Pediatric distal renal tubular acidosis

　　First, etiology

　　Primary dRTA is an autosomal dominant or recessive inheritance, and secondary dRTA is often caused by other diseases affecting renal tubular function, which can be seen in hypergammaglobulinemia, primary hyperparathyroidism, vitamin D intoxication, rejection reaction of transplanted kidney, medullary sponge kidney, obstructive nephropathy, idiopathic hypercalciuria renal calcification, Wilson's disease, salt-losing congenital adrenal cortical hyperplasia, renal damage caused by drugs and toxins (such as lithium, amphotericin B, toluene, digoxin, etc.).

　　Second, pathogenesis

　　1. The main defect in the pathogenesis of dRTA lies in the insufficient function of H+ secretion in the distal tubules. There is an intercalated cell (intercalated cell) in the renal cortex collecting tubule epithelial cells, which has H+-ATPase (proton pump) on its luminal membrane, capable of secreting H+. After H+ combines with NH3 and NaHP04 in the lumen, it is excreted out of the body in the form of NH+4 and H2PO-4. The principal cell of the medullary collecting tubule has the function of absorbing sodium and excreting potassium. The dysfunction of these two cells can lead to insufficient secretion of H+. It is currently believed that there are several mechanisms:

　　(1) Secretory defect (secretory defect): H+-ATPase dysfunction, the tubular epithelium cannot secrete H+.

　　(2) Backflow defect: The cell membrane defect increases the permeability of H+, causing H+ to reflux into the tubular epithelial cells.

　　(3) Rate-dependent defect: The rate of proton pump secretion of H+ decreases.

　　(4) Voltage-dependent defect: It reduces the negative potential difference inside the lumen, and there are two types of gene mutations in primary dRTA, mainly involving the mutation of the anion exchange transporter protein (AE1) gene of the cell in autosomal dominant inheritance, and the defect in the B subunit of the proton pump (ATP6B1) in autosomal recessive inheritance.

　　2. Pathophysiology Normally, in the distal tubules and collecting ducts, H+ is secreted through H+-Na+ exchange to regulate acid-base balance. In this disease, the distal tubules have difficulty in excreting H+, leading to the accumulation of H+ in the body, a decrease in the excretion of NH+4 and titratable acid (TA), and causing metabolic acidosis and acidosis. Due to the decrease in H+-Na+ exchange in the distal tubules, K+-Na+ exchange becomes dominant, causing a large loss of K+ and leading to hypokalemia. At the same time, the reduction in Na+ reabsorption causes hyponatremia and secondary hyperaldosteronism, which increases the absorption of Na+ and Cl-, causing hyperchloremia. Long-term hypokalemia impairs the concentrating function of the distal tubules, leading to polydipsia, polyuria, and persistent acidosis causing the body to mobilize the bone buffering system. Calcium and phosphorus in the bones are released into the blood, increasing urinary calcium excretion, decreasing blood calcium levels, and stimulating the parathyroid glands to secrete parathyroid hormone, promoting bone resorption and destruction, reducing bone formation, and further increasing urinary calcium. It inhibits the reabsorption of phosphorus, causing an increase in urinary phosphorus and a decrease in blood phosphorus levels. Alkaline urine helps to form kidney stones and renal parenchymal calcium deposition with increased urinary calcium and phosphorus, thereby causing interstitial renal damage and ultimately leading to renal insufficiency. Citrate is an important factor in the solubility of urinary calcium. During acidosis, the excretion of citrate decreases and reabsorption increases, promoting renal calcification.

　　Pediatric distal renal tubular acidosis patients are prone to malnutrition, rickets or osteomalacia, some may develop kidney stones or renal calcification, and in the late stage, it may develop into uremia. A few have neurological hearing loss, etc.

　　Clinically, it can be divided into infantile and幼儿型, the former onset within a few months after birth, more common in male infants, with autosomal recessive inheritance; the latter often appears symptoms after 2 years old, more common in females, with autosomal dominant inheritance. The main clinical characteristics of dRTA include:

　　First, age of onset

　　Primary dRTA may have clinical manifestations at birth, but the onset of typical symptoms usually occurs after 2 years of age.

