AKDH

Metabolic Acidosis
Keiko I. Greenberg and Stewart H. Lecker

Metabolic acidosis is a common disorder that occurs in a variety of clinical settings. The kidney maintains acid-base homeosta-
sis through the elimination of protons and reabsorption/generation of bicarbonate. Metabolic acidosis develops when these
mechanisms are overwhelmed or impaired, in situations such as rapid production of nonvolatile acids, abnormally high bicar-
bonate losses, and impaired acid excretion by the kidney. Determining the presence or absence of an anion gap is the first step in
ascertaining the etiology of metabolic acidosis. The presence or absence of an osmolal gap, urine pH, and serum potassium
levels may be useful in certain settings. We discuss a comprehensive approach to metabolic acidosis and present important clin-
ical scenarios.
Q 2025 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
Key words: Acid-base disorders, Metabolic acidosis, Anion gap acidosis, Renal tubular acidosis, Board review

T ogether, the kidneys and lungs maintain acid-base ho-

meostasis and regulate pH. The lungs eliminate
approximately 15,000 mmol of carbon dioxide (CO2)
D. Nonanion gap metabolic acidosis and respiratory
acidosis
E. High anion gap metabolic acidosis and respiratory
generated daily by normal cellular metabolism, while acidosis
the kidneys excrete 50 to 100 mEq of nonvolatile acids—
The correct answer is C.
largely sulfuric acid and phosphoric acid—produced daily
by consumption of a typical Western diet.1,2 Protons are
Acid-base disorders can be approached in a stepwise
eliminated by the kidney through the use of urinary
manner. First, the arterial blood pH of 7.20 and low serum
buffers to form titratable acid and generation of ammo-
bicarbonate indicate that this man has an acidemia. Next,
nium. The kidneys control serum bicarbonate concentra-
his anion gap is calculated as:Anion gap ¼ [sodium] –
tion by regulating reabsorption of bicarbonate and
generating new bicarbonate. Metabolic acidosis occurs ([CO2] 1 [chloride]) ¼ 143 mEq/L – (120 mEq/L 1 11
mEq/L) ¼ 12 mEq/L. His anion gap is slightly elevated.
when nonvolatile acids are produced more rapidly than
His albumin was noted to be low at 3.4 g/dL. Albumin
they can be excreted, bicarbonate losses are abnormally
high, or the kidney’s ability to excrete acid is impaired.2 carries a negative charge and is a significant component
of the anion gap.3 A low serum albumin will result in a
reduction of the anion gap, and a high serum albumin
CASE 1
A 54-year-old man with hypertension and chronic kidney will increase the anion gap. Hypoalbuminemia will lower
disease stage 3 (baseline creatinine 2.0 mg/dL) presents the anion gap by 2.5 mEq/L for each 1 g/dL below
with 4 days of diarrhea. He reports feeling lightheaded. 4.5 g/dL—in this case, the anion gap corrected for hypoal-
His blood pressure is 96/62 mmHg, and pulse is 94 beats buminemia is about 14.5 mEq/L.3 Then, the Winter’s
per minute. His exam is notable for dry mucous mem- formula assesses the appropriateness of respiratory com-
branes. pensation:Expected PCO2 ¼ (1.5 3 [CO2]) 1 8 6 2 ¼
Laboratory studies are as follows. (1.5 3 11) 1 8 6 2 ¼ 22.5 – 26.5 mmHg. The PCO2 pro-
vided falls within the expected range, indicating that there
is no respiratory disorder. Finally, the delta/delta ratio
Value Normal Range (change in anion gap/change in serum bicarbonate) evalu-
ates for a concomitant nonanion gap metabolic acidosis or
Serum
metabolic alkalosis. There are four possible scenarios:
Sodium 143 mEq/L 136-145 mEq/L
Potassium 4.5 mEq/L 3.4-5.0 mEq/L
 Delta/delta ratio less than 1—a high anion gap acidosis is
Chloride 120 mEq/L 98-107 mEq/L present, but the decrease in bicarbonate is greater than the
CO2 11 mEq/L 22-31 mEq/L change in anion gap indicating the presence of a concom-
Blood urea nitrogen (BUN) 80 mg/dL 9-23 mg/dL itant nonanion gap acidosis, such as diarrhea; and
Creatinine 4.3 mg/dL 0.6-1.1 mg/dL
Albumin 3.4 g/dL 3.2-4.8 g/dL
Arterial blood
pH 7.20 7.35-7.45 From the MedStar Georgetown University Hospital, Washington, DC
PCO2 26 mmHg 35-45 mmHg (K.I.G.); Beth Israel Deaconess Medical Center, Renal Unit, Libby 2, Harvard
Medical School, Boston MA (S.H.L.).
Financial Disclosure: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Keiko I. Greenberg, MD, MHS, MedStar George-
town University Hospital, 3800 Reservoir Rd NW, PHC 6, Washington, DC
What acid-base disorder(s) does he have? 20007. E-mail: [email protected]
A. Nonanion gap metabolic acidosis Ó 2025 Published by Elsevier Inc. on behalf of the National Kidney Founda-
B. High anion gap metabolic acidosis tion, Inc.
C. Nonanion gap metabolic acidosis and high anion gap 2949-8139/$36.00
metabolic acidosis https://doi.org/10.1053/j.akdh.2025.01.012

