OVERVIEW

What is the renal tubule?

Simply put, the renal tubules in the kidneys act as filters, processing bodily fluids and serving as essential "equipment" for urine production.

The renal tubule is a tubular structure connecting the glomerulus and renal pelvis. From the inside out, it can be divided into four parts: the proximal tubule, thin segment, distal tubule, and connecting tubule. Each segment of the renal tubule has distinct functions.

What are the functions of the renal tubule?

The renal tubule facilitates substance transport, including reabsorption and secretion. It primarily reabsorbs water, inorganic salts, glucose, and amino acids while secreting substances like ammonia.

The body's acid-base balance must be maintained within a normal range. The primary organs responsible for this are the lungs and the kidneys, with the renal tubules playing a key role.

The main function of the renal tubule is to stabilize urine pH. It achieves this by reabsorbing alkaline substances (bicarbonate) in the proximal tubule and secreting acidic substances (hydrogen ions) in the distal tubule, maintaining the body's acid-base balance.

Although the absorbed alkali and excreted acid are minimal in the bloodstream, they maintain an appropriate equilibrium.

Is normal urine acidic or alkaline?

Under normal conditions, urine is weakly acidic, with a pH of around 6.5. Food composition affects urine pH: consuming meat leads to acidic urine, while vegetables and fruits result in alkaline urine. Daily meals may cause fluctuations in urine pH, but it generally ranges between 5.0 and 7.0.

The weak acidity of urine and the body's average pH of about 7.4 (slightly alkaline) debunk the common myth that "acidic bodies cause cancer." If the entire body or blood were acidic, survival would be impossible.

What is renal tubular acidosis?

It occurs when the renal tubules malfunction, disrupting the body's acid-base stability and leading to disease.

More precisely, renal tubular acidosis is a clinical syndrome caused by impaired bicarbonate reabsorption, hydrogen ion secretion, or both in the renal tubules. It manifests as hyperchloremic metabolic acidosis, causing electrolyte imbalances (e.g., potassium, sodium, calcium).

Renal tubular acidosis is generally classified into at least four types. Types I and II are often hereditary; Type III is rare and a mix of Types I and II. Type IV is acquired, usually associated with hypoaldosteronism or reduced tubular response to mineralocorticoids.

How common is renal tubular acidosis? Is there a gender difference?

Incidence varies by type. Type I renal tubular acidosis can occur at any age but is most prevalent in adults aged 20–40, particularly women (70% of cases).

Type II primarily affects male children, with onset in early childhood; some cases resolve with age. Mixed-type combines features of Types I and II. Type IV is more common in older adults.

SYMPTOMS

What are the common manifestations of renal tubular acidosis?

The clinical manifestations of renal tubular acidosis are relatively subtle and difficult to detect in the early stages.

It often presents with complications as the initial symptoms, such as developmental delays in infants, eye diseases, or intellectual disabilities. About 20% of cases may present with bone diseases, such as osteomalacia or osteoporosis. Additionally, urinary stones and renal calcification may occur.

When should renal tubular acidosis be suspected?

If recurrent limb weakness occurs without triggers such as vomiting, diarrhea, or eating disorders, with serum potassium levels below 3.5 mmol/L and blood gas analysis indicating acidosis, renal tubular acidosis should be highly suspected.

What are the types of renal tubular acidosis?

Based on clinical manifestations and physiological mechanisms, renal tubular acidosis can be classified into four types:

• Distal renal tubular acidosis (Type I), caused by impaired hydrogen ion secretion in the distal tubule;

• Proximal renal tubular acidosis (Type II), caused by impaired bicarbonate reabsorption in the proximal tubule;

• A combination of proximal and distal renal tubular acidosis features (Type III);

• Renal tubular acidosis with hyperkalemia (Type IV).

Types I–III are all associated with hypokalemia.

What are the manifestations of Type I renal tubular acidosis?

• Hyperchloremic metabolic acidosis with a normal anion gap: Urine pH > 6.0, blood pH decreases, and paradoxical alkaline urine occurs;

• Hypokalemia: Severe hypokalemia may lead to hypokalemic paralysis, arrhythmias, and hypokalemic nephropathy;

• Calcium and phosphorus metabolism disorders: Acidosis can cause bone dissolution, inhibit renal tubular calcium reabsorption, and reduce 1,25(OH)2D3 production, leading to hypercalciuria, hypocalcemia, followed by hyperphosphaturia and hypophosphatemia, ultimately resulting in bone diseases (e.g., bone pain), kidney stones, and nephrocalcinosis.

Can renal tubular acidosis lead to uremia?

