Renal tubular acidosis (RTA)
Renal tubular acidosis (RTA) refers to the non-anion gap metabolic acidosis which develops due to derangement of usual metabolic processes in the kidneys. The kidneys have a critical role in maintaining stable physiologic pH and they do so through several mechanisms throughout the nephron. Proximally, filtered bicarbonate is resorbed and distally acid is excreted then buffered in the urine. If the kidneys lose the ability to carry out these functions, renal tubular acidosis results.
The three major forms of renal tubular acidosis are differentiated by the specific type and location of the mechanistic defect. An understanding of the basic physiology of the handling of acid by the kidney allows one to use clinical and laboratory clues to diagnose the type of RTA.
The three key renal mechanisms to handle acid are listed below with the form of RTA associated with defects at that site.
Reclaiming filtered bicarbonate in the proximal tubule – proximal (type 2) renal tubular acidosis
The reclamation of bicarbonate is accompanied by excretion of a proton (H+) and occurs primarily in the proximal tubule (90% of filtered bicarbonate). A decrease in proximal tubular bicarbonate resorptive capacity results in proximal (type 2) RTA. During the development of proximal RTA, bicarbonate is excreted into the urine because the filtered concentration exceeds the resorptive threshold of the proximal tubule, raising the urine pH. However, due to urinary loss, the subsequent serum and filtered bicarbonate concentrations decrease below the resorptive threshold such that filtered bicarbonate is then resorbed normally. Therefore the bicarbonaturia is self-limited and the serum bicarbonate concentration usually stabilizes between 14 and 20 meq/L. The urine pH is only transiently elevated during bicarbonaturia. It is important to note that distal urinary acidification is intact such that in proximal RTA in steady state, the urine pH is usually appropriately low (pH <5.5).
Most patients with type 2 RTA have other impairment of, proximal tubular resorptive function,leading to phosphaturia, glucosuria, bicarbonate, aminoaciduria, tubular proteinuria, and uricosuria. This is known as Fanconi syndrome.
In proximal RTA, the serum potassium concentration tends to be low. Potassium wasting (kaliuresis) is a result of increased sodium delivery to the distal tubule promoting potassium excretion and causing secondary hyperaldosteronism.
With alkali treatment in proximal RTA, serum and filtered bicarbonate concentrations rise above the resorptive threshold and bicarbonaturia with high urine pH results. Therefore, proximal RTA is challenging to treat and high doses of alkali are necessary.
Type 2 (proximal) RTA – key points:
Loss of bicarbonate is self-limited
Serum bicarbonate concentration usually 14-20 meq/L
Urine pH high only at onset with bicarbonaturia. Appropriately low (<5.5) in untreated patients in steady state
Serum K+ usually low due to tendency to kaliuresis
Other proximal renal tubular defects (leading to urinary wasting of phosphate, bicarbonate, glucose, amino acids) often occur (called Fanconi syndrome)
High doses of bicarbonate (10-15meq/kg) are required for treatment due to urinary losses
High urine pH during treatment
Excretion of acid (protons) in the distal nephron – distal (type 1) renal tubular acidosis
Type 1 (distal) RTA is a disorder of impaired proton excretion in the distal tubule resulting in the inability to acidify the urine appropriately during metabolic acidosis. The body produces approximately 1meq/kg acid per day primarily through protein catabolism. Because of ongoing acid retention, the acidosis can be severe at presentation with a serum bicarbonate concentration below 10meq/L.
In type 1 (distal) RTA, the impaired ability to excrete protons, and thereby acidify the urine, leads to urine pH above 5.5.
Distal (type 1) RTA may occur by one of three specific mechanisms. The urine pH is inappropriately elevated with each of the defects. The effect on potassium balance may differ and one may observe associated hypokalemia or hyperkalemia.
The most common mechanism is a secretory defect in the H+ATPase which pumps protons into the tubular lumen. Defects in these pumps in the distal nephron result in decreased proton (H+) excretion so that, in order to maintain electroneutrality within the tubular lumen, there is a tendency to excrete more potassium. Thus, hypokalemia is seen with this defect.
A gradient defect leading to a back leak of the protons secreted into the tubular lumen is similarly associated with potassium wasting due to the need to maintain electroneutrality. In addition, the permeability defect facilitates potassium wasting.
A voltage-dependent defect with impaired distal sodium transport leads decreased secretion of both protons and potassium and leads to hyperkalemia.
