Pediatric renal tubular acidosis

　　First, etiology

　　It is divided into primary and secondary:

　　1. Primary:It belongs to an autosomal recessive genetic disease, and there are also reports that it belongs to an autosomal dominant genetic congenital renal unit defect. It usually occurs in infancy, and sporadic cases can occur at any time.

　　2. Secondary:It can be caused by various reasons. Secondary to congenital genetic diseases such as sickle cell anemia, Marfan syndrome (Marfansyndrome), and Ehlers-Danlos syndrome (EhlersDanlossynohome); secondary to various autoimmune diseases, such as systemic lupus erythematosus, hypergammaglobulinemia, and chronic active hepatitis; various causes of calcium and phosphorus metabolism disorders, such as hyperparathyroidism, hyperthyroidism, etc.; it can also be caused by drugs such as vitamin D intoxication, toxic poisoning, in addition, pyelonephritis, obstructive renal diseases can also lead to DRTA.

　　Second, pathogenesis

　　It is divided into 4 types according to the site of renal tubular damage and its pathophysiological basis: Type I is distal renal tubular acidosis (distal renal tubular acidosis, DRTA), also known as classic renal tubular acidosis. Type II is proximal renal tubular acidosis (proximal renal tubular acidosis, PRTA). Type III is a mixture of Type I and II, also known as mixed type. Type IV renal tubular acidosis is a metabolic acidosis and hyperkalemia caused by insufficient aldosterone secretion or renal tubular insensitivity to aldosterone. Each type can be further divided into primary or secondary renal tubular acidosis according to its etiology.

　　This condition can exist alone or be associated with other multiple renal tubular dysfunction. The complications it causes are also numerous and severe. Pediatric renal tubular acidosis can be complicated by dehydration, slow growth, hyponatremia, hyperchloric metabolic acidosis, refractory rickets, renal calcification, kidney stones, renal colic, polyuria, chronic renal insufficiency, and associated renal tubular and interstitial diseases.

　　1. Primary proximal RTA (Type II):Defects in the reabsorption of bicarbonate by the proximal renal tubules are more common in boys, with slow growth, symptoms of acidosis, hyponatremia, anorexia, nausea, vomiting, fatigue, constipation, dehydration, and other symptoms. The renal threshold for bicarbonate is about 18-20 mmol/L or less. During the ammonium chloride loading test, pH can be excreted.

　　2. Primary distal RTA (type I):The secretion of H+ in the distal renal tubules is dysfunctional, causing the urine to fail to acidify and presenting as hyperchloremic metabolic acidosis. It is an autosomal dominant inheritance, with girls being more common (about 70%). Growth and development are lagging, with refractory rickets, which can manifest as bone pain and duck-like gait, renal calcification, renal calculi, renal colic, thirst, polyuria, dehydration, hypokalemia, hyperchloremic metabolic acidosis with alkaline or weakly acidic urine, and the urine pH cannot be reduced below 5.5 in the ammonium chloride load test, which is an important difference from proximal RTA.

　　3. Mixed type (type III):Combining the characteristics of types I and II, it is seen in infants, with early symptoms appearing as early as one month after birth, with polyuria being obvious.

　　4. Type IV:Its characteristics are persistent hyperkalemia and renal源性 hyperchloremic acidosis, often accompanied by some degree of chronic renal insufficiency and tubular and interstitial diseases, decreased renin secretion, aldosterone secretion defect, and renal acidification dysfunction similar to type II. The excretion of urinary bicarbonate is usually 2% to 3%, and there are no other proximal tubular function abnormalities. Children with the disease can experience a decrease in acidosis as they grow older.

　　Preventive measures refer to other preventive methods for birth defects. Prevention should start from before pregnancy to prenatal care:

　　1. Pre-marital physical examination plays a positive role in preventing birth defects:The size of the effect depends on the items and content of the examination, mainly including serological tests (such as hepatitis B virus, syphilis spirochete, HIV), reproductive system examinations (such as screening for cervical inflammation), general physical examination (such as blood pressure, electrocardiogram), and inquiring about the family history of diseases, personal past medical history, etc., and do a good job in genetic disease consultation work.

　　2. Pregnant women should try to avoid harmful factors:Including avoiding smoke, alcohol, drugs, radiation, pesticides, noise, volatile harmful gases, and toxic heavy metals, etc. During the process of prenatal care during pregnancy, systematic screening for birth defects should be carried out, including regular ultrasound examinations, serological screenings, and necessary chromosome examinations. Once abnormal results are found, it is necessary to determine whether to terminate the pregnancy; the safety of the fetus in the uterus; whether there are sequelae after birth, whether they can be treated, and what the prognosis is, etc. Take feasible diagnostic and treatment measures.

　　1. Biochemical examination:The characteristics are five lows and two highs, that is, low blood phosphorus, low blood potassium, low carbon dioxide binding power, low serum pH value, low blood calcium (or normal), high blood chloride, and high serum alkaline phosphatase.