Adv in Kidney Disease and Health 2025;32(1):61-68 61

62 Greenberg and Lecker

 Delta/delta ratio of approximately 1—a strong acid in- (Continued )

creases the anion gap and causes an equivalent decrease Value Normal Range
in bicarbonate concentration, such as in diabetic ketoaci-
dosis; Creatinine 4.85 mg/dL 0.6-1.1 mg/dL
 Delta/delta ratio of 1 to 2—hard to interpret. A high Glucose, random 86 mg/dL 3.2-4.8 g/dL
Lactic acid 13.1 mmol/L 0.7-2.0 mmol/L
anion gap acidosis is present, but the decrease in bi-
White blood cells 5.3 k/uL 4.0-10.8 k/uL
carbonate is less than the change in anion gap, sug- Arterial blood
gesting the possibility of a concomitant metabolic pH 7.22 7.35-7.45
alkalosis. PCO2 27 mmHg 35-45 mmHg
 Delta/delta ratio greater than 2—a high anion gap
acidosis is present, but the decrease in bicarbonate is
less than the change in anion gap indicating the pres-
ence of a concomitant metabolic alkalosis, such as What is the most likely cause of her metabolic acidosis?
vomiting. A. Diabetic ketoacidosis
B. Starvation ketosis
In this case, D anion gap/D [CO2] ¼ corrected anion gap – C. Lactic acidosis secondary to sepsis
normal anion gap/normal CO2 – observed CO2 ¼ 4.5/ D. Metformin-associated lactic acidosis
13 ¼ 0.35. E. D-lactic acidosis
The [CO2] decreased more than expected from the in-
crease in anion gap, indicating that there is a secondary The correct answer is D.
metabolic process, a nongap metabolic acidosis. In this sce-
nario, the high anion gap metabolic acidosis is likely due to Metabolic acidosis is a common disorder and can occur
reduced capacity to excrete acid in the setting of acute kid- in the setting of a variety of conditions (Table 1). The anion
ney injury, while the cause of the non-anion gap metabolic gap can be used to classify these conditions as high anion
acidosis is likely to be due to bicarbonate losses stemming gap metabolic acidoses or nonanion gap metabolic acido-
from diarrhea. ses (also called hyperchloremic metabolic acidoses). In a
high anion gap metabolic
Key References CLINICAL SUMMARY
acidosis, the presence of a
 Emmett M. Review of Clin- strong acid causes the [CO2]
ical Disorders Causing to fall, increasing the gap be-
 Metabolic acidosis is common disorder and can occur in
Metabolic Acidosis. Adv variety of clinical settings.
tween [sodium] and the sum
Chronic Kidney Dis. 2022; of [CO2] and [chloride].4 The
29(4):355-363.  Early recognition is key to successful management. mnemonic GOLD MARK
 Fenves AZ and Emmett  A systematic approach to diagnosis is essential in outlines the most common
M. Approach to Patients determining appropriate treatment strategies. causes of high anion gap
with High Anion Gap metabolic acidosis.5
Metabolic Acidosis: Core (Table 2).
Curriculum 2021. Am J Kidney Dis. 2021; 78(4):590-600. In this clinical scenario, the patient has a high anion gap
metabolic acidosis; the anion gap is 23 mEq/L. This ap-
pears to be due to the presence of lactic acid, making dia-
CASE 2
betic ketoacidosis and starvation ketosis (two of the other
A 48-year-old woman with hypertension, diabetes, and
answer options) unlikely. D-lactic acidosis occurs in short
CKD stage 3 (baseline creatinine 2.0 mg/dL) presents
gut syndrome and some other gastrointestinal disorders.6
with confusion. Her regular medications include lisinopril
Certain bacteria in the intestines produce D-lactate as a by-
and metformin. She reports that she has also been taking
product of carbohydrate metabolism—D-lactate accumu-
ibuprofen twice a day for about 2 weeks after she fell
lates in patients with short gut syndrome, possibly due
and injured her right ankle. She denies fever, chills, cough,
to reduced clearance of D-lactate. As most laboratory as-
nausea, vomiting, flank pain, dysuria, and urinary fre-
says for lactic acid measure L-lactic acid and not D-lactic
quency. She is afebrile, and her blood pressure is 92/
acid, D-lactic acidosis is not detected by standard labora-
52 mmHg.
tory testing. Therefore, this patient does not have D-lactic
Laboratory studies are as follows:
acidosis but has L-lactic acidosis. Lactic acidosis can be
classified as type A, which occurs in the setting of hypoper-
Value Normal Range fusion and impaired tissue oxygenation, or type B, in
which tissue hypoperfusion is not readily apparent.2,3
Serum
Common causes of type A lactic acidosis include hypovo-
Sodium 136 mEq/L 136-145 mEq/L
Potassium 6.1 mEq/L 3.4-5.0 mEq/L lemia, sepsis, heart failure, and cardiac arrest. Causes of
Chloride 101 mEq/L 98-107 mEq/L type B lactic acidosis include leukemia, lymphoma, signif-
CO2 12 mEq/L 22-31 mEq/L icant alcohol use, and medications such as metformin,
Blood urea nitrogen (BUN) 79 mg/dL 9-23 mg/dL nucleoside reverse transcriptase inhibitors, linezolid, and
(Continued ) high-dose propofol.2 Mechanisms leading to the

