Renal tubular acidosis
Introduction
Brief introduction of renal tubular acidosis Renal tubular acidosis (RTA) is a metabolic acidosis caused by congenital genetic defects and various secondary factors that lead to the absorption of sodium bicarbonate in the proximal renal tubules or/and the dysfunction of acid excretion in the distal renal tubules. Basic knowledge Prevalence rate: 0.002% - 0.003% Susceptible group: no special group Mode of infection: non infectious Complications: rickets, kidney stones, deafness, hematuria
Cause
Etiology of renal tubular acidosis
（1） Pathogenesis
1.1 Type (distal) renal tubular acidosis
(1) Primary: Most renal tubular functions have congenital defects, which may be sporadic, but most of them are autosomal recessive inheritance.
(2) Secondary: Pyelonephritis is the most common.
① Autoimmune diseases: Sjogren's syndrome, systemic lupus erythematosus, thyroiditis, chronic active hepatitis, high idiopathic γ Globulinemia, cryoglobulinemia, rheumatoid arthritis, pulmonary fibrosis, primary biliary cirrhosis, vasculitis, etc.
② Diseases related to renal calcification: hyperparathyroidism, hyperthyroidism, vitamin D poisoning, Milk Alkali syndrome, idiopathic hypercalciuria, hereditary fructose intolerance, Fabry disease, Wilson disease, etc.
③ Drugs or toxic nephropathy: amphotericin B, analgesic, lithium, gossypol, crude cottonseed oil, toluene cyclamate, etc.
④ Hereditary systemic diseases: Ehlens Danlos syndrome (skin hyperelasticity syndrome), sickle cell anemia, hereditary elliptical erythrocytosis, Marfan syndrome, osteosclerosis with carbonic anhydrase II deficiency, medullary sponge kidney, medullary cyst disease, etc.
⑤ Others: chronic pyelonephritis, obstructive nephropathy, kidney transplantation, hyperoxaluria, leprosy, etc.
Type 2.2 (proximal) renal tubular acidosis: simple HCO3 reabsorption defect (such as lack of carbonate dehydrogenase) is rare, while multiple substance compound reabsorption defect is common.
(1) Primary: Most of them are autosomal dominant inheritance or sporadic. For example, mutations in SLC4A4, the coding gene for Na HCO3 cotransporter protein in the kidney, can cause permanent simple proximal RTA with eye disease.
(2) Transient (temporary): It mostly occurs in infants.
(3) Change or lack of carbonic anhydrase activity: for example, CA Ⅱ gene mutation leads to bone sclerosis, RTA, brain calcification and sodium retention.
(4) Secondary:
① Drugs: deteriorated tetracycline, gentamicin, acetazolamide, p-aminobenzenesulfonamide, α Sulfonamides such as amino-p-methylsulfonamidoacetate, streptozotocin, etc.
② Poisoning: cadmium, lead, aluminum, mercury, etc.
③ Hereditary diseases: cystinuria, tyrosinuria, Lowe syndrome, Wilson disease, galactosis, hereditary fructose intolerance, pyruvate kinase deficiency, etc.
④ Multiple myeloma: light chains are absorbed from proximal tubules and deposited there, resulting in dysfunction of ion transport in tubular epithelial cells.
⑤ Vitamin D deficiency or tolerance, or some other conditions that can cause secondary hyperparathyroidism, may be related to the reduction of Na-K-ATPase activity.
⑥ Renal tubulointerstitial disease, nephrotic syndrome, renal amyloidosis, renal transplantation, etc.
Type 3.4 renal tubular acidosis
(1) Reduction of aldosterone secretion:
① Primary aldosterone deficiency: Addison's disease, bilateral adrenalectomy, various enzymes that synthesize adrenal mineralocorticoid, such as 21 hydroxylase deficiency, carbon chain lyase deficiency, etc; Methyl oxidase defect that catalyzes the methyl oxidation of corticosterone 18.
② Long term and extensive application of heparin can inhibit aldosterone synthesis.
