renal tubular acidosis


Introduction to renal tubular acidosis Renal tubular acidosis (RTA) is a metabolic acidosis caused by congenital genetic defects and various secondary factors leading to proximal tubular resorption of sodium bicarbonate or/and distal renal tubular dysfunction. basic knowledge The proportion of sickness: 0.002%-0.003% Susceptible people: no special people Mode of infection: non-infectious Complications: rickets, kidney stones, deafness, hematuria


Causes of renal tubular acidosis

(1) Causes of the disease

Type 1.1 (distal) renal tubular acidosis

(1) Primary: Renal tubular function has many congenital defects, which can be sporadic, but most of them are autosomal recessive.

(2) secondary: pyelonephritis is the most common.

1 autoimmune diseases: Sjogren's syndrome, systemic lupus erythematosus, thyroiditis, chronic active hepatitis, idiopathic hypergammaglobulinemia, cryoglobulinemia, rheumatoid arthritis, pulmonary fibrosis, original Biliary cirrhosis, vasculitis, etc.

2 diseases associated with renal calcification: hyperparathyroidism, hyperthyroidism, vitamin D poisoning, Milk-Alkali syndrome, idiopathic hypercalciuria, hereditary fructose intolerance, Fabry disease, Wilson Sick and so on.

3 drug or toxic nephropathy: amphotericin B (amfortericin B), analgesic, lithium (lithium), gossypol, crude cottonseed oil, toluene cyclamate (toluene cyclamate).

4 hereditary systemic diseases: Ehlens-Danlos syndrome (skin hyperextension syndrome), sickle cell anemia, hereditary elliptic polycythemia, Marfan syndrome, osteosclerosis with carbonic anhydrase II deficiency, medullary sponge Kidney, medullary cyst disease, etc.

5 other: chronic pyelonephritis, obstructive nephropathy, kidney transplantation, high oxalic aciduria, leprosy, etc.

Type 2.2 (proximal) renal tubular acidosis Simple HCO3-reabsorption defects (such as carbonic acid dehydrogenase deficiency) are rare, and multiple substance complex reabsorption defects are more common.

(1) Primary: Mostly autosomal dominant or sporadic, such as the SLC4A4 mutation in the Na-HCO3-cotransporter gene in the kidney can cause permanent proximal RTA with eye disease.

(2) Transient (temporary): mostly occurs in babies.

(3) Alteration or deficiency of carbonic anhydrase activity: such as CAII gene mutation leading to osteosclerosis, RTA, brain calcification and sodium retention.

(4) Secondary:

1 drugs: metamorphic tetracycline (tetracycline), gentamicin (gentamicin), acetazolamide (diamox), p-aminobenzenesulfonamide, alpha amino-methylsulfonamide acetate and other sulfonamides, chain stellate (streptozotocin) and so on.

2 poisoning: cadmium, lead, aluminum, mercury, etc.

3 hereditary diseases: cystineuria, tyrosineuria, Lowe syndrome, Wilson disease, galactose, hereditary fructose intolerance, pyruvate kinase deficiency and the like.

4 multiple myeloma: a large number of light chains are reabsorbed from the proximal tubules and sinking there, resulting in dysfunction of ion transport in the tubular epithelial cells.

5 Vitamin D deficiency or tolerance, or some other conditions that can cause secondary hyperparathyroidism, may be related to the decrease in Na-K-ATPase activity.

6 tubulointerstitial disease, nephrotic syndrome, renal amyloidosis, kidney transplantation, etc.

Type 3.4 renal tubular acidosis

(1) Reduced aldosterone secretion:

1 primary aldosterone deficiency: Addison disease, bilateral adrenalectomy, various enzymes that synthesize adrenal mineralocorticoids, such as 21-hydroxylase deficiency, carbon chain lyase deficiency, etc.; methyl group that catalyzes the methylation of corticosterone 18 Oxidase deficiency and the like.