Adv in Kidney Disease and Health 2025;32(1):61-68

 Metabolic Acidosis 63

Table 1. Disorders Causing Metabolic Acidosis

HAGMA Due to Abnormally Increased Rate of Systemic Acid Generation and/or the Ingestion/Infusion/Absorption of Acids or Acid
Precursors
L-lactic acidosis Type A
Type B
D-lactic acidosis Short bowel syndrome
Ketoacidosis Diabetic
Alcoholic
Congenital enzymatic defects
Toxins/poisons that increase endogenous Salicylate poisoning
strong acids Chronic acetaminophen ingestion (5-oxoproline)
Compounds metabolized to strong acids Methanol (formic acid)
Ethylene glycol (oxalic acid)
Diethylene glycol (2-hydroxyethoxyacetic acid)
Propylene glycol (lactic acid)
Toluene ingestion/inhalation (hippuric acid)
Kidney Failure
Uremic Acidosis
Hyperchloremic acidosis/nonanion gap acidosis
Infusion or ingestion of HCl or NH4Cl
molecules metabolized to HCl Arginine-HCl
Lysine-HCl
Loss of Na(K)HCO3 and/or Na(K) Proximal renal tubular acidosis (type II RTA)
organic metabolizable anion salts Watery diarrhea
Pancreatic fluid loss
Urine exposed to GI epithelium, especially colon or ileum
Excretion of Na(K) with the anions of Distal renal tubular acidosis (type I RTA)
strong acids that have been added to Reduced renal NH41 excretion
the ECF (instead of the excretion of  Type IV (hyperkalemic) renal tubular acidosis
these strong acid anions with either  Reduced renal NH41 excretion due to chronic kidney disease
NH41 or titratable acid) Conversion of high [AG] metabolic acidosis to hyperchloremic metabolic acidosis
 During recovery from ketoacidosis—loss of Na(K) with beta-hydroxybutyrate and
acetoacetate
 Toluene ingestion/inhalation—loss of Na(K) with hippurate and benzoate and retention
of the protons
 Conversion of other AG acidoses to hyperchloremic metabolic acidosis (D-lactate renal
excretion as Na(K) D-lactate)

