Metformin in autosomal dominant polycystic kidney disease: experimental hypothesis or clinical fact?

Pisani, Antonio; Riccio, Eleonora; Bruzzese, Dario; Sabbatini, Massimo

doi:10.1186/s12882-018-1090-3

Cited by 27 publications

(20 citation statements)

References 23 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One retrospective, case-control study, which selected 7 diabetic ADPKD patients treated with Metformin and 7 matched non-diabetic ADPKD controls, evaluated the effect of Metformin on renal function progression during a 3 year follow-up. An overall crude loss of eGFR of – 0.9 ml/min/1.73m 2 estimated by a linear mixed model at 36 months was reported in the Metformin group [28]. Our ITT analysis was in line with these results, as we found a change in mean eGFR of – 1.57 ml/min/1.73 m 2 after 24 months of treatment.…”

Section: Discussionsupporting

confidence: 88%

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease

et al. 2019

View full text Add to dashboard Cite

Background Metformin has shown promising results regarding cystogenesis inhibition in preclinical studies with autosomal dominant polycystic kidney disease (ADPKD) models. We designed a prospective, preliminary, single-arm study to evaluate the tolerability, safety and the effect of Metformin on kidney function and body mass index (BMI) in Romanian patients with ADPKD. Methods We enrolled 34 adult patients with ADPKD, chronic kidney disease (CKD) stages 1–5 not on dialysis and without diabetes mellitus. The primary endpoint was to assess the tolerability and safety of Metformin. The secondary endpoints evaluated changes in estimated glomerular filtration rate (eGFR), body mass index (BMI) and renal replacement therapy (RRT) necessity. Patients received an initial dose of Metformin of 500 mg/day within the first month that was increased to 1000 mg/day thereafter according to tolerability. Change in eGFR and BMI was expressed as mean difference with the corresponding 95% confidence intervals and as a percentage. For the primary endpoint, we included all 34 enrolled patients. To assess the secondary endpoint, intention-to-treat (ITT) and per-protocol (PP) analysis was performed. Results Sixteen patients out of 34 completed the follow-up period at 24 months. Eighteen patients developed adverse events and 63.6% of these events were gastrointestinal related. Nausea was the most common adverse event (17.6%). Two patients (5.8%) permanently discontinued medication due to adverse events. We recorded no case of hypoglycemia, lactic acidosis or death. Mean eGFR changed by − 1.57 ml/min/1.73m 2 (95%CI:-22.28 to 19.14, P = 0.87) in ITT and by − 4.57 ml/min/1.73m 2 (95%CI:-28.03 to 18.89, P = 0.69) in PP population. Mean BMI change was − 1.10 kg/m 2 (95%CI:-3.22 to 1.02, P = 0.30) in ITT population and − 0.80 kg/m 2 (95%CI:-3.27 to 1.67, P = 0.51) in PP analysis. Three patients (8.8%) needed RRT. Conclusions Metformin was well tolerated, had a good safety profile even in ADPKD patients with advanced CKD and it was not associated with change in eGFR or BMI across the follow-up period. Trial registration The study was retrospectively registered on https://www.isrctn.com (number ISRCTN 93749377); date registered: 02/25/2019.

show abstract

Section: Discussionsupporting

confidence: 88%

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Similarly, we found that AMPK activation via Metformin had no effect on cell proliferation. Although Metformin was suggested to have beneficial effects on disease progression 27 , the effect of Metformin on cell proliferation and cyst growth has been brought into question by another recent study 28 . Additionally, differences in concentration or time frame of compound treatment could account for the lack of activity observed.…”