　　2. Measure blood potassium:If it is hyperkalemia, it can be diagnosed as type IV RTA. If the blood potassium level is low or normal, the urine pH should be measured and further tests with sodium bicarbonate, neutral phosphate, and sodium sulfate should be performed to differentiate.

　　3. Measure urinary ammonia:The purpose is to exclude proximal tubular acidosis and non-renal hyperchloremic acidosis, such as urinary ammonia

　　4. X-ray examination:X-ray examination of the skeleton shows active rickets, osteoporosis, delayed bone age, or accompanied by pathological fractures, avascular necrosis of the femoral head, urinary system stones, and renal calcification.

　　5. Ultrasound examination:Kidney ultrasound may show diffuse damage to the renal cortex, maldevelopment of the kidneys, bilateral hydronephrosis, dilation of the bilateral renal ureters, or calcification of bilateral renal calcareous deposits.

　　6. Ultrasound examination:The renal medulla echo of Type I patients is significantly increased, the hyperechoic pyramids are arranged radially around the renal sinus, clearly demarcated from the cortex, with bright, fine-point echoes inside, with no shadow or faint shadow behind, the echo of the cortex and collecting system is normal. Color Doppler ultrasound shows: in the early stage, the renal vascular tree can still be displayed regularly to the interlobular arterioles between the renal lobes. With the extension of the course, the accumulation of deposits in the renal medulla gradually compresses the blood vessels, mainly affecting the segmental arteries and interlobar arteries. Below the arcuate arteries, blood flow decreases, and in severe cases, the blood supply to the cortical area appears star-like. No renal calcium accumulation was found in any case of Type II renal kidney.

　　1. Suitable diet: milk, eggs, lean meat, wheat starch noodles, wheat flakes, biscuits, or other wheat starch desserts, fruit juice, tea, green vegetable water, fruits, vegetables, etc. During oliguria, glucose, sucrose, fresh lemon juice, etc., can be used; during polyuria, various beverages such as fruit juice, green vegetable water, etc., can be used.

　　2. Limit intake of eggs, milk, and water according to the condition; avoid using fatty foods and high-protein foods. Limit intake of milk, eggs, or lean meat according to the condition; avoid刺激性 foods such as alcohol, coffee, and chili.

　　First, treatment

　　1. Alkaline drugs

　　Due to the reduced excretion of H+ in the distal renal tubules, acidic products accumulate in the body, causing metabolic acidosis. In the case of proximal renal tubular acidosis, the reabsorption function of HCO3- is impaired, and the renal threshold of bicarbonate in children is reduced to below 17-20 mmol/L (normal is 25-26 mmol/L, in small infants 22 mmol/L). Even when the plasma HCO3- is normal, due to the reduced renal threshold, a large amount of HCO3- in the filtrate is excreted into the urine, causing acidosis. The application of alkaline drugs is to correct acidosis, and early use can improve or completely disappear clinical symptoms. There are two commonly used preparations:

　　(1) A mixture of sodium bicarbonate and citrate salts. Sodium bicarbonate can act directly and can be used in both acute and chronic acidosis. Type I patients have little loss of bicarbonate, and only the acidic products in the body need to be neutralized, usually 1-5 mmol/(kg·d); for Type II renal tubular acidosis, in addition to neutralizing the retained acidic products in the body, it is also necessary to compensate for the lost bicarbonate in the urine, so a larger dose is required, starting with 5-10 mmol/(kg·d), administered intravenously or orally. During the treatment process, the dose needs to be adjusted according to blood bicarbonate or carbon dioxide binding capacity and 24-hour urine calcium excretion volume. The urine calcium excretion volume is a sensitive indicator for guiding treatment, and the dose should be adjusted to keep the 24-hour urine calcium excretion volume below 2 mg/kg. An excessive dose of sodium bicarbonate can produce side effects such as abdominal distension and belching.

　　(2) Citrate mixture: There are two preparations, one is sodium citrate and potassium citrate, each containing 100g, dissolved in water to 1000ml, with 2 mmol of base per milliliter. The other is 100g of sodium citrate and 140g of citric acid, dissolved in water to 1000ml, with 1 mmol of sodium per milliliter. The dose is 1 mmol/(kg·d), taken 4 to 5 times orally.

