Steve Dong, MD
BASICS
DESCRIPTION
• Renal tubular acidosis (RTA) is a metabolic condition characterized by abnormal urinary acidification due to a defect in renal tubules, resulting in hyperchloremic nonanion gap metabolic acidosis, increased pH of the urine
• 4 major types of RTA are now considered to be only 3:
– Type I (distal): Defective distal tubular H+ secretion
– Type II (proximal): Defective proximal tubular bicarbonate reabsorption
– Type III (mixed): No longer considered as a distinct entity
– Type IV: Aldosterone deficiency/resistance
EPIDEMIOLOGY
Incidence
• RTA I: More common in adults (2/3 adults, 1/3 children) and women; endemic in certain regions of Thailand
• RTA II: Usually more predominant in males associated with Fanconi syndrome; urinary loss of glucose, amino acids, uric acid, phosphate, and bicarbonates
• Most RTAs are sporadic occurring at any age. Familial RTA are rare and usually occurs in childhood.
RISK FACTORS
• Genetic disorders
• Secondary to systemic disease. See “Commonly Associated Conditions.”
Genetics
• Familial RTA I (1):
– Autosomal dominant (AD) form is associated with mutation in anion exchanger 1 gene
– Autosomal recessive (AR) form is due to a mutation in the B1 or H+-ATPase (V-ATPase) gene and associated with sensorineural deafness
• Familial RTA II:
– AD form is rare
– AR form associated with ocular abnormalities and mental retardation
– AR form associated with osteopetrosis and cerebral calcification
– AR form associated with Fanconi syndrome
• Familial RTA IV: Associated with pseudohypoaldosteronism type 1
PATHOPHYSIOLOGY
• Type I (distal) tubular acidosis: Secondary to impaired ability to secrete hydrogen ions into the distal tubule or collecting duct. Urine pH > 5.5.
• Type II (proximal) tubular acidosis: Impaired bicarbonate absorption in the proximal tubule. Urine pH may be <5.5.
• Type IV: Presence of aldosterone resistance or deficiency leading to hyperkalemia (not seen in type I and II) along with acidosis. Urine pH may be <5.5.
ASSOCIATED CONDITIONS
• Acquired RTA type I:
– Autoimmune disease: Systemic lupus erythematosus (SLE), Sjögren syndrome, primary biliary cirrhosis, chronic active hepatitis
– Chronic pyelonephritis
– Diseases causing nephrocalcinosis
– Drugs (amphotericin B, lithium, analgesics)
– Ehlers–Danlos syndrome
– Fabry disease
– Glycogenosis type III
– Hepatic cirrhosis
– Hypercalciuria
– Hypergammaglobulinemic syndrome
– Leprosy
– Malnutrition
– Medullary cystic disease
– Obstructive uropathy
– Sickle cell disease, hereditary elliptocytosis
– Toxins (toluene, glue)
– Vitamin D intoxication
– Wilson disease
• Acquired RTA type II:
– Fanconi syndrome due to toxin-related or immunologic nephrotoxic damage
– Tubular toxicity causing acute tubular necrosis:
Sepsis
Rhabdomyolysis
Hypotension
Nephrotoxins: Intravenous (IV) contrast, aminoglycoside antibiotics
– Interstitial renal disease:
Multiple myeloma
Heavy met al poisoning (cadmium, lead, mercury)
Medications (methicillin, cisplatin, adefovir, tenofovir, COX-2 inhibitors, cimetidine, acetazolamide, sulfanilamide, ifosfamide, tetracycline, Topamax)
Infections: Leptospirosis, corynebacterium, diptheria, polyomavirus, cytomegalovirus
Autoimmune disease: SLE, Sjögren’s syndrome, sarcoidosis
– Amyloidosis
• Acquired RTA type IV:
– Addison disease
– Diabetic nephropathy
– Hypertension
– Lupus nephropathy
– Obstructive nephropathy
– Tubulointerstitial nephropathies
• Gordon syndrome
• Sickle cell nephropathy
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• Failure to thrive, rickets, and osteomalacia in children
• Anorexia, nausea, vomiting
• Weakness and polyuria due to potassium loss
• Constipation
• Polydipsia
• History of hematuria, urinary tract infections (UTIs), passage of stones in urine
• History of recurrent, familial, or childhood renal stone disease
• Ask about systemic diseases causing RTA
PHYSICAL EXAM
• Urologic exam of genitalia, suprapubic area for swelling and tenderness
• Exam for osteomalacia, hypokalemic muscle weakness, and growth retardation
• Exam for other systemic diseases
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Renal function test usually normal
• Electrolytes and blood gas reveal hyperchloremic, nonanion gap metabolic acidosis:
– Hypokalemia or normokalemia in type I and II
– Hyperkalemia in type IV
• Urine pH (fasting, under oil, pH meter):
– pH > 5.5: Complete type I RTA
– pH > 5.5, but systemic acidosis mild or absent: Ammonium chloride loading test and measure urinary bicarbonates; failure of urine pH to go below 5.5 is diagnostic of RTA (1)[C]
• RTA II is diagnosed by bicarbonate loading test: After IV bicarbonate infusion, fractional excretion of bicarbonate >15% is diagnostic (1)[C]
• Urine calcium: High in type I, normal in type II
• Phosphaturia, glycosuria, and aminoaciduria in Fanconi’s syndrome
Imaging
• Plain x-ray and computed tomography (CT) urogram:
– Likely to demonstrate nephrocalcinosis and nephrolithiasis
Pathologic Findings
• Nephrocalcinosis
• Nephrolithiasis
• Osteomalacia
DIFFERENTIAL DIAGNOSIS
• Other causes of metabolic acidosis (2)[C]
– Lactic and ketoacidosis, chronic renal failure, chronic diarrhea, etc.
