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Quiz Page June 2011
QUIZ PAGE JUNE 2011 Profound Metabolic Acidosis and Abdominal Pain in a Diabetic Patient on Long-term Hemodialysis Table 1. Laboratory Studies
CLINICAL PRESENTATION A 62-year-old white man presented to the emergency department with profound abdominal pain. He had end-stage renal disease (ESRD) secondary to diabetic nephropathy and had been started on maintenance hemodialysis therapy 5 months earlier. The patient noted the onset of intermittent abdominal pain 3 days before admission, associated with nausea and diarrhea, but he denied vomiting or alleviating or worsening factors. He refused to go to dialysis therapy the day before admission because of abdominal pain, which progressively worsened. On examination, blood pressure was 239/97 mm Hg, heart rate was 126 beats/min, respiratory rate was 26 breaths/min, temperature was 35.2°C, and oxygen saturation was 96% on room air. He was in moderate distress and had a diffusely tender abdomen focused in the epigastric area, but no peritoneal signs. The rest of the examination findings were unremarkable. Initial laboratory results (Table 1) showed profound metabolic acidosis with the following values: arterial pH, 6.74; bicarbonate, 2.3 mEq/L (2.3 mmol/L); anion gap, 44 mEq/L (44 mmol/L); osmolar gap, 20 mOsm/kg; and lactate, 189.2 mg/dL (21 mmol/ L). Chest radiograph and computed tomography of the abdomen and pelvis with intravenous contrast were normal. After receiving morphine intravenously, blood pressure decreased to 162/84 mm Hg. What are possible causes of metabolic acidosis in this patient with ESRD? What is the pathogenesis of metabolic acidosis in this patient?
Parameter
Value
Reference Range
Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Anion gap (mEq/L) SUN (mg/dL) Creatinine (mg/dL) eGFR (mL/min/1.73 m2) Glucose (mg/dL) Calcium (mg/dL) Phosphorus (mg/dL) Albumin (g/dL) Lactate (mg/dL) Serum osmolality (measured; mOsm/kg) Serum osmolality (calculated; mOsm/kg) pH, arterial PCO2 (mm Hg)
145 5.2 99 ⬍5 44a 75 10.4 5.4b 44 10.3 2.4 4.7 189.2 339
135-145 3.6-5.2 101-111 22-29 10-15 9-21 0.6-1.3 ⬎60 70-110 8.4-10.2 2.5-4.5 3.4-4.8 4.5-19.8 275-300
319
277-303
PO2 (mm Hg) Bicarbonate (mEq/L)
6.74 16 121 2.3
7.35-7.45 35-45 80-100 22-29
Note: Conversion factors for units: SUN in mg/dL to mmol/L, ⫻0.357; creatinine in mg/dL to mol/L, ⫻88.4; eGFR in mL/min/ 1.73 m2 to mL/s/1.73 m2, ⫻0.01667; glucose in mg/dL to mmol/L, ⫻0.05551; calcium in mg/dL to mmol/L, ⫻0.2495; phosphorus in mg/dL to mmol/L, ⫻0.3229; albumin in g/dL to g/L, ⫻10; lactate in mg/dL to mmol/L, ⫻0.111. No conversion necessary for sodium, potassium, chloride, anion gap, and bicarbonate in mEq/L and mmol/L and serum osmolality in mOsm/kg and mmol/kg. Abbreviations: eGFR, estimated glomerular filtration rate; SUN, serum urea nitrogen. a Anion gap is calculated using the bicarbonate value from arterial blood gas data. b eGFR is calculated using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation.
