Type 1 RTA is either inherited or acquired. Inherited type 1 RTA can be either autosomal-dominant or autosomal-recessive. Autosomal-recessive type 1 RTA often presents in infancy, whereas autosomal-dominant type 1 RTA may not present until adolescence or young adulthood. Some patients with autosomal recessive distal RTA have associated sensorineural hearing loss. Mutations in the genes encoding carbonic anhydrase II, kidney anion exchanger 1, and subunits of the H+-ATPase have been identified in patients with distal RTA. Some genetic disorders, such as Ehler-Danlos syndrome, Fabry disease, or Wilson disease, have also been associated with type 1 RTA. In the acquired form, the disorder can be caused by drugs, autoimmune diseases, or by infection. Some of the more common acquired forms are caused by Sjögren syndrome, lupus, hepatitis, treatment with amphotericin B, toluene toxicity, and chronic pyelonephritis.
The clinical manifestations of type 1 RTA depend upon the disease severity and whether it is acquired or inherited. Inherited type 1 RTA causes similar metabolic abnormalities, but it is more likely to result in decreased bone mineralization and growth retardation. However, both forms feature hypokalemia, which results in muscle soreness, flaccid paralysis, and electrical cardiac disturbances. The most common cause of death related to type 1 RTA is hypokalemia-induced cardiac dysrhythmia.
Type 2 RTA (proximal RTA) is caused by an inability to reabsorb bicarbonate in the proximal tubules. Type 2 RTA may occur secondary to generalized dysfunction of the proximal tubules and can be associated with increased urinary excretion of glucose, uric acid, phosphate, amino acids, and protein. The disorder most often occurs in the context of Fanconi syndrome, light chain nephropathy, multiple myeloma, or drug exposures.
Because the clinical features of both type 1 and type 2 RTA can be similar, distinguishing between them can be a diagnostic challenge. However, these two causes of nonanion gap acidosis with hypokalemia can be distinguished relatively easily with some laboratory testing. The easiest and most readily obtained laboratory examination is the urine pH. In type 1 RTA, the distal tubule is unable to acidify the urine, resulting in a urine pH > 5.5. In contrast, distal acidification is intact in type 2 RTA; this, together with an ability of the proximal tubule to reabsorb filtered bicarbonate once its concentration has fallen below its abnormally low tubular reabsorptive capacity, results in a urine pH < 5.5. With these mechanisms, type 2 RTA usually does not cause as profound a serum acidosis as type 1 RTA. For example, a serum bicarbonate of < 10 mEq/L is not uncommon in type 1 RTA, whereas in type 2 RTA, the bicarbonate level is usually > 15 mEq/L.
Type 3 RTA is the rarest of the four forms and is basically a combination of both type 1 and type 2 RTA. Type 3 RTA is usually the result of an inherited carbonic anhydrase II mutation, and it gives rise to an autosomal-recessive syndrome of metabolic acidosis, hypokalemia, osteoporosis, cerebral calcification, and intellectual disability.
Type 4 RTA, also called "hyperkalemic RTA," is caused by either aldosterone deficiency or resistance of the renal tubule to the actions of aldosterone. This form is readily distinguished from type 1 and type 2 RTA because type 4 RTA results in hyperkalemia rather than hypokalemia.
The diagnostic studies used to diagnose type 1 RTA include serum electrolytes, renal electrolytes, urinalysis, and 24-hour urine citrate and calcium measurements. In a patient with borderline acidosis and hypokalemia, an acid load test can often be diagnostic. This test entails giving an acid load of 0.1 g/kg of ammonium chloride or fludrocortisone/furosemide and then checking the urine pH 4-6 hours later. The test is considered positive if the urine pH remains above 5.5. However, the acid load test is not advisable during periods of profound acidosis and should be used only for stable patients in otherwise nondiagnostic cases.
An ECG should be obtained if severe hypokalemia is suspected, which often presents as muscle weakness. Renal imaging can often show evidence of nephrolithiasis or nephrocalcinosis.
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