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Metabolic Acidosis Workup

  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Dec 18, 2015
 

Approach Considerations

Often the first clue to metabolic acidosis is a decreased serum HCO3- concentration observed when serum electrolytes are measured. Remember, however, that a decreased serum [HCO3-] level can be observed as a compensatory response to respiratory alkalosis. An [HCO3-] level of less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis.

The only definitive way to diagnose metabolic acidosis is by simultaneous measurement of serum electrolytes and arterial blood gases (ABGs), which shows pH and PaCO2 to be low; calculated HCO3- also is low. (For more information, see Metabolic Alkalosis.)

A low serum HCO3- and a pH of less than 7.40 upon ABG analysis confirm metabolic acidosis.

Go to Pediatric Metabolic Acidosis and Emergent Management of Metabolic Acidosis for complete information on these topics.

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Laboratory Evaluation

The diagnosis is made by evaluating serum electrolytes and ABGs. A low serum HCO3- and a pH of less than 7.40 upon ABG analysis confirm metabolic acidosis. The anion gap (AG) should be calculated to help with the differential diagnosis of the metabolic acidosis and to diagnose mixed disorders. In general, a high-AG acidosis is present if the AG is greater than 10-12 mEq/L, and a non-AG acidosis is present if the AG is less than or equal to 10-12 mEq/L. It is important to note that the AG decreases by 2.5 mEq for every 1 g/dL decrease in serum albumin.

If the AG is elevated, the osmolar gap should be calculated by subtracting the calculated serum osmolality from the measured serum osmolality. Ethylene glycol and methanol poisoning increase the AG and the osmolar gap. Acetone, produced by decarboxylation of acetoacetate, can also raise serum osmolality. Other tests can be performed, including a screen for toxins (eg, ethylene glycol, salicylate) and tests for metabolic disorders (eg, ketoacidosis, lactic acidosis), that are known to elevate the AG.

If the AG is not elevated, then a urinalysis should be performed and a urine pH obtained with a pH electrode on a fresh sample of urine collected under oil or in a capped syringe. A urine AG is calculated from the measurement of urine Na+, K+, and Cl-. This helps to differentiate between GI and renal losses of HCO3- in non-AG metabolic acidosis.

The change in AG (delta AG) helps in detecting the presence of a second acid-base disorder in patients with an elevated AG. It is calculated by the following equation:

(AG - 10)/(24 - HCO3-)

A value less than 1 indicates that the drop in serum HCO3- is not accompanied by a corresponding increase in the AG. This suggests that a portion of the H+ load is not accompanied by an unmeasured anion and indicates the presence of a mixed metabolic acidosis (eg, a non-AG acidosis and a high-AG acidosis).

A value greater than 1.6 indicates that the drop in serum HCO3- is associated with a larger-than-expected increase in the AG. This would occur if the serum HCO3- level was higher than normal prior to the onset of the metabolic acidosis and then dropped below normal with the addition of H+ coupled to an unmeasured anion. This indicates the presence of a mixed metabolic acidosis and metabolic alkalosis.

Special tests

Measuring the transtubular potassium gradient (TTKG) is useful in determining the etiology of hyperkalemia or hypokalemia associated with metabolic acidosis.

Plasma renin activity and plasma aldosterone levels are useful in determining the etiology of the hyperkalemia and hypokalemia that accompany metabolic acidosis.

FEHCO3- is useful in the diagnosis of proximal renal tubular acidosis (RTA).

The NH4 Cl loading test is useful in patients with nephrocalcinosis and/or nephrolithiasis, who may have an incomplete form of distal RTA. These patients may not have a pH less than 7.35 or a drop in serum HCO3-; metabolic acidosis can be induced by administration of NH4 Cl (0.1 g/kg for 3 d). Under these circumstances of induced acidemia, a urine pH greater than 5.3 indicates distal RTA.

A recently described alternative to the NH4 Cl loading test involves the simultaneous oral administration of furosemide to increase distal Na+ delivery and fludrocortisone to increase collecting duct Na+ absorption and proton secretion.[7] Under these circumstances, a urine pH greater than 5.3 indicates distal RTA.

Measuring the urine-blood PaCO2 gradient following an HCO3- load is useful in some patients with classic distal RTA to differentiate a permeability defect from other defects. This test is useful in patients with nephrocalcinosis in whom distal RTA is suspected but urine is acidified appropriately in the face of metabolic acidosis. Some of these patients have a rate-dependent defect in proton secretion, revealed by a low urine-blood PaCO2 gradient following HCO3- loading.

Abdominal radiographs (eg, kidneys, ureters, bladder), CT scans, and/or renal ultrasound images may show renal stones or nephrocalcinosis in patients with distal RTA.

