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Renal tubular acidosis

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  • 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.EpidemiologyIncidence • Predominant age: All ages • Predominant sex: Male > Female (with regard to type II RTA with isolated defect in bicarbonate reabsorption)Risk FactorsGenetics • 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 PreventionCareful use or avoidance of agents listed here as causativeEtiology • 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 nephropathyCommonly 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 • PolydipsiaDiagnostic Tests & InterpretationLab • 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 CholestyramineImagingNot 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 MedicationFirst 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 LineThiazide diuretics may be used as adjunctive therapy in type IIRTA (after maximal alkali replacement), but are likely to furtherincrease urinary K+ losses.Additional TreatmentGeneral MeasuresTreatment with appropriate medications to correct acidosisSurgery/Other ProceduresIf distal RTA is due to obstructive uropathy, surgical interventionmay be required.In-Patient ConsiderationsInitial Stabilization • Outpatient generally • Inpatient if acidosis severe, patient unreliable, emesis persistent, or infant with severe failure to thrive Ongoing Care Follow-Up RecommendationsPatient 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 scheduleDietVaries with type of acidosisPatient 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.orgPrognosis • 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)References1. Heering P, Ivens K, Aker S, et al. Distal tubular acidosis inducedby FK506. Clin Transplant. 1998;12:465–71.2. Rodríguez-Soriano J. New insights into the pathogenesis ofrenal tubular acidosis–from functional to molecular studies.Pediatr Nephrol. 2000;14:1121–36.3. Casaletto J. Differential diagnosis of metabolic acidosis. EmerMed 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 thespecialist: 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 urinaryabnormalities in pediatric distal renal tubular acidosis patients.Am J Kidney Dis. 2002;39:383–91.Additional ReadingIzzedine H, Launay-Vacher V, Deray G. Topiramate-induced renaltubular acidosis. Am J Med. 2004;116:281–2. See Also (Topic, Algorithm, Electronic Media Element) HyperkalemiaAlgorithm: Anuria or Oliguria Codes ICD9588.89 Other specified disorders resulting from impaired renalfunctionSnomed1776003 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

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