Of Nephrology and Nephrologists Spotlighting new and provocative developments in world nephrology and featuring nephrologists who occupy leadership roles Manuel Martínez-Maldonado, MD Editor-at-Large Hyperkalemic Metabolic Acidosis Thomas D. DuBose, Jr, MD HYPERKALEMIC hyperchloremic metabolic acidosis is an abnormality in potassium, ammonium, or hydrogen ion secretion that does not result from a reduction in functional renal mass. The decrease in whole kidney potassium and ammonium excretion is usually out of proportion to the degree of renal insufficiency and represents a generalized defect in function in the cortical or medullary collecting ducts. AMMONIUM PRODUCTION AND SECRETION Basic Physiology Ammoniagenic enzymes exist along the nephron, but most ammonium excreted in the urine is derived from the metabolism of glutamine in proximal tubule cells,1 where ammonium production is regulated by glutaminase and phosphoenolpyruvate carboxykinase activity. Chronic acidosis activates both enzymes and increases the abundance of their respective messenger RNA. At physiological pH, two ammonium ions and alpha ketoglutarate, a divalent anion, are the major products of glutamine metabolism. Ammonium is preferentially secreted into the proximal tubule lumen (Fig 1) across the apical membrane. Direct NH4+ secretion occurs through substitution of NH4+ for H+ on the apical membrane Na+/H+ exchanger. In the S3 segment of the proximal straight tubule, ammonium secretion is enhanced by an acid disequilibrium pH. Fig 1. Nephron sites of ammonium excretion include proximal convoluted tubule, proximal straight tubule, thin descending limb, thick ascending limb, and medullary collecting duct. See text for explanation. GLN = glutamine. Water abstraction from luminal fluid in the thin descending limb creates a more alkaline milieu that favors ammonia (NH3) efflux (Fig 1). Direct NH4+ transport across the thick ascending limb of Henle's loop (TALH) apical membrane by substitution of NH4+ for K+ on the Na+-2Cl--K+ cotransporter is a major mechanism for absorption and is responsible for generation of high medullary ammonium concentrations. A highly selective K+ channel sensitive to adenosine triphosphate (ATP) (ROMK-2) has been cloned and localized to medullary TALH (mTALH) that may be responsible for NH4+ exit across the basolateral membrane of the mTALH. Ammonia can reenter the proximal straight tubule from the interstitium, leading to countercurrent multiplication in which the "single effect" involves selective addition of ammonium by the proximal tubule and active ammonium absorption in the TALH. The countercurrent system in the loop then multiplies the effect. The net result of this system is an axial gradient for ammonium: medullary concentrations of NH4+ exceed cortical concentrations by severalfold. The concentrations of NH4+ and NH3 in the medullary interstitium exceed the concentration prevailing in the medullary collecting duct, favoring their entry into the medullary collecting duct lumen. Ammonium concentrations in the inner medullary interstitium reach greatest amplification over cortical levels during chronic metabolic acidosis. The high ammonia environment of the inner medulla can be dissipated by high flows leading to washout and by selective medullary destruction (eg, chronic tubulointerstitial diseases). Ammonium is secreted from the medullary interstitium into the medullary collecting ducts by a combination of NH3 diffusion and active H+ secretion (H+-ATPase and the H+,K+-ATPase), and it enters the tIMCD cell on the basolateral membrane by competition of NH4+ for K+ on the sodium pump (Na+,K+-ATPase),2 resulting in high concentrations of ammonium in urine. Chronic metabolic acidosis increases net ammonium secretion in the proximal tubule,1 which increases ammonium delivery to and absorption by the TALH. This augments inner medullary interstitial concentrations of ammonia (NH3), which in tandem with the increase in the acid disequilibrium pH in the inner medullary collecting duct and ammonium addition to the medullary collecting duct, increases net acid excretion. Clinical Correlation Disorders such as the renal tubular acidoses are associated with an inappropriately low ammonium