Base excess/base deficit

ABGs also measure base excess/base deficit (BE/BD), which is the best indicator of the degree of acidosis/alkalosis. BE/BD is measured by gauging the amount of acid or base that is required to titrate the patient's blood sample to a pH of 7.40, given a PCO2 level of 40 mm Hg at 37°C.

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Complete Blood Count

An elevation of the white blood cell (WBC) count is a nonspecific finding, but it should prompt consideration of septicemia, which causes lactic acidosis.

Severe anemia with compromised oxygen delivery may cause lactic acidosis.

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Urinalysis

A urine pH is normally acidic at less than 5.0. In acidemia, the urine normally becomes more acidic. If the urine pH is above 5.5 in the face of acidemia, this finding is consistent with a type I RTA. Alkaline urine is typical in salicylate poisoning.

Patients with ethylene glycol toxicity may present with calcium oxalate crystals, which appear needle shaped, in the urine.

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Urine Anion Gap

Calculating the urine AG is helpful in evaluating some cases of non-AG metabolic acidosis. The major measured urinary cations are Na+ and K+, and the major measured urinary anion is Cl-:

Urine AG = ([Na+] + [K+]) - [Cl-]

In the face of metabolic acidosis, the kidneys increase the amount of NH3 synthesized to buffer the excess H+ and NH4 Cl excretion increases. The increased unmeasured NH4+ thus increases the measured anion Cl- in the urine, and the net effect is a negative AG, representing a normal response to systemic acidification. The finding of a positive urine AG in the face of non-AG metabolic acidosis points toward a renal acidification defect (eg, RTA[8] ). See earlier section on urine anion gap.

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Ketone Level

Elevations of ketones indicate diabetic, alcoholic, and starvation ketoacidosis.

The nitroprusside test is used to detect the presence of ketoacids in the blood and the urine. This test measures only acetoacetate and acetone; therefore, it may underestimate the degree of ketonemia and ketonuria, because it will not detect the presence of beta-hydroxybutyrate (BOH). This limitation of the test can be especially problematic in patients with ketoacidosis who cannot convert BOH to acetoacetate because of severe shock or liver failure.

An assay for BOH is unavailable in some hospitals. An indirect method to circumvent this problem is to add a few drops of hydrogen peroxide to a urine specimen. This enzymatically will convert BOH into acetoacetate, which will be detected by the nitroprusside test.

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Serum Lactate level

The normal plasma lactate concentration is 0.5-1.5 mEq/L.

Lactic acidosis is considered present if the plasma lactate level exceeds 4-5 mEq/L in an acidemic patient.

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Salicylate levels and Iron levels

Therapeutic salicylate levels range up to 20-35 mg/dL.

Plasma levels exceeding 40-50 mg/dL are in the toxic range.

Plasma levels provide some information as to the severity of intoxication: 40-60 mg/dL is considered mild; 60-100 mg/dL is moderate; and greater than 100 mg/dL is considered severe.

Iron toxicity is associated with lactic acidosis. Iron levels greater than 300 mg/dL are considered toxic.

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Transtubular Potassium Gradient

Measuring the transtubular potassium gradient (TTKG; see the calculation below) is useful in determining the etiology of hyperkalemia or hypokalemia associated with metabolic acidosis.

TTKG = urine K+ × serum osmolality/serum K+ × urine osmolality

A TTKG of greater than 8 indicates that aldosterone is present and that the collecting duct is responsive to it. A TTKG of less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance. For the test to be interpretable, the urine Na+ level should be greater than 10 mEq/L and the urine osmolality should be greater than or equal to serum osmolality.

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Plasma Renin Activity, Plasma Aldosterone levels, and FEHCO3-

Plasma renin activity and plasma aldosterone levels are useful in determining the etiology of the hyperkalemia and hypokalemia that accompany metabolic acidosis.

Measurement of the fractional excretion of bicarbonate (FEHCO3-) is useful in the diagnosis of proximal RTA.

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Ammonium Chloride Loading Test

The ammonium chloride (NH4 Cl) loading test is useful in patients with nephrocalcinosis and/or nephrolithiasis, who may have an incomplete form of distal RTA. These patients may not have a pH of less than 7.35 or a drop in serum HCO3-; metabolic acidosis can be induced by administration of NH4 Cl (0.1 g/kg for 3 d). Under these circumstances of induced acidemia, a urine pH of greater than 5.3 indicates distal RTA.

An alternative to the NH4 Cl loading test involves the simultaneous oral administration of furosemide to increase distal Na+ delivery and fludrocortisone to increase collecting duct Na+ absorption and proton secretion.[7] Under these circumstances, a urine pH greater than 5.3 indicates distal RTA.

