1. Renal Tubular Acidosis
Basics
Description
• Renal tubular acidosis (RTA): A group of disorders
characterized by an inability of the kidney to resorb
bicarbonate or secrete hydrogen ions, resulting in
hyperchloremic, normal anion gap acidosis. Renal function
(glomerular filtration rate [GFR]) must be normal or near
normal.
• Several types have been identified:
o Type I (distal) RTA: Inability of the distal tubule to
acidify the urine. Due to impaired hydrogen ion
secretion, increased backleak of secreted hydrogen
ions, or impaired sodium reabsorption (causing less
negative potential in the lumen and hence less
hydrogen/potassium secretion). Urine pH >5.5.
o Type II (proximal) RTA: Defect of the proximal tubule
in bicarbonate (HCO3) reabsorption. HCO3 fully
reabsorbed only when plasma HCO3 concentration
<15–16 mEq/L (compared with normal threshold of 24
mEq/L). Urine pH <5.5 unless plasma HCO3 above
reabsorptive threshold.
o Type III RTA: Extremely rare autosomal recessive
syndrome with features of both type I and type II (may
be due to carbonic anhydrase II deficiency)
o Type IV RTA (hyporeninemic hypoaldosteronism): Due
to aldosterone resistance or deficiency that results in
hyperkalemia. Urine pH usually <5.5.
Epidemiology
Incidence
• Predominant age: All ages
• Predominant sex: Male > Female (with regard to type II RTA
with isolated defect in bicarbonate reabsorption)
Risk Factors
Genetics
• Type I RTA: Autosomal dominant or recessive. May occur in
association with other genetic diseases (e.g., Ehlers-Danlos
syndrome, hereditary elliptocytosis, or sickle cell
nephropathy). The autosomal recessive form is associated
with sensorineural deafness.

2. • Type II RTA: Autosomal dominant form is rare. Autosomal
recessive form is associated with ophthalmologic
abnormalities and mental retardation. Occurs in Fanconi
syndrome, which is associated with several genetic diseases
(e.g., cystinosis, Wilson disease, tyrosinemia, hereditary
fructose intolerance, Lowe syndrome, galactosemia, glycogen
storage disease, and metachromatic leukodystrophy).
• Type IV RTA: Some cases familial, such as
pseudohypoaldosteronism type I (autosomal dominant)
General Prevention
Careful use or avoidance of agents listed here as causative
Etiology
• Type I RTA:
o Genetic: Autosomal dominant, autosomal recessive
associated with sensorineural deafness
o Sporadic
o Ehlers-Danlos syndrome
o Autoimmune diseases: Sjögren syndrome, rheumatoid
arthritis (RA), systemic lupus erythematosus
o Hematologic diseases: Sickle cell disease, hereditary
elliptocytosis
o Medications: Amphotericin B, lithium, ifosfamide,
foscarnet, analgesics, K+-sparing diuretics (amiloride,
triamterene), trimethoprim
o Toxins: Toluene, glue
o Hypercalciuria, diseases causing nephrocalcinosis
o Vitamin D intoxication
o Medullary cystic disease
o Glycogenosis type III
o Fabry disease
o Wilson disease
o Hypergammaglobulinemic syndrome
o Obstructive uropathy
o Chronic pyelonephritis
o Chronic renal transplant rejection
o Leprosy
o Hepatic cirrhosis
o Malnutrition
• Type II RTA:
o Diseases associated with Fanconi syndrome (see
heading “Genetics”)
o Sporadic
o Multiple myeloma and other dysproteinemic states

3. o Amyloidosis
o Heavy-metal poisoning (e.g., cadmium, lead, mercury,
copper)
o Medications: Acetazolamide, sulfanilamide, ifosfamide,
outdated tetracycline, topiramate
o Autoimmune disease
o Interstitial renal disease
o Nephrotic syndrome
o Congenital heart disease
o Defects in calcium metabolism (hyperparathyroidism)
• Type IV RTA:
o Medications: Nonsteroidal anti-inflammatory drugs,
angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, heparin/LMW heparin, calcineurin
inhibitors (tacrolimus, cyclosporine) (1)
o Diabetic nephropathy
o Obstructive nephropathy
o Nephrosclerosis due to hypertension
o Tubulointerstitial nephropathies
o Primary adrenal insufficiency
o Pseudohypoaldosteronism (end-organ resistance to
aldosterone)
o Gordon syndrome (2)[C]
o Sickle cell nephropathy
Commonly Associated Conditions
• Type I RTA in children: Hypercalciuria leading to rickets,
nephrocalcinosis
• Type I RTA in adults: Autoimmune diseases (Sjögren
syndrome, RA), hypercalciuria
• Type II RTA: Fanconi syndrome (generalized proximal
tubular dysfunction resulting in glycosuria, aminoaciduria,
hyperuricosuria, phosphaturia, bicarbonaturia)
• Type II RTA in adults: Multiple myeloma, carbonic
anhydrase inhibitors (acetazolamide)
• Type IV RTA: Obstructive uropathy, renal insufficiency,
diabetic nephropathy
Diagnosis
History
• Often asymptomatic (particularly type IV)
• Failure to thrive in children