excretion rate for the degree of systemic acidosis. The urine anion gap (the urine net negative charge) has been used as a clinical tool to estimate the response of urinary ammonium excretion to metabolic acidosis. Hyperchloremic metabolic acidosis due to gastrointestinal losses can be differentiated from a renal tubular defect, because urinary NH4+ excretion is typically low in renal abnormalities but high in patients with extrarenal bicarbonate loss (eg, diarrhea). This estimation has not been validated in a wide variety of clinical circumstances and has a number of potential pitfalls, and the most reliable method is measurement of urinary [NH4+] in an appropriately diluted urine sample. RELATIONSHIP BETWEEN POTASSIUM AND AMMONIUM TRANSPORT Potassium has an effect on aldosterone elaboration that is also an important determinant of distal H+ secretion. Chronic potassium deficiency enhances but chronic hyperkalemia suppresses ammonium synthesis.3 Hyperkalemia reduces inner medullary ammonia concentration and markedly impairs ammonium absorption in the thick ascending limb3 that results from competition between K+ and NH4+ for the K+ secretory site on the Na-Cl-2K transporter. Hyperkalemia also may decrease entry of NH4+ into the medullary collecting duct through competition of NH4+ and K+ for the K+-secretory site on the basolateral membrane sodium pump.4 In summary, chronic hyperkalemia decreases ammonium production by proximal tubule and whole kidney, inhibits absorption of NH4+ in the mTALH, reduces medullary interstitial concentrations of NH4+ and NH3, and decreases entry of NH4+ and NH3 into the medullary collecting duct.4 Renal insufficiency, reduced functional renal mass, or aldosterone deficiency or resistance, when accompanied by hyperkalemia, augment the possibilities of hyperchloremic metabolic acidosis. This partly explains the hyperchloremic metabolic acidosis and reduction in net acid excretion characteristic of several experimental models of hyperkalemic-hyperchloremic metabolic acidosis, including obstructive nephropathy, selective aldosterone deficiency, and chronic amiloride administration.3,5 Drug-Induced Renal Tubular Secretory Defects Drugs may impair renin or aldosterone elaboration or produce mineralocorticoid resistance. Cyclo-oxygenase inhibitors (nonsteroidal antiinflammatory drugs) inhibit renin release and can generate hyperkalemia and metabolic acidosis. -Adrenergic antagonists cause hyperkalemia by reducing its entry into cells and by reducing renin/aldosterone secretion. Heparin is toxic to the zona glomerulosa and impairs aldosterone synthesis. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists can cause hyperkalemia and acidosis, particularly in patients with advanced renal insufficiency or with diabetic nephropathy. Inhibitors of Collecting Duct: Potassium Secretion Spironolactone, a competitive inhibitor of aldosterone, and amiloride and triamterene can cause hyperkalemia and metabolic acidosis in patients with renal insufficiency. Potassium-sparing diuretics block the apical Na+-selective channel in the collecting duct principal cell and alter the driving force for K+ secretion. Trimethoprim (TMP) and pentamidine are both related structurally to amiloride (and triamterene). Also, they are heterocyclic weak bases that in acid urine6 exist primarily in the protonated form that inhibits the highly selective Na+ channel in A6 distal nephron cells, and in rat late distal tubules perfused in vivo. Both TMP and pentamidine decrease the electrochemical driving force for K+ and H+ secretion in the cortical collecting tubule (CCT). Metabolic acidosis frequently accompanies the hyperkalemia so induced even in the absence of severe renal failure, adrenal insufficiency, severe tubulointerstitial disease, or hypoaldosteronism. Hyperkalemia may mediate the development of metabolic acidosis through a decrease in ammonium production and excretion. Cyclosporine A may induce hyperkalemia by decreasing renal blood flow and glomerular filtration rate and by inhibition of calcineurin activity and the basolateral Na+, K+-ATPase, thereby decreasing intracellular [K+] and the transepithelial potential. Treatment Reduction in serum potassium often will improve