BASICS
DESCRIPTION
- Renal tubular acidosis (RTA) is composed of a group of disorders characterized by an inability of the kidney to resorb bicarbonate/secrete hydrogen ions, resulting in normal anion gap metabolic acidosis. Renal function (glomerular filtration rate [GFR]) must be normal or near normal.
- Several types have been identified:
- Type I (distal) RTA: inability of the distal tubule to acidify the urine due to impaired hydrogen ion secretion, increased back leak of secreted hydrogen ions, or impaired sodium reabsorption (interfering with the generation of negative luminal charge required for hydrogen/potassium secretion). Urine pH >5.5.
- Type II (proximal) RTA: defect of the proximal tubule in bicarbonate (HCO3) reabsorption. Proximal tubular HCO3 reabsorption is absent; plasma HCO3 concentration stabilizes at 12 to 18 mEq/L due to compensatory distal HCO3 reabsorption. Urine pH <5.5 unless plasma HCO3 brought above reabsorptive threshold.
- Type III RTA: extremely rare autosomal recessive syndrome due to carbonic anhydrase II deficiency; causes mixed type I and type II RTA, osteopetrosis, cerebral calcification, mental retardation
- Type IV RTA (hypoaldosteronism): due to aldosterone resistance/deficiency that results in hyperkalemia. Urine pH usually is <5.5.
EPIDEMIOLOGY
Incidence
- Predominant age: all ages
- Predominant sex: male > female (with regard to type II RTA with isolated defect in bicarbonate reabsorption)
ETIOLOGY AND PATHOPHYSIOLOGY
- Type I RTA
- Genetic: autosomal dominant, autosomal recessive associated with sensorineural deafness
- Sporadic
- Other familial disorders: Ehlers-Danlos syndrome, glycogenosis type III, Fabry disease, Wilson disease
- Autoimmune diseases: Sj Άgren syndrome, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), thyroiditis (1)
- Hematologic diseases: sickle cell disease (hyperkalemic), hereditary elliptocytosis
- Medications: amphotericin B, lithium, ifosfamide, foscarnet, amiloride, triamterene, trimethoprim, pentamidine
- Toxins: toluene, glue
- Hypercalciuria, diseases causing nephrocalcinosis
- Vitamin D intoxication
- Medullary cystic disease
- Obstructive uropathy (hyperkalemic)
- Hypergammaglobulinemic syndrome
- Chronic pyelonephritis
- Chronic renal transplant rejection
- Leprosy
- Chronic active hepatitis, primary biliary cirrhosis
- Malnutrition
- Type II RTA
- Familial (cystinosis, tyrosinemia, hereditary fructose intolerance, galactosemia, glycogen storage disease type I, Wilson disease, Lowe syndrome, inherited carbonic anhydrase deficiency)
- Sporadic
- Multiple myeloma, other dysproteinemic states
- Amyloidosis
- Heavy metal poisoning (e.g., cadmium, lead, mercury, copper)
- Medications: acetazolamide, ifosfamide, tenofovir, sulfanilamide, outdated tetracycline, topiramate (2), aminoglycosides
- Interstitial renal disease
- Paroxysmal nocturnal hemoglobinuria
- Defects in calcium metabolism (hyperparathyroidism)
- Type IV RTA
- Medications: NSAIDs, ACE inhibitors, ARBs, heparin/low-molecular-weight heparin, ketoconazole, calcineurin inhibitors (tacrolimus, cyclosporine " by decreasing expression of mineralocorticoid receptor [3])
- Diabetic nephropathy
- Tubulointerstitial nephropathies
- Primary adrenal insufficiency
- Markedly decreased distal Na+ delivery
- Pseudohypoaldosteronism (PHA) (end-organ resistance to aldosterone)
- PHA type 1
- PHA type 2 (Gordon syndrome)
Genetics
- Type I RTA: Hereditary forms due to mutations affecting intercalated cells in collecting tubules (4). 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 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, metachromatic leukodystrophy)
- Type IV RTA: Some cases are familial, such as PHA type I (autosomal dominant).