4. • Anorexia, nausea/vomiting
• Weakness or polyuria (due to hypokalemia)
• Rickets in children
• Osteomalacia in adults
• Constipation
• Polydipsia
Diagnostic Tests & Interpretation
Lab
• Electrolytes reveal hyperchloremic metabolic acidosis.
• Plasma anion gap normal (anion gap = Na - [Cl + HCO 3]).
Normal values (in mEq/L): Neonates ≤16; infants/children
≤14–16; adolescents/adults 8 ± 4). Must correct calculated
anion gap for hypoalbuminemia. Increase calculated anion
gap by 2.5 mEq/L for each 1 g/dL decrease in albumin below
4 g/dL.
• Hypokalemia or normokalemia: Type I (if due to impaired
distal H+ secretion or increased H+ backleak), type II
• Hyperkalemia: Type IV, type I (if due to impaired distal Na
+
reabsorption)
• Plasma HCO3 (in untreated RTA): Type I: <15 mEq/L; type
II: 12–20 mEq/L; type IV: >17 mEq/L
• Blood urea nitrogen and creatinine usually normal (rules out
renal failure as cause of acidosis)
• Urine pH: Inappropriately alkaline (pH >5.5) despite
metabolic acidosis in type I or in type II when HCO3 above
reabsorptive threshold (15–16 mEq/L)
• Urine culture: Rule out urinary tract infection (UTI) with
urea-splitting organism (may elevate pH) and chronic
infection
• Urine anion gap (urine Na , K , and Cl on random urine):
+ + -
Reflects unmeasured urine anions, so inversely related to
urine NH4+ (or acid) excretion. Positive urine anion gap in an
acidemic patient indicates impaired renal acid excretion.
Results tend to be:
o Negative in HCO3 losses due to diarrhea, or UTI caused
by urea-splitting organisms
o Negative in other extrarenal causes of normal anion
gap metabolic acidosis
o Variable in type II RTA
o Positive in type I RTA, type IV RTA (3)[C]
o Positive in impaired acid excretion due to renal failure
• Urine calcium:
o High in type I

5. o Typically normal in type II
• Drugs that may alter lab results:
o Diuretics
o Sodium bicarbonate
o Cholestyramine
Imaging
Not needed except to rule out associated conditions (e.g.,
nephrocalcinosis)
Diagnostic Procedures/Surgery
• Helpful to measure urine pH on fresh sample with pH meter
for increased accuracy instead of dipstick. Pour film of oil
over urine to avoid loss of CO2 if pH cannot be measured
quickly.
• Urine NH4 excretion (anion gap is indirect measurement of
+
this but not as accurate)
• Ammonium chloride (NH4 ) loading to evaluate acid
+
excretion
• Fractional excretion of HCO3 >15% during HCO3 infusion
(type II RTA)
Pathological Findings
• Nephrocalcinosis
• Nephrolithiasis
• Rickets
• Osteomalacia
• Findings of an underlying disease causing renal tubular
acidosis.
Differential Diagnosis
• Plasma anion gap should be normal. If not, look for causes of
metabolic acidosis other than RTA. (MUDPILES: Metabolic
disease or methanol ingestion, uremia, diabetic ketoacidosis,
paraldehyde ingestion, iron or isoniazid ingestion, lactic
acidosis, ethylene glycol ingestion, salicylate ingestion)
• Extrarenal HCO3 losses:
o Diarrhea
o Small bowel, pancreatic, or biliary fistulas (3)[C]

6. o Urinary diversion (e.g., ureterosigmoidostomy, ileal
conduit)
• Acidosis of chronic renal failure (develops when GFR ≤20–
30% of normal) (4)[C]
• Excessive administration of acid load via chloride salts
(NaCl, HCl, NH4Cl, lysine hydrogen chloride, CaCl2, MgCl2)
Treatment
Medication
First Line
• Provide oral alkali to raise serum HCO3 to normal. Start at a
low dose and increase until HCO3 is normal. Give as sodium
bicarbonate or citrate mixtures (1 mEq citrate = 1 mEq
HCO3) such as Bicitra (1 mEq Na, 1 mEq citrate/mL, no K) or
Polycitra (1 mEq Na, 1 mEq K, 2 mEq citrate/mL) depending
on need for potassium. Sodium bicarbonate tablets are
available (7.7 mEq NaHCO3/650 mg tab) (5)[C].
• Type I RTA: Typical doses 1–4 mEq/kg/d p.o. alkali divided
3–4×/d (require much higher doses if HCO3 wasting is
present). May require K+ supplementation for hypokalemia
(6)[C].
• Type II RTA: Typical doses 10–15 mEq/kg/d alkali, divided
4–6×/d. Very difficult to restore plasma HCO3 to normal
because renal HCO3 losses increase once plasma HCO3 is
corrected above the resorptive threshold. Exogenous HCO3
increases K+ losses, requiring K+ supplementation. Often
need PO4 and vitamin D supplementation due to proximal
PO4 losses. May add thiazide diuretic to induce mild
hypovolemia, which increases proximal Na+/HCO3
reabsorption.
• Type IV RTA: Avoid inciting medications; restrict dietary K .
+
May augment K+ excretion with loop diuretic, thiazide
diuretic, or Kayexalate. Correcting hyperkalemia will actually
increase activity of the urea cycle, augmenting renal
ammoniagenesis and providing more substrate for renal acid
excretion. If necessary, 1–5 mEq/kg/d alkali divided 2–3×/d.
If mineralocorticoid deficiency, fludrocortisone: 0.1–0.3
mg/d.
• Contraindications: Refer to the manufacturers' literature.
• Precautions: Sodium bicarbonate may cause flatulence
because CO2 is formed, whereas citrate mixtures are
metabolized to HCO3 in the liver, thereby avoiding a gas