• Azotemia
• Bilateral stones
• Calcium phosphate stones
• Chronic pyelonephritis
• Hypocitraturia < 0.5 mmol/24 h
• Hypokalemia
• Medullary nephrocalcinosis
• Medullary sponge kidney
• Recurrent stones: >2/yr
TREATMENT
GENERAL MEASURES
• Identifiable causes, such as obstructive uropathy or drug-induced RTA, should be corrected or eliminated
• If there is no identifiable etiology, then direct treatment to correction of acidosis
MEDICATION
First Line
• Alkali therapy decreases stone formation and growth, prevents nephrocalcinosis, normalizes growth retardation in children, and corrects hypokalemia in most cases:
– Oral alkali therapy: In both type I and type II RTA with the goal of treatment to restore urinary citrate to high-normal levels, and not simply correct the metabolic acidosis (3)[C]
Sodium bicarbonate (7.7 mEq HCO3/tab)
Bicitra (1 mEq Na, 1 mEq citrate/mL)
Polycitra (1 mEq Na, 1 mEq K, 2 mEq citrate/mL)
– Type I RTA generally requires lifelong treatment:
1–4 mEq/kg/d of oral bicarbonate or citrate in 2–3 divided doses in adults (4)[C]
May require potassium supplementation for hypokalemia
• Type II (proximal) RTA:
– 5–20 mEq/kg/d in 4–6 doses/d due to the severe bicarbonate wasting.
– Adults with bicarbonate levels >10 mEq/mL and no evidence of bone disease may not require treatment.
– Supplemental potassium, calcium, vitamin D, and phosphate may become necessary.
• Type IV RTA treatment is directed toward correction of hyperkalemia rather than acidosis:
– Dietary potassium restriction
– Thiazide or loop diuretics
– Mineralocorticoid replacement in cases of adrenal disease or hyporeninemia (fludrocortisone 0.1 mg/d)
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Management of stone by shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy, and rarely, open surgery
• Management of obstructive uropathy
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
Monitor osteoporosis
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Primary RTA I: Although a permanent disease, prognosis is excellent if diagnosis and treatment initiated early.
• Prognosis of other RTAs depends on associated disease
COMPLICATIONS
• Hypercalciuria
• Hyperkalemia or hypokalemia
• Nephrocalcinosis
• Nephrolithiasis
• Osteomalacia/osteoporosis
FOLLOW-UP
Patient Monitoring
• Spot urine testing for NAG (N-acetyl-β-D-glucosaminidase) has eliminated the need for 24-hr urine collection. Levels increased secondary to renal tubular cell damage and hypercalciuria.
• Urinary calcium excretion should be kept <0.05 mmol/kg/d in infants and children
• Potassium levels should be monitored during alkali therapy and replaced appropriately
• Monitor underlying disease as indicated
Patient Resources
National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC) http://kidney.niddk.nih.gov/kudiseases/pubs/tubularacidosis/
REFERENCES
1. Laing CM, Unwin RJ. Renal tubular acidosis. J Nephrol. 2006;19(suppl 9):S46–S52.
2. Casaletto JJ. Differential diagnosis of metabolic acidosis. Emerg Med Clin North Am. 2005;23:771–787, ix.
3. Rodriguez SJ. Renal tubular acidosis: The clinical entity. J Am Soc Nephrol. 2002;13:2160–2170.
4. 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;39:383–391.
ADDITIONAL READING
Haque SK, Ariceta G, Batlle D. Proximal renal tubular acidosis: A not so rare disorder of multiple etiologies. Nephrol Dial Transplant. 2012;27(12):4273–4287.
See Also (Topic, Algorithm, Media)
• Calcifications, Renal
• Fanconi Syndrome
• Nephrocalcinosis
• Osteoporosis and Osteopenia, Urologic Considerations
• Urolithiasis, Renal
CODES
ICD9
• 255.42 Mineralocorticoid deficiency
• 276.7 Hyperpotassemia
• 588.89 Other specified disorders resulting from impaired renal function
ICD10
• E27.40 Unspecified adrenocortical insufficiency
• E87.5 Hyperkalemia
• N25.89 Oth disorders resulting from impaired renal tubular function
CLINICAL/SURGICAL PEARLS
• Type I RTA is the only type associated with increased stone formation, nephrocalcinosis.
• Potassium levels should be monitored during alkali therapy for RTA and replaced appropriately.
• A young person with multiple stones with systemic acidosis and high urine pH, a diagnosis of type I RTA should be considered.