Distal RTA is associated with nephrocalcinosis and nephrolithiasis as a result of several metabolic abnormalities. First acid retention leads to bone buffering. Calcium and phosphate release from bone causes hypercalciuria. Secondly, persistent alkaline urine promotes calcium phosphate stone formation. Finally, chronic acidosis causes increased proximal citrate resorption and hypocitraturia (urinary citrate is an important inhibitor of stone formation).
Because only enough alkali therapy to buffer the daily acid load is needed, treatment does not require high doses as in proximal RTA.
Type 1 (distal) RTA – key points:
Acidosis may be severe with serum bicarbonate concentration below 10meq/L
Urine pH inappropriately high, greater than 5.5
Serum potassium may be low or high depending on the specific tubular defect
Low doses of bicarbonate or citrate (1-2meq/kg/day) needed to treat
Hypercalciuria, hypocitriaturia and persistently high urine pH lead to tendency to form kidney stones
Excretion of ammonium – type 4 renal tubular acidosis
In type 4 RTA, the key defect is impaired ammoniagenesis. The kidneys produce and excrete ammonia to buffer acid. The normal renal response to metabolic acidosis is the generation of additonal ammonia (NH3) which buffers acid (H+) to form ammonium (NH4+). This is a critical mechanism to eliminate acid and without this buffering, the excretion of the daily load of acid would result in a urine pH of below 3. The usual daily excretion of ammonium is 30-40meq but the kidneys can increase ammonia excretion to 200-300 meq daily in metabolic acidosis to increase the kidney’s capacity to excrete acid.
Ammonia is produced in the proximal tubule by the catabolism of glutamine. The process of ammonia recycling leads to high medullary interstitial ammonia concentrations, facilitating diffusion into the tubular lumen, where it is trapped as NH4+ by secreted protons.
Type 4 RTA in adults is most often an acquired disorder of hypoaldosteronism which results in hyperkalemia. Aldosterone causes increased open luminal sodium channels leading to increased distal sodium resorption and thus the electrochemical gradient for the excretion of potassium and sodium to maintain electroneutrality. Hyperkalemia causes diminished ammonia production because potassium shifts into cells causing proton shifts out of cells, resulting in intracellular alkalosis in the renal tubules. In response, ammonia production by the proximal renal tubular cells is decreased.
In type 4 RTA, the key defect is impaired ammoniagenesis. The ability to acidify the urine (that is, to secrete protons) remains intact. Since H+ATPase pumps function normally to excrete acid and since there is less buffer in the urine, urinary acidification in response to acidosis is intact and urine pH is low (<5.5).
In type 4 RTA, the degree of acidosis tends to be mild.
Treatment is aimed at correcting the aldosterone deficiency with fludrocortisone and addressing the hyperkalemia.
Type 4 RTA – key points:
Hyperkalemia plays a mechanistic role
Usually due to acquired forms of hypoaldosteronism
Urinary acidification intact, urine pH below 5.5
II. Diagnostic Approach
A. What is the differential diagnosis for this problem?
Renal tubular acidosis is among the differential diagnoses of a non-anion gap metabolic acidosis. A non-anion gap metabolic acidosis is usually first considered when serum chemistries demonstrate a low bicarbonate concentration without an accompanying anion gap. A blood gas is helpful to confirm the presence of a metabolic acidosis because the low serum bicarbonate concentration may also indicate renal compensation in respiratory alkalosis instead of a metabolic acidosis.
A non-anion gap metabolic acidosis may occur because of the addition of acid (or acid equivalent) to the body or failure to excrete the daily acid load from metabolism as is seen in:
Renal tubular acidosis (types 1 and 4)
Chronic kidney disease (a non-gap metabolic acidosis resulting from chronic kidney disease [CKD] is not considered a form of RTA because, in contrast to RTA, each nephron in CKD appears to function normally, however the loss in number of working nephrons leads to an overall decreased capacity to handle acid)
Addition of ammonium chloride.
Alternatively, loss of bicarbonate from the body will result in a non-anion gap acidosis as seen with:
Proximal (type 2) RTA
Carbonic anhydrase inhibitors
Urethral (ileal loop) diversion.
The three major forms of renal tubular acidosis, differentiated by the specific type and location of the mechanistic defect, can be distinguished clinically by the clinical and laboratory clues. These include the severity of the acidosis, response to alkali therapy, urine pH, accompanying renal tubular abnormalities, and potassium imbalance.
Once RTA is established and the type of RTA diagnosed, the causative condition(s) should be sought. Some conditions associated with the major forms of RTA are listed below:
1. Proximal (type 2) RTA
Hereditary forms exists but are diagnosed in childhood.
When accompanied by Fanconi syndrome, one must rule out multiple myeloma and light chain disease.
