Chapter XIII.14. Renal Tubular Acidosis
Amanda Y. Beaman
August 2022

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An 8 month old boy presents to the ER. The boy's mother is concerned because he has not stooled in 5 days and has been urinating more often. He has been fussy, does not want to eat, and cries often. He was born at term, weighing 3.5 kg. He did not pass his initial hearing screen at birth, but his mother did not follow up for further testing.

Exam: VS T 37.0 degrees (rectal), P 160, R 45, BP 70/40. Weight 7.7 kg grams (10th percentile), length 66 cm (5th percentile), head circumference 43 cm (10th percentile). He is alert and active. He has sticky oral mucous membranes, and his capillary refill is 3 seconds. He appears to be 5% dehydrated based on clinical assessment. He is hypotonic.

Laboratory studies: Na 138 mEq/L, K 2.0 mEq/L, Cl 122 mEq/L, CO2 8 mEq/L. The anion gap is normal so additional urine studies are obtained: urine pH 6.5, urine Na 40 mEq/L, urine K 60 mEq/L, urine Cl 20 mEq/L. Notably, the urine anion gap (UAG) is positive.

Upon referral to a nephrologist, the diagnosis of Type 1 (distal) renal tubular acidosis (dRTA) is made. He is prescribed alkali therapy and referred to a geneticist who diagnoses him with autosomal recessive dRTA. Throughout the next few years, his serum bicarbonate is out of the normal range on multiple occasions, and he often complains of pain in his back and legs. At ages 3 and 5, he visits the emergency room and is found to have renal calculi.


Renal tubular acidosis (RTA) is a rare condition that often goes undiagnosed or is found incidentally on routine lab tests. RTA results from the inability of the kidneys to maintain acid-base balance due to defective bicarbonate (HCO3-) reabsorption or poor proton (H+) secretion. If symptomatic, pediatric patients will typically present with failure to thrive and hyperchloremic non-anion gap metabolic acidosis. Additional symptoms may include polyuria, dehydration, constipation, anorexia, and hypotonia (1).

Acid-base balance of the kidney

In the nephron, bicarbonate freely enters the filtrate but is normally reabsorbed in the proximal tubule. Bicarbonate reabsorption requires acid secretion into the lumen, achieved by the sodium-proton exchanger (NHE3) and H+ATPase. Through the action of carbonic anhydrase 4 in the lumen, secreted H+ and filtered HCO3- form H2O and CO2, which can freely enter the proximal tubular cell. Cytosolic carbonic anhydrase 2 (CA2) then reforms H+ and HCO3-. H+ is recycled across the apical membrane and HCO3- enters the blood via the sodium bicarbonate cotransporter NBCe1. This mechanism reclaims 80 to 90 percent of the filtered bicarbonate at the proximal tubule (2).

In the distal nephron, H+ is secreted by alpha intercalated cells in the collecting duct. H+ is generated by the action of CA2 and subsequently secreted via apical H+ATPase. The bicarbonate generated from this process is then absorbed into the blood via the HCO3-/Cl- antiporter (AE1). Secreted H+ is subsequently bound to ammonia (NH3) to form ammonium (NH4+) which is excreted in the urine (2).

Type 1 (distal) RTA

Type 1 (distal) RTA (dRTA) is due to the failure of intercalated cells in the collecting duct to secrete protons. In children, the most common causes are inherited single gene defects, but other etiologies include autoimmune diseases such as Sjogren syndrome, drugs such as amphotericin B, medullary sponge kidney, and primary hyperparathyroidism (2). Autosomal recessive forms of dRTA are due to mutations in genes that encode alpha4 and beta1 subunits of apical H+ATPase. Children with this mutation also have sensorineural hearing loss as these proteins have functional importance in the cochlea and endolymphatic sac of the ear. For this reason, children with suspected or confirmed dRTA should undergo audiometry (2). Mutations in the HCO3-/Cl- antiporter (AE1) cause autosomal dominant or recessive dRTA. Autosomal recessive AE1 mutations tend to present earlier in life in association with hemolytic anemia, since AE1 is also expressed in red blood cells (2). Defects in carbonic anhydrase isoform 2 (CA2) have effects on both distal and proximal bicarbonate production resulting in a mixed proximal and distal RTA (previously called type 3 RTA) (2).

