Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

GC-MS analysis of 4-hydroxyproline: elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients.

Metformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography-mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

Excess fermentation and lactic acidosis as detrimental functions of the gut microbes in treatment-naive TB patients.

Introduction: The link between gut microbiota and host immunity motivated numerous studies of the gut microbiome in tuberculosis (TB) patients. However, these studies did not explore the metabolic capacity of the gut community, which is a key axis of impact on the host's immunity. Methods: We used deep sequencing of fecal samples from 23 treatment-naive TB patients and 48 healthy donors to reconstruct the gut microbiome's metabolic capacity and strain/species-level content. Results: We show that the systematic depletion of the commensal flora of the large intestine, Bacteroidetes, and an increase in Actinobacteria, Firmicutes, and Proteobacteria such as Streptococcaceae, Erysipelotrichaceae, Lachnospiraceae, and Enterobacteriaceae explains the strong taxonomic divergence of the gut community in TB patients. The cumulative expansion of diverse disease-associated pathobionts in patients reached 1/4 of the total gut microbiota, suggesting a heavy toll on host immunity along with MTB infection. Reconstruction of metabolic pathways showed that the microbial community in patients shifted toward rapid growth using glycolysis and excess fermentation to produce acetate and lactate. Higher glucose availability in the intestine likely drives fermentation to lactate and growth, causing acidosis and endotoxemia. Discussion: Excessive fermentation and lactic acidosis likely characterize TB patients' disturbed gut microbiomes. Since lactic acidosis strongly suppresses the normal gut flora, directly interferes with macrophage function, and is linked to mortality in TB patients, our findings highlight gut lactate acidosis as a novel research focus. If confirmed, gut acidosis may be a novel potential host-directed treatment target to augment traditional TB treatment.

Association between lactic acidosis and multiple organ dysfunction syndrome after cardiopulmonary bypass.

Background: The relationship between hyperlactatemia and prognosis after cardiopulmonary bypass (CPB) is controversial, and some studies ignore the presence of lactic acidosis in patients with severe hyperlactacemia. This study explored the association between lactic acidosis (LA) and the occurrence of multiple organ dysfunction syndrome (MODS) after cardiopulmonary bypass. Methods: This study was a post hoc analysis of patients who underwent cardiac surgery between February 2017 and August 2018 and participated in a prospective study at Taizhou Hospital. The data were collected at: ICU admission (H0), and 4, 8, 12, 24, and 48 h after admission. Blood lactate levels gradually increased after CPB, peaking at H8 and then gradually decreasing. The patients were grouped as LA, hyperlactatemia (HL), and normal control (NC) based on blood test results 8 h after ICU admission. Basic preoperative, perioperative, and postoperative conditions were compared between the three groups, as well as postoperative perfusion and oxygen metabolism indexes. Results: There were 22 (19%), 73 (64%), and 19 (17%) patients in the LA, HL, and NC groups, respectively. APACHE II (24h) and SOFA (24h) scores were the highest in the LA group (P < 0.05). ICU stay duration was the longest for the LA group (48.5 (42.5, 50) h), compared with the HL (27 (22, 48) h) and NC (27 (25, 46) h) groups (P = 0.012). The LA group had the highest incidence of MODS (36%), compared with the HL (14%) and NC (5%) groups (P = 0.015). In the LA group, the oxygen extraction ratio (O2ER) was lower (21.5 (17.05, 32.8)%) than in the HL (31.3 (24.8, 37.6)%) and the NC group (31.3 (29.0, 35.4) %) (P = 0.018). In the univariable analyses, patient age (OR = 1.054, 95% CI [1.003-1.109], P = 0.038), the LA group (vs. the NC group, (OR = 10.286, 95% CI [1.148-92.185], P = 0.037), and ΔPCO2 at H8 (OR = 1.197, 95% CI [1.022-1.401], P = 0.025) were risk factor of MODS after CPB. Conclusions: We speculated that there was correlation between lactic acidosis and MODS after CPB. In addition, LA should be monitored intensively after CPB.

Metformin-Associated Lactic Acidosis-Is This on Your Radar?