③ Too low renin level stimulates too little aldosterone secretion: diabetic nephropathy, renal tubulointerstitial disease, drugs（ β Receptor blockers, ACEI or AT1 receptor blockers, etc.) block or inhibit the action of renin angiotensin system, the action of non steroidal antipyretic and analgesic drugs, etc.
(2) The reaction of distal renal tubules to aldosterone is weakened (aldosterone tolerance):
① Pseudo hypoaldosteronism:
A. Sodium retention type: represented by type II pseudoaldosteronism, it is often secondary to chronic renal interstitial diseases (such as interstitial nephritis, kidney transplantation, obstructive nephropathy, pyelonephritis, renal vein thrombosis, renal medullary necrosis, etc.), and very few are autosomal dominant genetic diseases. Some scholars suspect that there may be a short circuit of Cl - reabsorption in its pathogenesis, It increases the resorption of Cl - in the distal convoluted tubules, thus reducing the negative potential of the lumen, inhibiting the excretion of K and H, and forming renal tubular acidosis; At the same time, the reabsorption of Na also increases with Cl -, resulting in retention of water and sodium and increased blood volume, which is manifested as volume dependent hypertension. This type of RTA has no obvious effect on the supplementation of exogenous mineralocorticoid, while thiazide diuretics can alleviate symptoms in different degrees by inhibiting the reabsorption of chlorine.
B. Salt loss type: typical of type I pseudoaldosteropenia (Cheek Perry syndrome), most of them are autosomal dominant or recessive genetic diseases, which are high affinity of distal renal tubular epithelial cells or type I halocorticoid (aldosterone) receptor defects. The activity of cell Na K ATPase is reduced or even deficient, leading to increased urinary Na excretion and decreased H, K excretion, resulting in hyponatremia, In hypovolemic and hyperkalemic renal tubular acidosis, exogenous sodium salt supplementation can correct clinical abnormalities in this type of patients.
② Drugs or metal poisons inhibit aldosterone action: typical drugs are spironolactone, other cyclosporin A, triamterene, amiloride, trimethoprim, lithium salt, etc.
③ Others: sickle cell anemia, etc.
（2） Pathogenesis
Type 1.1 RTA mainly refers to the low hydrogen secretion ability of distal tubular epithelial cells, which cannot establish or maintain normal H concentration gradient inside and outside the lumen, so it was formerly called gradient deficient RTA, and the main abnormalities include: ① hydrogen pump dysfunction or failure theory; ② The theory of passive diffusion increases the pump: the function of tubular secreting H is normal, but the permeability of tubular epithelial cells is blocked, and the H secreted to the lumen quickly returns to the epithelial cells; ③ Cl -- HCO3 exchange barrier on the base side membrane; ④ Rate defect: the hydrogen pump transport status cannot reach the optimal level, and the rate of hydrogen secretion decreases.
At present, some data have shown that a small number of acquired distal RTAs have H-ATPase disorders, while some patients with autosomal dominant distal RTAs have found that Cl - HCO3 - on the basolateral membrane has an exchange disorder.
Recently, it has been reported that there are autoantibodies against carbonic anhydrase II in patients with Sjogren's syndrome with classical distal RTA, which may be one of its pathogenesis.
Acidosis can activate the renal buffering mechanism, increase urinary calcium, and increase the reabsorption of citric acid by proximal tubules, reduce the content of urinary citric acid, and easily form urinary calculi, which will aggravate the obstruction of acid excretion.
Type 2.2 RTA may directly or indirectly block the process of HCO3 reabsorption by affecting hydrogen secretion, HCO3 production or returning to the blood. ① Na-H reverse transporter function at the lumen side is abnormal, resulting in Na-H exchange disorder, and hydrogen secretion cannot proceed; ② The co transport of HCO3 -- Na at the basement membrane side is abnormal, making it impossible for the newly generated HCO3 - absorbed back into the cells and cells to return to the blood circulation; ③ The activity of carbonic anhydrase on the lumen side or in the cell is reduced or inhibited, and cannot produce enough HCO3 -; ④ Na permeability is impaired, and H cannot be discharged through Na H ion exchange; ⑤ Cell polarity disorder; ⑥ The activity of Na-K-ATPase decreases, the function is insufficient, or the intracellular ATP production decreases; ⑦ Widespread acidification dysfunction is caused by widespread transport disorder at the lumen side.
