Renal tubular acidosis (RTA) is a clinical syndrome caused by reduced hydrogen ion secretion in each nephron and/or decreased renal bicarbonate reabsorption. Its characteristics include hyperchloremic metabolic acidosis and relatively elevated urinary pH.

This condition results from various primary or secondary defects in renal tubular function, differing from the metabolic acidosis in chronic renal failure. The latter is primarily due to glomerular diseases, where the reduction in functional nephrons leads to insufficient total acid excretion despite increased acid excretion per remaining nephron.

Based on the primary site of involvement and the different pathological mechanisms, this syndrome is classified into four types.

1. Type I (distal renal tubular acidosis): The main defect is impaired hydrogen ion secretion in the distal renal tubule, leading to failure in urine acidification.
2. Type II (proximal renal tubular acidosis): Caused by dysfunction in proximal renal tubular bicarbonate reabsorption, the renal bicarbonate threshold is lowered in affected children, resulting in NaHCO₃ loss in urine and subsequent acidosis.
3. Type III: Exhibits features of Type I but also includes grade I bicarbonate reabsorption impairment, thus considered a mixed form of Types I and II.
4. Type IV: Results from congenital or acquired aldosterone deficiency or renal tubular insensitivity to aldosterone. Reduced renal tubular reabsorption of HCO₃^- and decreased acid and potassium excretion lead to acidosis and hyperkalemia.

bubble_chart Clinical Manifestations

1. Manifestations of chronic metabolic acidosis, such as growth retardation, lethargy, decreased appetite, nausea, vomiting, lack of strength, and deep and rapid breathing.
2. There is impaired urine concentration leading to polyuria, polydipsia, and nocturia.
3. There may be manifestations of hypokalemia (such as muscle weakness, muscle paralysis, abdominal distension and fullness, weakened borborygmi, etc.), skeletal changes of rickets (such as genu valgum, genu varum, etc.), kidney stones, nephrocalcinosis, and a history of urinary tract infections induced by these conditions. Such changes are more common in type I.
4. Past medical history may include recurrent gastrointestinal disturbances, dehydration, and episodes of acidosis. Type I may also be accompanied by congenital deafness.

bubble_chart Auxiliary Examination

1. Urinalysis: Clinical manifestations of acidosis but urine pH is alkaline or relatively elevated. Additionally, tests for urine glucose, amino acids, and urine calcium ("24-hour urine calcium >0.1 mmol/(kg·d) or >4 mg/(kg·d) indicates hypercalciuria"), titratable acid, and urine ammonia should be performed to aid in classification.
2. Blood tests: pH decreases, bicarbonate decreases, and sodium, potassium, calcium, and phosphorus should also be checked. Blood chloride is elevated.
3. Acid loading test: Also known as the NH₄Cl loading test, used to diagnose distal renal tubular acidosis. In individuals with normal distal renal tubular function, oral administration of the acidic drug NH₄Cl artificially induces acidemia. Normally, the body increases H⁺ secretion and ammonia (NH₃) production, which combines with H⁺ to form NH₄+, subsequently binding with Cl^- to form NH₄Cl, thereby excreting excess H⁺ in the urine and maintaining normal blood pH, with significant urine acidification. However, patients with distal renal tubular acidosis cannot handle this additional acid load, resulting in decreased blood pH without a corresponding decrease in urine pH. By measuring blood and urine pH at specific intervals after oral NH₄Cl administration, this dissociation between blood and urine can be detected, confirming the diagnosis. Specific procedure: Administer NH₄Cl orally at 0.1 g/kg per day, divided into 3–4 doses, for 3 consecutive days. Measure blood HCO₃^- or CO₂ combining power and urine pH before and after administration. If blood HCO₃^- or CO₂ combining power significantly decreases while urine pH remains >6, distal renal tubular acidosis can be diagnosed. Note that NH₄Cl may exacerbate acidosis, so this test should not be used in children with severe acidosis.
4. Alkali loading test: Also known as the bicarbonate ion reabsorption and excretion test, it is used to diagnose proximal renal tubular acidosis. In normal individuals, most (85-90%) of the bicarbonate ions (HCO₃^-) filtered by the glomerulus are reabsorbed into the blood by the proximal tubules, while 10-15% are reabsorbed by the distal tubules, with very little actually excreted (approximately 1/1000). In proximal renal tubular acidosis, due to impaired reabsorption of HCO₃^- by the proximal tubules, the renal threshold for HCO₃^- is lowered, leading to excessive excretion of NaHCO₃ in the urine. This results in insufficient NaHCO₃ in the blood, causing acidosis, while the urine becomes alkaline due to the higher NaHCO₃ content, creating a dissociation between blood pH and urine pH. Therefore, diagnosis can be aided by simultaneously measuring blood and urine pH. The method involves: orally administering sodium bicarbonate at 1-2 mmol/(kg·d), incrementally increasing the dose daily for 3 days, while continuously measuring blood NaHCO₃ levels. When the level reaches 26 mmol/L, urine is collected to measure urinary HCO₃^- and creatinine, along with blood HCO₃^- and creatinine. The bicarbonate excretion rate is then calculated: Percentage of bicarbonate excretion = (urinary bicarbonate × blood creatinine) / (blood bicarbonate × urinary creatinine) × 100%. In normal individuals, the excretion rate is ≤1%; in proximal renal tubular acidosis, this value is >15%, while in distal renal tubular acidosis, it is <5%.
5. Determination of bicarbonate renal threshold: The renal threshold in normal children is 25-26 mmol/L, and in infants, it is 22 mmol/L. In proximal renal tubular acidosis, the threshold decreases, often to 17-20 mmol/L. Intravenous infusion or oral administration of therapeutic doses of NaHCO₃ raises blood HCO₃^- to 20-22 mmol/L, at which point NaHCO₃ is excreted in the urine. A pH >6 indicates a decreased renal threshold. If the urine pH before medication is <5.5，給藥後尿pH>6.1, the measured plasma HCO₃^- approximates the renal threshold.
6. Skeletal X-rays assess for bone disease, while renal X-rays check for kidney stones or calcifications.

