Renal Tubular Acidosis (RTA)



  • Renal tubular acidosis (RTA) refers to a normal anion gap metabolic acidosis (also known as a hyperchloremic acidosis) caused by:
    • decreased excretion of hydrogen ions and/or
    • decreased reabsorption of sodium bicarbonate in the renal tubules
  • The abnormal acid-base transport within the tubules cannot be solely explained by decreased a glomerular filtration rate (GFR) secondary to chronic kidney disease, obstructive uropathy, or some other non-specific nephropathic mechanism  
  • The precise pathophysiological mechanism underlying the disorder varies across RTA sub-types (I-IV), which are described in detail below.


Normal Acid-Base Homeostasis within the Renal Tubules

  • Acid-base handling in the renal tubule can be broken down into two stages:
    • Proximal reabsorption of filtered bicarbonate
    • Distal acidification of the urine.  


 proximal_0.pngProximal Reabsorption of Bicarbonate Soriano JR. Renal Tubular Acidosis: The Clinical Entity. JASN. 2002


  • The reabsorption of filtered bicarbonate in the proximal tubule depends on the activity of carbonic anhydrase and several transporters:
    • Intracellular carbonic anhydrase (CA-II) creates carbonic acid from water and carbon dioxide, which in turn ionizes to form a hydrogen ion plus bicarbonate
    • The newly created bicarbonate is passively transported into the blood along with sodium by the co-transporter NBC-1
    • The newly created hydrogen ion is excreted into the tubule by NHE-3, which is driven by the anti-transport of sodium (down its concentration gradient)
    • Intraluminal carbonic anhydrase (CA-IV) combines the intraluminal bicarbonate and hydrogen ion into water and CO2, the latter of which diffuses back into the cell (and is used as substrate for CA-II), thus driving a net absorption of bicarbonate


distal_0.png Distal Acidification of Urine Soriano JR. Renal Tubular Acidosis: The Clinical Entity. JASN. 2002

  • The acidification of urine by the distal tubule depends on:
    • The secretion of ammonia in the proximal tubule
    • The continued reabsorption of bicarbonate within the loop of Henle
    • The secretion of hydrogen ions by the alpha-intercalated cells in the cortical collecting duct, which in turn is sensitive circulating levels of aldosterone (see below for details)  
  • The secretion of ammonia in the proximal tubule plays a particularly important role in renal acid-base homeostasis
    • Ammonia represents the primary buffer for the excreted hydrogen ions.
    • Secreted phosphate provides a buffer as well.
    • The alpha-intercalated cells play the largest direct role in the acidification of urine, which occurs via the following mechanisms:
      • Carbonic anhydrase (CA-II) creates carbonic acid which ionizes to form bicarbonate and a hydrogen ion, in a mechanism similar to that which occurs in the proximal tubule.
      • Bicarbonate ion is transported into the blood by the by the chloride-bicarbonate anti-porter AE1 
      • The resulting hydrogen ion is transported into the lumen by the vacuolar H+-ATPase and the H+-K+-ATPase, with the vacuolar H+-ATPase playing the dominant role.
      • Ammonia and phosphate buffer the secreted hydrogen ions
        • Note: there is no luminal carbonic anhydrase to drive the re-uptake of CO2, unlike in the proximal tubule


The Four Types of Renal Tubular Acidosis

Distal RTA (Type I)

  • A decreased secretion of hydrogen ions by the distal tubule in response to increased acidification of the serum. 
  • It can be caused by a variety of factors
    • Congenital: deleterious genetic variants in ion transport proteins 
    • Acquired: immunologic destruction of alpha-intercalated cells or medications 

Proximal RTA (Type II): 

  • A reduced reabsorption of bicarbonate in the proximal tubule
    • ​Often secondary to a failure of the renal tubule cells to maintain a low concentration of intracellular Na+. 
      • Concentration gradient is required to drive the reuptake of multiple compounds from the renal tubule
        • This pathology is seen in Fanconi syndrome
      • Rarely, the failed re-uptake of bicarbonate occurs in isolation; RTA Type II and Fanconi syndrome are not synonymous 
      • The underlying etiology can be"
        • Congenital (isolated RTA Type II)
        • Fanconi syndrome (secondary to cystinosis, galactosemia, or tyrosinemia)
        • Acquired (vitamin D deficiency, Sjogren’s)
        • Medication-induced (valproic acid, aminoglycosides) 
    • Mixed RTA (Type III)
      • A mixture of both RTA types I and II (distal and proximal). 
      • This designation is controversial, as most patients appear to have a predominant RTA type I with occasional proximal findings  
    • Hypoaldosteronism (Type IV):
      • Caused by either decreased aldosterone concentration or a decreased response of the alpha-intercalating cells to the hormone. 
        • Aldosterone promotes acidification of the urine through multiple mechanisms, which include maintaining a negative intraluminal electrical gradient (promoting proton excretion) and increasing the expression of carbonic anhydrase and the vacuolar H+-ATPase in the alpha-intercalating cells.
        • The underlying hypoaldosteronism can be:
          • Congenital (congenital adrenal hyperplasia, pseudohypoaldosteronism) 
          • Acquired (Addison’s disease, systemic lupus erythematous)
          • Medication-induced (ACE inhibitors, NSAIDs)  