Abbreviations: ECF, extracellular fluid; GI, gastrointestinal; HAGMA, high anion gap metabolic acidosis.
From: Emmett M. Review of Clinical Disorders Causing Metabolic Acidosis. Adv Chronic Kidney Dis. 2022; 29(4):355-363.

generation of lactic acid in type B lactic acidosis include the tions, metformin-associated lactic acidosis may be under-
presence of regional areas of hypoxia (eg, within tumors), recognized.8 Diagnosis requires a high index of
decreased lactate clearance (in liver disease), and impaired suspicion, as it may mimic sepsis or mesenteric ischemia.
oxidative metabolism in mitochondria (as in thiamine defi- Management is supportive—kidney replacement therapy
ciency and medications/toxins).2 In some malignancies, tu- may be needed to manage severe metabolic acidosis with
mor cells preferentially use glycolysis over oxidative or without hyperkalemia.
metabolism, generating large amounts of lactate in what
is known as the Warburg effect.7
Key References
This patient’s blood pressure is low, but her white blood
 Fenves AZ and Emmett M. Approach to Patients with
cell count is normal, and she has no obvious symptoms
High Anion Gap Metabolic Acidosis: Core Curriculum
suggesting that she has infection/sepsis. She developed
2021. Am J Kidney Dis. 2021; 78(4):590-600.
acute kidney injury presumably due to ibuprofen use—
 Mehta AN, Emmett JB, Emmett M. GOLD MARK: an
this likely led to accumulation of metformin, which re-
anion gap pneumonic for the 21st century. Lancet.
sulted in a type B lactic acidosis. Metformin has a black
2008; 372(9642):892.
box warning due to risk of lactic acidosis; the risk of devel-
oping lactic acidosis is higher with impaired kidney func-
tion, and it is for this reason that metformin use is not CASE 3
recommended when eGFR is ,30 mL/min/1.73 m2. As A 35-year-old man presents with altered mental status. He
metformin is among the most widely prescribed medica- is not able to provide any history, but his family reports

Adv in Kidney Disease and Health 2025;32(1):61-68

64 Greenberg and Lecker

Table 2. GOLD MARK Mnemonic for High Anion Gap Metabolic Acidosis
Letter Parameter Potential Causes
G Glycols Ingestion/infusion of ethylene, propylene, or diethylene glycol; metabolism generates
glyoxylic, oxalic, and D- and L-lactic acid.
O 5-oxoproline Chronic acetaminophen use can generate 5-oxoproline (a strong acid that is also called
pyroglutamic acid).
L L-lactic acidosis Multiple etiologies of types A and B lactic acidosis.
D D-lactic acidosis Carbohydrate loading in patients with short gut syndromes.
M Methanol Metabolism generates formic acid.
A Aspirin Toxic levels generate multiple organic acids including keto acids.
R Renal failure Accumulation of multiple inorganic and organic acids including sulfuric and phosphoric acid.
K Ketoacidosis b-hydroxybutyric and acetoacetic acid.

From: Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap pneumonic for the 21st century. Lancet. 2008; 372(9642):892.

