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Acid-Base Disorders be falsely negative or underestimate the total ketone load (see typically results in rapid resolution of ketones due to induc- Clinical Evaluation of Kidney Function and MKSAP 19 tion of insulin secretion and suppression of glucagon release. Endocrinology and Metabolism). For patients with chronic malnutrition related to alcohol use, Alcoholic ketoacidosis occurs in patients with chronic thiamine should be administered before glucose to decrease ethanol abuse who typically have a history of recent binge the risk for precipitating Wernicke encephalopathy. drinking, low caloric intake, and persistent vomiting. Medication and toxin exposures that cause increased Treatment with intravenous saline and intravenous glucose anion gap metabolic acidosis are described in Table 10. TABLE 10. Medication and Toxin Exposures that Cause Increased Anion Gap Metabolic Acidosis Condition Cause Clinical and Laboratory Treatment Comments Manifestations Ethylene Glycolic acid AKI and flank pain due to Fomepizole Found in antifreeze, glycol accumulation; calcium precipitation of calcium Vh : solvents, cosmetics ; ’ apn ae : ydration ingestion oxalate precipitation in oxalate in kidneys; hay bediieuttis renal tubules and hypocalcemic symptoms; Hemodialysis: in severe La Po Ae crystals in the urine cardiovascular collapse; acidemia, very large methanol ingestion pulmonary edema ingestions, severe CNS

Ethylene Glycolic acid AKI and flank pain due to Fomepizole Found in antifreeze, glycol accumulation; calcium precipitation of calcium Vh : solvents, cosmetics ; ’ apn ae : ydration ingestion oxalate precipitation in oxalate in kidneys; hay bediieuttis renal tubules and hypocalcemic symptoms; Hemodialysis: in severe La Po Ae crystals in the urine cardiovascular collapse; acidemia, very large methanol ingestion pulmonary edema ingestions, severe CNS Serum bicarbonate level depression, AKI, systemic <10 mEq/L(10 mmol/L); collapse plasma osmolal gap Pyridoxine and thiamine: in >10 mOsm/kg H2O suspected ethylene glycol toxicity Sodium bicarbonate

Serum bicarbonate level depression, AKI, systemic <10 mEq/L(10 mmol/L); collapse plasma osmolal gap Pyridoxine and thiamine: in >10 mOsm/kg H2O suspected ethylene glycol toxicity Sodium bicarbonate Methanol Formic acid CNS damage; optic nerve/ Fomepizole Found in windshield- ingestion accumulation eye damage with blindness; H dialysis: i washing fluid, papilledema; mydriasis; i, lalyels la Severe commercial solvents, afferent pupillary defect; sp eine ged ne ENS paints, some antifreezes abdominal pain; pancreatitis oe — «ce. epression, any visual May be difficult to Serum bicarbonate level impairment differentiate from bil pao Folic acid: in suspected ethylene glycol Ingestion >10 mOsm/kg H,O methanol toxicity 80%-90% mortality rate . : with methanol ingestion; Sodium bicarbonate permanent blindness may occur

>10 mOsm/kg H,O methanol toxicity 80%-90% mortality rate . : with methanol ingestion; Sodium bicarbonate permanent blindness may occur Salicylate Salicylate anion Respiratory alkalosis; Bicarbonate infusion: Toxicity can develop from toxicity accumulation; ingestion __ tinnitus; nausea/vomiting; alkalinization mitigates ingestion or of as littleas 10 gramsof impaired mental status; CNS toxicity; aim for urine mucocutaneous aspirin in adults cerebral edema and pH>7.5 exposure to salicylate brainstem herniation; H islstl preparations such as tachypnea; noncardiogenic Heune ace “i : methy| salicylate (oil of pulmonary edema; hepatic IMPalFech Mental Stats, wintergreen) Sey : fate cerebral edema, serum injury; lactic acidosis or : ketoacidosis with severe te deer Ssleyate levels aio paral: with acute ingestion and levels >60 mg/dL with chronic ingestion, refractory acidemia, pulmonary edema

