Serum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series

Abstract

Background: The current practice concerning timing, mode, and dose of renal replacement therapy (RRT) in patients with metformin-associated lactic acidosis (MALA) with renal failure remains unknown. To investigate whether serum lactate level and prescription pattern of RRT are associated with mortality in patients with MALA requiring RRT.

Methods: We searched PubMed/Medline and EMBASE from inception to Sep 2014 and applied predetermined exclusion criteria. Case-level data including case's demographics and clinical information related to MALA were abstracted. Multiple logistic regression modeling was used to examine the predictors of mortality.

Results: A total of 253 unique cases were identified with cumulative mortality of 17.2%. Eighty-seven percent of patients had acute kidney injury. Serum lactate level was significantly higher in non-survivors (median 22.5 mmol/L) than in survivors (17.0 mmol/L, p-value <0.01) and so did the median blood metformin concentrations (58.5 vs. 43.9 mg/L, p-value = 0.05). The survival advantage was not significantly different between the modalities of RRT. The adjusted odds ratio of mortality for every one mmol/L increase in serum lactate level was 1.09 (95% CI 1.02-1.17, p-value = 0.01). The dose-response curve indicated a lactate threshold greater than 20 mmol/L was significantly associated with mortality.

Conclusions: Our study suggests that predialysis level of serum lactate level is an important marker of mortality in MALA patients requiring RRT with a linear dose-response relationship. To better evaluate the optimal prescription of RRT in MALA, we recommend fostering an international consortium to support prospective research and large-scale standardized case collection.

Keywords: Acute kidney injury; Lactate; Metabolic acidosis; Metformin; Renal replacement therapy.

Fig. 1

The distribution of modality of renal replacement therapy (RRT) of the enrolled cases published from 1974 to 2000 and from 2001 to 2014 by survival status. Abbreviations: CRRT, continuous renal replacement therapy; IRRT, intermittent renal replacement therapy; PD, peritoneal dialysis; PIRRT, prolonged intermittent renal replacement therapy; RRT, renal replacement therapy

Fig. 2

Levels of serum metformin are plotted versus the serum lactate levels (a) and the estimated metformin dosage (b). There are significant positive correlation between serum metformin and lactate levels and between serum metformin levels and the estimated metformin dosage

Fig. 3

Odds ratio for metformin-associated lactic acidosis (MALA) mortality by serum lactate level in this systematic review. Solid lines represent adjusted odds ratios based on restricted quadratic splines for the serum lactate level, with knots at the 10th, 50th, and 90th percentiles. The shaded green region represent upper and lower 95% CIs. The reference value was set at 10th percentile. Adjustment factors were the same as those in Table 3. The bars represent a histogram of serum lactate distribution among enrolled cases (the extreme tails of the histogram were truncated)

Fig. 4

The extracellular ionic compositional progression by Gamblegrams from our MALA case (The detailed information of the case was described in the Additional file 1: Figure S4). a normal physiology composition of major ions in extracellular fluid (ECF). b A 50-year-old woman case initially presented with severe lactic acidosis a few hours after suicidal metformin ingestion. Intracellular lactate was transported along with equivalent amount of protons into ECF via monocarboxylate transporters. Excess ECF protons were then buffered by bicarbonate and turned into H₂O and CO₂. Consequently, the increased amounts of lactate were approximately equivalent to the decreased consumption of bicarbonate. However, the failing kidney function could not replenish the consumed bicarbonate through renal ammoniagenesis or enhanced reabsorption, leading to increasingly severe acidosis. c To reverse acidosis, 622.5 mmol of sodium bicarbonate was infused to neutralize protons moving out of the cell to ECF, along with lactate. The iatrogenic hypernatremia to 168 mmol/L created an extra anion space that allowed more lactate to move from intracellular fluid to ECF, resulting in more significant hyperlactatemia