7. production. The use of sodium-containing compounds or
mineralocorticoids may lead to hypertension and/or edema.
Second Line
Thiazide diuretics may be used as adjunctive therapy in type II
RTA (after maximal alkali replacement), but are likely to further
increase urinary K+ losses.
Additional Treatment
General Measures
Treatment with appropriate medications to correct acidosis
Surgery/Other Procedures
If distal RTA is due to obstructive uropathy, surgical intervention
may be required.
In-Patient Considerations
Initial Stabilization
• Outpatient generally
• Inpatient if acidosis severe, patient unreliable, emesis
persistent, or infant with severe failure to thrive
Ongoing Care
Follow-Up Recommendations
Patient Monitoring
• Varies with patient response. Suggested: Electrolytes every
2–4 weeks at onset of therapy, every 2 weeks for 1–2 months
after bicarbonate concentration normal, then monthly for
several months
• Monitor underlying disease as indicated.
• Poor compliance common due to 3–6×/d alkali dosing
schedule
Diet
Varies with type of acidosis
Patient Education
• National Kidney & Urologic Diseases Information
Clearinghouse, Box NKUDIC, Bethesda, MD 20893, (301)
468-6345; http://www.niddk.nih.gov/health/kidney
• National Kidney Foundation: http://www.kidney.org
Prognosis
• Depends on associated disease, otherwise good with therapy
• Transient forms of all types of RTA may occur.
Complications
• Nephrocalcinosis, nephrolithiasis (type I)

8. • Hypercalciuria (type I)
• Hypokalemia (type I, type II if given bicarbonate)
• Hyperkalemia (type IV, some causes of type I)
• Osteomalacia (type II due to phosphate wasting)
References
1. Heering P, Ivens K, Aker S, et al. Distal tubular acidosis induced
by FK506. Clin Transplant. 1998;12:465–71.
2. Rodríguez-Soriano J. New insights into the pathogenesis of
renal tubular acidosis–from functional to molecular studies.
Pediatr Nephrol. 2000;14:1121–36.
3. Casaletto J. Differential diagnosis of metabolic acidosis. Emer
Med Clin N Am. 2005;23(3):771–87.
4. Kurtzman NA. Renal tubular acidosis syndromes. South Med J.
2000;93:1042–52.
5. Chan JC, Scheinman JI, Roth KS. Consultation with the
specialist: renal tubular acidosis. Pediatr Rev. 2001;22:277–87.
6. Domrongkitchaiporn S, Khositseth S, Stitchantrakul W, et al.
Dosage of potassium citrate in the correction of urinary
abnormalities in pediatric distal renal tubular acidosis patients.
Am J Kidney Dis. 2002;39:383–91.
Additional Reading
Izzedine H, Launay-Vacher V, Deray G. Topiramate-induced renal
tubular acidosis. Am J Med. 2004;116:281–2.
See Also (Topic, Algorithm, Electronic Media Element)
Hyperkalemia
Algorithm: Anuria or Oliguria
Codes
ICD9
588.89 Other specified disorders resulting from impaired renal
function
Snomed
1776003 renal tubular acidosis (disorder)
Clinical Pearls
• Consider RTA in cases of nonanion gap metabolic acidosis
with normal or near-normal renal function.
• Type I RTA: Urine pH >5.5 in setting of acidemia; positive
urine anion gap; HCO3 <15 mEq/L
• Type II RTA: Urine pH <5.5 unless HCO3 raised above
reabsorptive threshold (15–16 mEq/L)
• Type IV RTA: Most common subtype; hyperkalemia; urine
pH <5.5; acidemia usually mild

9. • Treatment includes avoidance of inciting causes, provision of
oral alkali (HCO3 or citrate), and measures to supplement
(type II, many type I) or restrict (type IV) potassium.
Thank you