RENAL TUBULAR ACIDOSIS

RENAL TUBULAR ACIDOSIS - Richard F. Salmon, DO; David E. Hall, MD
BASICS
DESCRIPTION
A group of disorders characterized by an abnormality of renal tubular acidification, which results in hyperchloremic acidosis and a normal anion gap. Several types have been identified
• Classic distal renal tubular acidosis (Type I): Usually secondary to impaired ability to secrete hydrogen ions into the distal tubule or collecting duct. Urine pH >5.5.
• Proximal renal tubular acidosis (Type II): Due to impaired bicarbonate reabsorption in the proximal tubule. Bicarbonate spills into the urine at lower than normal plasma bicarbonate concentrations. If the plasma bicarbonate level is low enough (typically between 15 and 18), the urine may be acidified (pH 5.5), in contrast to type I.
• Type III: No longer considered a distinct entity
• Distal hyperkalemic renal tubular acidosis (Type IV): Several subtypes are recognized, but all are characterized by aldosterone resistance or deficiency. This leads to hyperkalemia (not seen in Types I or II) along with acidosis. The urine pH may be 5.5.
• System(s) Affected: Endocrine/Metabolic; Renal/Urologic
GENERAL PREVENTION
Careful use or avoidance of agents listed as causative here
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Male >Female (with regard to type II renal tubular acidosis with isolated defect in bicarbonate reabsorption)
RISK FACTORS
Genetics
• Type I renal tubular acidosis: 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.
• Type II renal tubular acidosis: 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, metachromatic leukodystrophy).
• Type IV renal tubular acidosis: Some cases familial, such as pseudohypoaldosteronism Type I (autosomal dominant)
ETIOLOGY
• Type I
- Genetic: Autosomal dominant
- Genetic: Autosomal recessive associated with sensorineural deafness
- Sporadic
- Ehlers-Danlos syndrome
- Hematologic diseases: Sickle cell disease, hereditary elliptocytosis
- Hypercalciuria
- Vitamin D intoxication
- Medullary cystic disease
- Glycogenosis Type III
- Autoimmune disease
- Diseases causing nephrocalcinosis
- Fabry disease
- Wilson disease
- Drug induced (amphotericin B, lithium, analgesics)
- Toxin induced (toluene, glue)
- Hypergammaglobulinemic syndrome
- Obstructive uropathy
- Chronic pyelonephritis
- Chronic renal transplantation rejection
- Leprosy
- Hepatic cirrhosis
- Malnutrition
• Type II
- Diseases associated with Fanconi syndrome (see Genetics)
- Sporadic
- Multiple myeloma and other dysproteinemic states
- Heavy metal poisoning (cadmium, lead, mercury)
- Medications: Acetazolamide, sulfanilamide, ifosfamide, outdated tetracycline, topama-4 [C]
- Autoimmune disease
- Amyloidosis
- Interstitial renal disease
- Nephrotic syndrome
- Congenital heart disease
- Defects in calcium metabolism (hyperparathyroidism)
• Type IV
- Lupus nephropathy
- Diabetic nephropathy
- Obstructive nephropathy
- Nephrosclerosis due to hypertension
- Tubulointerstitial nephropathies
- Addison disease
- Acute adrenal insufficiency
- Pseudohypoaldosteronism (end-organ resistance to aldosterone)
- Gordon syndrome (2)[C]
- Sickle cell nephropathy
ASSOCIATED CONDITIONS
• Type I in children: Hypercalciuria leading to rickets, nephrocalcinosis
• Type I in adults: Autoimmune diseases such as Sjogren disease
• Type II: Fanconi syndrome: A generalized tubular defect with bicarbonaturia, aminoaciduria, glycosuria, phosphaturia
• Type IV: Obstructive uropathy, renal insufficiency, diabetic nephropathy


DIAGNOSIS
SIGNS AND SYMPTOMS
• Failure to thrive in children
• Anorexia, nausea
• Vomiting
• Weakness due to potassium loss
• Polyuria due to potassium loss
• Rickets in children
• Osteomalacia in adults
• Constipation
• Polydipsia
TESTS
Lab
• Electrolytes reveal hyperchloremic metabolic acidosis
• Plasma anion gap normal (anion gap = plasma Na-(Cl+CO2)). Normal values: Neonates 18; infants and children 16; adolescents and adults 14).
