Indian Journal of Pediatrics, Volume 74âJuly, 2007. 679 ... Department of Pediatrics, All India Institute of Medical Sciences,. Ansari Nagar, New Delhi 110029, ...
Symposium on New Diagnostics
Evaluation of Renal Tubular Acidosis Arvind Bagga and Aditi Sinha Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
ABSTRACT Renal tubular acidoses (RTA) comprises of a group of disorders characterized by a low capacity for net acid excretion and persistent hyperchloremic, metabolic acidosis. The RTAs are classified into chiefly three types (types 1,2 and 4) based on clinical and laboratory characteristics. Correct diagnosis involves careful evaluation, including exclusion of other entities causing acidosis. A variety of tests are required to be administered in a stepwise fashion for the diagnosis and characterization of RTA. [Indian J Pediatr 2007; 74 (7) : 679-686] E-mail : arvindbagga@ hotmail.com
Key words : Renal tubular disorders; Metabolic acidosis
Renal tubular acidosis (RTA) is a group of transport defects secondary to reduced proximal tubular reabsorption of bicarbonate (HCO3-), the distal secretion of protons (hydrogen ion, H +) or both, resulting in impaired capacity for net acid excretion and persistent hyperchloremic metabolic acidosis. In this review, we discuss the pathophysiological basis and clinical and laboratory diagnosis of this condition. Physiology The proximal renal tubule is the site of the bulk of solute and water reabsorption in the nephron. Approximately 60% of the filtered sodium (Na +) is reabsorbed in the proximal segments, along with water, potassium (K+), bicarbonate (HCO3-), phosphate, amino acids and low molecular weight proteins. In contrast, the distal tubule has a specialized role in the final modification of urine concentration and pH. Specialized transporters are involved in the regulation of Na+ and K+ reabsorption and H+ secretion, which are shown in Figs. 1-3.
Pathophysiological basis The proximal tubule is the major site for reabsorption of filtered HCO3– (Fig. 1). The primary defect in proximal RTA is reduced renal threshold for HCO3–, resulting in bicarbonaturia. The proposed mechanisms include defective pump secretion or function of the H+ ATPase, the Na+/H+ antiporter, the Na+/K+ ATPase or deficiency of carbonic anhydrase in the brush-border membrane. Proximal RTA may represent isolated or generalized proximal tubular dysfunction, the latter (Fanconi syndrome) characterized by tubular proteinuria and aminoaciduria and variable degrees of bicarbonaturia, phosphaturia, Na+ and K+ wasting and glucosuria. K+ wasting is enhanced due to increased distal tubular delivery of Na+ and hyperaldosteronism secondary to volume contraction.
Classification of RTA Based on pathophysiology, RTA has been classified into three types: type 1 (distal) RTA; type 2 (proximal) RTA; and type 4 RTA secondary to true or apparent hypoaldosteronism. The above conditions are either secondary to other causes,1 or primary, with or without known genetic defects.
Correspondence and Reprint requests : Dr. Arvind Bagga, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. [Received January 24, 2007; Accepted February 2, 2007]
Indian Journal of Pediatrics, Volume 74—July, 2007
Fig. 1. Bicarbonate absorption in the proximal tubule. The secreted H+ combines with luminal HCO3- to form H2 CO3, which, under the action of carbonic anhydrase (CA) dissociates to H2O and CO2. The CO2 travels across the membrane into the cell where it combines with OH- to generate HCO3-; HCO3and Na+ cross the basolateral membrane using the Na +/ HCO3 - symporter. Na+ also exits the cell via the Na+ /K + ATPase.
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Fig. 2. Mechanism of distal acidification. Intercalated cells in distal tubule mediate HCO3- absorption through secretion of H+ through H+ ATPase and H+/K+ ATPase. The hydroxyl (OH -) ions generated in the cell through H+ secretion exit the cell by the HCO3 -/Cl- exchanger. The secreted H+ is buffered by luminal ammonia forming NH4 + and phosphate (titrable acids), to prevent a drop in luminal pH that would prevent further H+ secretion.
Fig. 3. Sodium transport in the principal cells. The apical membrane of the principal cells contains an amiloride sensitive Na+ channel, which transports Na + into the cell that exits basolaterally via Na+/K + ATPase. Na+ transport creates a lumen negative transepithelial potential that increases the rate of H + secretion (by intercalated cells). (Fig. 2). Aldosterone enhances Na+ absorption and increases H+ and K+ secretion.
