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Hyperchloremic Acidosis Workup

  • Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
Updated: Jul 08, 2014

Approach Considerations

Metabolic acidosis due to loss of intestinal secretions, medications, or exogenous acid intake is usually apparent from the history. An exception is diarrhea due to laxative abuse, for which the history is difficult to obtain. When this condition is suggested because of hypokalemia and a normal AG metabolic acidosis, it may be confirmed by findings of low sodium concentration in the urine from volume contraction, positive test results for stool phenolphthalein, or high fecal magnesium levels.

Loss of intestinal secretions as the cause of acidosis may be confirmed by measuring the pH and AG ([Na+] + [K+] - [Cl-]) of the volume lost; an alkaline pH and elevated AG suggest bicarbonate loss.

If the cause of acidosis is not apparent from the history and physical examination findings, the next step is to determine whether hyperchloremic acidosis is present. Urinary ammonium excretion and urine pH can be used to define the etiology of the disorder.


Urinary Ammonium Excretion

Urinary ammonium excretion (urine AG; urine net charge) is inferred from the urine AG, also known as the urine net charge, when direct measurement of ammonium is not possible.

The urine net charge is defined as follows: UNA+ + UK+ - UCl-. In this equation, UNA+ is the urinary concentration of sodium, UK+ is the urinary concentration of potassium, and UCl- is the urinary concentration of chloride. The urinary net charge and ammonium excretion have a linear relationship. When excretion of Cl- exceeds that of Na+ and K+, the urinary net charge is negative, and the assumption is that a substantial concentration of ammonium is present in the urine, which would be the case in metabolic acidosis of nonrenal origin.

Conversely, in hypokalemic and hyperkalemic dRTA, the urine concentration of ammonium is insufficient, excretion of Na+ and K+ exceed that of Cl-, and the urinary net charge is positive.

This method of analysis has potential pitfalls. A negative urine AG is also observed in patients whose acidosis is due to nonrenal causes but in whom maximal acidification fails because of decreased presentation of sodium to the distal nephron. In these cases, the urinary sodium concentration is very low. Urinary excretion of ketoanions secondary to systemic ketoacidosis can cause a positive AG despite adequate ammonium excretion. Thus, ketonuria should also be excluded in cases of metabolic acidosis in which the etiology is uncertain enough to warrant calculation of the urine AG.

The urine net charge is also less useful when large amounts of bicarbonate are present in the urine (pH >6).


Urinary pH and Urinary Anion Gap

Urinary pH tends to be increased in the presence of large amounts of ammonia in the urine.

An inability to lower the urinary pH to less than 5.5 despite systemic acidemia was formerly considered the hallmark of dRTA. Given that a lower pH implies increased excretion of acid if the concentration of urinary buffers stays constant, an inability to decrease urinary pH was interpreted as signifying decreased excretion of urinary acid. Although this is true in many cases, it is not in all cases.

The presence of large amounts of ammonia in the urine, which typically occurs with chronic metabolic acidosis, tends to increase the urinary pH. In hyperkalemic dRTA, urine pH can be maximally acidic. Decreased acid excretion is due to other concurrent defects, mainly decreased production of ammonia.

In patients with normal AG acidosis due to diarrhea, the pH can be greater than 5.5. This is because volume contraction results in decreased availability of Na+ for reabsorption in the collecting duct, lessening the negative intratubular electrochemical potential and, thus, the rate of proton secretion.

Infection with urea-splitting organisms (eg, Proteus species) can also cause elevated urinary pH and may lead to an incorrect diagnosis of RTA.

The urinary AG is calculated using the following formula: UAG = UNA+ + UK+ - UCl-.

Na+ + K+ + unmeasured cations = Cl- + unmeasured anions. In the absence of ketonuria and bicarbonaturia, there are no significant unmeasured anions in the urine. The principal unmeasured cation is NH4+ and when present in substantial concentration is evident by a negative AG. UAG is thus a measure of the urinary concentration of NH4+.

Urinary pH and urinary AG values in patients with RTA are as follows:

  • dRTA - Urinary pH greater than 5.3, urinary AG positive
  • pRTA - Urinary pH usually less than 5.3, urinary AG variable
  • dRTA type IV - Urinary pH less than 5.3, urinary AG positive
  • Renal failure - Urinary pH less than 5.3, urinary AG positive
  • Diarrhea - Urinary pH variable, urinary AG negative

Acid-Loading Tests

The most common acid-loading test uses ammonium chloride (NH4 Cl). This test consists of the oral administration of 0.1 g/kg (1.9 mEq/kg) of ammonium chloride to induce metabolic acidosis. Urine is collected hourly 2-8 hours after administration, and urinary pH is tested. Failure to acidify urine below a pH of 5.5 supports the diagnosis of dRTA or incomplete dRTA, in which systemic acidosis is absent.

Urinary pH would decrease normally in pRTA and hypoaldosteronism. In the setting of a preexisting acidosis, administration of an acidifying agent is unnecessary and potentially harmful.

Calcium chloride and arginine hydrochloride can also be used to induce systemic acidosis, with interpretation of results the same as for the ammonium chloride test.


Urinary PCO2 Test

The urinary PCO2 during alkaline diuresis reflects the rate of proton secretion in the distal tubule. In an alkaline diuresis induced by infusions of NaHCO3, the intratubular pH is high, and this results in a high rate of proton secretion. Because of the high concentration of bicarbonate in the urine, large quantities of carbonic acid (H2 CO3) form. The carbonic acid dehydrates and forms water and carbon dioxide, thus raising the urinary PCO2.