Section: Resultsmentioning

confidence: 99%

A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells

Asawa

Danchik

Zahkarov

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADpKD) is one of the most common inherited monogenic disorders, characterized by a progressive decline in kidney function due in part to the formation of fluid-filled cysts. While there is one FDA-approved therapy, it is associated with potential adverse effects, and all other clinical interventions are largely supportive. Insights into the cellular pathways underlying ADpKD have revealed striking similarities to cancer. Moreover, several drugs originally developed for cancer have shown to ameliorate cyst formation and disease progression in animal models of ADpKD. these observations prompted us to develop a high-throughput screening platform of cancer drugs in a quest to repurpose them for ADPKD. We screened ~8,000 compounds, including compounds with oncological annotations, as well as FDA-approved drugs, and identified 155 that reduced the viability of Pkd1-null mouse kidney cells with minimal effects on wild-type cells. We found that 109 of these compounds also reduced in vitro cyst growth of Pkd1-null cells cultured in a 3D matrix. Moreover, the result of the cyst assay identified therapeutically relevant compounds, including agents that interfere with tubulin dynamics and reduced cyst growth without affecting cell viability. Because it is known that several ADpKD therapies with promising outcomes in animal models failed to be translated to human disease, our platform also incorporated the evaluation of compounds in a panel of primary ADPKD and normal human kidney (NHK) epithelial cells. Although we observed differences in compound response amongst ADPKD and NHK cell preparation, we identified 18 compounds that preferentially affected the viability of most ADPKD cells with minimal effects on NHK cells. Our study identifies attractive candidates for future efficacy studies in advanced pre-clinical models of ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) has a prevalence of 1 in 500-1,000 individuals and is the most common inherited kidney disease, accounting for 6-9% of patients on renal replacement therapy. ADPKD is caused mainly by mutations in PKD1 and to a lesser extent in PKD2, GANAB and DNAJB11 genes. The disease is characterized by a progressive decline in kidney function due to the formation of fluid-filled cysts as well as activation of inflammatory and proliferative pathways, typically leading to end-stage renal disease by the fifth or sixth decade of life 1. Although cyst formation in the kidneys is the hallmark of ADPKD, other epithelial organs including the liver and pancreas are also commonly affected 2,3. With the 2018 FDA approval of Tolvaptan, a vasopressin V 2-receptor antagonist, there is now one therapy available to slow disease progression; however, the drug was only approved for patients at risk of rapid disease progression due to its potential side effects. Nevertheless, most interventions focus on alleviating disease-related symptoms.

show abstract

“…Metformin was first clinically used as a hypoglycemic agent (18,19). Subsequent studies demonstrated that metformin had different effects on various tissues and systems (29,30). Metformin was revealed to prevent the sevoflurane-induced apoptosis of neurons, which was reversed by a specific S1P1 antagonist (31).…”

Section: Discussionmentioning

confidence: 99%

Metformin protects against sevoflurane‑induced neuronal apoptosis through the S1P1 and ERK signaling pathways

Yue

Luo

et al. 2018

Exp Ther Med

View full text Add to dashboard Cite

The aim of the current study was to investigate whether metformin could counteract sevoflurane-induced neurotoxicity. In vitro experiments on the sevoflurane-induced nerve injury were performed using hippocampal neurons. Neuronal apoptosis was detected by an MTT assay. Protein expression levels of apoptosis-associated genes, including cleaved-caspase-3, apoptosis regulator BAX and apoptosis regulator Bcl-2 were detected by western blot analysis. The mechanism of the effect of metformin on sevoflurane-induced neuronal apoptosis was investigated using a sphingosine 1-phosphate receptor 1 (S1P1) antagonist (VPC23019) and mitogen-activated protein kinase kinase inhibitor (U0126). The current study revealed that metformin may reduce sevoflurane-induced neuronal apoptosis via activating mitogen-activated protein kinase (ERK)1/2 phosphorylation. VPC23019 and U0126 eliminated the neuroprotective effects of metformin on neuronal apoptosis, which suggests that metformin is able to protect against sevoflurane-induced neurotoxicity via activation of the S1P1-dependent ERK1/2 signaling pathway.

show abstract

Metformin in autosomal dominant polycystic kidney disease: experimental hypothesis or clinical fact?

Cited by 27 publications

References 23 publications

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease

A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells

Metformin protects against sevoflurane‑induced neuronal apoptosis through the S1P1 and ERK signaling pathways

Contact Info

Product

Resources

About