Children with dRTA will present with hyperchloremic normal anion gap (non-anion gap) metabolic acidosis with significant hypokalemia. Due to the failure of intercalated cells to acidify the urine, they will have inappropriately alkaline urine with pH > 5.5 (1,2). Excess HCO3- in the urine causes an increase in chloride absorption and hyperchloremia. Deficient H+ in the urine results in compensatory potassium secretion distally, causing hypokalemia (3).

Acidosis causes rapid dissolution of hydroxyapatite in bone which buffers the plasma pH and releases calcium into the blood. Metabolic acidosis also decreases calcium reabsorption in the distal nephron. Patients typically present with hypercalciuria. Increased filtered calcium load from bone and suppressed calcium reabsorption in the kidney precipitate nephrocalcinosis and/or nephrolithiasis and bone disease (2,3). Calcium deposition in the renal tubules is further promoted by the hypocitraturia seen in dRTA (3).

A definitive diagnosis of dRTA requires demonstration of the inability of the kidney to excrete protons as NH4+. Since NH4+ cannot be measured directly, and NH4+ excretion is coupled to Cl-, the urine anion gap is used as a surrogate. UAG = Na+ + K+ - Cl- which should be less than 10. Systemic metabolic acidosis typically results in a negative UAG as high NH4+ excretion results in high Cl- excretion. In contrast, dRTA results in a positive UAG due to failure to acidify the urine (2).

Patients with incomplete dRTA present with normal acid-base status under physiologic conditions but cannot acidify their urine after an acid load. This type has been associated with heterozygous mutations of the H+ATPase beta 1 and alpha 4 subunits. Diagnosis of this subtype requires failure to acidify the urine following an ammonium chloride challenge or loop diuretic (furosemide) test (2).

Treatment of pediatric dRTA patients should focus on growth and prevention of bone disease, kidney stones, and nephrocalcinosis (2). Potassium citrate is the treatment of choice. Young children require higher doses of alkali to support the formation of hydroxyapatite for bone growth. Dosage requirements subsequently decrease with age (4):
  - Infants up to 6 years old: 5 to 8 mEq/kg/day
  - Children after 6 years old: 3 to 4 mEq/kg/day
  - Adults: 1 to 2 mEq/kg/day
Dosing should be adjusted to maintain normal plasma bicarbonate and potassium levels. Patients with persistent hypokalemia may benefit from amiloride (2) a potassium sparing diuretic.

A prolonged release oral combination drug of potassium citrate and potassium bicarbonate known as ADV7103 has been developed to treat dRTA. Although not yet FDA approved, it decreases dosing frequency from 3 to 6 times daily to twice daily. It also showed improved palatability and higher gastrointestinal safety compared to the current standard of care oral alkalinizers (5).

Patients should be monitored for hypercalciuria. The development of nephrocalcinosis or nephrolithiasis may require thiazide diuretics to reduce urinary calcium excretion (3). Thiazide diuretics can also help lower bicarbonate requirements if poorly tolerated (6).

Early treatment, diagnosis, and adherence to therapy provide a favorable prognosis with preserved GFR (glomerular filtration rate) and improved growth. Prompt diagnosis of dRTA is essential since a delayed diagnosis and persistent acidosis can lead to growth impairment, severe bone deformity, and chronic kidney disease (2). Progression to CKD has been documented to be as high as 80 percent of patients. The development of CKD is associated with late diagnosis, nephrocalcinosis/nephrolithiasis, chronic hypokalemia, and recurrent pyelonephritis (7).

Type 2 (proximal) RTA

Type 2 (proximal) RTA is characterized by an inability of the proximal tubule to reclaim filtered bicarbonate (8), resulting in inappropriate urinary bicarbonate wasting and a normal anion gap (non-anion gap) metabolic acidosis (2,8). Due to intact distal acidification mechanisms, acidic urine is produced to compensate for metabolic acidosis. This results in a urine pH of less than 5.5 (2).

Most cases of pRTA in children will occur as part of generalized proximal tubular dysfunction known as Fanconi syndrome (as distinct from Fanconi anemia which is a different disease). Patients with Fanconi syndrome may have impaired reabsorption of bicarbonate, phosphate, glucose, amino acids, uric acid, and low molecular-weight proteins. Fanconi syndrome can be acquired, idiopathic, or hereditary. In children, Fanconi syndrome is most associated with nephropathic cystinosis (8). Rarely pRTA occurs due to an isolated defect of proximal bicarbonate reabsorption. The only known genetic cause is a mutation in the sodium bicarbonate cotransporter 1 (NBCe1). Children with this autosomal recessive condition have concomitant ocular abnormalities (2). pRTA may also occur secondary to medications that inhibit carbonic anhydrase such as acetazolamide (6) or tubulotoxic medications (2).