Among them, the RTA caused by the first six mechanisms is relatively rare in clinical practice, which is manifested as simple renal acidification dysfunction, called selective proximal tubular RTA, while the last mechanism produces non selective proximal tubular RTA, with Fanconi syndrome. In addition to renal tubular acidosis, there are often low blood phosphorus, low blood uric acid, high urine phosphorus, high urine calcium, high uric acid, and glucose urine at the same time, Amino acid urine, albuminuria, etc.
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 (the normal value is about 27 mmol/L), it will reach saturation. During type 2 RTA, the threshold will be reduced to 18~20 mmol/L. Too much HCO3 - cannot be reabsorbed and reaches the distal tubules, making the urine pH value alkaline, When the blood HCO3 - level decreases to a certain extent, the proximal tubules can reabsorb most of HCO3 -, and the distal tubules can secrete hydrogen normally, so the urine can be acidified at this time, and the urine pH value is acidic.
3. The pathogenesis of mixed renal tubular acidosis has the characteristics of both type 1 and type 2 RTA. The distal tubular acidosis disorder is more serious than type 1, and the HCO3 - excreted in urine is also more (up to 5%~10% of excess filtration), so the acidosis degree is more serious 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 act on aldosterone, which reduces the excretion of H and K in distal tubules. Aldosterone promotes the urinary acidification function of distal tubules, which is manifested in: ① direct stimulation α Cell hydrogen secretion; ② It acts on the sodium channel on the lumen side of the main cell and the Na K ATPase on the basal membrane to promote Na reabsorption, and indirectly stimulates H excretion by increasing the negative potential on the lumen side; ③ By affecting the metabolism of potassium, the latter can directly affect the secretion of hydrogen or indirectly through the action of aldosterone. For example, low potassium can directly stimulate the secretion of hydrogen but inhibit the secretion of aldosterone, so the final result depends on the joint action of the two; On the other hand, potassium affects the metabolism and transport of NH4 in the kidney, and also plays a role in the excretion of H.
Too little aldosterone secretion or pathological changes in the distal renal tubules weaken the reaction to aldosterone, reduce hydrogen secretion, and cause metabolic acidosis. In addition, after the aldosterone function is weakened, the blood potassium increases, which inhibits the generation of NH3 in the renal interstitium. The reduction of urine NH4 excretion is also an important mechanism.
Prevention
Prevention of renal tubular acidosis
This syndrome is a metabolic acidosis caused by the dysfunction of proximal and/or distal renal tubules. It is not uncommon in clinical practice. The clinical symptoms vary in severity. The mild symptoms can be asymptomatic, and the severe cases can be treated with polyuria, thirst, excessive drinking, bone and muscle pain. Hyperchloric acidosis (but no azotemia) and increased urine acidity and alkalinity can be found during the examination, There are also patients with double kidney stones or renal calcification of unknown cause, who have a good prognosis after early treatment, and those who have seen a doctor in the late stage still have a poor prognosis when complications occur. At present, the symptomatic treatment of this disease can still be alleviated, and they can still live and work normally. If they have the above manifestations, they can be diagnosed and treated as soon as possible, so as to avoid the further development of the disease leading to a bad prognosis.
In short, we should actively treat the primary disease and complications, such as bone disease or severe calcium deficiency, calcium and active vitamin D preparations can be given.
Complication
Complications of renal tubular acidosis complication Rickets, kidney stones, deafness, hematuria
Renal rickets or osteomalacia may occur if not treated in time; Bone calcification and (or) kidney stones, a few patients with deafness, sudden fracture, renal colic with hematuria, loose teeth.
Symptom
Symptoms of renal tubular acidosis common symptom Increased excretion of phosphate in urine; polyuria; nausea; vomiting; bone pain; nausea; dull pain in renal region Dehydration fatigue and anorexia
The location and severity of renal tubular damage vary, but the common manifestations are metabolic acidosis of varying degrees.