2 Long-term application of heparin can inhibit the synthesis of aldosterone.

3 low levels of renin are irritating to aldosterone secretion: diabetic nephropathy, tubulointerstitial disease, drugs (beta blockers, ACEI or AT1 blockers, etc.) block or inhibit renin-angiotens The role of the prime system, the role of non-steroidal antipyretic analgesics.

(2) Attenuation of aldosterone by distal renal tubules (aldosterone tolerance):

1 pseudo-low aldosteronism:

A. Sodium retention type: represented by type II pseudo aldosterone reduction, often secondary to chronic renal interstitial diseases (such as interstitial nephritis, renal transplantation, obstructive nephropathy, pyelonephritis, renal vein thrombosis) , renal medullary necrosis, etc., very few are autosomal dominant genetic diseases, some scholars suspect that there may be Cl- reabsorption short-circuit (shunt) in the pathogenesis, so that the far-curved tubule Cl- reabsorption increases, thus the lumen Negative potential decreased, K, H excretion was inhibited, and renal tubular acidosis was formed. At the same time, due to the reabsorption of Na, the increase in Cl-, resulting in sodium retention, increased blood volume, manifested as volume-dependent hypertension, this type of RTA The effect of supplementing exogenous mineralocorticoids is not obvious, and thiazide diuretics can relieve symptoms to varying degrees by inhibiting the reabsorption of chlorine.

B. Salt loss type: typical of type I pseudoaldosteronism (Cheek-Perry syndrome), mostly autosomal dominant or recessive genetic disease, high affinity of renal proximal tubular epithelial cells or type I salt cortex Hormone (aldosterone) receptor deficiency, decreased or even lack of cellular Na-K-ATPase activity, leading to increased urinary Na excretion and decreased H and K excretion, causing hyponatremia, hypovolemia and hyperkalemia of renal tubular acid Poisoning, this type of patient supplemented with exogenous sodium salt can correct clinical abnormalities.

2 drugs or metal poisons inhibit aldosterone: typical drugs are spironolactone, other cyclosporin A, triamterene, amiloride, trimethoprim, lithium salt Wait.

3 other: sickle cell anemia and so on.

(two) pathogenesis

Type 1.1 RTA is mainly for the low-level hydrogen secretion of distal tubule epithelial cells, and can not establish or maintain a normal H concentration gradient inside and outside the lumen, so it is also known as gradient-defective RTA. The main abnormalities are: 1 hydrogen pump disorder or failure theory; 2 Passive diffusion increased pump theory: small tube secretion of H function is normal, but there is a small tube epithelial cell permeability disorder, H secreted into the lumen quickly returned into the epithelial cells; 3 Cl--HCO3- exchange on the basement membrane Barrier; 4 rate defect: The hydrogen pump transport state is not optimal, and the secretion rate is reduced.

There are data available for the presence of H-ATPase disorders in a small number of acquired distal RTAs, and some of the autosomal dominant distal RTA patients have a disorder of Cl--HCO3- on the basal membrane.

It has recently been reported that the presence of autoantibodies against carbonic anhydrase II in patients with Sjogren's syndrome and classic distal RTA may be one of its pathogenesis.

Acidosis can activate the renal buffer mechanism, which increases urinary calcium. At the same time, the proximal tubules increase the reabsorption of niacin, which reduces the urinary citrate content and easily forms urinary calculi, which in turn increases the acid dysfunction.

Type 2.2 RTA may directly or indirectly affect the HCO3-reabsorption process by affecting hydrogen secretion, HCO3-generation or return to blood, and 1 Nasal side Na-H reverse transporter function abnormality produces Na-H exchange disorder, secretion Hydrogen can not be carried out; 2 HCO3--Na co-transport abnormality on the basement membrane side, so that newly regenerated HCO3- regenerated into cells and intracellular can not return to the blood circulation; 3 luminal side or intracellular carbonic anhydrase activity is reduced or inhibited Can not produce enough HCO3-; 4Na permeability barrier, H can not be discharged by Na-H ion exchange; 5 cell polarity disorder; 6Na-K-ATPase activity decreased, lack of function, or intracellular ATP production Reduction; 7 extensive dysfunction of the luminal side caused widespread acidification dysfunction.