Metabolic acidosis secondary to decreased secretion of H + ions in the absence of marked decrease in the glomerular filtration rate is characteristic of distal RTA. Patients with distal RTA are unable to excrete ammonium (NH4 +) ions in amounts adequate to keep pace with a normal rate of acid production. In hypokalemic distal RTA, urine pH cannot reach maximal acidity (i.e., remains >5.5) despite systemic acidemia indicating low H+ concentration in the collecting duct. In hypokalemic distal RTA, also known as classic RTA or type 1 RTA, the deficiency is secondary to either a secretory (rate) defect or a gradient (permeability) defect. In the secretory defect, the rate of secretion of H+ is low for the degree of acidosis. Ideally, with a rate defect the ability to maximally acidify the urine should be retained. 680
However, with a severe rate defect, the time spent in tubule lumen may be insufficient for acidification, and there is failure to maximally decrease the urine pH. The defect in secretory distal RTA may be secondary to defective function of H+ ATPase, H+/K+ ATPase, or the Cl - /HCO 3 - exchanger. Patients with the gradient (permeability) defect show normal secretory capacity of H+ but an increased backleak resulting in dissipation of the pH gradient. A subtype exists, where the backleak is due to enhanced membrane permeability to HCO3-, as seen with amphotericin induced RTA. In distal RTA, the titrable acidity and NH4 + secretion is low resulting in systemic acidosis. The cause of hypokalemia is attributed to increased K+ loss in the tubular lumen, urinary Na+ loss and volume contraction leading to aldosterone stimulation that increases tubular K+ secretion, and decreased proximal K+ reabsorption.2 Incomplete distal RTA is a variant or milder form of classic distal RTA, in which there is defective tubular H+ secretion but plasma HCO 3- levels are normal. Daily net acid excretion is maintained by enhanced ammoniagenesis. Hypercalciuria and hypocitraturia are present, and there is a risk for nephrolithiasis and nephrocalcinosis. Distal RTA associated with hyperkalemia may occur due either to a voltage-defect or rate-defect due to aldosterone deficiency or resistance. The voltage-defect is uncommon and caused by an insufficient negative intratubular potential at the level of cortical collecting duct (Fig. 3), which results in reduced secretion of H+ and K+, with decreased trapping and excretion of NH4+ and hyperkalemia. Inadequate voltage generation may be due to drugs such as amiloride that inhibit Na+ transport in the cortical collecting tubules, structural defects that inhibit active Na+ reabsorption in the tubules such as sickle cell nephropathy and obstructive uropathy, and increased epithelial permeability to Cl - causing its reabsorption and attenuating the negative voltage linked to Na+ reabsorption. The laboratory parameters in the voltage-defect (hyperkalemic distal RTA) resemble classic distal RTA, except for the presence of normo- or hyperkalemia (Table 2). More commonly, hyperkalemia with distal RTA is due to aldosterone resistance or deficiency (type 4 RTA). Aldosterone increases Na+ absorption and results in a negative intratubular potential (Fig. 3). It also increases luminal membrane permeability to K+ and stimulates basolateral Na+/K+/ATPase, causing increased urinary K+ losses. Since aldosterone also directly stimulates the proton pump, aldosterone deficiency or resistance is expected to cause hyperkalemia and acidosis. Another major factor in decreasing net H+ excretion in type 4 RTA is the inhibition of ammoniagenesis due to hyperkalemia. In type 4 RTA, maximally acidic urine (100 mOsm/Kg. Step 3. Determine urine pH Urine pH is useful for assessing the overall integrity of distal urinary acidification. In the presence of systemic acidosis, present spontaneously or induced by ammonium chloride load, the urine pH is normally 5.5 during metabolic acidosis suggests defective distal secretion of H +. It should however be appreciated that the urine pH measures the concentration of free H+ in the urine. This constitutes 5.5 >5.5
Further decline >5.5 5.5
K+ excretion Baseline After frusemide Normal Normal Normal Decreased
Increased Increased Increased Unchanged
CT collecting tubule
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Evaluation of Renal Tubular Acidosis administration of either of these agents results in decrease in urine pH to 10-15% >20 Normal Often present Absent Common
Classic
Distal RTA
Normal/low > 5.5 Positive Low 5.5 Positive Low 20 Normal/low Absent Absent Absent
U-B PCO2 urine to blood PCO2 gradient.
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A. Bagga and A. Sinha Hyperchloremic (normal anion gap) Metabolic Acidosis
Urine anion gap
Negative
Positive
Gastrointestinal losses Acid intake
Suspect RTA Urine pH Serum K+ Sodium bicarbonate loading
Urine pH 20 mm Hg FEHCO3 >10-15% Proximal RTA
Screen for other proximal tubular defects
Urine pH >5.5 Serum K+ low/normal U–B CO2 5.5 Serum K+ high/normal U–B CO2 20 mm Hg FEHCO3