What is the treatment for this patient’s metabolic acidosis?
xxv
QUIZ PAGE
Am J Kidney Dis. 2011;57(6):xxv-xxvii
QUIZ PAGE JUNE 2011 ANSWERS DISCUSSION
QUIZ PAGE
f What are the possible causes of metabolic acidosis in this patient with ESRD? Our patient had life-threatening high-anion-gap metabolic acidosis with appropriate respiratory compensation. Striking increases in anion gap are uncommon. In a review of 26 patients with anion gaps ⬎45 mEq/L (⬎45 mmol/L), lactic acidosis, ketoacidosis, methanol and ethylene glycol toxicities, and exogenous phosphate intoxication were most common. Most patients also had kidney failure, which leads to the accumulation of organic acids or phosphate.1 Our patient had an anion gap of 44 mEq/L (44 mmol/L) and a mild increase in osmolar gap (20 mOsm/kg). Accumulation of unmeasured osmoles from the missing hemodialysis treatment may explain the osmolar gap.2,3 Based on laboratory findings and a negative alcohol screen result, the most likely cause was lactic acidosis. There are 2 types of lactic acidosis: type A lactic acidosis is due to marked tissue hypoperfusion, whereas type B is due to inadequate oxygen utilization. Causes of type B lactic acidosis include mitochondrial myopathy, thiamine deficiency, malignancy, and a long list of drugs that interfere with oxidative metabolism, such as biguanides, or damage mitochondria, such as antiretroviral agents.4 Our patient was not in shock, but given his abdominal symptoms, xxvi
Figure 1. Time course of changes in serum bicarbonate (mEq/L), lactate (mmol/L), and anion gap values (mEq/L). Time 0 is the beginning of a 4-hour hemodialysis treatment (arrow). All parameters improved after hemodialysis and returned to reference range values the next day. Conversion factors for units: serum lactate in mg/dL to mmol/L, ⫻0.111. No conversion units necessary for serum bicarbonate and anion gap in mEq/L and mmol/L.
ischemic bowel was ruled out as the cause of lactic acidosis using enhanced abdominal computed tomography. Therefore, it is most likely that the patient has type B lactic acidosis. f What is the pathogenesis of metabolic acidosis in this patient? After further questioning, it was found that 10 days before presentation, our patient was started on treatment with metformin, 1,000 mg, twice daily by his primary care provider, who was unaware of its contraindication in patients with advanced chronic kidney disease. Metformin is the most commonly used hypoglycemic agent for type 2 diabetes. Metformin directly inhibits complex I of the mitochondrial respiratory chain, thereby decreasing hepatic energy level, inhibiting gluconeogenesis, promoting glucose uptake by cells, and increasing lactate production through accel-
erated anaerobic glycolysis.5 Metformin is excreted by the kidney without metabolism. Its half-life ranges from 2-6 hours in healthy individuals, but is prolonged in patients with decreased glomerular filtration rate.6 In our patient, metformin accumulation from ESRD resulted in metformin-associated lactic acidosis. f What is the treatment for this patient’s metabolic acidosis? Metformin-associated lactic acidosis is a life-threatening condition with a mortality rate in the range of 33%-50%.6,7 Metformin (molecular weight, 165 Da) has negligible plasma protein binding and hence is removed effectively using hemodialysis. Urinary clearance of metformin is ⬃450 mL/ min, and hemodialysis clearance is 170 mL/min.6 Continuous venovenous hemofiltration or hemodiafiltration is less effective at clearing metformin and usually is Am J Kidney Dis. 2011;57(6):xxv-xxvii
reserved for patients with hemodynamic compromise.7 The main challenge is how long to dialyze in treating metforminassociated lactic acidosis. Metformin has a large volume of distribution in the range of 63-276 L6 because it is preferentially transported into cells, particularly hepatocytes, through the organic cation transporter 1. Furthermore, because the quanidium group would be positively charged at physiologic pH, metformin is bioaccumulated 100-fold in the mitochondria.8 In a series of metformin-associated lactic acidosis, it was estimated that a cumulative duration of 15 hours is needed to decrease metformin levels to therapeutic values.6 Our patient received a 4-hour hemodialysis treatment with remarkable improvement: abdominal pain, hypertension, hypoglycemia, and hypothermia all resolved. Posthemodialysis lactate level was 63.1 mg/dL (7 mmol/L), anion gap was 27 mEq/L (27 mmol/L), and bicarbonate level was 13 mEq/L (13 mmol/L). He then received a sodium bicarbonate infusion, with correction of acidosis by 8 hours after stopping hemodialysis (Fig 1). Similar outcomes with a single session of 4-6 hours of hemodialysis have been reported by others.9 More importantly, it was found that metformin-associated lactic acidosis
FINAL DIAGNOSIS Metformin-associated lactic acidosis.