Salicylate Salicylate anion Respiratory alkalosis; Bicarbonate infusion: Toxicity can develop from toxicity accumulation; ingestion __ tinnitus; nausea/vomiting; alkalinization mitigates ingestion or of as littleas 10 gramsof impaired mental status; CNS toxicity; aim for urine mucocutaneous aspirin in adults cerebral edema and pH>7.5 exposure to salicylate brainstem herniation; H islstl preparations such as tachypnea; noncardiogenic Heune ace “i : methy| salicylate (oil of pulmonary edema; hepatic IMPalFech Mental Stats, wintergreen) Sey : fate cerebral edema, serum injury; lactic acidosis or : ketoacidosis with severe te deer Ssleyate levels aio paral: with acute ingestion and levels >60 mg/dL with chronic ingestion, refractory acidemia, pulmonary edema Propylene Large doses of AKI; anion gap metabolic Discontinue infusion Monitor acid-base status glycol toxicity — propylene glycol acidosis with increased 4 dialysi and serum osmolality (a solvent used for IV plasma osmolal gap; toxicity emodlalysis when lorazepam doses medications), most when propylene glycol levels >1 mg/kg/d; unlikely to commonly lorazepam >25 mg/dL or plasma develop if 24-h diluted in propylene osmolal gap >10 mOsm/kg lorazepam dose is glycol (80%) HO limited to <166 mg/d

Propylene Large doses of AKI; anion gap metabolic Discontinue infusion Monitor acid-base status glycol toxicity — propylene glycol acidosis with increased 4 dialysi and serum osmolality (a solvent used for IV plasma osmolal gap; toxicity emodlalysis when lorazepam doses medications), most when propylene glycol levels >1 mg/kg/d; unlikely to commonly lorazepam >25 mg/dL or plasma develop if 24-h diluted in propylene osmolal gap >10 mOsm/kg lorazepam dose is glycol (80%) HO limited to <166 mg/d Pyroglutamic Chronic acetaminophen Impaired mental status; on Discontinue acetaminophen Female preponderance (5-oxoproline) ingestion; most urine testing for organic : : (80%); genetic factors acidosis anon in critically ill anions, tea peonce tations Consider is ee may By arole patients, those with of urine pyroglutamate or emehig’ epi’ poor nutrition, liver (5-oxoproline) SENOS Stee disease, or CKD, and in vegetarians AKI = acute kidney injury; CKD = chronic kidney disease; CNS = central nervous system; IV = intravenous. 22

Acid-Base Disorders urine NH,* will be low, with proportionately greater sodium and potassium excretion resulting in a positive urine anion gap. e Lactic acidosis is the most common cause of increased The urine anion gap, together with serum potassium lev- anion gap metabolic acidosis. els and urine pH, can help further distinguish the causes of e Ethylene glycol or methanol ingestion should be sus- normal anion gap metabolic acidosis (Table 11). pected in patients with an increased anion gap meta- bolic acidosis associated with a serum bicarbonate Type 2 (Proximal) Renal Tubular Acidosis level <10 mEq/L (10 mmol/L) and a plasma osmolal gap The primary defect in type 2 (proximal) renal tubular acidosis >10 mOsm/kg H,O. (RTA) is failure of the proximal tubule to adequately absorb filtered bicarbonate, resulting in bicarbonate loss and acidosis. Type 2 RTA is usually accompanied by other evidence of proxi- Normal Anion Gap Metabolic Acidosis mal tubular dysfunction, including complete or partial Normal anion gap metabolic acidoses most often result from Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria, gastrointestinal bicarbonate losses (diarrhea), kidney bicarbo- hypouricemia). As blood bicarbonate levels decrease, less nate losses (type 2 renal tubular acidosis), or inability of the bicarbonate is filtered and eventually the resorptive threshold kidney to adequately excrete acid (types 1 and 4 renal tubular is reached, such that serum bicarbonate levels stabilize (around acidosis; chronic kidney disease). Although a patient history 12-14 mEq/L [12-14 mmol/L]). Because the distal nephron may elucidate the cause, the urine anion gap may help to nar- functions appropriately in type 2 RTA, urine can still be acidi- row down the cause. fied to a pH <5.5 and NH,* production will be normal, usually In response to acidemia, the kidneys should increase acid making the urine anion gap negative. Hypokalemia is also excretion. This is achieved primarily by increased tubular pro- often present due to increased distal tubular potassium secre- duction of ammonia (NH) and secretion of protons, resulting in tion. This occurs because sodium accompanies bicarbonate to increased urine ammonium (NH,"*). The amount of urine ammo- the distal tubule, where sodium is reabsorbed in exchange for nium reflects the ability of the kidneys to respond appropriately potassium. to acidemia and indicates if the kidney is a cause of the acidosis. The most common causes of type 2 RTA include myeloma Because urine ammonium is difficult to measure, the urine anion light chains as well as nephrotoxic medications such as ifosfa- gap is used as a surrogate to assess kidney acid excretion: mide, carbonic anhydrase inhibitors (acetazolamide and topira- Urine Anion Gap = (Urine Sodium + Urine Potassium) mate), and tenofovir disoproxil fumarate (although toxicity is ~ Urine Chloride much less likely with tenofovir alafenamide). In patients with gastrointestinal losses of bicarbonate Alkali replacement is the mainstay of treatment for type 2 (diarrhea; laxative abuse) or those exposed to an acid load, urine RTA. Thiazide diuretics may help by causing mild volume NH,* should increase. Ammonium cation excretion results in depletion with subsequent aldosterone-driven proximal reab- proportionately less excretion of sodium and potassium (the sorption of sodium and bicarbonate. predominant urine cations). Chloride anion excretion contin- ues with ammonium cation excretion to maintain electrical Type 1 (Hypokalemic Distal) Renal Tubular Acidosis neutrality. In the context of increased urine NH,* production, In type 1 (hypokalemic distal) RTA, a distal tubular defect therefore, the urine anion gap will be negative (less than zero). results in impaired excretion of hydrogen ions by the distal A positive urine anion gap in a patient with acidemia suggests nephron (hence, low urine ammonium and positive urine the presence of a distal renal tubular acidosis. Proton secretion anion gap) with inability to acidify urine below a pH of 6.0. in the distal nephron generates NH,", and in distal renal tubular Serum bicarbonate may fall below 10 mEq/L (10 mmol/L) as acidosis there is a defect in this proton secretion. Therefore, levels fail to stabilize as is seen with type 2 (proximal) RTA;