that he has a history of alcohol use. Blood pressure is 95/ Diagnosis of toxic alcohol ingestion can be challenging as
52 mmHg. Urine microscopy shows abundant crystals the patient may not be able to provide a history, and many
(Fig 1). laboratories may not have assays that measure toxic
Laboratory studies are as follows: alcohol levels in a timely manner.10 Some of the clinical fea-
tures that are associated with a specific toxic alcohol
Value Normal Range include:
 Acute kidney injury and urinary calcium oxalate crys-
Serum
Sodium 146 mEq/L 136-145 mEq/L
tals (Fig 1) that are suggestive of ethylene glycol intoxi-
Potassium 5.2 mEq/L 3.4-5.0 mEq/L cation,
Chloride 112 mEq/L 98-107 mEq/L  Vision impairment, even permanent blindness, that can
CO2 7 mEq/L 22-31 mEq/L occur with methanol intoxication,
Blood urea nitrogen 45 mg/dL 9-23 mg/dL  Lactic acidosis and acute kidney injury in patients on a
(BUN) high-dose infusion of lorazepam, which contains pro-
Creatinine 1.9 mg/dL 0.6-1.1 mg/dL pylene glycol,
Glucose, random 132 mg/dL 65-140 mg/dL  Gastrointestinal symptoms (abdominal pain, nausea,
Lactic acid 2.8 mmol/L 0.7-2.0 mmol/L vomiting, acute pancreatitis), neuropathy, and severe
Osmolality 350 mOsm/kg 275-300 mOsm/kg
acute kidney injury requiring hemodialysis seen in di-
ethylene glycol intoxication, and
 The presence of acetone, and possibly a spuriously high
This presentation is most likely due to the ingestion of creatinine due to interference of the Jaffe reaction by
which of the following:
A. Ethylene glycol
B. Methanol
C. Propylene glycol
D. Diethylene glycol
E. Isopropyl alcohol
The correct answer is A.

This patient has a high anion gap of 27 mEq/L. Calculation

of the expected serum osmolality, as:(2 3 [Na1]) 1 ([BUN]/
2.8) 1 ([glucose]/18) z 292 1 16 1 7 z 315 mOsm/kg, Re-
veals a large osmolal gap. These findings suggest toxic
alcohol ingestion. Ingestion of all of the above substances
will cause an osmolal gap. Isopropyl alcohol does not cause
a metabolic acidosis—it is directly toxic, unlike the others,
which are metabolized to toxic acids (ethylene glycol to ox-
alic acid and glycolic acid, methanol to formic acid, propyl-
ene glycol to D- and L-lactic acid, and diethylene glycol to
2-hydroxyethoxyacetic acid and diglycolic acid).9 Alcohol
dehydrogenase catalyzes the oxidation of all of these toxic
alcohols. Isopropyl alcohol is converted to acetone by
alcohol dehydrogenase; the others are converted to alde- Figure 1. Biswas, Arif. (Photographer). Calcium oxalate crys-
hydes, which then are further oxidized by aldehyde dehy- tal micrograph from urine sediment [digital image].
drogenase. Retrieved from http:www.shutterstock.com.

Adv in Kidney Disease and Health 2025;32(1):61-68

 Metabolic Acidosis 65

acetone, associated with isopropyl alcohol intoxica- The correct answer is E.