Clinical Features  

In general, pediatric patients with RTA will present with:

  • Failure to thrive and a generally ill appearance
  • Normal anion gap metabolic acidosis (either compensated or uncompensated) with associated hyperchloremia
  • Polyuria
  • Vomiting
  • Dehydration 
  • Depending on the RTA sub-type, a child may have additional clinical features
    • In type I RTA, patients may also suffer from nephrolithiasis, nephrocalcinosis, rickets, osteomalacia, hyperammonemia, and hypokalemia 
    • Patients with Type II RTA will often have glucosuria, amino aciduria, and hypophosphatemia in addition to other findings associated with the disease underlying their Fanconi syndrome
    • In Type IV RTA, patients are often hyperkalemic  


Differential Diagnosis

When a patient has failure to thrive and a normal anion gap metabolic acidosis, the following pathologies beyond RTA are in the differential:

  • Congenital hypothyroidism
  • Obstructive uropathy
  • Uremic acidosis (kidney failure)
  • Bicarbonate loss secondary to:
    • Diarrhea, intestinal fistula, and medications (cholestyramine, magnesium sulfate, calcium chloride, acetazolamide)
  • Acid loading with accompanying chloride (ammonium chloride, arginine hydrochloride)


Laboratory Analyses Required to Diagnose and Distinguish Among the RTA Sub-Types

  • A thorough diagnostic evaluation for the etiology of an RTA is generally performed by a pediatric nephrologist  
  • Listed below are a few simple tests that can help delineate the etiology of the underlying RTA  
  • The interpretation of the following evaluations is summarized in Table 1.
  1. Determine the presence of a normal anion gap metabolic acidosis. 
    • This can be done using a BMP (Na+, Cl-, and bicarbonate)
    • Serum potassium levels can aid in distinguishing RTA types I and IV (elevated in Type IV), although a hyperkalemic Type I RTA does exist.
  2. Obtain an early morning urine pH. 
    • A urine pH > 5.5 in the setting of metabolic acidosis is indicative of RTA Type I
    • A urine pH < 5.5 suggests either RTA Type II or IV.
  3. A 24 hr urine study for calcium, citrate, sodium, and potassium (see Table 1 for interpretation of the findings). 
    • Use the results to compute the urine anion gap: (Na++K+ )-Cl- ≈ -1*[NH4+]
    • The gap is normally negative but will be positive in RTA Types I and IV due to decreased acidification of the urine.
  4. Ultrasonography of the kidneys to rule out an obstructive uropathy or other anatomic anomaly (e.g. polycystic kidney disease). 
    • Evaluate for nephrocalcinosis/nephrolithiasis.  

labeval RTA_0.png Table 1: Diagnostic evaluation results for the various sub-types of RTA.  Adapted from Soriano JR. Renal Tubular Acidosis: The Clinical Entity. JASN. 2002



  • The goal of treatment for RTA is to correct the underlying acidosis with alkali supplementation (generally a mixture sodium bicarbonate and potassium citrate) in order to maximize growth and development.
  • However, the individual sub-types of RTA may require additional or modified treatment regimens depending on the underlying etiology:
    • An RTA secondary to primary hypoaldosteronism can be corrected with exogenous fludrocortisone
    • Type II RTA secondary to cystinosis (one form of Fanconi’s syndrome) can be treated with cysteamine, a compound that helps break down intracellular cystine.  


  1. Chan JCM, Scheinman JI, Roth KS. Consultation With the Specialist: Renal Tubular Acidosis. Pediatr Rev. 2001;22: 277–287. doi:10.1542/pir.22-8-277
  2. Quigley R. Renal Tubular Acidosis. In: Avner E, Harmon W, Niaudet P, Yoshikawa N, editors. Pediatric Nephrology. Springer Berlin Heidelberg; 2009. pp. 979–1003. Available:
  3. Soriano JR. Renal Tubular Acidosis: The Clinical Entity. J Am Soc Nephrol. 2002;13: 2160–2170. doi:10.1097/01.ASN.0000023430.92674.E5
  4. Adedoyin O, Gottlieb B, Frank R, Vento S, Vergara M, Gauthier B, et al. Evaluation of Failure to Thrive: Diagnostic Yield of Testing for Renal Tubular Acidosis. Pediatrics. 2003;112: e463–e466.
  5. Belldina EB, Huang MY, Schneider JA, Brundage RC, Tracy TS. Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients. Br J Clin Pharmacol. 2003;56: 520–525. doi:10.1046/j.1365-2125.2003.01927.x


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