REFERENCES 1. Oster JR, Singer I, Contreras GN, Ahmad HI, Vieira CF. Metabolic acidosis with extreme elevation of anion gap: case report and literature review. Am J Med Sci. 1999;317(1): 38-49. 2. Sklar AH, Linas SL. The osmolal gap in renal failure. Ann Intern Med. 1983;98(4):481-482. 3. Dursun H, Noyan A, Cengiz N, et al. Changes in osmolal gap and osmolality in children with chronic and end-stage renal failure. Nephron Physiol. 2007;105(2):19-21. 4. Fall PJ, Szerlip HM. Lactic acidosis: from sour milk to septic shock. J Intensive Care Med. 2005;20(5): 255-271. 5. Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355-2369. 6. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and thera-
peutic study. Crit Care Med. 2009; 37(7):2191-2196. 7. Kruse JA. Metformin-associated lactic acidosis. J Emerg Med. 2001;20(3):267-272. 8. Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol. 2008;233(2):203-210. 9. Lalau JD, Westeel PF, Debussche X, et al. Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin. Intensive Care Med. 1987; 13(6):383-387. CASE PROVIDED AND AUTHORED BY Chong Parke, MD,1 and YeongHau H. Lien, MD, PhD,2 1Department of Medicine, University of Arizona, and 2Arizona Kidney Disease and Hypertension Center, Tucson, AZ. Address correspondence to YeongHau H. Lien, MD, PhD, Arizona Kidney Disease and Hypertension Center, Tucson, AZ 85718. E-mail: [email protected] © 2011 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2010.12.015 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
xxvii
QUIZ PAGE
Am J Kidney Dis. 2011;57(6):xxv-xxvii
resolved despite a persistent increase in serum metformin levels after hemodialysis.9 The underlying mechanisms for resolution of metformin-associated lactic acidosis by hemodialysis without elimination of metformin are unknown.
CLINICAL PRESENTATION A 62-year-old white man presented to the emergency department with profound abdominal pain. He had end-stage renal disease (ESRD) secondary to diabetic nephropathy and had been started on maintenance hemodialysis therapy 5 months earlier. The patient noted the onset of intermittent abdominal pain 3 days before admission, associated with nausea and diarrhea, but he denied vomiting or alleviating or worsening factors. He refused to go to dialysis therapy the day before admission because of abdominal pain, which progressively worsened. On examination, blood pressure was 239/97 mm Hg, heart rate was 126 beats/min, respiratory rate was 26 breaths/min, temperature was 35.2°C, and oxygen saturation was 96% on room air. He was in moderate distress and had a diffusely tender abdomen focused in the epigastric area, but no peritoneal signs. The rest of the examination findings were unremarkable. Initial laboratory results (Table 1) showed profound metabolic acidosis with the following values: arterial pH, 6.74; bicarbonate, 2.3 mEq/L (2.3 mmol/L); anion gap, 44 mEq/L (44 mmol/L); osmolar gap, 20 mOsm/kg; and lactate, 189.2 mg/dL (21 mmol/ L). Chest radiograph and computed tomography of the abdomen and pelvis with intravenous contrast were normal. After receiving morphine intravenously, blood pressure decreased to 162/84 mm Hg. What are possible causes of metabolic acidosis in this patient with ESRD? What is the pathogenesis of metabolic acidosis in this patient?