BACKGROUND: Metformin is a biguanide hyperglycemic agent used to manage non-insulin-dependent diabetes mellitus. Adverse reactions include mainly mild gastrointestinal adverse effects, but severe complications, such as metformin-associated lactic acidosis (MALA) can occur. Metformin is excreted renally and, therefore, not recommended in patients with renal impairment. The reported incidence of MALA is 3 cases per 100,000 patient-years. CASE REPORT: A 79-year-old woman with a complex medical history, including end-stage renal disease on dialysis and type 2 diabetes, presented to the emergency department (ED) for altered mental status. Prior to arrival, she was found to be hypoglycemic. Her laboratory results were significant for creatinine of 6.56 mg/dL and an anion gap of 52 mmol/L. The venous blood gas revealed a venous pH of 6.857 [reference range (7.32-7.43)], pCO2 of 15.9 mm Hg (40.6-60 mm Hg), HCO3 of 2.7 mmol/L (21-30 mmol/L), lactate of 27 mmol/L (0.5-2 mmol/L), and ammonia of 233 µmol/L. The patient was dialyzed emergently in the ED; repeat laboratory test results showed blood urea nitrogen of 10 mg/dL, creatinine of 1.65 mg/dL, carbon dioxide of 26 mmol/L, and anion gap of 13 mmol/L. The repeat ammonia was 16 µmol/L. The patient's metabolic encephalopathy resolved, and she was discharged home on hospital day 3. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: MALA has a high mortality rate (36%). Laboratory markers have not been found to be a reliable predictor of mortality. Sodium bicarbonate is controversial, but a pH < 7.15 indicates consideration of its use. A pH < 7.1 and a lactate level > 20 mmol/L indicate the need for emergent hemodialysis. Prompt recognition and management in the ED with early hemodialysis can result in good patient outcomes, with a return to their baseline function despite severe laboratory findings.

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging.

Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.

Factors associated with D-lactic acidosis in pediatric intestinal failure: A case-control study.

BACKGROUND: D-lactic acidosis (DLA) is a serious complication of short bowel syndrome (SBS) in children with intestinal failure (IF). Malabsorbed carbohydrates are metabolized by bacteria in the intestine to D-lactate which can lead to metabolic acidosis and neurologic symptoms. METHODS: A retrospective chart review was performed in children ≤18 years old with SBS who had one of the following criteria: unexplained metabolic acidosis, neurologic signs or symptoms, history of antibiotic therapy for small bowel bacterial overgrowth, or high clinical suspicion of DLA. Cases had serum D-lactate concentration >0.25 mmol/L; controls with concentrations ≤0.25 mmol/L. RESULTS: Of forty-six children, median age was 3.16 (interquartile range (IQR): 1.98, 5.82) years, and median residual bowel length was 40 (IQR: 25, 59) cm. There were 23 cases and 23 controls. Univariate analysis showed that cases had significantly lower median bicarbonate (19 vs. 24 mEq/L, p = 0.001), higher anion gap (17 vs. 14 mEq/L, p < 0.001) and were less likely to be receiving parenteral nutrition, compared with children without DLA. Multivariable analysis identified midgut volvulus, history of intestinal lengthening procedure, and anion gap as significant independent risk factors. Midgut volvulus was the strongest independent factor associated with DLA (adjusted odds ratio = 17.1, 95% CI: 2.21, 133, p = 0.007). CONCLUSION: DLA is an important complication of pediatric IF due to SBS. Patients with IF, particularly those with history of midgut volvulus, having undergone intestinal lengthening, or with anion gap acidosis, should be closely monitored for DLA.

Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine.