Among them, the first six mechanisms of RTA are rare in clinical manifestations, characterized by simple renal acidification dysfunction, called selective proximal tubule RTA, and the last mechanism produces non-selective proximal tubule RTA, with Fanconi Syndrome manifestations, in addition to renal tubular acidosis, often have low blood phosphorus, hypouricemia, high urine phosphorus, high urine calcium, high uric aciduria, glucoseuria, amino acid urine, proteinuria and so on.

Under normal circumstances, the reabsorption of HCO3- in the proximal tubules increases with the increase of filtration. When the blood HCO3-level rises to a certain extent, that is, the maximum reabsorption threshold (normal value is about 27mmol/L), it will reach saturation. At the time of RTA, the threshold was reduced to 18-20 mmol/L. Excessive HCO3- was not reabsorbed and reached the distal tubule, which made the pH of the urine alkaline. When the blood HCO3-level decreased to a certain extent, the proximal tubule Most of the HCO3- can be reabsorbed, and the distal tubules have normal hydrogen secretion function. Therefore, the urine can be acidified and the urine pH is acidic.

3. The pathogenesis of mixed renal tubular acidosis is characterized by type 1 and type 2 RTA. The distal tubule acidification disorder is heavier than type 1 and the HCO3- discharged from the urine is also more (5% to 10% of the filtration excess) %), so the degree of acidosis is heavier than the first two types, and the incidence is also more.

Type 4.4 RTA is due to the lack of aldosterone or the failure of renal tubules to aldosterone to reduce the excretion of distal tubules H and K. The effect of aldosterone on the urinary acidification of distal tubules is as follows: 1 direct stimulation of alpha cell hydrogen secretion 2 acts on the sodium channel on the luminal side of the main cell and the Na-K-ATPase on the basal membrane to promote Na reabsorption, indirectly stimulates the excretion of H by increasing the negative potential on the luminal side; Metabolism, the latter can directly affect the hydrogen secretion or indirectly through the action of aldosterone, such as low potassium can directly stimulate hydrogen secretion but inhibit aldosterone secretion, so the final performance depends on the joint effect of the two; on the other hand, potassium It affects the metabolism and transport of NH4 in the kidney and also has an effect on the excretion of H.

Excessive aldosterone secretion or distal tubular lesions weaken the response to aldosterone, reduce hydrogen secretion, and cause metabolic acidosis. In addition, aldosterone weakens blood potassium and inhibits NH3 production in renal interstitium. The reduction of urinary NH4 emissions is also one of the important mechanisms.


Prevention of renal tubular acidosis

This syndrome is caused by metabolic acidosis caused by proximal and/or distal renal tubular dysfunction. It is not uncommon in clinical practice. The clinical symptoms are different. The mild ones can be asymptomatic, the severe ones are polyuria and annoying. Thirsty, polydipsia, bone and muscle pain, examination, high chloride acidosis (but no azotemia), increased urinary acidity and other manifestations, there are also unexplained double kidney stones or renal calcification, early treatment has a good prognosis In the late stage, when the complication occurs, the prognosis is still not optimistic. At present, the symptomatic treatment of this disease can still be alleviated, and normal life and work as usual. If any of the above-mentioned manifestations can be diagnosed and treated early, so as to avoid further development of the disease and lead to poor prognosis. .

In short, it is necessary to actively treat the primary disease and complications, such as calcium and active vitamin D preparations when bone disease or severe calcium deficiency occurs.


Complications of renal tubular acidosis Complications, kidney stones, deafness, hematuria

If not treated promptly, renal rickets or osteomalacia; bone calcification and/or kidney stones, etc., a small number of patients with deafness, sudden fractures, renal colic with hematuria, loose teeth.


Symptoms of renal tubular acidosis Common symptoms Increased urinary phosphate excretion polyuria nausea and vomiting bone pain nausea kidney area dull pain dehydration lack of appetite

It varies with the location and severity of renal tubular damage, but the common performance has varying degrees of metabolic acidosis.

