This describes a number of pathophysiologically distinct entities of tubular function whose common feature is the presence of a non-anion-gap metabolic acidosis. Diarrhea, CKD, and RTA together constitute the vast majority of cases of non-anion-gap metabolic acidosis. Pts with earlier stages of CKD (Table 48-1 The Classification of Chronic Kidney Disease) typically develop a non-anion-gap acidosis, with a superimposed increase in the anion gap at later stages (Chap. 2 Acid-Base Disorders). Acidosis may develop at an earlier stage of CKD in those with prominent injury to the distal nephron, as for example in reflux nephropathy.
Distal Hypokalemic (Type I) RTA 
Pts are unable to acidify the urine despite systemic acidosis; the urinary anion gap is positive, reflective of a decrease in ammonium excretion (Chap. 2 Acid-Base Disorders). Distal hypokalemic RTA may be inherited (both autosomal dominant and autosomal recessive) or acquired due to autoimmune and inflammatory diseases (e.g., Sjögren's syndrome, sarcoidosis), urinary tract obstruction, or amphotericin B therapy. Chronic type I RTA is typically associated with hypercalciuria and osteomalacia, a consequence of the long-term buffering of acidosis by bone.
There is a defect in bicarbonate reabsorption, usually associated with features of Fanconi syndrome, including glycosuria, aminoaciduria, phosphaturia, and uricosuria (indicating proximal tubular dysfunction). Isolated proximal RTA is caused by hereditary dysfunction of the basolateral sodium-bicarbonate cotransporter. Fanconi syndrome may be inherited or acquired due to myeloma, chronic IN (e.g., Chinese herbal nephropathy), or drugs (e.g., ifosfamide, tenofovir). Treatment requires large doses of bicarbonate (5-15 mmol/kg per day), which may aggravate hypokalemia.
This may be due to hyporeninemic hypoaldosteronism or to resistance of the distal nephron to aldosterone. Hyporeninemic hypoaldosteronism is typically associated with volume expansion and most commonly seen in elderly and/or diabetic pts with CKD. The hyperkalemia associated with NSAIDs and cyclosporine is at least partially due to hyporeninemic hypoaldosteronism. Pts with hyporeninemic hypoaldosteronism are typically hyperkalemic; they may also exhibit a mild non-anion-gap acidosis, with urine pH <5.5 and a positive urinary anion gap. Acidosis often improves with reduction in serum [K+ ]; hyperkalemia appears to interfere with medullary concentration of ammonium by the renal countercurrent mechanism. Should reduction in serum [K+ ] not improve acidosis, pts should be treated with oral bicarbonate or citrate. Finally, various forms of distal tubular injury and tubulointerstitial disease, e.g., IN, are associated with distal insensitivity to aldosterone; urine pH is classically >5.5, again with a positive urinary anion gap.