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

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lactic acidosis 13 endocrinologydiseases
metabolic syndrome 1 endocrinologydiseases
metformin 66 endocrinologydiseasesdrugs

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metformin 58 Title: BMC NephrologySerum lactate level and mortality in metformin -associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports
metformin 473 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
metformin 1309 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
metformin 2549 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],
metformin 2701 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
metformin 2872 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
metformin 3039 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
metformin 3418 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
metformin 3473 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
metformin 3639 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)
metformin 3866 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.
metformin 4793 Meta-Analyses (PRISMA) Statement criteria [[10]]. We searched PubMed/Medline and EMBASE for case reports of metformin -associated lactic acidosis (MALA) requiring renal replacement therapy by combining three key research
metformin 5021 from relevant MeSH and text-word terms such as “renal replacement therapy”, “dialysis”, “ metformin ”, and “lactic acidosis”. Additional file 1: Table S1 showed the full search strategy. The search
metformin 5469 series, editorials, and research letters that did not provide individual biochemical data; 2) when metformin was not the only offending factor causing lactic acidosis; 3) cases that did not received renal replacement
metformin 7051 refers to an arterial pH less than 7.35 and a serum lactate level above 5 mmol/L in association with metformin exposure, or based on the author’s clinical diagnosis where papers not providing measurements of either
metformin 8225 authors of the source paper or by an absolute decline from baseline renal function. Inappropriateness of metformin dosing was defined by (1) the contraindicated use of metformin if serum creatinine higher than 1.4 and
metformin 8288 renal function. Inappropriateness of metformin dosing was defined by (1) the contraindicated use of metformin if serum creatinine higher than 1.4 and 1.5 mg/dL in women and men, respectively, based on the US-FDA
metformin 9562 variablesMetformin usage was categorized into three groups: regular, suicidal and accidental. The daily and total metformin dosage was recorded, respectively, in patients with regular metformin use and suicidal or accidental
metformin 9632 accidental. The daily and total metformin dosage was recorded, respectively, in patients with regular metformin use and suicidal or accidental ingestion. Medications that may impair kidney function and predispose
metformin 10867 were evaluated with Chi-square test.The relationships between serum lactate concentration and serum metformin concentration and between the estimated metformin ingestion dose and serum metformin concentration were
metformin 10917 relationships between serum lactate concentration and serum metformin concentration and between the estimated metformin ingestion dose and serum metformin concentration were described using both parametric and nonparametric
metformin 10952 concentration and serum metformin concentration and between the estimated metformin ingestion dose and serum metformin concentration were described using both parametric and nonparametric methods. Multiple logistic regression
metformin 11209 predictors of mortality. The proposed adjustment variables included blood lactate, age, sex, RRT modality, metformin usage, and peak creatinine level. We also conducted several sensitivity analyses including (1) restricting
metformin 11359 also conducted several sensitivity analyses including (1) restricting the analyses only to cases whose metformin levels were available, (2) additional adjustment for baseline and trough eGFR, or (3) additional adjustment
metformin 11500 additional adjustment for baseline and trough eGFR, or (3) additional adjustment for appropriateness of metformin dosing (Inapproriateness vs. appropriateness) in the multiple logistic model shown in Table 3. The results
metformin 12425 16.2% (41 deaths). There was no statistical difference in age at event, diabetes status, the use of metformin (including the estimated dosage), and the use of predisposing medication and other anti-diabetic agents
metformin 13814 15.5%]0.11 Regular medication76.7%79.1%63.9% Suicidal22.8%20.4%36.1% Accidental0.4%0.5%0.0% Estimated metformin dosage at MALAa (g)2.6 (1.7–5.1) [181, 72.0%]2.6 (1.7–4.0) [154, 85.0%]2.6 (1.0–24.5) [27, 14.9%]0.79 Predisposing
metformin 14112 8.2%]0.67 Other anti-diabetic agents95.7% [47, 18.6%]97.5% [40, 85.1%]85.7% [7, 14.9%]0.15Appropriateness of metformin use Creatinine criteria28.8% [80, 31.6%]25.0% [68, 85%]50.0% [12, 15%]0.08 eGFR-dosing criteria57.5%
metformin 16648 therapy, eGFR estimated glomerular filtration rate, IRRT intermittent renal replacement therapy, MALA metformin -associated lactic acidosis, PD peritoneal dialysis, PIRRT prolonged intermittent renal replacement therapyaDaily
metformin 16771 lactic acidosis, PD peritoneal dialysis, PIRRT prolonged intermittent renal replacement therapyaDaily metformin dosage (g/day) for patient on regular metformin; total dosage (g) for patients with suicidal or accidental
metformin 16819 prolonged intermittent renal replacement therapyaDaily metformin dosage (g/day) for patient on regular metformin ; total dosage (g) for patients with suicidal or accidental metformin exposurebMedication that may predispose
metformin 16888 (g/day) for patient on regular metformin; total dosage (g) for patients with suicidal or accidental metformin exposurebMedication that may predispose the development of MALA included nonsteroidal anti-inflammatory
metformin 18068 survivors (17.0 mmol/L, p-value <0.01) (Table 1). We found no statistical difference in pH, blood metformin , and bicarbonate levels between the two groups. The distributions of renal replacement modalities, attempts
metformin 18819 prolonged intermittent renal replacement therapy; RRT, renal replacement therapyAppropriateness of metformin useAmong patients receiving regular metformin dose, the proportion of inappropriate prescription of
metformin 18865 therapy; RRT, renal replacement therapyAppropriateness of metformin useAmong patients receiving regular metformin dose, the proportion of inappropriate prescription of metformin was 28.9% and 57.5% based on FDA warning
metformin 18929 useAmong patients receiving regular metformin dose, the proportion of inappropriate prescription of metformin was 28.9% and 57.5% based on FDA warning and a recently proposed eGFR-dosing algorithm, respectively