OBJECTIVE: This study investigates the efficacy of using a long-acting insulin analog, along with the infusion of regular insulin, in achieving appropriate glycemic control and correcting lactic acidosis in patients post orthotopic heart transplant who demonstrate severe lactic acidosis and insulin resistance. METHODS: This was a retrospective study of two cohorts (IRB FLA 20-003) of patients post orthotopic heart transplant with severe lactic acidosis and insulin resistance who were admitted to a tertiary intensive care unit and treated with (group 1) or without long-acting insulin analog (group 2) within the first 24 h of admission to the intensive care unit. Insulin resistance is defined as the requirement for intravenous regular insulin infusion of more than 20 units/h without the ability to achieve appropriate serum glucose level (120-180 mg /dL). Severe lactic acidosis is defined as arterial lactic acid of more than 10 mmol/L. The following parameters were investigated: time to correct lactic acidosis, duration of postoperative mechanical ventilation, the need for periprocedural mechanical circulatory support, and 28-day mortality. RESULTS: The 28-day mortality was zero in both groups. Two patients required periprocedural mechanical support in group one, and ten patients required mechanical support in group two (RR = 0.224, 95%, confidence interval 0.052-0.95, Z = 2.029, p = 0.042). Three patients required tracheostomy in group one, and four patients required tracheostomy in group two (RR 0.84, 95 confidence interval 0.20-3.48, Z = 0.23, P = 0.81). Wilcoxon rank-sum test was used to compare time to correct lactic acidosis, with lactic acid resolution being faster in group one ([Formula: see text]1 = 19.7 h, SD ± 12.6 h [Formula: see text]2 = 29.3 h, SD ± 19.6 h, Z-value - 2.02, p-value 0.043). The duration of mechanical ventilation was less in group one ([Formula: see text]1 = 29 h, SD ± 12.7 h, [Formula: see text]2 = 55.1 h, SD ± 44.5 h, Z-value: - 1.92, p-value 0.05). CONCLUSION: Administration of low-dose long-acting insulin glargine led to the resolution of the lactic acidosis, insulin resistance, and decreased requirements for pressor and inotropic support, which led to decreased need for mechanical circulatory support.

Adult-onset mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): a diagnostic challenge.

Rare causes of stroke-like presentations can be difficult to diagnose. We report a case of a man in his 40s who first presented with stroke symptoms, but whose clinical course was not typical for a stroke. A detailed investigation of the patient's medical history revealed bilateral sensorineural hearing loss which prompted a wider diagnostic assessment.Furthermore, lack of vascular risk factors and a normal angiogram strengthened our suspicion of an unusual underlying condition. Raised lactic acid levels and genetic analysis confirmed a diagnosis of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

Linezolid-induced lactic acidosis.

Linezolid is a commonly prescribed antibiotic in clinical practice. Although thrombocytopenia and peripheral neuropathy are frequently encountered following prolonged administration of linezolid, lactic acidosis is a rare adverse drug reaction. We present the case of a patient on linezolid for disseminated multidrug-resistant tuberculosis who presented with vomiting, dyspnoea, hypotension and high anion gap metabolic acidosis. The initial presentation mimicked sepsis syndrome. Ketoacidosis and renal dysfunction were ruled out. There was no history of ingestion of toxins/toxic alcohols. Sepsis was unlikely because extensive radiological and microbiological testing could not identify an infection. Given the possibility of linezolid-induced lactic acidosis (LILA), linezolid was discontinued on admission. The patient's lactic acidosis resolved, and his overall condition improved. A retrospective diagnosis of LILA was thus established. LILA should be considered when patients on linezolid present with lactic acidosis and other causes for the lactic acidosis have been ruled out.

Leadership Behaviors of Frontline Nurse Managers: A Mixed-Methods Research Study Identifying Essential Areas for Social Support.

OBJECTIVE: This study examined how frontline nurse managers (FLNMs) perceive and experience formal and informal social support and how personal factors and social support relate to their transformational leadership (TL) behaviors. BACKGROUND: Ineffective leadership by FLNMs is associated with costly outcomes. Evidence suggests that leadership development is a function of personal and social factors; however, a better understanding of this process is needed. METHODS: A convergent mixed-methods design was used. The quantitative strand included a cross-sectional survey in a sample of FLNMs. The qualitative strand used a semistructured interview and a descriptive qualitative approach with a subset of this sample. RESULTS: Formal and informal social support is positively related to the TL behaviors of FLNMs as evidenced by the convergent data. The influence of family members in the work-related decisions of FLNMs has been underreported in the literature and is an area for consideration in supporting retention and desired leadership behaviors. CONCLUSION: The findings of this study imply a need for organizations to establish systems that endorse the growth of FLNMS, create opportunities for career advancement, and integrate members of the FLNMs' personal support systems into recognition initiatives.