the metabolic acidosis by increasing ammonium excretion. Patients with hyporeninemic-hypoaldosteronism may respond to a cation exchange resin (sodium polystyrene sulfonate), alkali therapy, or treatment with a loop diuretic to induce renal potassium and salt excretion. Supraphysiologic doses of mineralocorticoids may be necessary but should be administered in combination with a loop diuretic to avoid volume overexpansion or aggravation of hypertension and to increase potassium excretion. Patients with type II pseudohypoaldosteronism should receive thiazide diuretics along with dietary salt restriction. REFERENCES 1. Good DW, DuBose TD Jr: Ammonia transport by early and late proximal convoluted tubule of the rat. J Clin Invest 79:689-691, 1987 2. Wall SM: NH4+ augments net acid secretion by a ouabain-sensitive mechanism in isolated perfused inner medullary collecting ducts. Am J Physiol 270 (Renal Fluid Electrol Physiol) 39:F432-F439, 1996 3. DuBose TD Jr, Good DW: Effects of chronic hyperkalemia on renal production and proximal tubule transport of ammonium in the rat. Am J Physiol 260:F680-F687, 1991 4. DuBose TD Jr, Good DW: Chronic hyperkalemia impairs ammonium transport and accumulation in the inner medulla of the rat. J Clin Invest 90:1443-1449, 1992 5. DuBose TD Jr, Caflisch CR: Validation of the U-B PCO2 gradient as an index of distal nephron acidification in experimental models of distal renal tubular acidosis. J Clin Invest 75:1116-1123, 1985 6. Kleyman TR, Roberts C, Ling BN: A mechanism for pentamidine-induced hyperkalemia: Inhibition of distal nephron sodium transport. Ann Intern Med 122:103-106, 1995 Thomas D. DuBose, Jr, MD Director, Renal Diseases/Hypertension Vice Chair, Department of Internal Medicine University of Texas Medical School at Houston ANYONE interested in acid-base metabolism recognizes Tommy DuBose as one of the leaders in the field and one of the top nephrologists in America. What may not be apparent to many is that behind the friendly, professorial demeanor lives an accomplished skier and sailor. Born and raised in Gadsden, Alabama--close to the Georgia border, not far from Atlanta--he had his first sailing experiences in the lakes that cling to the southern portion of Gadsden as a rudder to a boat. DuBose received both his BS and MD from the University of Alabama, where he also did his internship. He then moved to Dallas to complete his residency at Parkland Hospital and became a renal fellow under the direction of Juha Kokko and Donald Seldin. On completion of his training, he remained on the faculty at Southwestern Medical School for 4 years. In 1981, he moved to the University of Texas Medical Branch in Galveston, where he became professor of medicine in 1984 and nephrology division head in 1986. At Galveston, he was active in medical school-wide activities, including the appointment, promotion, and tenure committee of the Department of Medicine. Along the way, his original research had been widely recognized, and he held a National Institutes of Health (NIH) career development award (among other grants) and was elected to the prestigious American Society for Clinical Investigation. Since 1991, he has been at the University of Texas Medical School at Houston, where he directs the Division of Nephrology and Hypertension and is vicechair of the Department of Medicine. DuBose has established an impressive clinical and research training program in nephrology and renal physiology in Houston. He has continued to obtain funding from the NIH and other sources and to achieve national and international recognition. In 1992, he was elected to membership in the Association of American Physicians, the oldest honor medical society in the United States. He serves on several editorial boards, including the American Journal of Kidney Diseases, and has served the National Kidney Foundation with distinction in various regional and national capacities. Low-key in person, DuBose is always on key when he sings with the Houston Symphony Chorus. His wife, Linda, a social worker, and his children Nathan, 22, and Emily, 19, agree that, in addition to having a good voice, he is an accomplished sailor with an unerring sense of direction. --Manuel Martínez-Maldonado, MD