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Urine-Blood PaCO2 Gradient Following HCO3- Loading

Measuring the urine-blood PaCO2 gradient following an HCO3- load is useful in some patients with classic distal RTA to differentiate a permeability defect from other defects. This test is useful in patients with nephrocalcinosis in whom distal RTA is suspected but urine is acidified appropriately in the face of metabolic acidosis. Some of these patients have a rate-dependent defect in proton secretion, revealed by a low urine-blood PaCO2 gradient following HCO3- loading.

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Imaging Studies and Electrocardiography

Abdominal radiographs (eg, kidneys, ureters, bladder), computed tomography (CT) scans, and/or renal ultrasonographic images may show renal stones or nephrocalcinosis in patients with distal RTA.

If iron ingestion is suspected, perform imaging studies on the abdominal area, including the kidneys, ureters, and bladder.

An electrocardiogram (ECG) may be used to detect abnormalities that result from the effects of electrolyte imbalances (eg, hyperkalemia).

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Contributor Information and Disclosures
Author

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Royal College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Khaled Hamawi, MD, MHA Director, Multi Organ Transplant Center, King Fahad Specialist Hospital, Dammam

Khaled Hamawi, MD, MHA is a member of the following medical societies: American Society of Transplantation, American Society of Nephrology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, International Society of Nephrology, American Society for Biochemistry and Molecular Biology, American Federation for Medical Research, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, Kentucky Medical Association, National Kidney Foundation, Phi Beta Kappa

Disclosure: Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology for asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contract payment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor; Received contract payment from Healthcare Quality Strategies, Inc for independent cont.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Additional Contributors

James W Lohr, MD Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

James W Lohr, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Central Society for Clinical and Translational Research

Disclosure: Partner received salary from Alexion for employment.

References
  1. Hamm LL, Nakhoul N, Hering-Smith KS. Acid-Base Homeostasis. Clin J Am Soc Nephrol. 2015 Dec 7. 10 (12):2232-42. [Medline].

  2. Reddy P, Mooradian AD. Clinical utility of anion gap in deciphering acid-base disorders. Int J Clin Pract. 2009 Oct. 63(10):1516-25. [Medline].

  3. Noritomi DT, Soriano FG, Kellum JA, et al. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med. 2009 Oct. 37(10):2733-9. [Medline].

  4. Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st century. Lancet. 2008 Sep 13. 372(9642):892. [Medline].

  5. Maciel AT, Park M. Differences in acid-base behavior between intensive care unit survivors and nonsurvivors using both a physicochemical and a standard base excess approach: a prospective, observational study. J Crit Care. 2009 Dec. 24(4):477-83. [Medline].

  6. Morimatsu H, Toda Y, Egi M, et al. Acid-base variables in patients with acute kidney injury requiring peritoneal dialysis in the pediatric cardiac care unit. J Anesth. 2009. 23(3):334-40. [Medline].

  7. Walsh SB, Shirley DG, Wrong OM, Unwin RJ. Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int. 2007 Jun. 71(12):1310-6. [Medline].

  8. Pereira PC, Miranda DM, Oliveira EA, Silva AC. Molecular pathophysiology of renal tubular acidosis. Curr Genomics. 2009 Mar. 10(1):51-9. [Medline]. [Full Text].

  9. Starke A, Corsenca A, Kohler T, Knubben J, Kraenzlin M, Uebelhart D, et al. Correction of metabolic acidosis with potassium citrate in renal transplant patients and its effect on bone quality. Clin J Am Soc Nephrol. 2012 Sep. 7(9):1461-72. [Medline]. [Full Text].

  10. Kraut JA, Madias NE. Metabolic Acidosis of CKD: An Update. Am J Kidney Dis. 2015 Oct 15. [Medline].

  11. Abramowitz MK, Melamed ML, Bauer C, Raff AC, Hostetter TH. Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol. 2013 May. 8(5):714-20. [Medline]. [Full Text].

  12. Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013 Mar. 8(3):371-81. [Medline]. [Full Text].

 
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Table. Comparison of Types 1, 2, and 4 RTA
Characteristics Proximal (Type 2) Distal (Type 1) Type 4
Primary defect Proximal HCO3 - reabsorption Diminished distal H+ secretion Diminished ammoniagenesis
Urine pH < 5.5 when serum HCO3 - is low >5.5 < 5.5
Serum HCO3 - >15 mEq/L Can be < 10 mEq/L >15 mEq/L
Fractional excretion of HCO3 - (FEHCO3) >15-20% during HCO3 - load < 5% (can be as high as 10% in children) < 5%
Serum K+ Normal or mild decrease Mild-to-severe decrease* High
Associated features Fanconi syndrome ... Diabetes mellitus, renal insufficiency
Alkali therapy High doses Low doses Low doses
Complications Osteomalacia or rickets Nephrocalcinosis, nephrolithiasis ...
*K+ may be high if RTA is due to volume depletion.
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