Exploring the relationship between hyperlactatemia and anemia.

Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers, and genetic disorders. For instance, hyperlactatemia leads to iron restriction by upregulating hepatic hepcidin expression. Increasing evidence also points to lactate as a crucial signaling molecule rather than merely a metabolic byproduct. Here, we discuss the mutual influence between anemia and hyperlactatemia. This opinion calls for a reconsideration of the multifaceted roles of lactate and lactylation in anemia and emphasizes the need to fill knowledge gaps, including the dose dependence of lactate's effects, its sources, and its subcellular localization.

The synergism of cytosolic acidosis and reduced NAD+/NADH ratio is responsible for lactic acidosis-induced vascular smooth muscle cell impairment in sepsis.

BACKGROUND: During sepsis, serve vascular dysfunctions lead to life-threatening multiple organ failure, due to vascular smooth muscle cells (VSMC) impairments, resulting in vasoplegia, hypotension and hypoperfusion. In addition, septic patients have an altered cell metabolism that leads to lactic acidosis. Septic patients suffering from lactic acidosis have a high risk of mortality. In addition, septic survivors are at risk of secondary vascular disease. The underlying mechanisms of whether and how lactic acidosis leads to the changes in VSMCs is not well understood. The aim of this study was to comprehensively investigate the effect of lactic acidosis on VSMCs and additionally compare the effects with those induced by pure acidosis and sodium lactate. METHODS: Primary human aortic smooth muscle cells (HAoSMCs) were treated for 48 h with lactic acidosis (LA_pH 6.8), hydrochloric acid (HCl_pH 6.8), sodium lactate (Na+-lactate_pH 7.4) and the respective controls (ctrl._pH 7.4; hyperosmolarity control: mannitol_pH 7.4) and comparatively analyzed for changes in (i) transcriptome, (ii) energy metabolism, and (iii) phenotype. RESULTS: Both types of acidosis led to comparable and sustained intracellular acidification without affecting cell viability. RNA sequencing and detailed transcriptome analysis revealed more significant changes for lactic acidosis than for hydrochloric acidosis, with lactate being almost ineffective, suggesting qualitative and quantitative synergism of acidosis and lactate. Bioinformatic predictions in energy metabolism and phenotype were confirmed experimentally. Lactic acidosis resulted in strong inhibition of glycolysis, glutaminolysis, and altered mitochondrial respiration which reduced cellular ATP content, likely due to increased TXNIP expression and altered NAD+/NADH ratio. Hydrochloric acidosis induced significantly smaller effects without changing the NAD+/NADH ratio, with the ATP content remaining constant. These metabolic changes led to osteo-/chondrogenic/senescent transdifferentiation of VSMCs, with the effect being more pronounced in lactic acidosis than in pure acidosis. CONCLUSIONS: Overall, lactic acidosis exerted a much stronger effect on energy metabolism than pure acidosis, whereas lactate had almost no effect, reflecting the qualitative and quantitative synergism of acidosis and lactate. As a consequence, lactic acidosis may lead to acute functional impairments of VSMC, sustained perturbations of the transcriptome and cellular dedifferentiation. Moreover, these effects may contribute to the acute and prolonged vascular pathomechanisms in septic patients.

Malignancy Associated Type B Lactic Acidosis: A Rare, yet Fascinating Oncological Emergency.