urine NH,* will be low, with proportionately greater sodium and potassium excretion resulting in a positive urine anion gap. e Lactic acidosis is the most common cause of increased The urine anion gap, together with serum potassium lev- anion gap metabolic acidosis. els and urine pH, can help further distinguish the causes of e Ethylene glycol or methanol ingestion should be sus- normal anion gap metabolic acidosis (Table 11). pected in patients with an increased anion gap meta- bolic acidosis associated with a serum bicarbonate Type 2 (Proximal) Renal Tubular Acidosis level <10 mEq/L (10 mmol/L) and a plasma osmolal gap The primary defect in type 2 (proximal) renal tubular acidosis >10 mOsm/kg H,O. (RTA) is failure of the proximal tubule to adequately absorb filtered bicarbonate, resulting in bicarbonate loss and acidosis. Type 2 RTA is usually accompanied by other evidence of proxi- Normal Anion Gap Metabolic Acidosis mal tubular dysfunction, including complete or partial Normal anion gap metabolic acidoses most often result from Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria, gastrointestinal bicarbonate losses (diarrhea), kidney bicarbo- hypouricemia). As blood bicarbonate levels decrease, less nate losses (type 2 renal tubular acidosis), or inability of the bicarbonate is filtered and eventually the resorptive threshold kidney to adequately excrete acid (types 1 and 4 renal tubular is reached, such that serum bicarbonate levels stabilize (around acidosis; chronic kidney disease). Although a patient history 12-14 mEq/L [12-14 mmol/L]). Because the distal nephron may elucidate the cause, the urine anion gap may help to nar- functions appropriately in type 2 RTA, urine can still be acidi- row down the cause. fied to a pH <5.5 and NH,* production will be normal, usually In response to acidemia, the kidneys should increase acid making the urine anion gap negative. Hypokalemia is also excretion. This is achieved primarily by increased tubular pro- often present due to increased distal tubular potassium secre- duction of ammonia (NH) and secretion of protons, resulting in tion. This occurs because sodium accompanies bicarbonate to increased urine ammonium (NH,"*). The amount of urine ammo- the distal tubule, where sodium is reabsorbed in exchange for nium reflects the ability of the kidneys to respond appropriately potassium. to acidemia and indicates if the kidney is a cause of the acidosis. The most common causes of type 2 RTA include myeloma Because urine ammonium is difficult to measure, the urine anion light chains as well as nephrotoxic medications such as ifosfa- gap is used as a surrogate to assess kidney acid excretion: mide, carbonic anhydrase inhibitors (acetazolamide and topira- Urine Anion Gap = (Urine Sodium + Urine Potassium) mate), and tenofovir disoproxil fumarate (although toxicity is ~ Urine Chloride much less likely with tenofovir alafenamide). In patients with gastrointestinal losses of bicarbonate Alkali replacement is the mainstay of treatment for type 2 (diarrhea; laxative abuse) or those exposed to an acid load, urine RTA. Thiazide diuretics may help by causing mild volume NH,* should increase. Ammonium cation excretion results in depletion with subsequent aldosterone-driven proximal reab- proportionately less excretion of sodium and potassium (the sorption of sodium and bicarbonate. predominant urine cations). Chloride anion excretion contin- ues with ammonium cation excretion to maintain electrical Type 1 (Hypokalemic Distal) Renal Tubular Acidosis neutrality. In the context of increased urine NH,* production, In type 1 (hypokalemic distal) RTA, a distal tubular defect therefore, the urine anion gap will be negative (less than zero). results in impaired excretion of hydrogen ions by the distal A positive urine anion gap in a patient with acidemia suggests nephron (hence, low urine ammonium and positive urine the presence of a distal renal tubular acidosis. Proton secretion anion gap) with inability to acidify urine below a pH of 6.0. in the distal nephron generates NH,", and in distal renal tubular Serum bicarbonate may fall below 10 mEq/L (10 mmol/L) as acidosis there is a defect in this proton secretion. Therefore, levels fail to stabilize as is seen with type 2 (proximal) RTA; TABLE 11. Diagnostic Approach to Normal Anion Gap Metabolic Acidosis