1.1 type
It is the most common type in clinic. Like Type 2, hereditary diseases occur in infancy and childhood, and can also be seen in early adulthood. Secondary diseases are common. Children are often found due to unstable gait. This symptom is related to osteomalacia in patients. The most common clinical manifestation of adult patients is recurrent hypokalemic paralysis, which usually occurs at night or after fatigue, When the attack is mild, the patient only feels weak in his/her limbs, and he/she should rely on his/her hands to support him/her when sitting up. In severe cases, except for the head and neck, the limbs completely lose their ability to move independently, and even cause paralysis of the respiratory muscles and dyspnea. The attack lasts for several hours or 1 to 2 days, and the mild patient can recover by himself/herself; In severe cases, it can be recovered only after intravenous drip of potassium chloride. The mechanism of hypokalemic paralysis is directly related to the gradient of intracellular and extracellular potassium ions, but not to the absolute level of potassium in plasma. Due to increased urinary calcium excretion and secondary hyperparathyroidism, renal calcinosis and urinary calculi are prone to occur. The latter can have renal colic, and is prone to recurrent episodes of pyelonephritis, Because of bone mineralization disorder, children are prone to rickets and incomplete fractures, while adults are prone to osteomalacia. Children also have growth retardation, which may be caused by the lack of IGF-1 receptor in cartilage due to acidosis.
Type 2.2
Hereditary persons are mostly born in children with a family history, which is autosomal dominant inheritance. Secondary persons can also be infected in adults. Sporadic and secondary persons are more common than familial and hereditary ones, respectively. The clinical manifestations are mainly metabolic acidosis, hypokalemia and myopathy. Children have growth retardation due to the loss of sugar, amino acid, phosphate and other nutrients in urine, Malnutrition and rickets, hypokalemia can cause muscle weakness, fatigue, and hypokalemia on ECG, but hypokalemic paralysis is rare, which may be related to this type of "limited" tubular acidosis.
3.3 type (mixed type)
The clinical manifestations of this type of patients are mainly metabolic acidosis and normal blood potassium, so there is no muscle weakness and hypokalemic paralysis, and some clinical manifestations of type 1 and type 2 patients can appear.
4.4 type
In addition to hyperchloric metabolic acidosis, the main clinical characteristics of patients are hyperkalemia, low blood sodium, and some patients may have postural hypotension due to reduced blood volume.
In addition to the above clinical manifestations, there are also clinical manifestations of primary diseases in secondary patients with various types of renal tubular acidosis.
Examine
Examination of renal tubular acidosis
1. Urine examination
The urine pH value of type 1 patients is often above 5.5 and often increases to 7 (although there is obvious acidosis in the blood). This situation occurs only after the ammonium chloride load test for incomplete patients. The urine pH value of type 2 patients only increases when there is serious acidosis. The urine pH value of type 3 and 4 patients can be<5.5 when there is no serious acidosis. Except type 1, titratable acid and ammonium in other types of urine are reduced, Except type 3 urinary potassium excretion did not increase, the urine sodium, potassium, calcium and phosphorus of other types increased. Except type 2 patients with increased urine sugar and amino acids, the urine sugar and amino acids of other types did not increase. The glomerular filtration rate of type 1 and 2 was normal, while that of type 3 and 4 was decreased.
2. Blood biochemistry
All types of patients have decreased blood pH values. Only incomplete type 1 patients have blood pH values that can be within the normal range. The blood CO2 binding force is the same as the blood pH value. Type 1 and 2 blood potassium decreases, type 3 is normal, and type 4 is increased. In the case of severe distal renal tubular acidosis, there may be secondary increase in blood ammonia. Miller et al reported that one infant may have increased renal synthetic ammonia in the case of severe distal renal tubular acidosis, But it is not excreted from urine, so that ammonia will expand back into the blood circulation and cause the rise of blood ammonia.
3. Load test
Incomplete type 1 renal tubular acidosis can be diagnosed by ammonium chloride loading test. The test method is to take 2g of ammonium chloride orally three times a day for five consecutive days after fasting acidic or alkaline drugs. If the blood pH value drops and the urine pH value still cannot fall below 5.5, it can be diagnosed as incomplete type 1 renal tubular acidosis. After taking 0.2g/kg of calcium chloride orally for five hours, If the urine pH value cannot fall below 5.5, it indicates that there is an obstacle in urine acidification. It can be diagnosed as incomplete type 1 renal tubular acidosis. Intravenous drip of 400ml sodium bicarbonate within 2h. High concentration of HCO3 in urine supports the diagnosis of type 2 renal tubular acidosis.