tion.9,10
Defects in the absorption of bicarbonate result in a
Treatment may include fomepizole and/or hemodialysis. proximal renal tubular acidosis (type 2 RTA). This can
Fomepizole inhibits alcohol dehydrogenase, slowing the occur due to impaired bicarbonate transport across the
generation of toxic metabolites, except in the case of iso- basolateral membrane or impaired carbonic anhydrase
propyl alcohol, which is metabolized to less toxic acetone. activity (Fig 2, right). These defects essentially reduce
Hemodialysis may be helpful in removing the parent the threshold for bicarbonate reabsorption. Initially,
alcohol and toxic metabolites and should be considered reduced bicarbonate absorption results in greater bicar-
for severe acidemia or acute kidney injury. For this patient, bonate delivery to the distal nephron, where the capac-
urinary calcium oxalate crystals suggest ethylene glycol ity for bicarbonate reabsorption is limited), and high
intoxication. Treatment would include fomepizole and levels of urinary bicarbonate. When the reduced
possibly hemodialysis. Some of the scenarios in which threshold for bicarbonate reabsorption is reached, a
the Extracorporeal Treatments in Poisoning Workgroup steady state is established where all filtered bicarbonate
recommends hemodialysis for ethylene glycol poisoning is reabsorbed and urine pH is ,5.5. Proximal RTA can
include: ethylene glycol concentration .310 mg/dL when occur in isolation or, more commonly, as part of gener-
fomepizole is available or .62 mg/dL when fomepizole alized proximal tubular dysfunction in which hypo-
(or ethanol) is not available, osmolal gap .50 in when fo- phosphatemia, hypouricemia, glucosuria, and
mepizole is available or .10 when fomepizole (or ethanol) aminoaciduria may be present (Fanconi syndrome).12
is not available, anion gap .23, and the presence of coma, Isolated RTA can be hereditary (due to mutations in
seizure, or acute kidney injury.11 the gene encoding NBCe1) or acquired (due to use of
acetazolamide or other carbonic anhydrase inhibitors).
Key References There are some inherited causes of Fanconi syndrome,
 Kraut JA, Mullins ME. Toxic alcohols. N Engl J Med. but acquired Fanconi syndrome—due to systemic dis-
2018; 378: 270-80. eases such as multiple myeloma or amyloidosis, or med-
 Mullins ME, Kraut JA. The Role of the Nephrologist in ications such as tenofovir, ifosfamide, topiramate, and
Management of Poisoning and Intoxication: Core Cur- aminoglycosides—is much more common.13
riculum 2022. Am J Kidney Dis. 2021; 79(6):877-889 Proximal RTA should be suspected in patients with non-
anion gap metabolic acidosis, urine pH , 5.5, and hypo-
CASE 4 kalemia—hypokalemia appears to occur due to increased
A 26-year-old man with osteosarcoma treated with distal sodium delivery and increased aldosterone levels
cisplatin and ifosfamide is admitted to the hospital with (possibly from bicarbonate wasting).12,14 Other signs of
worsening pain and failure to thrive. He is found to have proximal tubular dysfunction also support the diagnosis.
laboratory abnormalities that persist several days into his The urine anion gap has been used as a diagnostic tool in
admission. evaluating RTAs as it was thought to be an indicator of
Laboratory studies are as follows: urinary ammonium. In theory, the urine anion gap should
be high in proximal RTA as high levels of ammonium are
Value Normal Range
present in the setting of metabolic acidosis. However,
recent data suggest that the urine anion gap does not
Serum correlate well with urine ammonium levels and should
Sodium 139 mEq/L 136-145 mEq/L not be used as a surrogate for urinary ammonium.15
Potassium 3.1 mEq/L 3.4-5.0 mEq/L
Treatment of proximal RTA is bicarbonate supplementa-
Chloride 112 mEq/L 98-107 mEq/L
CO2 17 mEq/L 22-31 mEq/L
tion, usually potassium citrate—high doses (5 mEq/kg
Blood urea nitrogen (BUN) 4 mg/dL 9-23 mg/dL or more per day) are usually required.12 Medications
Creatinine 0.9 mg/dL 0.6-1.1 mg/dL thought to be causing acquired proximal RTA should be
Glucose, random 125 mg/dL 65-140 mg/dL discontinued when possible. With bicarbonate supple-
Urine mentation, serum bicarbonate usually remains below
pH 5.3 5.0-8.5 normal while urine pH increases due to bicarbonate
Glucose 21 Negative wasting.
Protein 11 Negative This patient has a nonanion gap metabolic acidosis;
anion gap is 10 mEq/L. Urine pH is ,5.5, suggesting a
proximal RTA. The presence of glucosuria and low-
grade proteinuria suggests generalized tubular dysfunc-
Which additional laboratory abnormality would sup- tion, likely an acquired Fanconi syndrome due to
port the most likely diagnosis? ifosfamide. As noted above, other findings in generalized
A. Hyperuricemia proximal tubular dysfunction include urinary phosphorus
B. Hypomagnesemia wasting/hypophosphatemia and urinary uric acid
C. Hypercalciuria wasting/hypouricemia. Cisplatin and other drugs can
D. Hypocitraturia cause hypomagnesemia, but hypomagnesemia is not a
E. Hyperphosphaturia clinical feature of proximal RTA. Hypercalciuria and

Adv in Kidney Disease and Health 2025;32(1):61-68

66 Greenberg and Lecker

Figure 2. Bicarbonate reabsorption in the proximal tubule. (Left) Approximately 80% of filtered bicarbonate is reabsorbed in
the proximal tubule. Filtered bicarbonate combines with hydrogen ions (H1) that have been secreted into the tubular lumen
by the sodium/hydrogen exchanger 3 (NHE3) and H1-ATPase on the apical membrane.12,13 There, the H1 combines with
filtered bicarbonate to form H2CO3, then H2O and CO2, which is catalyzed by a carbonic anhydrase (CA). CO2 diffuses into
the cell, where a cytosolic carbonic anhydrase converts CO2 and H2O to H1 and bicarbonate. Bicarbonate is absorbed into
bloodstream through the sodium/bicarbonate cotransporter (NBCe1). The movement of sodium and bicarbonate is driven
by the basolateral membrane potential generated by the Na1/K1 ATPase and the two-pore domain acid-sensing K1 channel.
(Right) In proximal RTA, impairment of CA or NBCe1 reduces bicarbonate reabsorptive capacity, leading to higher bicarbon-
ate levels in the tubular lumen. Abbreviation: RTA, renal tubular acidosis.