Use of carbonic anhydrase inhibitors (e.g., acetazolamide)
Other less common causes include:
2. Distal (type 1) RTA
Autoimmune diseases: systemic lupus erythematosis, Sjogren’s syndrome, chronic active hepatitis, primary biliary cirrhosis, thyroiditis, rheumatoid arthritis
Renal diseases: hypercalciuria, obstructive nephropathy, renal transplant rejection
Drugs and toxins: amphotericin B (gradient defect), lithium, analgesic abuse, toluene, amiloride, trimethoprim, pentamidine
Genetic diseases (present in childhood): sickle cell disease, Wilson’s disease, congenital adrenal hyperplasia
Voltage-dependent defects are seen in conditions such as sickle cell disease, obstructive uropathy and amiloride use. These are hyperkalemic forms of RTA.
3. Type 4 RTA
Mineralocorticoid deficiency without renal diseases: Addison’s disease (also known as primary adrenal insufficiency), congenital adrenal hyperplasia
Hyporeninemic hypoaldosteronism as in patients with diabetic nephropathy, systemic lupus erythematosis, AIDS nephropathy, obstructive uropathy
Impaired renin-aldosterone elaboration (cyclo-oxygenase inhibitors, ACE inhibitors, heparin)
Impaired renal K+ secretion (K+-sparing diuretics, trimethoprim, cyclosporine A, pentamidine)
B. Describe a diagnostic approach/method to the patient with this problem
First, confirm that that patient has a non-anion gap metabolic acidosis:
1. Note a low serum bicarbonate concentration.
2. Rule out a gap acidosis by checking that the serum anion gap is normal.
3. Check a blood gas to rule out a respiratory alkalosis with accompanying renal compensation as an explanation for the low bicarbonate concentration.
Once the finding of non-anion gap metabolic acidosis is confirmed:
4. Check for the presence of clinical clues:
History of diarrhea suggests stool bicarbonate loss (urine anion gap should be negative). See below.
Chronic or acute kidney disease suggested by elevated serum Cr or low calculated CrCl.
Check for use of relevant medications:
Amiloride: prevents distal Na resorption by competing for distal sodium channels impairing excretion of H+ and K+. Often seen with accompanying hyperkalemia.
Carbonic anhydrase inhibitors: Prevents proximal resorption of bicarbonate. Accompanying hypokalemia and high urine pH.
History of diabetes, chronic kidney disease and interstitial nephritis can be associated with type 4 RTA.
5. Calculate the urinary anion gap. The urine anion gap (UAG = [Na+] +[ K+] -[Cl–]) can be used to estimate the excretion of ammonium ion. In normal subjects, without metabolic acidosis, the urinary anion gap is positive. In metabolic acidosis, an increased amount of ammonium is excreted as ammonium chloride. As the ammonium concentration increases, so too does the chloride concentration and the urine anion gap decreases and becomes negative in patients with intact ammonia production. Thus, in patients with metabolic acidosis due to diarrhea or proximal (type 2) RTA (where ammonia production is normal), one will usually find a negative urine anion gap. The urine anion gap will remain positive in patients with non anion gap metabolic acidosis and diminished ammonium excretion such as in those with distal (type 1) RTA, hypoaldosteronism (type 4 RTA), and chronic kidney disease.
6. Check the urine pH. Recall that in distal (type 1) RTA, urinary acidification is impaired and urine pH in metabolic acidosis is greater than 5.5.
7. Check the serum potassium concentration. Hypokalemic forms of RTA are proximal (type 2) and the most common form of distal (type 1) RTA. Hyperkalemia suggests type 4 RTA, which is most common however the voltage defect form of distal (type 1) RTA is also possible.
8. Check for other tubular defects which could suggest Fanconi Syndrome. A fast clinical clue is a positive urine dipstick for glucose in a patient without hyperglycemia.
9. Clinical clues: nephrolithiasis, nephrocalcinosis, confirm medications (NSAIDs, amiloride, ifosfamide).
1. Historical information important in the diagnosis of this problem.
Assessing the severity of the problem: Ask about a feeling of breathlessness.
It is critical to gather an accurate medication list including over-the-counter medications and history of chemotherapy.
Past medical history is very important as there are often clues to the etiology of the RTA.
Is there a history of calcium phosphate kidney stones?
When interpreting the laboratory findings, it is important to know if the patient is on treatment for the RTA currently.
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
Renal tubular acidosis is essentially a laboratory diagnosis. When present in the pediatric patient, symptoms and signs tend to be more severe, including growth defects. In adults, there are few clinical signs or symptoms that would point to a diagnosis of RTA.