Patients with pRTA present with a normal anion gap (non-anion gap) metabolic acidosis with hypokalemia, similar to dRTA. In contrast to dRTA, the urine pH will be acidified below pH 5.5. High urine pH can occur in the setting of plasma bicarbonate levels above 17 mEq/L, UTI due to urease producing organisms, or severe hypovolemia. Additionally, the UAG will be zero or negative, consistent with metabolic acidosis with intact distal acidification mechanisms (see UAG discussion above) (8).

pRTA is most commonly diagnosed clinically. A definitive diagnosis of pRTA requires measuring the patient’s fractional excretion of bicarbonate at low and normal serum bicarbonate levels. This is done by infusing NaHCO3 at a rate of 0.5 to 1 mEq/kg per hour to increase the serum bicarbonate toward normal (18 to 20 mEq/L). Patients with pRTA will have a fractional excretion above 15%. In contrast, patients with dRTA will have normal fractional excretion of bicarbonate (< 5%) despite increasing serum bicarbonate (8).

Unlike dRTA, patients with pRTA do not develop hypercalciuria, nephrolithiasis, or nephrocalcinosis despite the increased filtered load of calcium in metabolic acidosis (discussed earlier). This is due to increased citrate excretion in pRTA. The luminal alkaline pH in the proximal tubule of those with pRTA inhibits the reabsorption of citrate in this location. Citrate then binds to calcium preventing the formation of calcium oxalate or calcium phosphate salts (2).

Alkali supplementation is typically required in large quantities to achieve normal serum pH and restore growth. Starting dosage is 5 to 10 meq/kg/day given in 4 to 5 divided doses (6). Dosages as high as 15 meq/kg/day may be needed to achieve blood HCO3- greater than 20 to 22 mEq/L. Thiazide diuretics may be used to lower bicarbonate dosage (8). In addition to potassium supplementation for hypokalemia, patients with Fanconi syndrome may also require phosphate and vitamin D supplementation to prevent hypophosphatemic rickets (8). While correction of serum bicarbonate levels improves growth, normal plasma bicarbonate levels can be challenging to maintain in pRTA. Progression to chronic kidney disease has not been reported (2).

Type 3 RTA is extremely rare and is beyond the scope of this chapter.

Type 4 (hyperkalemic) RTA

In contrast with other types of RTA, the hallmark of type 4 RTA is hyperkalemia. Type 4 RTA is caused by aldosterone deficiency or resistance. This leads to a normal anion gap metabolic acidosis due to aldosterone’s role in stimulating H+ATPase in the collecting duct. Hyperkalemia occurs because aldosterone normally stimulates potassium secretion. The resultant hyperkalemia has the additional effect of inhibiting ammoniagenesis, which is necessary for the excretion of H+ as NH4+(3). Additionally, the lack of sodium reabsorption in the collecting duct via the aldosterone-regulated epithelial sodium channel (ENaC) results in decreased potassium and proton secretion (2).

Potassium sparing diuretics that act on the distal tubule may cause type 4 RTA. These include spironolactone and triamterene which block the actions of aldosterone in principal cells, and amiloride which blocks ENaC directly. Renal conditions such as obstructive uropathy, pyelonephritis, and lupus nephritis can cause transient aldosterone unresponsiveness (2,3). Aldosterone deficiency can result from Addison disease, congenital adrenal hyperplasia, iatrogenic Addisonian crisis, or other adrenal insufficiencies (3).

Type 4 RTA can also be due to genetic conditions known as pseudohypoaldosteronism. These conditions result in serum and urine studies consistent with hypoaldosteronism, yet the serum aldosterone is elevated. Type 1 pseudohypoaldosteronism is due to mutations in the mineralocorticoid receptor gene or the ENaC subunits leading to mineralocorticoid resistance (2). These patients may present with life-threatening hyperkalemia (3). Pseudohypoaldosteronism type II (Gordon’s syndrome) is due to activating mutations of the sodium chloride cotransporter (NCC) in the distal tubule leading to chloride-dependent sodium retention. This inhibits sodium reabsorption from the collecting duct and consequently diminishes potassium and proton secretion. The hallmark of pseudohypoaldosteronism type II is hyperkalemic RTA and hypertension (2).