If treated promptly, renal tubular acidosis generally does not cause renal insufficiency and rarely progresses to uremia. However, for distal renal tubular acidosis (Type I), if initial treatment is delayed until adolescence or adulthood, end-stage renal failure is usually unavoidable. Therefore, early and timely treatment is crucial.

CAUSES

Is renal tubular acidosis hereditary?

Not entirely.

• Primary renal tubular acidosis can manifest as sporadic cases, but there are also genetic factors involved, meaning it can be inherited.

• Due to different genetic variations, some offspring may exhibit symptoms while others do not. All four types of renal tubular acidosis can present as autosomal dominant inheritance, while some may show autosomal recessive inheritance.

What causes renal tubular acidosis?

The etiology of renal tubular acidosis is complex and can be divided into primary and secondary causes. Primary cases are mostly sporadic, while secondary cases result from various underlying diseases affecting renal tubular function.

The correlation between specific diseases and the subtypes of renal tubular acidosis is not definitive.

Currently, it is believed that Sjögren's syndrome and systemic lupus erythematosus may trigger type I renal tubular acidosis, while multiple myeloma, Wilson's disease, and hyperparathyroidism may induce type II. Nonsteroidal anti-inflammatory drugs and beta-blockers may contribute to type IV renal tubular acidosis.

What factors can lead to secondary distal renal tubular acidosis?

Many diseases can cause secondary distal renal tubular acidosis. Common causes include:

• Autoimmune diseases: Hypergammaglobulinemia, cryoglobulinemia, Sjögren's syndrome, thyroiditis, pulmonary fibrosis, chronic active hepatitis, systemic lupus erythematosus, primary biliary cirrhosis, vasculitis;

• Cystic diseases, hereditary elliptocytosis;

• Conditions associated with renal calcification: Primary or secondary hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, hyperthyroidism, idiopathic hypercalciuria, hereditary fructose intolerance, medullary sponge kidney, Fabry disease, Wilson's disease;

• Drugs and toxins: Amphotericin B, analgesics, lithium, toluene, cyclamate;

Other causes include tubulointerstitial diseases, chronic pyelonephritis, obstructive nephropathy, hyperoxaluria, kidney transplantation, and leprosy.

What are the common causes of proximal renal tubular acidosis (type II)?

Proximal renal tubular acidosis has numerous potential causes, including:

• Isolated bicarbonate reabsorption defects: Primary or due to altered carbonic anhydrase activity;

• Proximal tubular reabsorption disorders: Primary or associated with genetic diseases (multiple myeloma, dysproteinemia, vitamin D3 deficiency, secondary hypocalcemia and hyperparathyroidism, tyrosinemia, hereditary fructose intolerance, Wilson's disease, cystinosis), drugs or toxins (streptozocin, gentamicin, arginine, lead, mercury), outdated tetracycline, tubulointerstitial diseases, kidney transplantation, and others.

DIAGNOSIS

What is Type I Renal Tubular Acidosis?

Primary Type I renal tubular acidosis is a lifelong condition requiring permanent treatment. The treatment goals not only aim to correct biochemical abnormalities as much as possible but, more importantly, to improve children's growth and development and treat bone disease.

It is caused by dysfunction of distal renal tubular acidification, manifested as the inability to establish a high hydrogen ion gradient between the tubular lumen and peritubular fluid, failing to reduce urine pH below 5.5 even under systemic acidemia stimulation. Possible mechanisms for this dysfunction include:

• Failure of the hydrogen pump in renal tubular cells;

• Non-secretory acidification dysfunction.

What is Type II Renal Tubular Acidosis?

If treated early and medication is adhered to, Type II renal tubular acidosis generally has a good prognosis, with some mild cases resolving spontaneously. The treatment duration varies depending on the type.

Autosomal dominant renal tubular acidosis and autosomal recessive renal tubular acidosis with ocular disease are usually permanent conditions requiring lifelong alkali supplementation. In contrast, sporadic renal tubular acidosis is temporary, with tubular defects improving naturally as the child grows.

It is caused by impaired bicarbonate reabsorption in the proximal tubule, leading to a decreased renal bicarbonate reabsorption threshold.

What is Type III Renal Tubular Acidosis?

Type III renal tubular acidosis may transiently appear in infants with primary distal renal tubular acidosis without an independent genetic basis, or it may result from hereditary carbonic anhydrase II deficiency.

Due to simultaneous dysfunction of the proximal and distal renal tubules, the urine cannot be maximally acidified even in severe acidosis. The clinical symptoms are severe, hence it is also called mixed renal tubular acidosis.

What is Type IV Renal Tubular Acidosis?