hypocitraturia are not associated with proximal RTA— (Continued )

these are discussed below. Value Normal Range

Key References Arterial blood

 Palmer BF, Keleporis E, Clegg DJ. Renal Tubular pH 7.21 7.35-7.45
Acidosis and Management Strategies: A Narrative Re- PCO2 38 mmHg 35-45 mmHg
Urine
view. Adv Ther. 2021; 38:949-968.
pH 6.5 5.0-8.5
 Kashoor I, Batlle D. Proximal renal tubular acidosis with
and without Fanconi syndrome. Kidney Res Clin Pract.
2019; 38(3):267-281.
What is the most likely cause of her laboratory abnor-
CASE 5 malities?
A 50-year-old woman with hypertension, diabetes melli- A. Diarrhea
tus, and Sjogren’s syndrome who presents with weak- B. Proximal renal tubular acidosis
ness. She reports that she was in her usual state of C. Distal renal tubular acidosis
health until a few hours prior to presentation. Blood pres- D. Type 4 renal tubular acidosis due to diabetes
sure is 128/75 mmHg. She reports that she has been E. Gordon’s syndrome (pseudohypoaldosteronism type 2)
adherent to all of her medications, which include meto- The correct answer is C.
prolol 50 mg twice a day and insulin glargine 20 units
subcutaneously nightly. Defects in the excretion of H1 result in a distal RTA (type
Laboratory studies are as follows: 1 RTA). This can occur as a result of impaired H1 secretion
or increased permeability of the luminal membrane to H1
Value Normal Range (Fig 3, right). Urine pH is elevated, reflecting impaired uri-
nary acidification. Hypokalemia is also present—this may
Serum be due to impaired function of H1/K1-ATPase or increased
Sodium 139 mEq/L 136-145 mEq/L aldosterone levels in the setting of acidemia and increased
Potassium 2.0 mEq/L 3.4-5.0 mEq/L
distal sodium delivery.12,16 Distal RTA can be hereditary;
Chloride 112 mEq/L 98-107 mEq/L
CO2 17 mEq/L 22-31 mEq/L
mutations in the genes encoding AE1 and H1-ATPase
Blood urea nitrogen (BUN) 6 mg/dL 9-23 mg/dL have been identified. Acquired distal RTA is more com-
Creatinine 1.22 mg/dL 0.6-1.1 mg/dL mon and is most often caused by Sjogren’s syndrome.
Glucose, random 185 mg/dL 65-140 mg/dL Other causes of distal RTA include other autoimmune dis-
(Continued ) eases such as rheumatoid arthritis and systemic lupus

Adv in Kidney Disease and Health 2025;32(1):61-68

 Metabolic Acidosis 67

Figure 3. Acid and bicarbonate excretion in the collecting duct. (Left) In the a-intercalated cell, carbonic anhydrase catalyzes
the conversion of CO2 and H2O to H1 and bicarbonate. H1 is secreted via the H1/K1-ATPase and H1-ATPase, and bicarbonate
is absorbed through anion exchange protein 1 (AE1).12,16 Ammonia buffers the secreted H1 in the tubular lumen. In the b-
intercalated cell, carbonic anhydrase also forms H1 and bicarbonate. Bicarbonate is secreted in exchange for chloride by pen-
drin. H1 is absorbed by H1-ATPase on the basolateral membrane. Other bicarbonate transporters include anion exchanger 4
(AE4) and Na1-dependent chloride-bicarbonate exchanger (NDBCE). In the principal cell, the reabsorption of sodium by the
epithelial sodium channel (ENaC) generates the transepithelial voltage gradient that drives H1 and K1 excretion by a-interca-
lated cells. (Right) In distal RTA, impairment of H1/K1-ATPase and H1-ATPase leads to decreased H1 excretion by a-interca-
lated cells. In hyperkalemic RTA, hypoaldosteronism reduces Na reabsorption through ENaC, which lessens the
transepithelial voltage gradient that drives H1 and K1 excretion by a-intercalated cells. Abbreviation: RTA, renal tubular
acidosis.

