among the subset of patients selected from the DIPAK Biobank for renal tissue (n=19), mean age was 49.8 years. Due to the advanced stage of disease among those patients, mean eGFR was 9.5 mL/min/1.73 m², and total kidney weight was 2704 grams.

At baseline, the researchers examined associations between excretion of urinary EGF and markers of disease severity in the patients with ADPKD. There was a positive association between urinary EGF excretion and eGFR (R=0.54; P<.001). Following adjustment for age, sex, height-adjusted total kidney volume (htTKV), PKD mutation, and urinary biomarkers (b2MG, HFABP, and MCP-1), the association between EGF and eGFR remained significant (R=0.49; P<.001). Opposite findings were observed for HB-EGF.

Urinary HB-EGF was higher with more severe disease (R=–.016; P=.007). After adjusting for age, sex, htTKV, and PKD mutation, the association remained significant (R=–.014; P=.02). In the final model that added urinary damage biomarkers, the association disappeared (R=–0.001; P=.99).

There were no associations between urinary EGF and HB-EGF and htTKV in the ADPKD patient cohort in either unadjusted or adjusted models.

The study also examined possible associations between urinary concentrations of the EGFR ligands with decline in kidney function and TKV growth in the patients with ADPKD in the group receiving standard of care (n=149). During mean follow-up of 2.4 years, on average 15 eGFR values were obtained per patient, resulting in an annual rate of decline in eGFR of –3.85 mL/min/1.73 m². There was a significant association between higher baseline urinary EGF excretion and less decline in kidney function (b=1.08; P<.001).

Analyses assessing whether the association was influenced by patient characteristics such as age, sex, body mass index, blood pressure, eGFR, htTKV, urine volume, and urinary damage biomarkers did not find any influence of those factors. The use of  renin-angiotensin-aldosterone system inhibitors had no impact on the level of urinary EGF excretion or any interaction with urinary EGF excretion for the outcome of decline in eGFR. There was no association between urinary EGF and percentage change in TKV during the study period.

The potential effect of unilateral nephrectomy on urinary EGF excretion was assessed in 72 healthy kidney donor controls by comparing measurements prior to and following kidney donation. On average, there were 5.5 months between those visits. Unilateral nephrectomy resulted in a decrease of 46.4% in urinary EGF excretion, and a decrease of 35.2% in eGFR and 36.8% in measured GFR (all P<.0001). Removing one kidney resulted in a decrease in urinary EGF from 51.0 µg/24 hours predonation to 26.3 µg/24 hours postdonation, a change of –46.4% (P<.0001).

The researchers cited some limitations to the study findings, including the small number of participants who were randomized to standard of care, the short follow-up period of 2.5 years, the lack of data on plasma levels of EGF and HB-EGF, and examining only the associations between EGFR ligands and ADPKD progression.

In conclusion, the authors said, “Our study shows that lower urinary EGF excretion is strongly associated with more severe disease at baseline, and with more rapid eGFR loss during follow-up. These data indicate that lower urinary EGF excretion may be a valuable biomarker to predict future kidney function decline in patients with ADPKD. We argue that lower urinary EGF excretion indicates that there is a less functional tubular mass and less regenerative capacity for repair.”

Takeaway Points

1. Researchers reported results of a study testing the hypothesis that urinary epidermal growth factor receptor (EGFR) ligands are associated with decline in kidney function in patients with autosomal dominant polycystic kidney disease.
2. At baseline, there was a positive association between baseline urinary EGF, and a lower EGF was strongly associated with a more rapid decline in glomerular filtration rate (GFR).
3. There was no association between heparin-binding EGF-like growth factor and a more rapid decline in GFR.

Source: Nephrology Dialysis Transplantation