urine NH,* will be low, with proportionately greater sodium and potassium excretion resulting in a positive urine anion gap. e Lactic acidosis is the most common cause of increased The urine anion gap, together with serum potassium lev- anion gap metabolic acidosis. els and urine pH, can help further distinguish the causes of e Ethylene glycol or methanol ingestion should be sus- normal anion gap metabolic acidosis (Table 11). pected in patients with an increased anion gap meta- bolic acidosis associated with a serum bicarbonate Type 2 (Proximal) Renal Tubular Acidosis level <10 mEq/L (10 mmol/L) and a plasma osmolal gap The primary defect in type 2 (proximal) renal tubular acidosis >10 mOsm/kg H,O. (RTA) is failure of the proximal tubule to adequately absorb filtered bicarbonate, resulting in bicarbonate loss and acidosis. Type 2 RTA is usually accompanied by other evidence of proxi- Normal Anion Gap Metabolic Acidosis mal tubular dysfunction, including complete or partial Normal anion gap metabolic acidoses most often result from Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria, gastrointestinal bicarbonate losses (diarrhea), kidney bicarbo- hypouricemia). As blood bicarbonate levels decrease, less nate losses (type 2 renal tubular acidosis), or inability of the bicarbonate is filtered and eventually the resorptive threshold kidney to adequately excrete acid (types 1 and 4 renal tubular is reached, such that serum bicarbonate levels stabilize (around acidosis; chronic kidney disease). Although a patient history 12-14 mEq/L [12-14 mmol/L]). Because the distal nephron may elucidate the cause, the urine anion gap may help to nar- functions appropriately in type 2 RTA, urine can still be acidi- row down the cause. fied to a pH <5.5 and NH,* production will be normal, usually In response to acidemia, the kidneys should increase acid making the urine anion gap negative. Hypokalemia is also excretion. This is achieved primarily by increased tubular pro- often present due to increased distal tubular potassium secre- duction of ammonia (NH) and secretion of protons, resulting in tion. This occurs because sodium accompanies bicarbonate to increased urine ammonium (NH,"*). The amount of urine ammo- the distal tubule, where sodium is reabsorbed in exchange for nium reflects the ability of the kidneys to respond appropriately potassium. to acidemia and indicates if the kidney is a cause of the acidosis. The most common causes of type 2 RTA include myeloma Because urine ammonium is difficult to measure, the urine anion light chains as well as nephrotoxic medications such as ifosfa- gap is used as a surrogate to assess kidney acid excretion: mide, carbonic anhydrase inhibitors (acetazolamide and topira- Urine Anion Gap = (Urine Sodium + Urine Potassium) mate), and tenofovir disoproxil fumarate (although toxicity is ~ Urine Chloride much less likely with tenofovir alafenamide). In patients with gastrointestinal losses of bicarbonate Alkali replacement is the mainstay of treatment for type 2 (diarrhea; laxative abuse) or those exposed to an acid load, urine RTA. Thiazide diuretics may help by causing mild volume NH,* should increase. Ammonium cation excretion results in depletion with subsequent aldosterone-driven proximal reab- proportionately less excretion of sodium and potassium (the sorption of sodium and bicarbonate. predominant urine cations). Chloride anion excretion contin- ues with ammonium cation excretion to maintain electrical Type 1 (Hypokalemic Distal) Renal Tubular Acidosis neutrality. In the context of increased urine NH,* production, In type 1 (hypokalemic distal) RTA, a distal tubular defect therefore, the urine anion gap will be negative (less than zero). results in impaired excretion of hydrogen ions by the distal A positive urine anion gap in a patient with acidemia suggests nephron (hence, low urine ammonium and positive urine the presence of a distal renal tubular acidosis. Proton secretion anion gap) with inability to acidify urine below a pH of 6.0. in the distal nephron generates NH,", and in distal renal tubular Serum bicarbonate may fall below 10 mEq/L (10 mmol/L) as acidosis there is a defect in this proton secretion. Therefore, levels fail to stabilize as is seen with type 2 (proximal) RTA; TABLE 11. Diagnostic Approach to Normal Anion Gap Metabolic Acidosis Diagnosis Urine Anion Gap (Uy, + Ux) — Uc Serum Potassium Urine pH