erythematosus, sickle cell disease, lithium, amphotericin excretion by a-intercalated cells (Fig 3, left).12,17 Aldoste-
B, and toluene. Topiramate can inhibit carbonic anhydrase rone increases the activity of the Na1/K1-ATPase on the
in multiple segments of the nephron and cause a mixed basolateral surface of the principal cell, which reduces
acidosis with features of both proximal and distal RTA intracellular [Na1] and promotes the influx of Na1 into
(type 3 RTA).16 the cell via ENaC. In addition, aldosterone increases the
Distal RTA should be suspected in patients with nonan- number of ENaCs in the apical membrane of the principal
ion gap metabolic acidosis, urine pH . 5.3, and hypoka- cell and increases the number of H1-ATPases in the apical
lemia. Nephrocalcinosis and nephrolithiasis are common membrane of the a-intercalated cells. Aldosterone has still
in distal RTA, as acidosis causes increased bone resorp- other effects on urinary acid excretion through effects on
tion leading to hypercalciuria and also increases proximal urinary K1.17
citrate reabsorption causing hypocitraturia. Calcium Hypoaldosteronism leads to a hyperkalemic RTA (type
phosphate stones are common due to increased urinary 4). Decreased Na1 absorption through ENaC reduces the
pH. Treatment of distal RTA is bicarbonate supplementa- transepithelial voltage gradient, leading to decreased
tion (1-2 mEq/kg/day).12,16 In stone formers with hyper- excretion of H1 and K1 (Fig 3, right). Hyperkalemia in-
calciuria, restricting intake of sodium and animal hibits ammoniagenesis in the proximal tubule, further
proteins and using a thiazide diuretic may be appro- reducing acid excretion.12,17 Hypoaldosteronism also
priate. leads to Na 1 wasting that causes volume contraction
The principal cells in the collecting duct indirectly play a and decreased distal delivery that further reduces excre-
role in H1 secretion. Sodium is reabsorbed from the lumen tion of H1 and K1. Diabetes mellitus is the most common
by the epithelial sodium channel (ENaC)—this generates a cause of hyperkalemic RTA—the majority of patients have
transepithelial voltage gradient that drives H1 and K1 hyporeninemic hypoaldosteronism.17 Renin release from

Adv in Kidney Disease and Health 2025;32(1):61-68

68 Greenberg and Lecker

the juxtaglomerular apparatus may be low due to chronic of H1 excretion (which also generates bicarbonate). In
interstitial fibrosis. Several medications, including distal RTAs, impaired H1 excretion leads to high urine
NSAIDs, angiotensin-converting enzyme inhibitors, pH. In hyperkalemic RTA, hypoaldosteronism reduces so-
angiotensin II blockers, potassium-sparing diuretics, calci- dium absorption through ENaC, diminishing the transepi-
neurin inhibitors, heparin, and trimethoprim can cause a thelial voltage gradient that normally drives H1 and K1
hyperkalemic RTA. Type 4 RTA should be suspected in pa- excretion.
tients with a nonanion gap metabolic acidosis and hyper- Learning objectives.
kalemia; typically patients have at least moderate CKD. As - Recognize common and rare causes of metabolic
this condition results from relative hypoaldosteronism, acidosis.
mineralocorticoid replacement with fludrocortisone could - Use the anion gap as the first step in ascertaining the
be considered, but most patients have hypertension and/or cause of metabolic acidosis.
volume overload, which precludes this approach. Bicar- - Understand the pathophysiology of renal tubular
bonate supplementation for the acidosis and loop diuretics acidosis and distinguish between proximal and distal
or potassium binders for hyperkalemia may be warranted. forms.
There are inherited disorders that mimic hypoaldoster-
onism, such as pseudohypoaldosteronism (PHA) type 1
and PHA type 2 (Gordon syndrome). PHA type 1 involves REFERENCES
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