Type 1.1

It is the most common type in clinical practice. Like type 2, hereditary people develop in infants and children, and can also be seen in early adulthood. It is more common in secondary animals. Children are often found because of gait instability. It is related to the patient's osteomalacia. The most common clinical manifestation of adult patients is recurrent hypokalemia, which is usually more likely to occur at night or after exertion. In the case of episodes, only the limbs are weak, and the support is supported by the hand. In addition to the head and neck, the limbs completely lose their ability to move autonomously, and even cause respiratory muscle spasm and have difficulty breathing. The episode lasts for several hours or 1-2 days, and the light can recover on its own; in severe cases, it needs to be intravenously dripped with potassium chloride. Recoverable, the mechanism of hypokalemia is directly related to intracellular and extracellular potassium ion gradients. It is independent of the absolute level of potassium in plasma. It is prone to renal calcinosis due to increased urinary calcium excretion and secondary hyperparathyroidism. And urinary tract stones, the latter may have renal colic, and easy to have recurrent pyelonephritis, due to bone mineralization disorders, children are prone to rickets and incomplete fractures, and osteomalacia occurs in adults. Child patients also have growth retardation, which may be caused by acidosis that causes a deficiency in the IGF-1 receptor in the cartilage.

Type 2.2

Hereditary people mostly occur in children, have a family history, are autosomal dominant, secondary can also occur in adults, sporadic and secondary are more common than familial and hereditary, clinical manifestations of metabolic Acidosis, hypokalemia and myopathy are the main causes. Children lose nutrients such as sugar, amino acids and phosphates in the urine, so they have growth retardation, malnutrition and rickets. Hypokalemia can have muscle weakness and weakness. Tiredness, hypokalemia image on the electrocardiogram, but the occurrence of hypokalemia is rare, may be related to this type of "limited" renal tubular acidosis.

Type 3.3 (mixed type)

The clinical manifestations of this type of patients are mainly metabolic acidosis, normal potassium, so there is no muscle weakness and hypokalemia, and some clinical manifestations of type 1 and type 2 patients may occur.

Type 4.4

In addition to high-chlorine metabolic acidosis, the main clinical features are hyperkalemia, decreased blood sodium, decreased blood volume in patients, and some patients may have orthostatic hypotension.

In addition to the above clinical manifestations, various types of renal tubular acidosis have clinical manifestations of primary diseases in secondary patients.


Examination of renal tubular acidosis

Urine check

The urine pH of patients with type 1 is often above 5.5, often increased to 7 (although there is significant acidosis in the blood), and incompleteness occurs after the ammonium chloride load test. Type 2 patients only have severe acidosis. The pH value of urine is increased. When the acidosis is not serious, the pH value of urine can be <5.5. The urine pH value of patients with type 3 and type 4 is <5.5. Except for type 1, the titratable acid and urinary ammonium in other types of urine are reduced. The type 3 urinary potassium excretion did not increase, the other types of urine sodium, potassium, calcium, phosphorus increased, except for type 2 patients with increased urine sugar and amino acids, the other types of urine sugar and urine amino acid did not increase, 1 The type 2 glomerular filtration rate is normal, and the type 3 and type 4 are reduced.

2. Blood biochemistry

All patients have blood pH reduction, only the incomplete type 1 patient blood pH can be in the normal range, blood CO2 binding force and blood pH value, type 1, 2 blood potassium is reduced, type 3 is normal, type 4 Increased, there may be secondary increase in blood ammonia in severe distal renal tubular acidosis, Miller et al reported that in a case of severe distal renal tubular acidosis, the kidney may have increased ammonia synthesis, but not excreted from the urine, resulting in Ammonia expands into the blood circulation and causes an increase in blood ammonia.