metformin 19092 recently proposed eGFR-dosing algorithm, respectively (Table 2) [[12], [13]]. Patients with inappropriate metformin dosing had significantly lower baseline renal function but trough eGFR was comparable between the two
metformin 19329 classification criteria. When using the criteria according to FDA warning, patients with inappropriate metformin prescription were more likely to experience mortality and received a lower dose of metformin with a
metformin 19422 inappropriate metformin prescription were more likely to experience mortality and received a lower dose of metformin with a concomitantly lower serum lactate level compared to those of patients with appropriate dosing
metformin 19673 approach, patients with inappropriate prescription were found to receive a significant higher dose of metformin (2550 mg vs. 1700 mg, p-value < 0.01) than the appropriate dosing group. However, there was no statistical
metformin 19836 appropriate dosing group. However, there was no statistical difference in mortality proportion, serum metformin concentration, and serum lactate level between the two groups (Table 2).Table 2Clinical characteristics
metformin 20014 2).Table 2Clinical characteristics of published cases with available baseline serum creatinine and metformin dosage data stratified by dosing appropriatenessaAppropriate dosingInappropriate dosingp-valueFDA black-box
metformin 21897 Chi-squared and Wilcoxon signed rank test, respectivelyAssociation among serum lactate level, blood metformin concentration, and mortalitySerum lactate level was positively correlated with blood metformin concentration
metformin 21992 blood metformin concentration, and mortalitySerum lactate level was positively correlated with blood metformin concentration (Fig. 2a). Blood metformin concentration was also positively related to the metformin
metformin 22033 mortalitySerum lactate level was positively correlated with blood metformin concentration (Fig. 2a). Blood metformin concentration was also positively related to the metformin dose (Fig. 2b). For each increase in one
metformin 22092 metformin concentration (Fig. 2a). Blood metformin concentration was also positively related to the metformin dose (Fig. 2b). For each increase in one unit of serum lactate, there was an associated 9% (95% CI,
metformin 22601 MALA-related mortality, particularly in the range of greater than 20 mmol/L (Fig. 3).Fig. 2Levels of serum metformin are plotted versus the serum lactate levels (a) and the estimated metformin dosage (b). There are significant
metformin 22677 3).Fig. 2Levels 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
metformin 22756 (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 dosageTable 3Odds
metformin 22803 There are significant positive correlation between serum metformin and lactate levels and between serum metformin levels and the estimated metformin dosageTable 3Odds ratios (ORs) with 95% of confidence interval (CI)
metformin 22838 correlation between serum metformin and lactate levels and between serum metformin levels and the estimated metformin dosageTable 3Odds ratios (ORs) with 95% of confidence interval (CI) of metformin-associated lactic acidosis
metformin 22919 and the estimated metformin dosageTable 3Odds ratios (ORs) with 95% of confidence interval (CI) of metformin -associated lactic acidosis (MALA)-related mortality for potentially predictive factors by univariable
metformin 24034 prolonged intermittent renal replacement therapy, RRT renal replacement therapyFig. 3Odds ratio for metformin -associated lactic acidosis (MALA) mortality by serum lactate level in this systematic review. Solid
metformin 26303 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
metformin 26568 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
metformin 26609 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
metformin 26761 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
metformin 26981 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
metformin 27200 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
metformin 27446 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
metformin 27528 [[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
metformin 27578 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
metformin 29312 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
metformin 30035 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
metformin 31387 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
metformin 33187 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
Select Disease Character Offset Disease Term Instance
lactic acidosis 79 Title: BMC NephrologySerum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case seriesHung-Chieh YehI-Wen
lactic acidosis 494 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
lactic acidosis 2718 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
lactic acidosis 2893 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
lactic acidosis 4814 Statement criteria [[10]]. We searched PubMed/Medline and EMBASE for case reports of metformin-associated lactic acidosis (MALA) requiring renal replacement therapy by combining three key research concepts derived from relevant
lactic acidosis 5042 and text-word terms such as “renal replacement therapy”, “dialysis”, “metformin”, and “ lactic acidosis ”. Additional file 1: Table S1 showed the full search strategy. The search period was January 1966
lactic acidosis 5521 not provide individual biochemical data; 2) when metformin was not the only offending factor causing lactic acidosis ; 3) cases that did not received renal replacement therapy in the disease course; 4) phenformin- or buformin-related
lactic acidosis 5653 did not received renal replacement therapy in the disease course; 4) phenformin- or buformin-related lactic acidosis cases; 5) when survival status of an individual patient could not be ascertained. Duplicate publication
lactic acidosis 16669 glomerular filtration rate, IRRT intermittent renal replacement therapy, MALA metformin-associated lactic acidosis , PD peritoneal dialysis, PIRRT prolonged intermittent renal replacement therapyaDaily metformin dosage
lactic acidosis 17860 times higher than non-survivors (7.2 vs. 3.2 mg/dL, p-value <0.01). Regarding metabolic markers of lactic acidosis , serum lactate level was significantly higher in non-survivors (median 22.0 mmol/L) than in survivors
lactic acidosis 22940 metformin dosageTable 3Odds ratios (ORs) with 95% of confidence interval (CI) of metformin-associated lactic acidosis (MALA)-related mortality for potentially predictive factors by univariable and multiple logistic regressionVariableDeceased/survivor
lactic acidosis 24055 intermittent renal replacement therapy, RRT renal replacement therapyFig. 3Odds ratio for metformin-associated lactic acidosis (MALA) mortality by serum lactate level in this systematic review. Solid lines represent adjusted odds
lactic acidosis 29992 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
metabolic syndrome 2604 [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

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