In healthy individuals undergoing a bicarbonate diuresis, the urine PCO2 should rise to above 70 mm Hg. In patients with secretory defects, ie, the inability to secrete protons in the collecting duct, the urine PCO2 fails to rise above 55 mm Hg. In patients with permeability defects, the CO2 tension rises normally because of the normal proton-pump function and because the H+ gradient does not favor the back-diffusion of protons under conditions of alkaline diuresis. Normal results are also observed in hypoaldosteronism RTA and reversible voltage-dependent defects.

The test is performed by infusing a quantity of NaHCO3 sufficient to raise plasma bicarbonate to greater than 30 mEq/L and urine pH to higher than 7. This can be accomplished with intravenous or oral NaHCO3. With the intravenous route, 7.5% NaHCO3 is infused at a rate of 1-2 mL/min for 2 hours, with hourly samples taken for the duration of the test. The infusion is stopped when the pH from at least 3 urine collections is greater than 7.8. With the oral route, 200 mEq of NaHCO3 is given in divided doses the evening prior to testing, and overnight dehydration is necessary.

An important disadvantage of this test is that false-positive results can occur in persons with concentration defects, because urine bicarbonate concentrations are lower and lead to less carbon dioxide generated. This is significant, because concentration defects are common in persons with dRTA and are a consistent finding in persons with chronic renal failure.

Contraindications to the test are other sodium-retaining states and congestive heart failure.


Sodium Sulfate and Furosemide Test

In healthy individuals, administering a sodium salt of a nonreabsorbable anion in the presence of a sodium-avid state results in negative intratubular potential and thus in increased proton and potassium secretion. In patients with either secretory or voltage defects, the urine will not become maximally acidic.

The test is performed by restricting salt to less than 1 g/d Na+ for 3 days and orally administering 1 mg of fludrocortisone in the evening, 12 hours before the sodium sulfate infusion, in order to ensure a sodium-avid state. The following morning, 500 mL of 4% sodium sulfate is administered intravenously over 1 hour. Urine pH, potassium excretion, and net acid excretion should be obtained.

A normal response does not necessarily rule out an acidification defect, because a normal response can be observed in patients with hyperkalemic dRTA and in those with reversible voltage-dependent defects, as with lithium.

False-positive results can occur when the infusion is too rapid or when sodium avidity is absent because inadequate preparation or aldosterone resistance causes a bicarbonate-losing osmotic diuresis, thus raising the urine pH.

Because sodium sulfate is not commercially available, this method is largely limited to research settings. A more practical method involves orally administering 1 mg fludrocortisone the evening before testing and then giving 1 mg/kg of oral or intravenous furosemide the following morning. Evidence suggests furosemide enhances distal acidification by increasing distal sodium delivery, and results should be interpreted in the same manner as for the sodium sulfate test.

Contributor Information and Disclosures

Sai-Ching Jim Yeung, MD, PhD, FACP Professor of Medicine, Department of Emergency Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center

Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, Endocrine Society

Disclosure: Nothing to disclose.


Mahendra Agraharkar, MD, MBBS, FACP FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine; President and CEO, Space City Associates of Nephrology

Mahendra Agraharkar, MD, MBBS, FACP is a member of the following medical societies: American College of Physicians, American Society of Nephrology, National Kidney Foundation

Disclosure: Received ownership interest/medical directorship from South Shore DaVita Dialysis Center for other; Received ownership/medical directorship from Space City Dialysis /American Renal Associates for same; Received ownership interest from US Renal Care for other.

Nicholas J Sarlis, MD, PhD, FACP Vice President, Head of Medical Affairs, Incyte Corporation

Nicholas J Sarlis, MD, PhD, FACP is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American Association of Clinical Endocrinologists, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Radiation Oncology, American Thyroid Association, Endocrine Society, New York Academy of Sciences, Royal Society of Medicine, Association for Psychological Science, American College of Endocrinology, European Society for Medical Oncology, American Society of Clinical Oncology

Disclosure: Received salary from Incyte Corporation for employment; Received ownership interest from Sanofi-Aventis for previous employment; Received ownership interest/ stock & stock option (incl. rsu) holder from Incyte Corporation for employment.

Mark T Fahlen, MD Private Practice, Mark T Fahlen, MD, Inc

Mark T Fahlen, MD is a member of the following medical societies: American College of Physicians, Renal Physicians Association

Disclosure: Nothing to disclose.

Kanwarpreet Baweja, MD Fellow in Nephrology, University of Texas Health Science Center

Kanwarpreet Baweja, MD is a member of the following medical societies: American Medical Association, American Society of Nephrology, National Kidney Foundation, Medical Council of India

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.


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

Disclosure: Medscape Salary Employment

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, 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 Federation for Medical Research, American Heart Association, American Society of Nephrology, American Society of Transplantation, American Thoracic Society, International Society of Nephrology, and Royal College of Physicians

Disclosure: Genzyme Grant/research funds Other

  1. Liborio AB, Daher EF, de Castro MC. Characterization of acid-base status in maintenance hemodialysis: physicochemical approach. J Artif Organs. 2008. 11(3):156-9. [Medline].

  2. Davenport A. Potential adverse effects of replacing high volume hemofiltration exchanges on electrolyte balance and acid-base status using the current commercially available replacement solutions in patients with acute renal failure. Int J Artif Organs. 2008 Jan. 31(1):3-5. [Medline].

  3. Blake-Palmer KG, Karet FE. Cellular physiology of the renal H+ATPase. Curr Opin Nephrol Hypertens. 2009 Jun 24. [Medline].

  4. Basic DT, Hadzi-Djokic J, Ignjatovic I. The history of urinary diversion. Acta Chir Iugosl. 2007. 54(4):9-17. [Medline].

  5. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009 May. 5(5):270-6. [Medline].

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