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

Metformin is recommended as the first-line pharmacological agent for type 2 diabetes by international guidelines for its weight-neutrality and strong evidence-based cost-effectiveness in preventing diabetic vasculopathy [1, 2]. The spectrum of clinical application of metformin has continued to widen and presently include metabolic syndrome and polycystic ovarian syndrome [3, 4]. The most feared adverse effect of metformin use is lactic acidosis due to the historically reported mortality of approximately 50% during the period of 1960–2000 and about 25% since 2000 [5]. Although metformin-associated lactic acidosis (MALA) is rare, with a stable estimated incidence of 1 to 10 per 100,000 [6‐8], the stigma concern greatly limit the use of metformin in elderly populations where heart failure and renal impairment are common conditions [9].

The rarity and fatality of MALA make it difficult to obtain conclusive evidence regarding predisposing and prognostic factors as most studies performed to date have been retrospective single-center or registry-based ecological studies with small sample sizes and without blood metformin levels. Consequently, whether to discontinue metformin in patients with cardiac or renal dysfunction remains undetermined and a growing body of evidence demands a critical re-evaluation of contraindications for metformin [7]. More importantly, standard management of MALA is uncertain albeit renal replacement therapy (RRT) has been considered crucial in treating severe form of MALA for its ability to provide renal support, eliminate metformin, and optimize acid-base status [7]. The role of timing, dose, and mode of RRT in MALA is also unknown. To understand the current practice and trend of RRT in MALA, we systematically reviewed all case reports of MALA requiring RRT in the literature worldwide. As the selection of RRT mode is highly institutionalized and inherent spectrum bias in a single-center study, a systematic review of all case reports would be more informative to describe the RRT prescription pattern in MALA. We also evaluated the epidemiological and clinical prognostic factors that associate with mortality of MALA complicated by at least renal failure.

This systematic review suggests that the cumulative mortality of MALA with kidney failure in case reports or case series published between 1977 and 2014 with biochemical data available at individual level is 17.2%, which is much lower than previously documented high mortality rates to about 50% based on single center experience [18]. We also found serum lactate level is a significant predictor for MALA-related mortality with a positive linear relationship particularly at greater than 20 mmol/L. From a treatment planning perspective, renal replacement therapy (RRT) may play a critical role in reversing disturbances of lactic homeostasis but no single RRT modality shows superior performance than the other. Although our study contributes novel observations regarding MALA with kidney failure, the results need to be interpreted with caution due to publication bias, heterogeneity between studies, and moderate sample size.

The observed positive association between inappropriate dosing defined by conventional FDA serum creatinine criteria and mortality among MALA patients requiring RRT suggested the iatrogenic and preventable nature of MALA [12]. More interestingly, this association was inverted if the inappropriateness was defined by a recently proposed dosing recommendation (eGFR-dosing algorithm) [13]. Thus, the increasing sensitivity of alarming inappropriateness gained by applying the eGFR-dosing algorithm was of questionable clinical significance in the context of risk prevention. Furthermore, most cases with classification disagreement between the two different definitions were patients with CKD stage 3. This finding indirectly supports that a cautious expansion of metformin use in patients with CKD stage 3 or 4 may be appropriate and the optimal dosing requires more evidence to justify its long term efficacy and safety profile among CKD population [9]. The drastic decline of kidney function among patients with appropriate metformin dose with concomitantly higher metformin and lactate concentration implied the primary etiologies of AKI played an important role in the development of MALA.

The traditional target of metformin is inhibition of mitochondrial complex-1, which subsequently impair the efficiency of mitochondrial oxidative phosphorylation and Adenosine triphosphate (ATP) production [19]. Mechanistic studies have linked metformin to activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) or inhibition of cyclic AMP formation following the drop of cellular energy charge [20, 21]. A recent study demonstrated that metformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD) causing an increased cytosolic redox state (increased cytosolic NADH/NAD⁺ ratio) that hinder the conversion of lactate to pyruvate by lactate dehydrogenase [22]. When serum metformin level increases abnormally due to either ingestion of a large amount of metformin and/or to decreased kidney clearance of metformin, excessive production of lactate and proton will ensue.