4. ECG examination
Hypokalemia patients have ST segment depression, T wave inversion, and U wave.
5. X-ray bone examination
Osteoporosis, obvious softening, with lower limbs and pelvis as the main body, and some of them present fractures. The radionuclide bone scan shows that the radionuclide absorption is sparse and uneven.
6. Others
The urinary citrate/creatinine ratio of patients with complete or incomplete type 1 renal tubular acidosis was lower than 2.5, and the urine and blood CO2 gradient (urine and blood CO2 gradient<14 mmHg) was measured; Although the bicarbonate in urine is as high as 89mEq/L, the gradient of urine and blood CO2 only increases to 20mmHg after dropping carbonate and neutral phosphate, indicating that the neutron pump in the collector is not fully functional.
Diagnosis
Diagnosis and differential diagnosis of renal tubular acidosis
diagnosis
It includes clinical diagnosis, typing diagnosis and etiological diagnosis.
1. Clinical diagnosis
In clinical practice, type 1 renal tubular acidosis is the most common. The clinical diagnosis can be based on the following points: ① Age of onset, which is hereditary in infants and children; Most of the cases occurred in adults are secondary. ② Family history. Hereditary cases may have a family history. Without a family history, hereditary tubular acidosis cannot be denied. ③ Repeated hypokalemic paralysis occurs clinically; The blood test showed acidosis, normal anion gap, and alkaline urine pH value after repeated determinations; Weak muscles and low blood potassium persistently; There are clinical signs of rickets, such as unstable gait, large head, beaded ribs, and lower limb bone deformity; Adult X-ray pictures with osteomalacia; Older people with a history of kidney disease in the past and persistent low or high blood potassium at present; At present, patients with diseases that can cause secondary renal tubular acidosis, metabolic acidosis and low blood potassium in laboratory tests, persistent urine sugar in children's urine tests, high urine pH and low blood sugar can exclude diabetes, all support the diagnosis of this disease.
For suspicious patients, urine routine examination is mainly performed, especially urine pH value, urine sugar, urine protein and microscopic examination. Urine biochemical examination should include sodium, potassium, calcium, phosphorus, titratable acid and bicarbonate. Blood examination includes blood pH value, CO2 binding force, serum electrolyte, especially blood potassium. If necessary, ammonium chloride load test should be performed.
2. Typing diagnosis
The typing diagnosis can be made according to clinical manifestations and laboratory tests.
3. Etiological diagnosis
Hereditary type 1 and type 2 renal tubular acidosis can be diagnosed by mutations in the regulatory region of carbonic anhydrase II and AEI respectively, which can be clearly diagnosed by molecular biological technology. However, the function of renal tubules to acidify urine is complex. As mentioned earlier, some patients with H-ATPase have not detected this enzyme in renal distal tubular cells by immunohistochemical method, but the gene expressing this enzyme has not been determined. Therefore, Genes related to urinary acidification function need to be further searched. There are many causes of secondary renal tubular acidosis, and relevant examinations should be carried out according to the suspected diseases to confirm the diagnosis.
differential diagnosis
1. People with hypokalemic paralysis should be differentiated from the following diseases: familial peripheral paralysis, barium poisoning hypokalemic paralysis, hyperthyroidism (Graves disease) complicated with hypokalemic paralysis and hypokalemic paralysis caused by gossypol poisoning.
2. Children with renal tubular acidosis with rickets should be differentiated from vitamin D deficiency, vitamin D resistant rickets or osteomalacia and vitamin D dependent rickets type 1.
3. None of the following diseases has metabolic acidosis and hypokalemia, and the urine is acidic. Type 4 renal tubular acidosis has elevated blood potassium. Those with impaired renal function should be differentiated from chronic renal failure. According to the former, although there is renal function damage, it is not serious enough to have uremia.