Type B lactic acidosis has been described infrequently in hematologic malignancies, but even less often in solid tumors. Since 1978, there have been only 58 cases of solid tumor associated Type B lactic acidosis described in the literature. Lung cancer (neuroendocrine) is the most common tumor; others frequently have a poorly/undifferentiated histology. The prognosis is dismal. Malignancy associated type B lactic acidosis is not associated with hypoxemia. The most highlighted pathogenetic mechanism is the Warburg effect (aerobic glycolysis of tumor cells causing excess lactate). We describe a patient with metastatic GI neuroendocrine carcinoma with profound lactic acidosis, who died within 24 hours. When extremely ill cancer patients present with lactic acidosis, sepsis is usually a primary concern. This case highlights the need for providers to consider malignancy associated lactic acidosis (MA-LA) in the differential diagnosis, particularly in patients with advanced malignancies, of lung origin, of neuroendocrine or poorly/undifferentiated histologic subtypes. The implications and approach are distinct from Type A/D lactic acidosis, and would involve treatment of the underlying malignancy at the earliest.

Adverse Impact of Sodium Bicarbonate Administration on Multiple Outcomes in Acute Pancreatitis Patients With Hyperlactatemia.

OBJECTIVE: Hyperlactatemia is likely to occur among patients with acute pancreatitis (AP). Sodium bicarbonate (SB) therapy could be applied to correct potential detrimental acidic disturbances, but the exact impact of SB treatment is unknown. This study aims to investigate the impact of SB on AP patients complicated with hyperlactatemia. METHODS: The study was conducted based on the database named Medical Information Mart for Intensive Care-IV (MIMIC-IV). Propensity matching (PSM) and inverse probability weighting (IPTW) were used to balance the baseline differences. Multivariate regression and marginal structural Cox models were performed to investigate the association between SB and multiple outcomes. RESULTS: Three hundred fifty-three AP patients with hyperlactatemia (initial serum lactate, >2.0 mmol/L) were extracted from the MIMIC-IV database. We found that SB treatment was significantly associated with worse multi-outcomes of AP patients with hyperlactatemia (in-hospital mortality: hazard ratio, 2.46; 95% confidence interval, 1.38-4.39; P < 0.01). Further analysis through marginal structural Cox models showed that SB had adverse impact on in-hospital prognosis of patients with severe lactic acidosis (pH < 7.15,lactate > 2.0 mmol/L). CONCLUSION: Sodium bicarbonate might not be an appropriate treatment for AP patients with hyperlactatemia (lactate > 2.0 mmol/L) or with severe lactic acidosis (pH < 7.15, lactate > 2.0 mmol/L).

A case of exacerbated encephalopathy with stroke-like episodes and lactic acidosis triggered by metformin in a patient with MELAS.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in mitochondrial DNA that result in cellular energy deficiency. MELAS affects the most metabolically active organs, including the brain, skeletal muscles, cochlea, retina, heart, kidneys, and pancreas. As a result, about 85% of carriers of m.3243A > G, the most common mutation in MELAS, develop diabetes by the age of 70. Although metformin is the most widely prescribed drug for diabetes, its usefulness in mitochondrial dysfunction remains controversial. Here, we present the case of a 32-year-old Korean patient diagnosed with MELAS who presented with exacerbated stroke-like episodes and lactic acidosis triggered by metformin.

Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors.

The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.

Metformin-Cimetidine Drug Interaction and Risk of Lactic Acidosis in Renal Failure: A Pharmacovigilance-Pharmacokinetic Appraisal.

OBJECTIVE: This study aimed to evaluate lactic acidosis (LA) risk when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure (RF). RESEARCH DESIGN AND METHODS: This study analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of LA associated with metformin alone or combined with H2RI. Using a disproportionality approach, LA risk signal in the overall population and in patients with RF was assessed. A physiologically based pharmacokinetic (PBPK) model was developed to predict metformin and cimetidine pharmacokinetic changes following conventional doses of the combinations in patients with various degrees of RF. To explore its correlation with LA risk, a peak plasma metformin concentration of 3 mg/L was considered the threshold. RESULTS: Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, the percentage of patients with RF reporting LA associated with metformin combined with H2RI increased. Disproportionality analysis showed reported LA risk signal associated with metformin and cimetidine in the overall population within the study timeframe only. Furthermore, with PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold. CONCLUSIONS: Metformin combined with cimetidine at conventional doses may cause LA in patients with mild-to-moderate RF.