• Hypokalemia or normokalemia
- Type I
- Type II
• Hyperkalemia: Type IV
• Blood urea nitrogen and creatinine usually normal (rules out renal failure as cause of acidosis)
• Urine pH: Not acidified (pH >5.5) despite metabolic acidosis in type I
• Urine culture: Rule out urinary tract infection (UTI) with urea splitting organism (may elevate pH) and chronic infection
• Urine anion gap, an estimate of urine ammonium excretion (urine Na+K-Cl on random urine). Measure before treatment. Most useful if measured when patient is acidotic. Results tend to be
- Negative in bicarbonate losses secondary to diarrhea
- Negative in UTI due to urea splitting organism
- Positive in Type I
- Positive in Type IV (5)[C]
• Urine calcium
- Typically normal in Type II
- High in Type I
• Drugs that may alter lab results
- Diuretics
- Sodium bicarbonate
- Cholestyramine
Imaging
Not needed except to rule out underlying conditions (e.g., nephrocalcinosis, complications)
Diagnostic Procedures/Surgery
• May be helpful to measure urine pH on fresh specimens with pH meter for increased accuracy instead of dipstick. Place oil over urine to avoid loss of carbon dioxide if pH cannot be measured quickly.
• Urine ammonium excretion (anion gap is indirect measurement of this, but is not as accurate)
• Ammonium chloride (NH4+) loading to evaluate acid excretion
• Bicarbonate titration curves
Pathological Findings
• Nephrocalcinosis
• Nephrolithiasis
• Rickets
• Osteomalacia
• Findings of an underlying disease causing renal tubular acidosis
DIFFERENTIAL DIAGNOSIS
• Anion gap should be normal. If not, look for causes of metabolic acidosis other than renal tubular acidosis. (MUDPILES: Metabolic disease or methanol ingestion, Uremia, Diabetic ketoacidosis, Paraldehyde ingestion, Iron or isoniazid ingestion, Lactic acidosis, Ethylene glycol ingestion, Salicylate ingestion)
• Diarrhea with bicarbonate loss in stools
• Acidosis of chronic renal failure
• Urinary diversion (e.g., ureterosigmoidostomy, ileal conduit)
• Ingestion of hydrochloric acid, ammonium chloride, lysine hydrogen chloride, excess calcium, or magnesium chloride
• Small bowel, pancreatic, or biliary fistulae (5)[C]
TREATMENT
STABILIZATION
• Outpatient generally
• Inpatient if acidosis severe, patient unreliable, emesis persistent, infant with severe failure to thrive
GENERAL MEASURES
Treatment with appropriate medications to correct acidosis
Diet
Varies with type of acidosis
Activity
As tolerated
MEDICATION (DRUGS)
First Line
Provide oral alkali to raise serum bicarbonate to normal. Start at a low dose and increase until serum bicarbonate 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 HCO3/tab). (1)[C]
• Type I: Typical doses 1-4 mEq/kg/d PO alkali divided t.i.d. or q.i.d., unless bicarbonate wasting present, in which case much larger doses required. May require potassium supplementation if serum potassium low. (3)[C]
• Type II: Typical doses 5-10 mEq/kg/d alkali. May be difficult to control and require 4-6 doses/d. May require potassium supplementation if serum potassium low.
• Type IV: 1-5 mEq/kg/d alkali b.i.d. or t.i.d. Avoid potassium. In some cases, furosemide used to lower potassium levels, but avoid if patient wastes salt. Fludrocortisone: 0.1-0.3 mg/d, if mineralocorticoid deficient.
• Contraindications: Refer to the manufacturer's literature.
• Precautions: Sodium bicarbonate may cause flatulence as carbon dioxide is formed, whereas citrate mixtures are metabolized to bicarbonate in the liver, thereby avoiding gas production.
Second Line
Hydrochlorothiazide: Use as an adjunct in Type II after maximal alkali replacement, but it may exacerbate already existing kaliuresis
SURGERY
If distal renal tubular acidosis is due to obstructive uropathy, surgical intervention may be required.
FOLLOW-UP
PROGNOSIS
• Depends on associated disease, otherwise good with therapy
• Transient forms of all types of renal tubular acidosis may occur.
COMPLICATIONS
• Nephrocalcinosis
• Hyperkalemia or hypokalemia
• Nephrolithiasis
• Rickets
• Osteomalacia
• Hypercalciuria
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 t.i.d. or q.i.d. alkali dosing schedule
REFERENCES
1. Chan JC, Scheinman JI, Roth KD. Consultation with the specialist: Renal tubular acidosis. Ped in Review. 2001;22(8):277-287.
2. Rodriguez-Soriano J. New insights into the pathogenesis of renal tubular acidosis: From functional to molecular studies. Pediatr Nephrol. 2000;14:1121-1136.
3. Domrongkitchaiporn S, et al. Dosage of potassium citrate in the correction of urinary abnormalitites in pediatric distal renal tubular acidosis patients. Am J Kidney Dis. 2002;39(2):383-391.
4. Izzedine H, Launay-Vacher V, Deray G. Topiramate-induced renal tubular acidosis. Am J Med. 2004;116(4):281-282.
5. Casaletto J. Differential diagnosis of metabolic acidosis. Emer Med Clin N Am. 2005;23(3):771-87.
MISCELLANEOUS
See also: Hyperkalemia