bubble_chart Diagnosis

After diagnosing renal tubular acidosis, it is necessary to distinguish the {|###|}disease cause{|###|} in order to treat the {|###|}disease cause{|###|} accordingly. Examples are as follows:

1. Type I renal tubular acidosis {|###|}disease cause{|###|} (1) Primary: idiopathic or sporadic. (2) Genetic-related: familial, Marfan syndrome, Ehler-Donlos syndrome, Wilson disease. (3) Calcium metabolism disorders with renal calcification: idiopathic hypercalciuria, vitamin D excess, hyperparathyroidism. (4) Hypergammaglobulinemia: multiple myeloma, cryoglobulinemia, amyloidosis. (5) Drugs and toxins: amphotericin B, lithium carbonate, toluene. (6) Autoimmune diseases: Sjögren's syndrome, thyroiditis, chronic active hepatitis, primary biliary cirrhosis. (7) Others: cirrhosis, medullary sponge kidney.
2. Type II renal tubular acidosis {|###|}disease cause{|###|} (1) Hereditary disorders: cystinosis, tyrosinemia, hepatolenticular degeneration, glycogen storage disease type I, pyruvate carboxylase deficiency, galactosemia. (2) Acquired: multiple myeloma, vitamin D deficiency, nephrotic syndrome, amyloidosis, Sjögren's syndrome, renal transplant rejection, drugs or toxins (lead, mercury, copper, outdated tetracycline, acetazolamide). (3) Primary.
3. Type IV renal tubular acidosis {|###|}disease cause{|###|} (1) Aldosterone deficiency: (a) Selective: idiopathic, hyporeninemic hypoaldosteronism, 18-hydroxylase deficiency. (b) With glucocorticoid deficiency: Addison's disease, bilateral adrenalectomy, 21-hydroxylase deficiency. (2) Renal tubular hyporesponsiveness to aldosterone: pseudohypoaldosteronism, chronic tubulointerstitial disease. (3) Others: hereditary hyperkalemia and renal tubular acidosis (Gordon syndrome), acute glomerulonephritis.
4. Clinically, hyperchloremia must first exclude common {|###|}disease cause{|###|} before considering renal tubular acidosis. The {|###|}disease cause{|###|} of hyperchloremia includes: (1) Dehydration. (2) Respiratory alkalosis. (3) Metabolic acidosis. (4) HCl intake: such as the use of NH₄Cl, arginine hydrochloride, lysine hydrochloride, intravenous hyperalimentation. (5) Loss of HCO₃^-: (a) Gastrointestinal loss including diarrhea, biliary-pancreatic-small intestinal fistula, cholestyramine, intake of MgCl₂, CaCl₂, MgSO₄. (b) Renal loss such as distal renal tubular acidosis, proximal renal tubular acidosis, primary or secondary hyperparathyroidism, hypoaldosteronism. (6) Others: bromism.

The diagnosis of renal tubular acidosis can be made if persistent hyperchloremic acidosis is accompanied by alkaline urine.

bubble_chart Treatment Measures

1. Disease cause Treatment: Treat if the disease cause can be clearly identified.
2. Alkaline medications: Used to correct acidosis, often requiring long-term or even lifelong administration. Alkaline medications may include oral sodium bicarbonate or a syrup containing 10% potassium citrate and 10% sodium citrate. Each milliliter of this solution provides 1 mmol each of sodium and potassium, and 2 mmol of HCO₃^-. Dosage varies by type. For Type I, bicarbonate loss is minimal, and alkaline agents are only used to neutralize acidic byproducts in the body, with a daily dose of 1–5 mmol/kg sufficient to maintain daily urinary calcium excretion. <2mg/kg。型尿中丟失碳酸氫鹽量大，每日常需5～l0mmol/kg。分次24小時均勻服。
3. Potassium supplementation: Severe hypokalemia should be corrected first. Potassium citrate is commonly used instead of potassium chloride, at a daily dose of 2–4 mmol/kg. Potassium is contraindicated in Type IV.
4. Hydrochlorothiazide can enhance renal bicarbonate retention at a daily dose of 1–3 mg/kg. Combined with alkaline agents, it helps improve their efficacy. Discontinue after acidosis is corrected.
5. For Type IV renal tubular acidosis, if caused by aldosterone deficiency, replacement therapy with 9-α-fluorocortisone at 0.05–0.2 mg daily is recommended. If due to renal tubular resistance to aldosterone, alkaline medications and diuretics should be used.
6. Other measures: Due to impaired renal concentrating ability, adequate daily fluid intake is essential. For bone disorders, provide vitamin D and calcium. Discontinue once bone disorders are resolved to avoid increasing the risk of nephrocalcinosis.