title: Dose-related effects of metformin on acid-base balance and renal function in patients with diabetes who develop acute renal failure: a cross-sectional study.
abstract: OBJECTIVE
  The role of metformin in the development of lactic acidosis (LA) in the setting of acute renal failure (ARF) is debated. Moreover, recent experiments suggested that metformin can also be nephrotoxic, but little clinical data exist about this topic. We sought to investigate these possible associations in a large cohort of patients with diabetes who developed ARF.
  
  
  METHODS
  We analyzed data from patients with diabetes admitted to our emergency department between 2007 and 2011 with ARF and a previously normal renal function (n = 126). We compared acid-base balance and renal function of patients taking metformin (n = 74) with patients not taking it (n = 52).
  
  
  RESULTS
  Patients taking metformin had decreased pH (7.31 ± 0.16 vs 7.39 ± 0.11, p = 0.008) and higher lactates (4.54 ± 4.30 vs 1.71 ± 1.14 mmol/L, p < 0.001). Both acidosis (pH < 7.35) and LA (lactates >5 mmol/L and pH < 7.35) were more frequently observed in this group (p = 0.0491 and p < 0.001, respectively). Multivariate analysis ruled out the role of some possible confounders, especially decreased renal function. The influence of metformin on pH and lactates grew significantly with higher doses of the drug (p = 0.259 and p = 0.092 for <1 g/day, p = 0.289 and p < 0.001 for 1-2 g/day, p = 0.009 and p < 0.001 for 2-3 g/day, for pH and lactates, respectively). Metformin influenced creatinine levels in a dose-related manner as well (p = 0.925 for <1 g/day, p = 0.033 for 1-2 g/day, p < 0.001 for 2-3 g/day).
  
  
  CONCLUSIONS
  In patients with diabetes who were admitted to our emergency department with ARF, the use of metformin was associated in a dose-related fashion with both LA and worse renal function.
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy. david.cucchiari@gmail.com.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-7594-1070
authors.initials: D
authors.lastname: Cucchiari
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Manuel Alfredo
authors.initials: MA
authors.lastname: Podestà
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merizzoli
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Albania
authors.initials: A
authors.lastname: Calvetta
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Morenghi
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Angelini
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ponticelli
authors.affiliation: Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Badalamenti
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000140:Acidosis, Lactic / Q000139:chemically induced*; D058186:Acute Kidney Injury / Q000150:complications*; D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D003920:Diabetes Mellitus / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Acute kidney injury; Diabetes; Lactic acidosis; Metformin; Mitochondrial dysfunction; Nephrotoxicity