Establishing the diagnosis of type 4 RTA includes identifying a normal anion gap metabolic acidosis with accompanying hyperkalemia. Although not necessary for diagnosis, the UAG should be positive or zero (2).

Treatment is dependent on etiology. Underlying kidney disease (e.g., obstructive uropathy) should be treated accordingly. Causative medications should be discontinued. Alkali therapy should be used to correct the plasma bicarbonate level. Supplementation with NaCl may be needed in the context of sodium wasting. Pseudohypoaldosteronism type 2 can be effectively managed with thiazide diuretic therapy (2).


Questions
1. What is the best initial test to differentiate dRTA from pRTA?
2. Explain why carbonic anhydrase 2 (CA2) deficiency will result in a mixed proximal and distal RTA.
3. What excretory product is urine anion gap (UAG) measuring? What does it mean for the UAG to be positive in the context of metabolic acidosis?
4. In patients with dRTA, what is the most likely cause of continued back and leg pain? How is this related to renal calculi?


References
1. Gallo PM. Chapter 19. Nephrology. In: Kleinman K, McDaniel L, Molloy M (eds). The Harriet Lane Handbook, 22nd edition. 2021. Elsevier, Philadelphia. pp: 472-501.
2. Alexander RT, Bitzan M. Renal Tubular Acidosis. Pediatr Clin North Am. 2019;66(1):135-157. doi:10.1016/j.pcl.2018.08.011
3. Dixon BP. Chapter 547. Renal Tubular Acidosis. In: Kleigman RM, St Geme JM, Blum NJ, Shah SS, Tasker RC, Wilson KM (eds). Nelson Textbook of Pediatrics, 21st edition, 2020. Elsevier, Philadelphia. pp. 2761-2766.
4. Watanabe T. Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead. Pediatric Health Med Ther. 2018;9:181-190. doi:10.2147/PHMT.S174459
5. Bertholet-Thomas A, Guittet C, Manso-Silván MA, et al. Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments [published correction appears in Pediatr Nephrol. 2021]. Pediatr Nephrol. 2021;36(1):83-91. doi:10.1007/s00467-020-04693-2
6. Elsevier point of care. Clinical Overview: Renal Tubular Acidosis. https://www-clinicalkey-com.eres.library.manoa.hawaii.edu/#!/content/clinical_overview/67-s2.0-909a50f2-37d9-42c4-8fff-0ffd6753ab69 Updated June 2022. Accessed July 2022.
7. Gómez-Conde S, García-Castaño A, Aguirre M, et al. Molecular aspects and long-term outcome of patients with primary distal renal tubular acidosis. Pediatr Nephrol. 2021;36(10):3133-3142. doi:10.1007/s00467-021-05066-z
8. Finer G, Landau D. Clinical Approach to Proximal Renal Tubular Acidosis in Children. Adv Chronic Kidney Dis. 2018;25(4):351-357. doi:10.1053/j.ackd.2018.05.006


Answers to questions
1. Urine pH would be the best initial test to use. In dRTA, the pH is greater than 5.5 (inappropriately high despite metabolic acidosis) due to an inability to acidify the urine. In pRTA, while the HCO3- is not appropriately reabsorbed, the nephron can still acidify the urine distally, resulting in a urine pH less than 5.5.
2. In the proximal nephron, CA2 is needed to convert absorbed H2O and CO2 back into H+ and HCO3- within the cell for reabsorption of HCO3- into the blood. In the distal nephron, CA2 is needed to produce H+ for secretion into the urine. In this way, CA2 deficiency will cause both pRTA and dRTA.
3. UAG = Na+ + K+ - Cl-
The UAG is used as a surrogate measure of H+ secretion (as NH4+) because NH4+ is excreted coupled to Cl-. A positive UAG would mean that Cl- (coupled to NH4+) is not being excreted in large amounts, as would be expected in metabolic acidosis. This means that there is an inability to acidify the urine by secreting H+, which is the case in dRTA.
4. The patient likely has bone disease secondary to metabolic acidosis. Metabolic acidosis causes the dissolution of hydroxyapatite in bone and inhibits calcium reabsorption in the distal nephron. Increased filtered load of calcium leads to the development of calcium phosphate/calcium oxalate kidney stones.


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