Parameter
Value
Reference Range
Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Anion gap (mEq/L) SUN (mg/dL) Creatinine (mg/dL) eGFR (mL/min/1.73 m2) Glucose (mg/dL) Calcium (mg/dL) Phosphorus (mg/dL) Albumin (g/dL) Lactate (mg/dL) Serum osmolality (measured; mOsm/kg) Serum osmolality (calculated; mOsm/kg) pH, arterial PCO2 (mm Hg)
145 5.2 99 ⬍5 44a 75 10.4 5.4b 44 10.3 2.4 4.7 189.2 339
135-145 3.6-5.2 101-111 22-29 10-15 9-21 0.6-1.3 ⬎60 70-110 8.4-10.2 2.5-4.5 3.4-4.8 4.5-19.8 275-300
319
277-303
PO2 (mm Hg) Bicarbonate (mEq/L)
6.74 16 121 2.3
7.35-7.45 35-45 80-100 22-29
Note: Conversion factors for units: SUN in mg/dL to mmol/L, ⫻0.357; creatinine in mg/dL to mol/L, ⫻88.4; eGFR in mL/min/ 1.73 m2 to mL/s/1.73 m2, ⫻0.01667; glucose in mg/dL to mmol/L, ⫻0.05551; calcium in mg/dL to mmol/L, ⫻0.2495; phosphorus in mg/dL to mmol/L, ⫻0.3229; albumin in g/dL to g/L, ⫻10; lactate in mg/dL to mmol/L, ⫻0.111. No conversion necessary for sodium, potassium, chloride, anion gap, and bicarbonate in mEq/L and mmol/L and serum osmolality in mOsm/kg and mmol/kg. Abbreviations: eGFR, estimated glomerular filtration rate; SUN, serum urea nitrogen. a Anion gap is calculated using the bicarbonate value from arterial blood gas data. b eGFR is calculated using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation.
What is the treatment for this patient’s metabolic acidosis?
xxv
QUIZ PAGE
Am J Kidney Dis. 2011;57(6):xxv-xxvii
QUIZ PAGE JUNE 2011 ANSWERS DISCUSSION
QUIZ PAGE
f What are the possible causes of metabolic acidosis in this patient with ESRD? Our patient had life-threatening high-anion-gap metabolic acidosis with appropriate respiratory compensation. Striking increases in anion gap are uncommon. In a review of 26 patients with anion gaps ⬎45 mEq/L (⬎45 mmol/L), lactic acidosis, ketoacidosis, methanol and ethylene glycol toxicities, and exogenous phosphate intoxication were most common. Most patients also had kidney failure, which leads to the accumulation of organic acids or phosphate.1 Our patient had an anion gap of 44 mEq/L (44 mmol/L) and a mild increase in osmolar gap (20 mOsm/kg). Accumulation of unmeasured osmoles from the missing hemodialysis treatment may explain the osmolar gap.2,3 Based on laboratory findings and a negative alcohol screen result, the most likely cause was lactic acidosis. There are 2 types of lactic acidosis: type A lactic acidosis is due to marked tissue hypoperfusion, whereas type B is due to inadequate oxygen utilization. Causes of type B lactic acidosis include mitochondrial myopathy, thiamine deficiency, malignancy, and a long list of drugs that interfere with oxidative metabolism, such as biguanides, or damage mitochondria, such as antiretroviral agents.4 Our patient was not in shock, but given his abdominal symptoms, xxvi
Figure 1. Time course of changes in serum bicarbonate (mEq/L), lactate (mmol/L), and anion gap values (mEq/L). Time 0 is the beginning of a 4-hour hemodialysis treatment (arrow). All parameters improved after hemodialysis and returned to reference range values the next day. Conversion factors for units: serum lactate in mg/dL to mmol/L, ⫻0.111. No conversion units necessary for serum bicarbonate and anion gap in mEq/L and mmol/L.