Hereditary Type IV renal tubular acidosis is common in children, with causes broadly categorized as primary Type I pseudohypoaldosteronism and primary Type II pseudohypoaldosteronism (also known as Gordon syndrome).

Another subtype seen in infancy presents as transient hyperkalemia and metabolic acidosis without renal salt wasting.

Also called hyperkalemic renal tubular acidosis, it involves acidosis accompanied by hyperkalemia.

It is generally believed that reduced aldosterone secretion or weakened distal tubular response to aldosterone is a key pathogenic factor, impairing sodium reabsorption, hydrogen and potassium excretion, and ammonia production, ultimately leading to acidosis and hyperkalemia.

What Tests Should Be Done for Renal Tubular Acidosis?

• First, a urine test should be performed to monitor urine pH, bicarbonate, and potassium levels.

• Next, arterial blood gas analysis should be done to assess blood pH and determine the presence of acidemia.

• Then, electrolytes, blood calcium, and phosphorus levels should be checked to evaluate potassium, calcium, and phosphorus status, determining whether hypokalemia or hyperkalemia is present.

How is Proximal Renal Tubular Acidosis Diagnosed?

Diagnosis requires combining clinical manifestations and laboratory tests. Clinical symptoms are usually mild, including growth retardation, malnutrition, fatigue, weakness, anorexia, polyuria, polydipsia, or hypokalemia.

Typical cases present with hyperchloremic acidemia but normal distal tubular acidification function, with urine pH dropping below 5.5, or accompanied by bone abnormalities (osteomalacia, osteoporosis), glycosuria, aminoaciduria, etc.

Laboratory findings include:

• Normal anion gap hyperchloremic metabolic acidosis;

• Hypokalemia with increased urinary potassium excretion;

• Elevated urinary bicarbonate, with a fractional excretion of bicarbonate >15%. Suspected cases may undergo a bicarbonate reabsorption test.

TREATMENT

How to treat renal tubular acidosis?

For secondary renal tubular acidosis with a clear cause, the underlying condition should be addressed whenever possible (e.g., restricting fructose intake in fructose intolerance). Symptomatic treatment mainly includes:

• Correcting acidosis: For proximal renal tubular acidosis, a mixture of sodium citrate and potassium citrate should be supplemented, with an alkali dosage of 10–20 mmol/kg per 24 hours, divided into multiple oral doses daily to ensure balanced day-night loads. For distal renal tubular acidosis, adults require 1–2 mmol/kg, while children need 1–24 mmol/kg.

• Potassium supplementation: Potassium citrate is often prescribed (usually combined with citrate or sodium citrate).

• Preventing kidney stones, nephrocalcinosis, and bone disease: Monitor alkali supplementation and blood calcium levels, maintain adequate hydration to prevent kidney stones and nephrocalcinosis, and supplement active vitamin D3 to manage bone disease.

Does renal tubular acidosis require lifelong treatment?

The duration of treatment for renal tubular acidosis varies by type.

Primary distal renal tubular acidosis, autosomal dominant proximal renal tubular acidosis, and autosomal recessive renal tubular acidosis with ocular disease are usually permanent conditions requiring lifelong alkali therapy, as they cannot be cured.

Secondary renal tubular acidosis may resolve after addressing the underlying cause. Sporadic isolated proximal renal tubular acidosis is transient, and the tubular defect often improves with development, allowing discontinuation of medication within 3–5 years without recurrence.

Does renal tubular acidosis require regular follow-ups?

Since primary renal tubular acidosis is a lifelong condition, regular follow-ups are necessary—at least twice a year—to adjust medication dosages based on test results.

DIET & LIFESTYLE

Can you get pregnant with renal tubular acidosis?

Renal tubular acidosis generally does not affect kidney function and rarely affects blood pressure, so pregnancy is possible. However, during pregnancy, regular monitoring of blood potassium, blood pH, and routine urine tests should be performed. If back pain occurs during pregnancy, seek medical attention promptly.

Are there any dietary restrictions for renal tubular acidosis?

Since renal tubular acidosis is often associated with bone disease, kidney stones, and renal calcification, high-calcium foods should be avoided in the diet. Additionally, due to the increased risk of urinary tract infections, it is important to drink plenty of water and urinate frequently.

PREVENTION

How to prevent renal tubular acidosis?

There is currently no effective prevention method for primary renal tubular acidosis, while prevention of secondary diseases should start with treating the underlying condition to control its progression to renal tubular acidosis. For patients already affected, active treatment is necessary to prevent disease progression and achieve a favorable prognosis.

Currently, there is no genetic screening available in clinical practice to determine whether a fetus has renal tubular acidosis.