　　2. Potassium salts

　　Supplementing for renal tubular acidosis, in addition to hyperchlorhydric acidosis, due to the secretion disorder of H+ in the distal renal tubule renal units, the exchange of H+-Na+ decreases, and the competitive exchange of K+-Na+ increases, causing excessive potassium excretion and hypokalemia; in the proximal renal tubule, due to the large loss of NaHCO3, plasma volume decreases, leading to secondary aldosterone increase, resulting in increased reabsorption of NaCl to replace the lost NaHCO3 and produce hyperchlorhydric acidosis; the absorption of sodium and excretion of potassium can cause significant hypokalemia, so potassium supplementation is very important. When there is significant hypokalemia, potassium salts should be supplemented first before correcting acidosis to avoid triggering a dangerous phase of potassium competition. Potassium salts commonly contained in citrate preparations can start with a dose of 2 to 4 mmol/(kg·d), taken 3 to 4 times orally. For patients with proximal renal tubular acidosis, the maximum dose should be 4 to 10 mmol/(kg·d) to maintain normal blood potassium levels. The dosage should be adjusted according to the condition and blood potassium concentration during the treatment process. Potassium chloride should be used with caution as it contains chloride ions.

　　3. Calcium preparations

　　Chronic acidosis can lead to increased excretion of calcium in urine, hinder the conversion of 25(OH)D to 1.25(OH)2D, and in addition, some patients have a lack of gastric acid, which affects the absorption of calcium in the intestines, leading to low blood calcium levels. Low blood calcium can cause secondary hyperparathyroidism, increase phosphorus clearance, and when blood phosphate and calcium ions decrease, it prevents bone mineralization, leading to rickets; hypocalcemia may also occur during the correction of acidosis, even seizures. Calcium supplements are needed in all cases. Severe hypocalcemia can be treated with intravenous infusion of 10% calcium gluconate, 0.5 to 1.0 mg/kg or 5 to 10 mg per dose, diluted and infused slowly. Meanwhile, cardiac monitoring should be conducted; if the heart rate is below 60 beats per minute, the injection should be stopped to prevent sudden cardiac arrest. If necessary, it can be repeated every 6 to 8 hours. Generally, oral calcium supplements can be taken for mild hypocalcemia, with a calcium ion supplement of 15 mg/kg.

　　4. Vitamin D treatment

　　Chronic acidosis can affect vitamin D and calcium metabolism, especially when there is no endogenous renal tubular acidosis and significant rickets, vitamin D supplementation is required. It can promote the absorption of calcium by the gastrointestinal mucosa and renal tubules, increase blood calcium concentration, and benefit bone mineralization. The following vitamin D preparations can be selected:

　　(1) Common vitamin D2 or D3 can start with a dose of 5000 to 10000 U and gradually increase, with some individuals reaching as high as 100,000 U/day.

　　(2) 25(OH)D, 50μg/d, or dihydrotachysterol 0.1-0.2mg/d.

　　(3) 1.25(OH)2D, with a dose of 0.5-1.0μg/d, can achieve good efficacy. During the treatment process, blood calcium must be closely monitored. Initially, it should be checked once a week, and then once a month. When blood calcium returns to normal and rickets symptoms are relieved, the dosage should be reduced to prevent hypercalcemia and vitamin D intoxication.

　　5. Diuretics

　　For type I and III cases, it can reduce the deposition of calcium salts in the kidneys; for severe type II cases that require a large amount of bicarbonate, not only can it increase the renal threshold of bicarbonate, reduce the loss in urine, but also reduce the dosage of alkaline drugs; for type IV renal tubular acidosis, the use of diuretics at the same time can help correct acidosis and reduce blood potassium concentration.

　　6. Treatment of Type IV Renal Tubular Acidosis

　　In addition to correcting acidosis according to the principle, due to the lack of aldosterone or low aldosterone response of the distal renal tubules and collecting ducts, the reabsorption of NaHCO3 by the renal tubules is reduced, the excretion of NaHCO3 is increased, and the excretion of acid, potassium, and ammonium in urine is reduced, leading to the retention of H+ and K+ in the body, causing metabolic acidosis and hyperkalemia. Therefore, potassium supplementation is contraindicated in type IV children. Type IV renal tubular acidosis is common in Addison's disease, congenital adrenal cortical hyperplasia (also known as adrenal genitourinary syndrome), and renal hypoplasia, and requires the supplementation of glucocorticoids or mineralocorticoids. Currently, the commonly used glucocorticoid is hydrocortisone, with a dose of 10-20mg/m2, and mineralocorticoids are often used with fludrocortisone, with a dose of 0.15mg/m2. If renal tubular acidosis is accompanied by impaired renal concentrating function, sufficient water must be supplied, about 2-5l/m2 per day.

　　II. Prognosis

　　The prognosis of RTA is related to its type, whether it is diagnosed early and treated in time. It is generally believed that the prognosis of proximal RTA is better, and some RTA infants with incomplete kidney development may gradually recover after 2 years of age. Early diagnosis and timely treatment can improve rickets and other bone deformities, prevent calcification of the spinal cord caused by hypercalciuria, and prevent kidney stones. Growth and development can also be improved, even catching up with peers. Intractable kidney stone cases can be treated with subtotal parathyroidectomy. For those with renal calcification and renal insufficiency, the prognosis is poor.