GENERAL PREVENTION
Careful use/avoidance of causative agents
COMMONLY ASSOCIATED CONDITIONS
- Type I RTA in children: hypercalciuria leading to rickets, nephrocalcinosis
- Type I RTA in adults: autoimmune diseases (Sj Άgren syndrome, RA, SLE), 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) (5)
- Type IV RTA: diabetic nephropathy
DIAGNOSIS
HISTORY
- Often asymptomatic (particularly type IV)
- In children: failure to thrive, rickets
- Anorexia, nausea/vomiting, constipation
- Weakness or polyuria (due to hypokalemia)
- Polydipsia
- Osteomalacia in adults
DIFFERENTIAL DIAGNOSIS
- Plasma anion gap should be normal. If not, evaluate for causes of anion-gap metabolic acidosis. (MUDPILES: methanol, uremia, diabetic ketoacidosis, propylene glycol/paraldehyde, iron/isoniazid ingestion, lactic acidosis, ethylene glycol, salicylates)
- Extrarenal HCO3 losses
- Diarrhea
- Small bowel, pancreatic, or biliary fistulas
- Urinary diversion (e.g., ureterosigmoidostomy, ileal conduit)
- Acidosis of chronic renal failure (develops when GFR ≤20 to 30 mL/min)
- Excessive administration of acid load via chloride salts (NaCl, HCl, NH4Cl, lysine HCl, CaCl2, MgCl2)
DIAGNOSTIC TESTS & INTERPRETATION
- Electrolytes reveal hyperchloremic metabolic acidosis.
- Plasma anion gap normal (anion gap = Na ’ [Cl + HCO3]). Normal values (in mEq/L) depend on analyzer used: infants/children 5 to 15; adolescents/adults 4 to 12) (6). Must increase calculated anion gap by 2.5 mEq/L for each 1 g/dL decrease in albumin below 4 g/dL
- Plasma K+: Low in type I (if due to impaired distal H+ secretion/increased H+ back leak), type II; high in type IV, type I (if due to impaired distal Na+ reabsorption)
- Plasma HCO3 (in untreated RTA): type I: <10 to 20 mEq/L; type II: 12 to 18 mEq/L (1); type IV: >17 mEq/L
- BUN/Cr normal or near normal (rules out renal failure as cause of acidosis)
- Urinalysis: Urine pH inappropriately alkaline (>5.5) despite metabolic acidosis in type I; also in type II if HCO3 above reabsorptive threshold (12 to 18 mEq/L)
- Urine culture: Rule out UTI with urea-splitting organism (may elevate pH) and chronic infection
- Urine anion gap (UAG; urine [Na+ + K+] ’ Cl- on a random specimen): reflects unmeasured urine anions, so inversely related to urine NH4+ (or acid) excretion. Positive UAG in an acidemic patient indicates impaired renal acid excretion. Urine Na+ >25 mEq/L required for accurate interpretation of UAG. Results tend to be
- Negative in HCO3 losses due to diarrhea, UTI caused by urea-splitting organisms, and other extrarenal causes of nonanion gap metabolic acidosis
- Variable in type II RTA
- Positive in type I RTA (7), type IV RTA
- Positive in impaired acid excretion due to renal failure
- Urine calcium
- High in type I
- Typically normal in type II
- Drugs that may alter lab results
- Diuretics
- Sodium bicarbonate (and other alkali)
- Cholestyramine
Initial Tests (lab, imaging)
Serum electrolytes; consider urinalysis, urine culture
Diagnostic Procedures/Other
- 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 only provides a qualitative estimate)
- Urinary acidification (impaired in type I RTA) can be assessed by oral administration of furosemide and fludrocortisone; patients with type I RTA unable to reduce urine pH to <5.3 (8)
- Fractional excretion of HCO3 >15% during HCO3 infusion (type II RTA) (1)
Test Interpretation
- Nephrocalcinosis
- Nephrolithiasis
- Rickets
- Osteomalacia, osteopenia
- Findings of an underlying disease causing RTA
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 (7.7 mEq NaHCO3/650 mg tab), sodium citrate (oral solution, 1 mEq HCO3 equivalent/mL), sodium/potassium citrate (oral solution), or potassium citrate (tablet, powder, or oral solution: 2 mEq K/mL, 2 mEq HCO3/mL), depending on need for potassium.