3. Load test

For incomplete type 1 renal tubular acidosis, the ammonium chloride load test can be used to help confirm the diagnosis. After the fasting of acidic or basic drugs, the oral ammonium chloride 2g, 3 times / d, and even served for 5 days, When the blood pH value drops, the urine pH value can not be reduced to below 5.5, then it can be diagnosed as incomplete type 1 renal tubular acidosis. Oral calcium chloride 0.2g/kg. After 5h, the urine pH value cannot be reduced to below 5.5. That is to say, uric acid has a disorder, can be diagnosed as incomplete type 1 renal tubular acidosis, intravenous infusion of 400ml of sodium bicarbonate within 2h, high concentration of HCO3- in urine supports the diagnosis of type 2 renal tubular acidosis.

4. ECG examination

In patients with hypokalemia, the ST segment is moved down, the T wave is inverted, and U waves appear.

5. X-ray bone examination

Osteoporosis, softening is obvious, the lower limbs and pelvis are heavy, and some are fractured. The radionuclide bone scan shows that the nuclide absorption is sparse and uneven.

6. Other

The urinary citrate/creatinine ratio of patients with complete or incomplete type 1 renal tubular acidosis was lower than 2.5, and the CO2 gradient in urine and blood was measured (urinary and blood CO2 gradient <14 mmHg); although urinary bicarbonate The salt is as high as 89mEq/L. After the attention to carbonate and neutral phosphate, the urine and blood CO2 gradient only increases to 20mmHg, suggesting that the neutron pump of the collecting tube is incomplete.


Diagnosis and diagnosis of renal tubular acidosis


Includes clinical diagnosis, typing diagnosis and etiological diagnosis.

Clinical diagnosis

Clinically, type 1 renal tubular acidosis is the most common. The clinical diagnosis can be based on the following points: 1 age of onset, age of onset is mostly hereditary in infants and children; occurs in adults mostly secondary, 2 families History, hereditary person may have a family history, no family history can not negate hereditary renal tubular acidosis, 3 clinical manifestations of recurrent hypokalemia; blood tests for acidosis, anion gap normal, and urine pH value Sub-assay increased alkaline; muscle weakness, blood potassium persistence; clinical signs of rickets, such as gait instability, head size, rib beading, lower extremity skeletal deformities; adult X-ray photographs with osteomalacia In the past, there was a history of kidney disease, and there were currently older people with persistent low or elevated potassium levels; currently there are diseases that can cause secondary renal tubular acidosis, laboratory tests for metabolic acidosis and low potassium levels. Children, urine test has persistent urine sugar, urine pH is high and blood sugar is not high can rule out the diagnosis of the disease.

For suspicious patients, mainly check urine routine, especially urine pH, urine sugar, urine protein and microscopic examination, urine biochemical examination should include sodium, potassium, calcium, phosphorus, titratable acid and bicarbonate, blood test including blood pH, CO2 binding, serum electrolytes, especially blood potassium, if necessary, do ammonium chloride load test.

2. Classification diagnosis

Typing diagnosis can be made based on clinical performance and laboratory tests.

3. Etiology diagnosis

Hereditary type 1 and 2 renal tubular acidosis can be confirmed by carbonic anhydrase II regulatory region and AEI mutation, respectively, and can be clearly diagnosed by molecular biological techniques, but the renal tubular uric acid function is complicated, and H-ATP has been mentioned above. Some enzymes have not been detected by immunohistochemistry in renal distal convoluted tubule cells, but the gene expressing this enzyme has not been determined. Therefore, genes related to urinary acid function need to be further searched for secondary kidney. There are many causes of tubulic acidosis, and should be checked according to the suspected disease to confirm the diagnosis.

Differential diagnosis

1. Patients with hypokalemia should be identified with familial peripheral palsy, sputum poisoning, hypokalemia, hyperthyroidism (Graves disease), hypokalemia and hypokalemia caused by gossypol poisoning. paralysis.

2. Children with rickets with renal tubular acidosis should be identified with vitamin D deficiency, anti-vitamin D rickets or osteomalacia and vitamin D-dependent rickets.

3. The following diseases have no metabolic acidosis and hypokalemia, urine is acidic, type 4 renal tubular acidosis has elevated blood potassium, and patients with impaired renal function should be differentiated from chronic renal failure, according to the former Although there is kidney damage, it is not serious enough to have uremia.

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