ADPKD and metformin: from bench to bedside

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of end-stage renal disease in adults. In the last years, tolvaptan has been approved for the treatment of ADPKD patients in Europe, Canada, Japan, and recently in the USA as the first targeted therapy for this disease [1]. A very attractive strategy is the use of drugs with long-term clinical experience for other indications and a good safety profile such as metformin. Metformin activates the 5′ AMP-activated protein kinase (AMPK), which is a negative regulator of two central pathways in ADPKD mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), involved in the epithelial fluid secretion, and by the mammalian target of rapamycin (mTOR), involved in the cyst formation. Interestingly, metformin has been shown to inhibit cystogenesis in two mouse models and a zebrafish model of ADPKD [2, 3]. Furthermore, two phase 2 placebo-controlled trials have recently started to investigate the potential use of metformin in ADPKD [4]. We retrospectively collected the data of three sisters affected by ADPKD followed in our CKD Clinic from 2008 to 2018. The diagnosis of ADPKD was made on the basis of family history and of clinical criteria. Their brother was on replacement therapy with hemodialysis since he was 50 years old. Sister 1 was 47 years old with an eGFR at baseline of 68 ml/min/1.73 m2 according to the MDRD equation and no urine protein excretion. Sister 2 at baseline was 44 years old with an eGFR of 58 ml/min/1.73 m2 and urine protein of 0.42 g/day; Sister 3 at baseline was 39 years old with an eGFR of 66 ml/min/1.73 m2 and urine protein of 0.34 g/day. Data about htTKV were not available. Sister 1 developed diabetes mellitus in 2016, so metformin at the dosage of 1500 mg/day was prescribed with a satisfactory control of the diabetic disease, despite the poor compliance to the dietary restriction, associated with stable BMI (28 kg/ m2). We aimed to investigate the potential effect of metformin on eGFR. A linear model was used to determine the regression coefficients for the decrease of patients’ eGFR. Comparison between regression coefficients was first performed by analysis of variance (ANOVA), and then Tukey test was used as post hoc analysis. Differences between regression coefficients were considered statistically significant when p < 0.05. eGRF decline of sister 1 and 2 was significantly slower than sister 3 (p < 0.0001 and p = 0.001, respectively); no differences were found in renal disease progression between sister 1 and 2 (p = 0.1898). Moreover, eGFR decline of sister 1 after metformin introduction was about threefold slower than before the beginning of metformin treatment and this difference was statistically significant. This is the first record in the literature of the beneficial effect of metformin on ADPKD progression in the same family: during 10 years of follow-up, eGFR decreased in all the three sisters, but in Sister 1, it decreased slower after the introduction of metformin and without adverse event (Fig. 1). Our results confirm the beneficial effect of metformin in delaying the progression of renal dysfunction in ADPKD patients with moderately impaired eGFR [5].