Cumulating intracellular lactate is then transported into extracellular fluid (ECF) concomitantly with hydrogen 1:1 by proton-coupled monocarboxylate transporters (MCTs) [23]. To maintain acid-base homeostasis in ECF, proton reacts with bicarbonate to form water and carbon dioxide whereas lactate is metabolized by gluconeogenesis or oxidation after converting to pyruvate. Bicarbonate is then replenished by kidney via tubular reabsorption or net acid secretion [24, 25]. This homeostasis is energy dependent and driven by decreased NADH/NAD⁺ ratio at cytosol, which is highly vulnerable in the context of MALA featuring with energy failure and increased intracellular redox status. As a result, the rapidly accumulating extracellular lactate and proton will consume equivalent amounts of bicarbonate in ECF until the maximum tolerable lactate threshold, around 20 mmol/L (Fig. 4b), is reached. Beyond this intrinsic threshold, the export of intracellular lactate/proton is then severely limited, followed by irreversible cellular damage. However, among patients suffering from severe volume contraction and pre-existing metabolic alkalosis, the endogenous bicarbonate in ECF prior to the development MALA may raise this lactate threshold beyond 20 mmol/L [26]. To reverse the severe uncompensated acidosis, exogenous sodium bicarbonate infusion not only raises serum bicarbonate to neutralize proton acidity but also causes iatrogenic hypernatremia to create an extra “anion space” for excessive lactate in the price of systemic hyperosmolality (Fig. 4c). In this scenario, timely renal replacement therapy is the therapy of choice to remove excessive metformin and to correct intracellular acidosis while maintaining osmolar homeostasis as exemplified in a patient with MALA and an extremely high serum lactate level of 55 mmol/L successfully treated at our hospital (Additional file 1: Figure S4). This case highlighted the dynamics of how prescription of RRT was tailored to meet incredibly high metabolic demand.

Our findings are well consistent with a recent comprehensive review by Calello et al., in which a decision making algorithm for RRT in MALA was proposed [27]. The decision to initiate RRT is mainly triggered by serum lactate level and refractory severe acidosis. The proposed cut-off value of lactate, 20 mmol/L, coincides with our dose-response analysis indicating a linear increase in mortality, particularly at lactate concentrations greater than 20 mmol/L [27]. The role of serum lactate in metformin-related acidosis remains controversial from the diagnostic perspective as the elevation of lactate are usually induced from mutually reinforcing factors, for instance, predisposing impaired kidney function and resultant acidemia-related circulatory failure. But reversely, serum lactate could serve as a useful integrated marker to guide the initiation and adjustment of RRT. Compared to the general intensive care unit (ICU) population in which baseline serum lactate level is a reliable predictor of ICU mortality, the proposed lactate threshold for an increased mortality risk, 20 mmol/L, is much higher than the usual alarming lactate range of 2.0–4.0 mmol/L in patient’s lactemia mainly due to hypo-perfusion (e.g., sepsis and trauma) [28]. Such discrepancy may reflect the unique pathogenesis of MALA – cellular energy failure and impaired redox state [21, 22]. More than half of the study population had hypothermia on arrival at the care hospital. This provides indirect evidence of cellular energy failure, as thermogenesis driven by ATP turnover would be compromised in MALA [29]. In the era of practicing individualized medicine, the bottom-line is that the modality of RRT should match to the patient’s hemodynamic stability and the dosing of RRT has to properly correct acidosis and avoid iatrogenic hypernatremia, and should be adjusted to meet patient’s metabolic demand (exemplified in Additional file 1: Figure S4). To address this current knowledge gap regarding the RRT prescription in MALA patients with severe acute kidney injury (e.g., Acute Kidney Injury Network (AKIN) stage 3) [16], an international consortium is needed to prospectively enroll patients worldwide using a standardized case report form to record detailed information about the metformin toxicokinetics and the three domains of RRT including mode, dose, and timing.

There were several interesting but unexpected findings in this study. First, a higher peak level of serum creatinine was associated with favorable survival. Indeed, apparent renal failure may help clinicians generate a high index of suspicion for MALA with appropriate evaluation resulting in earlier diagnosis and expedient delivery of RRT. On the other hand, patients with higher serum creatinine level at the initial presentation may also have a relatively indolent disease course rather than an acute episode of fulminant metabolic acidosis and circulatory collapse. However, our data was not sufficient to determine whether the timing of RRT was early or late as it is difficult, if not impossible, to define the onset of MALA. Second, female patients had a better survival than male patients. Although it is likely that the efficiency of RRT may be better among female patients due to smaller body size, the information of body mass index (BMI) was rarely available in the published reports. Future prospective research is warranted to clarify the sex difference or the effect of BMI.

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. There is no differential survival advantage among RRT modalities and significant knowledge gaps remain regarding the optimal timing, mode, and dose of RRT. Standardization of MALA case report form would be the fundamental step toward guideline development.