ischemic bowel was ruled out as the cause of lactic acidosis using enhanced abdominal computed tomography. Therefore, it is most likely that the patient has type B lactic acidosis. f What is the pathogenesis of metabolic acidosis in this patient? After further questioning, it was found that 10 days before presentation, our patient was started on treatment with metformin, 1,000 mg, twice daily by his primary care provider, who was unaware of its contraindication in patients with advanced chronic kidney disease. Metformin is the most commonly used hypoglycemic agent for type 2 diabetes. Metformin directly inhibits complex I of the mitochondrial respiratory chain, thereby decreasing hepatic energy level, inhibiting gluconeogenesis, promoting glucose uptake by cells, and increasing lactate production through accel-
erated anaerobic glycolysis.5 Metformin is excreted by the kidney without metabolism. Its half-life ranges from 2-6 hours in healthy individuals, but is prolonged in patients with decreased glomerular filtration rate.6 In our patient, metformin accumulation from ESRD resulted in metformin-associated lactic acidosis. f What is the treatment for this patient’s metabolic acidosis? Metformin-associated lactic acidosis is a life-threatening condition with a mortality rate in the range of 33%-50%.6,7 Metformin (molecular weight, 165 Da) has negligible plasma protein binding and hence is removed effectively using hemodialysis. Urinary clearance of metformin is ⬃450 mL/ min, and hemodialysis clearance is 170 mL/min.6 Continuous venovenous hemofiltration or hemodiafiltration is less effective at clearing metformin and usually is Am J Kidney Dis. 2011;57(6):xxv-xxvii
reserved for patients with hemodynamic compromise.7 The main challenge is how long to dialyze in treating metforminassociated lactic acidosis. Metformin has a large volume of distribution in the range of 63-276 L6 because it is preferentially transported into cells, particularly hepatocytes, through the organic cation transporter 1. Furthermore, because the quanidium group would be positively charged at physiologic pH, metformin is bioaccumulated 100-fold in the mitochondria.8 In a series of metformin-associated lactic acidosis, it was estimated that a cumulative duration of 15 hours is needed to decrease metformin levels to therapeutic values.6 Our patient received a 4-hour hemodialysis treatment with remarkable improvement: abdominal pain, hypertension, hypoglycemia, and hypothermia all resolved. Posthemodialysis lactate level was 63.1 mg/dL (7 mmol/L), anion gap was 27 mEq/L (27 mmol/L), and bicarbonate level was 13 mEq/L (13 mmol/L). He then received a sodium bicarbonate infusion, with correction of acidosis by 8 hours after stopping hemodialysis (Fig 1). Similar outcomes with a single session of 4-6 hours of hemodialysis have been reported by others.9 More importantly, it was found that metformin-associated lactic acidosis
FINAL DIAGNOSIS Metformin-associated lactic acidosis.
REFERENCES 1. Oster JR, Singer I, Contreras GN, Ahmad HI, Vieira CF. Metabolic acidosis with extreme elevation of anion gap: case report and literature review. Am J Med Sci. 1999;317(1): 38-49. 2. Sklar AH, Linas SL. The osmolal gap in renal failure. Ann Intern Med. 1983;98(4):481-482. 3. Dursun H, Noyan A, Cengiz N, et al. Changes in osmolal gap and osmolality in children with chronic and end-stage renal failure. Nephron Physiol. 2007;105(2):19-21. 4. Fall PJ, Szerlip HM. Lactic acidosis: from sour milk to septic shock. J Intensive Care Med. 2005;20(5): 255-271. 5. Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355-2369. 6. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and thera-
peutic study. Crit Care Med. 2009; 37(7):2191-2196. 7. Kruse JA. Metformin-associated lactic acidosis. J Emerg Med. 2001;20(3):267-272. 8. Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol. 2008;233(2):203-210. 9. Lalau JD, Westeel PF, Debussche X, et al. Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin. Intensive Care Med. 1987; 13(6):383-387. CASE PROVIDED AND AUTHORED BY Chong Parke, MD,1 and YeongHau H. Lien, MD, PhD,2 1Department of Medicine, University of Arizona, and 2Arizona Kidney Disease and Hypertension Center, Tucson, AZ. Address correspondence to YeongHau H. Lien, MD, PhD, Arizona Kidney Disease and Hypertension Center, Tucson, AZ 85718. E-mail: [email protected] © 2011 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2010.12.015 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
xxvii
QUIZ PAGE
Am J Kidney Dis. 2011;57(6):xxv-xxvii
resolved despite a persistent increase in serum metformin levels after hemodialysis.9 The underlying mechanisms for resolution of metformin-associated lactic acidosis by hemodialysis without elimination of metformin are unknown.