　　Second, manifestations of chronic acidosis

　　Growth and development lag and anorexia, nausea, vomiting, diarrhea, constipation, and other chronic metabolic acidosis manifestations. Sometimes, growth lag is the only manifestation. Incomplete dRTA may not show acidosis but only hypokalemia, muscle weakness, or renal calcification.

　　Three, decreased urine concentrating function polydipsia

　　Polyuria, unexplained dehydration, and dehydration fever, shock may occur, which is due to the decreased urine concentrating function caused by hypokalemia.

　　Four, hypokalemia

　　Muscle weakness and even periodic paralysis and other hypokalemia manifestations are prominent, caused by reduced secretion of H+ leading to hypokalemia, which can affect the heart in severe cases, leading to premature contractions and other serious arrhythmias and circulatory failure.

　　Five, rickets manifestations

     Manifestations of rickets, such as demineralization of bone, osteomalacia, skeletal deformities, large anterior fontanelle and delayed closure, and vitamin D treatment is ineffective.

　　Six, renal calcification and renal calculi

     Renal calculi are common in older children and adults, and can occur simultaneously or alone with renal calcification, and can be accompanied by hematuria, hydronephrosis, and urinary tract infection. The stones are mostly calcium phosphate, a few are calcium oxalate and struvite, and purulent urine often persists, which may be related to renal calcification.

　　Seven, several special dRTA

　　1, Combined with proximal and distal renal tubular acidosis (type III): seen in infants, may occur as early as 1 month after birth, as age increases, HCO3- loss can be reduced.

　　2, Incomplete dRTA: may be accompanied by renal calcification but without metabolic acidosis, although there is a barrier to urine acidification, but NH+4 excretion is more, and TA excretion is less, most of which are found in the screening of families with complete dRTA, and there are also many sporadic cases or secondary to other diseases.

　　3, dRTA with deafness: autosomal recessive inheritance, both males and females can be affected, the onset of deafness varies from neonatal period to late childhood.

　　4, Transient renal tubular acidosis: first reported by Lightwood in 1935, acidosis is transient, may be caused by some unrecognized environmental factors, such as vitamin D intoxication, sulfonamide drug kidney damage, or mercury intoxication, and most of them are self-healed around the age of 2.

　　5, Secondary dRTA: seen in various systemic diseases or kidney diseases, patients have clinical manifestations of the primary disease, the diagnosis of this disease is not difficult, based on the manifestations of growth and development delay, polydipsia, polyuria, refractory rickets, and renal calcification, renal calculi, and other features, blood biochemical examination has the characteristics of five lows and two highs, that is, low blood phosphorus, low blood potassium, low blood calcium, low blood sodium, and low carbon dioxide binding power (or low serum pH value), as well as high blood chloride, high serum alkaline phosphatase, and in acidosis, urine pH >

　　6, diagnosis can be confirmed. The following diagnostic tests are mainly used for the diagnosis of incomplete dRTA with不明显 acidosis, and to understand whether dRTA is a defect in the secretion of H+, a voltage-dependent defect (hyperkalemic dRTA), or a gradient defect (reverse leakage type).

　　Secondary RTA can be seen in interstitial nephritis of the renal tubules, primary hyperthyroidism or hyperparathyroidism, vitamin D intoxication, liver cirrhosis, chronic active hepatitis, lithium intoxication, and other diseases, therefore, actively treating and preventing these diseases is a reliable method to prevent secondary RTA.

　　1. Urine pH:Urine pH reflects the amount of H+ in urine. In dRTA, although the blood pH is less than 7.35, the urine pH is still ≥6.0, and can even reach 6.5, 7.0 and above. The determination of urine pH must be carried out using a pH meter. The results of pH paper and urine analyzer are not accurate enough, and the determination of urine pH alone has certain limitations. Urine pH less than 5.5 does not necessarily mean that the acidification function is perfect. For example, if the child has an obstacle in the secretion of NH3, but a small amount of H+ cannot combine with NH3 to form NH+4, the urine pH can still be less than 5.5. Therefore, both urine pH and urine NH+4 should be measured simultaneously for comprehensive analysis and judgment.

　　2. Determination of urinary titratable acid and urinary NH+4:Most of the H+ secreted by the distal renal tubules combine with NH3 to form NH+4 and excreted, and the other part is excreted in the form of titratable acid. Therefore, the sum of titratable acid in urine and NH+4 represents the net acid excretion of the kidney. When there is an increase in acidic substances in the body, the normal urine pH can be less than 5.5, and the excretion rate of titratable acid and NH+4 in urine can reach 25μmol/min and 39μmol/min, respectively. In distal renal tubular acidosis, both are significantly reduced.

　　3. Urinary electrolytes and urinary anion gap:dRTA mostly has increased urinary sodium excretion and increased urinary calcium, with urinary Ca/Cr > 0.21, and 24h urinary calcium > 4mg/(kg·d). The urinary anion gap = Na+ + K+ - Cl- can reflect the level of urinary NH+4, and a positive value indicates reduced excretion of urinary NH+4.

　　4. Blood gas analysis and electrolytes:The typical change of dRTA is hyperchloremic metabolic acidosis with normal anion gap, and incomplete dRTA can manifest as compensatory metabolic acidosis or normal. The blood anion gap (anion gap, AG) = Na+ + K+ - (Cl- + HCO3-), which is normally 8-16mmol/L, and an increase indicates the retention of inorganic acid radicals (such as nitrate, sulfate) or (and) organic acid radical ions, etc. In RTA, Cl- compensates for the decrease of HCO3-, so the AG is normal. The decrease in blood potassium is also an important manifestation of dRTA, even the only manifestation of incomplete dRTA, and blood sodium and blood calcium can be normal or decreased.

　　5. Urinary carbon dioxide partial pressure detection:After normal people are given sodium bicarbonate or neutral phosphate, the increase of HCO3- or HPO42- in the distal tubules; the former combines with H+ to form H2CO3; the latter combines with H+ to form H2PO4-, then combines with HCO3- to form H2CO3, and further generates CO2, increasing the partial pressure of CO2 in urine. In dRTA, due to hydrogen secretion impairment, the partial pressure of CO2 in urine does not increase, and the difference between the partial pressure of CO2 in urine and blood is less than 20mmHg, while in normal people, it is more than 30mmHg. The level of citrate in 24h urine is often reduced in dRTA, and imaging examination can understand the condition of bone disease and find kidney stones. Ultrasonic examination can understand whether there is calcification and stones in the kidneys, and electrocardiogram examination can detect electrolyte disorders, such as hypokalemia and heart damage, etc.

　　Pay attention to eating vegetables rich in potassium, calcium, and vitamins in the diet, and the specific foods high in potassium are mainly underground tubers such as potatoes, sweet potatoes, and yams, fruits such as oranges and bananas. If the kidney function is still normal, calcium supplementation is also very important. In terms of correcting acidosis, it is sodium bicarbonate, calcium carbonate, and kidney disease diet.
　　1. General principles of diet: Eat more light food, avoid drinking alcohol and spicy food, and eat less greasy and animal protein-rich food (such as fatty meat, shrimp, crab, etc.). Different kidney diseases have different diets.
　　2. The normal salt intake of an adult is about 5 to 6 grams per day. Salt is sodium chloride, alkali is sodium carbonate, and baking soda is sodium bicarbonate. Excessive intake of sodium and alkali in food can easily cause water retention in the body, induce edema, so for patients with renal edema, the intake of salt and alkali should be controlled. Each person's intake of 2 to 3 grams of salt is considered low-salt diet. A salt-free diet is also not scientific, and it can easily cause fatigue and dizziness if it lasts for a long time.
　　3. The normal urine volume of a healthy person is generally 1500 to 2000 ml per day. For patients with acute nephritis, acute renal failure oliguria stage, nephrotic syndrome, and chronic renal failure with oliguria and edema, water intake (including drinking water, water content in food, and intravenous medication fluid) should be controlled. Because the water intake cannot be excreted, water retention in the body can worsen edema and also easily increase hypertension. At this time, the water intake should be about 500 ml more than the urine output. After the urine output increases, the water intake can be relaxed. While patients with normal urine output can drink water normally. In addition, for patients with urinary system infections such as acute pyelonephritis, urethritis, cystitis, etc., in addition to timely medical treatment, drinking more water and urinating more are very beneficial for the recovery of the disease.
　　4. For kidney disease patients, the quality protein diet is 0.7 to 1.0 gram per kilogram of body weight per day, which needs to be guided by individual urine protein quantity and kidney function.
　　5. Some kidney disease patients have a long course of disease and slow recovery, and they often discuss and exchange information and experiences with each other. It should be noted that everyone has their own characteristics and should not imitate each other.
　　6. During the treatment period, if symptoms such as cold, fever, infection, etc. occur, contact a specialist doctor in an emergency to receive timely treatment and avoid the aggravation of complications.
　　7. Avoid overeating and consuming unclean food. 8. Maintain smooth bowel movements, which is beneficial for the excretion of waste and reducing the absorption of toxins. Develop a regular bowel movement habit, eat more vegetables and fruits, and use softeners if necessary.

　　I. Treatment

　　The treatment of dRTA is based on controlling acidosis, correcting electrolyte imbalance, preventing skeletal deformities, and preventing renal calcification. For secondary dRTA, it is as far as possible to eliminate the cause. For congenital dRTA, lifelong medication adherence is particularly important during the period of children's growth and development:

　　1. Correcting acidosis dRTA should be given 2-5mmol/(kg·d) of alkaline drugs to correct acidosis and prevent the occurrence of various bone diseases and growth retardation. Options include:

　　(1) Sodium bicarbonate 0.2-0.4g/(kg·d), (2) Shohl's mixture, containing 14% citric acid and 9.8% sodium citrate, 2-5ml/(kg·d).

　　(3) A mixture of 10% sodium citrate and 10% potassium citrate, 2-5ml/(kg·d).

　　2. Correcting electrolyte imbalance Severe hypokalemia can be treated with potassium chloride for a short period of time. Long-term use can easily worsen hyperchloremic acidosis. Generally, Shohl's mixture or 10% potassium citrate alone can be used orally, with a dose of 2-4ml/(kg·d); for those with hypocalcemia, calcium supplements can be appropriately supplemented, such as 2ml/(kg·d) of 10% calcium gluconate, with a total dose of less than 20ml/d.

　　3. Prevention and treatment of bone disease and renal calcification Correcting acidosis is the key to preventing and treating bone disease and renal calcification. For those with bone disease, vitamin D preparations such as vitamin D 5000 to 10,000 U/d, 1,25-(OH)2D3 (Rocaltrol, 0.25 mg/d) can be used for treatment. Attention should be paid to the occurrence of hypercalcemia. For hypercalciuria, the aforementioned citric acid preparations can be taken for treatment, and hydrochlorothiazide (dihydrochlorothiazide) can be added if necessary, 2mg/(kg·d), taken orally, which can often alleviate hypercalciuria and promote the dissolution and excretion of stones.

　　4. Surgical treatment is applicable to severe skeletal deformities that affect function.

　　II. Prognosis

　　The prognosis of primary distal renal tubular acidosis is generally good, closely related to the timing of treatment initiation and whether reasonable treatment is persisted with. If treatment can be started in the early infancy, not only will the growth and development be normal, but also the occurrence of renal calcification and kidney stones can be prevented, with a significantly reduced incidence rate. This can prevent renal parenchymal damage. If treatment is discontinued, acidosis and related symptoms will recur. The prognosis of secondary dRTA is related to the primary disease.