- Type I RTA: Typical doses 1 to 2 mEq/kg/day (in adults), 3 to 4 mEq/kg/day (in children) PO alkali divided 3 to 4 times per day (require much higher doses if HCO3 wasting is present). May require K+ supplementation
- Type II RTA: Typical doses 10 to 15 mEq/kg/day alkali, divided 4 to 6 times per day. Very difficult to restore plasma HCO3 to normal, as renal HCO3 losses increase once plasma HCO3 is corrected above resorptive threshold. Exogenous HCO3 increases K+ losses, requiring supplemental K+. Often need supplemental PO4 and vitamin D 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 increases activity of the urea cycle, augmenting renal ammoniagenesis and adding substrate for renal acid excretion. If necessary, 1 to 5 mEq/kg/day alkali divided 2 to 3 times per day. If mineralocorticoid deficiency, fludrocortisone: 0.1 to 0.3 mg/day
- Precautions
- Sodium-containing compounds will increase urinary calcium excretion, potentially increasing the risk of nephrolithiasis.
- Mineralocorticoids and sodium-based alkali may lead to hypertension and/or edema.
- Aluminum-containing medications (antacids, sucralfate) should be avoided if solutions containing citric acid are prescribed because citric acid increases aluminum absorption.
- Sodium bicarbonate may cause flatulence because CO2 is formed, whereas citrate is metabolized to HCO3 in the liver, avoiding gas production.
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.
SURGERY/OTHER PROCEDURES
If distal RTA is due to obstructive uropathy, surgical intervention may be required.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Generally managed as outpatient; inpatient if acidosis severe, patient unreliable, emesis persistent, or infant with severe failure to thrive
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Electrolytes 1 to 2 weeks following initiation of therapy, monthly until serum HCO3 corrected to desired range, then as clinically indicated
- Monitor underlying disease as indicated.
- Poor compliance common due to 3 to 6 times per day alkali dosing schedule
DIET
Varies based on serum K+ level and volume status
PATIENT EDUCATION
- National Kidney & Urologic Diseases Information Clearinghouse, Box NKUDIC, Bethesda, MD 20893, 301-468-6345: http://www.kidney.niddk.nih.gov/
- National Kidney Foundation: https://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)
- 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), osteopenia (due to buffering of acid in bone)
REFERENCES
11 Reddy P. Clinical approach to renal tubular acidosis in adult patients. Int J Clin Pract. 2011;65(3):350 " 360.22 Liamis G, Milionis HJ, Elisaf M. Pharmacologically-induced metabolic acidosis: a review. Drug Saf. 2010;33(5):371 " 391.33 Heering PJ, Kurschat C, Vo DT, et al. Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression. Clin Transplant. 2004;18(2):186 " 192.44 Batlle D, Haque SK. Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant. 2012;27(10):3691 " 3704.55 Casaletto JJ. Differential diagnosis of metabolic acidosis. Emerg Med Clin North Am. 2005;23(3):771 " 787.66 Lolekha PH, Vanavanan S, Teerakarnjana N, et al. Reference ranges of electrolyte and anion gap on the Beckman E4A, Beckman Synchron CX5, Nova CRT, and Nova Stat Profile Ultra. Clin Chim Acta. 2001;307(1 " 2):87 " 93.77 Goswami RP, Mondal S, Karmakar PS, et al. Type 3 renal tubular acidosis. Indian J Nephrol. 2012;22(6):466 " 468.88 Walsh SB, Shirley DG, Wrong OM, et al. Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int. 2007;71(12):1310 " 1316.
CODES
ICD10
N25.89 Oth disorders resulting from impaired renal tubular function
ICD9
588.89 Other specified disorders resulting from impaired renal function
SNOMED
- 1776003 Renal tubular acidosis (disorder)
- 236461000 Distal renal tubular acidosis (disorder)
- 24790002 Proximal renal tubular acidosis (disorder)
CLINICAL PEARLS
- Consider RTA in cases of normal anion gap metabolic acidosis with normal/near-normal renal function.
- Type I RTA: urine pH >5.5 in setting of acidemia; positive urine anion gap; acidemia can be severe.
- Type II RTA: urine pH <5.5 unless HCO3 raised above reabsorptive threshold (12 to 18 mEq/L)
- Type IV RTA: most common subtype; hyperkalemia; urine pH < 5.5; acidemia usually mild
- 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.