Changes in tubular biomarkers with dietary intervention and metformin in patients with autosomal dominant polycystic kidney disease: a post-hoc analysis of two clinical trials

Abstract

Background: Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury.

Methods: 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m² who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression.

Results: Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m², and baseline BMI was 30.5 ± 5.9 kg/m². None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics.

Conclusions: Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.

Keywords: ADPKD; Biomarkers; Clinical; Diet; Epidemiology; Metformin.

Fig. 1

Urinary concentrations of kidney injury molecule-1 (KIM-1; Panel A); fatty-acid binding protein 4 (FABP4; Panel B); interleukin-18 (IL-18; Panel C); monocyte chemoattractant protein-1 (MCP-1; Panel D); neutrophil gelatinase-associated lipocalin (NGAL; Panel E); clusterin (Panel F); human cartilage glycoprotein-40 (YKL-40; Panel G), normalized to urine creatinine and log-transformed, at baseline (month 0, gold) and 12 months (dark gray). Groups are control, metformin, daily caloric restriction (DCR), and intermittent fasting (IMF). Horizontal lines represent median and individual data points are shown as circles