Autori: Enrica Cascone, Angela Maria Pellegrino, Luigi Annicchiarico Petruzzelli, Fortunato Petrillo, Maria Amicone, Cristina Marchetiello, Eleonora Riccio, Antonio Pisani
Affiliazioni: Chair of Nephrology, Department of Public Health, University Federico II of Naples, Naples, Italy
INTRODUCTION. Autosomal dominant polycystic kidney disease (ADPKD) accounts for 8–10% of end-stage chronic kidney disease (CKD) patients worldwide. In the last decade, the advanced knowledge in genetics and molecular pathobiology of ADPKD focused some aberrant molecular pathways involved in the pathogenesis of the disease leading to controlled clinical trials aimed to delay its progression with the use of mTOR inhibitors , somatostatin or tolvaptan, which, to date, is the only approved drug for ADPKD treatment. Recently, preclinical studies have suggested that metformin, worldwide used in type 2 diabetes,could play some role in treatment of ADPKD by activating the metabolic sensor AMP-activated protein kinase (AMPK). Activated AMPK inhibits the cystic fibrosis trans-membrane conductance regulator (CFTR), which suppresses the secretion of fluid and electrolytes into renal cysts, a critical process for their expansion. Moreover, AMPK also phosphorylates tuberin, an indirect inhibitor of the mTOR pathway, which regulates tubular cell turnover and whose abnormal activation leads to proliferation of tubular cystic cells and to apoptosis of normal tubular cells. Therefore, AMPK hinders two important pathways involved in ADPKD progression: this strongly suggests that its activation by metformin could represent a therapeutic tool in renal cystic diseases.
METHODS. We have retrospectively examined the records of all ADPKD patients in regular follow-up at our CKD Clinic, to select diabetic ADPKD patients under metformin treatment. To evaluate any possible effect of metformin on ADPKD progression, we compared the modification of kidney function in the last 3 years of the selected diabetic patients (n=7, Metformin Group) to a Control Group of 7 ADPKD non-diabetic patients matched for sex, age, and basal eGFR (Table 1).
RESULTS. During the first year of observation, retrospective data showed that the GFR decreased by 2.5% in the Metformin Group and by 16% in Control patients. Thereafter, renal function remained quite stable in Metformin Group and further decreased in Control Group, reaching a 50% difference in GFR decline rate between Groups from the first to the third year of observation; accordingly, the overall crude loss of GFR, resulted slower in the Metformin than in Control Group (-0.9; 95% C.I.: -2.7 to 0.9 vs – 5.0; 95% C.I.: -6.8 to -3.2 mL/min/1.73 m2 per year, p=0.002), (Picture1).
DISCUSSION. This is the first report that suggests a potential beneficial effect of metformin in delaying the progression of renal dysfunction in ADPKD patients with moderately impaired GFR. The results of this preliminary observation deserve attention for several reasons. First, the rate of GFR decline was extremely reduced in Metformin patients compared to controls, with an annual slope of decrease even lower than those reported in previous controlled trials. Second, GFR remained quite stable throughout the observation period, indicating a sustained effect with time. Third, metformin had an enviable safety profile, with no serious side effect in the setting of ADPKD. Last, despite our Metformin patient had diabetes as further comorbidity their GFR was better preserved than in non-diabetic controls.
CONCLUSION. This preliminary observation suggests that metformin could represent an option for long-term treatment of ADKPD and strengthen the need for a large enrollment of patients into the ongoing trials to confirm the beneficial effect of such drug.
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