Dyspnea may be experienced in patients with severe acidosis.
Patients with distal (type 1) RTA may present with signs and symptoms of renal colic.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
Basic metabolic panel with calculation of the anion gap (hyperchloremic non anion gap metabolic acidosis)
Blood urea nitrogen (BUN) and creatinine
Urine sodium, potassium and chloride concentrations with calculation of urine anion gap (UAG = [Na+] +[ K+] -[Cl–])
Urinalysis including urine pH
More specialized tests with nephrology consultation could include: fractional K excretion, fractional HCO3 excretion, 24-hour urine collection for creatinine, calcium, and citrate
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Proximal (type 2) renal tubular acidosis
Serum bicarbonate 14-20 meq/L
Urine pH in steady state below 5.5 (not on alkali treatment)
Serum K+ usually low
Urine anion gap in metabolic acidosis negative indicating appropriate ammoniagenesis.
Response to alkali therapy: high doses required (10-20meq/kg/day) due to urinary loss. Treatment worsens hypokalemia and K+ supplement required. Treatment will result in bicarbonaturia and high urine pH.
Accompanying resorptive defects (Fanconi syndrome) may occur with phosphaturia, glucosuria, aminoaciduria, uricosuria.
Distal (type 1) renal tubular acidosis
Serum bicarbonate can be severely decreased, less than 10meq/L
Urine pH above 5.5 (impaired urinary acidification)
Serum K+ may be low or high depending on defect
Urine anion gap in metabolic acidosis positive (impaired ammonium excretion)
Response to alkali therapy: smaller doses of alkali needed (1-2meq/kg/day) compared to proximal (type 2)
Associated clinical clues: nephrocalcinosis, nephrolithiasis (particularly calcium phosphate stones), hypercalcemia, hypocitraturia.
Hypoaldosteronism (type 4 RTA)
Serum bicarbonate mildly decreased(>17meq/L)
Urine anion gap in metabolic acidosis positive (impaired ammoniagenesis)
Urine pH less than 5.5
Response to treatment: depends on the etiology. Withdraw any causative medications. Fludrocortisone can be effective in hyporeninemic hypoaldosteronism.
Associated medical conditions: primary or acquired hypoaldosteronism, chronic interstitial nephropathies, K+-sparing diuretics.
III. Management while the Diagnostic Process is Proceeding
A. Management of renal tubular acidosis.
The key principles are treatment of the acidosis with alkali therapy and management of potassium derangement:
Proximal (type 2) renal tubular acidosis
The acidosis is usually not severe
Sodium bicarbonate in very high doses
Need potassium supplement when treating
Distal (type 1) renal tubular acidosis
Alkali replacement (Sodium bicarbonate + citrate)
K+ supplement may be necessary
Type 4 renal tubular acidosis
Withdraw causative or contributing medications
Manage hyperkalemia, including stopping potassium-sparing medications
Fludrocortisone for primary adrenal insufficiency and for hyporeninemic hypoaldosteronism (may require concurrent loop diuretic to avoid volume overload)
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
Treatment of proximal RTA can worsen hypokalemia
Follow-up of urine and serum studies, see key points
Fludrocortisone can cause volume overload (edema, hypertension) and hypokalemia
Potassium citrate can be used in hypokalemic forms of RTA but should not be used in type 4 RTA or in hyperkalemic distal (type 1) RTA.
What's the evidence?
Igarashi, T, Sekine, T, Watanabe, H. “Molecular basis of proximal renal tubular acidosis”. . vol. 15. pp. S135-141.
Laing, CM, Tove, AM, Capassa, G, Unwin, RJ. “Renal tubular acidosis: Developments in our understanding of the molecular basis”. . vol. 37. 2005. pp. 1151-1161.
Laing, CM, Unwin, RJ. “Renal tubular acidosis”. . vol. 19. 2006. pp. S46-52.
Shayakul, C, Alper, SL. “Inherited renal tubular acidosis”. . vol. 9. 2000. pp. 541-546.
Soriano, JF. “Renal tubular acidosis: The clinical entitiy”. . vol. 13. 2002. pp. 2160-2170.
Reddy, P. “Clinical approach to renal tubular acidosis in adult patients”. Int J Clin Pract. vol. 65. 2011 Mar. pp. 350-360.
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- Renal tubular acidosis (RTA)
- I. Problem/Condition.
- II. Diagnostic Approach
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem
- 1. Historical information important in the diagnosis of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- III. Management while the Diagnostic Process is Proceeding
- A. Management of renal tubular acidosis.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem