OVERVIEW
Mixed renal tubular acidosis (mixed RTA) is the coexistence of type I and II RTA with the clinical manifestations of both type I and II RTA. Some people categorize this type into two types: mixed type and type III RTA. It is believed that the mixed type has the clinical features of both type I and type II RTA and is called a subtype of type II RTA.
Etiology
Mixed RTA is characterized by the clinical features of both type I and type II RTA, so the cause of the disease is also characterized by both type I and type II RTA.
1. Primary disease
Disseminated and hereditary.
2.Secondary diseases
Bone petrification disease, neurodeafness, carbonic anhydrase B deficiency or reduced function, pyruvate hydroxylase deficiency, hereditary decreased fructose tolerance, cystine deposition, Lowe’s syndrome, Wilson’s disease and so on.
3. Drugs and poisoning
Amphotericin B, toluene. Heavy metals (lead, cadmium, mercury, copper, lithium), carbonic anhydrase inhibitors, taking expired tetracycline.
4. Abnormal calcium metabolism
Primary calcium deposition nephropathy, idiopathic hypercalcemia, vitamin D overdose or toxicity, hyperthyroidism, hyperparathyroidism.
5. Systemic immune disease and hypergammaglobulinemia
Idiopathic hypergammaglobulinemia, multiple myeloma, systemic lupus erythematosus, Sjögren’s syndrome, thyroiditis, cirrhosis, primary biliary sclerosis, chronic active hepatitis.
6. Interstitial renal disease
Obstructive nephropathy, renal transplant rejection, sickle cell hemoglobinopathy, sponge kidney, painkiller nephropathy.
Symptoms
Clinical manifestations of the typical person with mixed RTA are:
1. Acidosis
Typical cases have hyperchloremia, and urine pH can drop below 5.5. Or there may be glycosuria, phosphaturia, amino aciduria, etc.
2. Metabolic acidosis with hyponatremia and hypokalemia
Secondary aldosterone increase promotes the excretion of K+, there are hyponatremia and hypokalemia manifestations such as weakness, fatigue, muscle weakness, constipation, etc. There can also be growth retardation, nausea, vomiting and other manifestations of acidosis.
3. Urinary stones.
4. Bone disease
The occurrence of bone disease is more common than that of type I RTA patients, which is vitamin D deficiency in children and osteosclerosis in adults.
5. Secondary hyperparathyroidism
Some patients have decreased urinary phosphorus excretion, and blood phosphorus decrease and secondary hyperparathyroidism occur.
Examination
1. Blood tests
The main manifestations are low blood K+, Ca2+, Na+, PO43-, increased blood Cl-, decreased plasma HCO3-, decreased CO2 binding capacity, increased blood chlorine, decreased blood HCO3-, and normal or decreased blood potassium.
2. Urinalysis
There is no cellular component in urine, HCO3- excretion fraction is more 4++, K+, Ca2+, PO43-excretion increases. Urine pH>5.5, increased urinary potassium excretion.
3. Load test
(1) Ammonium chloride test Commonly used test for suspected and incomplete type I RTA; give the subject ammonium chloride 0.1g/(kg-d), orally in 3 times for 3 days. On the third day, urine was retained once every hour, and urine pH and blood HCO3- were measured; when blood HCO3- fell below 20 mmol/L and urine pH>5.5, it had diagnostic value. For those with liver disease, calcium chloride 1mmol/(kg-d) was used instead, and the method and the determination of positive results were the same as ammonium chloride loading test.
(2) Urine ammonium measurement Normal people’s urinary ammonium excretion is about 40mmol/d, type I RTA urinary ammonium excretion <40mmol/d.
(3) Urine PCO2 measurement 5% sodium bicarbonate intravenous drip, so that the blood pH is maintained at 0.5 or more, when the urine pH>blood pH, urine PCO2>blood PCO22.66kPa or more is diagnostic significance. That is, once the urine is alkaline, regardless of whether the blood HCO3- concentration returns to normal or not, if the urine PCO2>9.3kPa can be considered that the collecting duct H+ secretion ability is not abnormal.
(4) Urine cystine test Cystinuria is often present in proximal tubular disorders, and a positive test is helpful for diagnosis. (Cyanide nitrohydrocyanate test: take 5 ml of urine and add 1 drop of concentrated ammonia and 3 drops of 5% sodium cyanide, and a purplish-red coloration is considered as a positive reaction). In the acid load test, if the urine pH is <5.5 or lower, the subtype of type II RTA is diagnosed.
(5) Alkali loading test ①Oral sodium bicarbonate method Start with 1 mmol/(kg-d) and increase the dosage to 10 mmol/(kg-d) day by day. After the acidosis is corrected, measure the blood and urinary HCO3- concentration and glomerular filtration rate, and calculate the percentage of urinary HCO3-. Urinary HCO3- was zero in normal subjects; type II and mixed RTA >15%, type I RTA ② Intravenous sodium bicarbonate drip method 5% NaHCO3 at a rate of 4 ml/min for 2 hours. Measure blood pH, PCO2, HCO3-concentration and urine pH and HCO3-concentration before injection; then measure blood pH, PCO2, HCO3- after 30 and 90 minutes of injection; and measure urine pH and HCO3- at 60 and 120 minutes, respectively; and when the patient’s blood HCO3- returns to normal, the urinary excretion of HCO3- is > 15% of the glomerular filtration, which suggests impaired HCO3-absorption in the proximal tubule. HCO3- absorption is impaired. When plasma HCO3- concentration is normalized, type II RTA HCO3- excretion fraction is >15%, and type I RTA <5%. This method can identify type I and type II RTA.
4. Imaging
Fish seed-like kidney stones can be found in KUB plain film or IVP film. It can also help to understand the bone disease.
5. Ultrasonography
It can know whether there are calcification and stones in the kidney.
Diagnosis
Mixed renal tubular acidosis is similar to type I RTA. The diagnosis is based on the presence of causes of type I RTA. Hyperchloremic acidosis. Urine ammonium>40mmol/d, ammonium chloride loading test urine pH>5.5, sodium bicarbonate loading test, (U-B) PCO26.0; acid and alkali loading test is positive can be diagnosed with mixed RTA.
Differential diagnosis
Mixed RTA needs to be differentiated from type I and type II RTA and metabolic acidosis due to glomerular disease, which often has a decreased glomerular filtration rate and clinical manifestations of azotemia. It also needs to be differentiated from other diseases with acidosis due to nitrogen retention and other types of tubular acidosis. For example, distal renal tubular acidosis can sometimes be confused with uremic acidosis, but the metabolic acidosis of uremia has azotemia and increased blood phosphorus, so it is not difficult to distinguish.
Renal calcinosis due to hereditary idiopathic hypercalciuria can cause distal tubular acidosis, which also needs to be differentiated from the primary. The stones in this case may be calcium phosphate stones without hypokalemia or metabolic acidosis. Incomplete RTA is most easily confused with idiopathic hypercalcemia, in which case an ammonium chloride loading test may be performed. Secondary distal tubular acidosis due to other diseases has its own clinical features.
Complications
Metabolic acidosis, hypokalemia, achondroplasia, growth retardation, vitamin D deficiency disease or osteochondrosis, some of them develop renal stone or renal calcification, and develop uremia in late stage, and a few of them have neurodeafness.
Treatment
The treatment of mixed type renal tubular acidosis and type III renal tubular acidosis should refer to type I and II. However, the dosage of alkaline drugs for type III should be larger, and the treatment of those similar to type I RTA should be the same as that of type I.
1. Treatment of etiology
Most patients with type I RTA have an etiologic cause, and if the etiologic cause can be treated, the disorders of potassium and acid secretion can be corrected.
If there are obvious secondary causes, such as treatment of drug or metal poisoning, multiple myeloma, nephrotic syndrome, tubulointerstitial disease, etc., the primary cause should be actively treated. At the same time, the corresponding treatment should be carried out according to the treatment principle of type II RTA.
2. Application of alkaline drugs
The dosage of alkaline drugs for type I RTA should be small, and large dosage can cause convulsions. Because the liver can convert sodium citrate into sodium bicarbonate, so it is often given with compound citrate syrup, i.e., Shohl’s solution.
3. Treatment of potassium disorders
For low potassium, potassium citrate is often used. Potassium supplementation should also start with small doses and gradually increase. Potassium chloride should not be used.
4. Calcium and vitamin D application
The dosage of vitamin D is on the high side, with daily injection of vitamin D2 or D3.3 million U. When blood calcium >2.5 mmol/L or serum alkaline phosphatase returns to normal, it will be discontinued to avoid hypercalcemia; the application of vitamin D must be used in conjunction with alkalizing drugs. Treatment of those similar to type II RTA is the same as type II renal tubular acidosis.
Prognosis
The prognosis of mixed renal tubular acidosis and type III renal tubular acidosis is generally good if they are diagnosed and treated at an early stage and no renal calcinosis occurs. Timely alkali supplementation can delay the emergence of nephrocalcinosis and renal stones; some patients can have spontaneous remission; some patients with nephrocalcinosis, especially when interspersed with urinary tract infections, can develop into chronic renal failure and die.
Prevention
There is no effective prophylaxis for type III renal tubular acidosis. The prevention of secondary disease should start from the treatment of the underlying disease to control its development to renal tubular acidosis. Patients who are already ill should be actively treated to prevent the progression of the disease and strive for a favorable prognosis.