urine NH,* will be low, with proportionately greater sodium and potassium excretion resulting in a positive urine anion gap. e Lactic acidosis is the most common cause of increased The urine anion gap, together with serum potassium lev- anion gap metabolic acidosis. els and urine pH, can help further distinguish the causes of e Ethylene glycol or methanol ingestion should be sus- normal anion gap metabolic acidosis (Table 11). pected in patients with an increased anion gap meta- bolic acidosis associated with a serum bicarbonate Type 2 (Proximal) Renal Tubular Acidosis level <10 mEq/L (10 mmol/L) and a plasma osmolal gap The primary defect in type 2 (proximal) renal tubular acidosis >10 mOsm/kg H,O. (RTA) is failure of the proximal tubule to adequately absorb filtered bicarbonate, resulting in bicarbonate loss and acidosis. Type 2 RTA is usually accompanied by other evidence of proxi- Normal Anion Gap Metabolic Acidosis mal tubular dysfunction, including complete or partial Normal anion gap metabolic acidoses most often result from Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria, gastrointestinal bicarbonate losses (diarrhea), kidney bicarbo- hypouricemia). As blood bicarbonate levels decrease, less nate losses (type 2 renal tubular acidosis), or inability of the bicarbonate is filtered and eventually the resorptive threshold kidney to adequately excrete acid (types 1 and 4 renal tubular is reached, such that serum bicarbonate levels stabilize (around acidosis; chronic kidney disease). Although a patient history 12-14 mEq/L [12-14 mmol/L]). Because the distal nephron may elucidate the cause, the urine anion gap may help to nar- functions appropriately in type 2 RTA, urine can still be acidi- row down the cause. fied to a pH <5.5 and NH,* production will be normal, usually In response to acidemia, the kidneys should increase acid making the urine anion gap negative. Hypokalemia is also excretion. This is achieved primarily by increased tubular pro- often present due to increased distal tubular potassium secre- duction of ammonia (NH) and secretion of protons, resulting in tion. This occurs because sodium accompanies bicarbonate to increased urine ammonium (NH,"*). The amount of urine ammo- the distal tubule, where sodium is reabsorbed in exchange for nium reflects the ability of the kidneys to respond appropriately potassium. to acidemia and indicates if the kidney is a cause of the acidosis. The most common causes of type 2 RTA include myeloma Because urine ammonium is difficult to measure, the urine anion light chains as well as nephrotoxic medications such as ifosfa- gap is used as a surrogate to assess kidney acid excretion: mide, carbonic anhydrase inhibitors (acetazolamide and topira- Urine Anion Gap = (Urine Sodium + Urine Potassium) mate), and tenofovir disoproxil fumarate (although toxicity is ~ Urine Chloride much less likely with tenofovir alafenamide). In patients with gastrointestinal losses of bicarbonate Alkali replacement is the mainstay of treatment for type 2 (diarrhea; laxative abuse) or those exposed to an acid load, urine RTA. Thiazide diuretics may help by causing mild volume NH,* should increase. Ammonium cation excretion results in depletion with subsequent aldosterone-driven proximal reab- proportionately less excretion of sodium and potassium (the sorption of sodium and bicarbonate. predominant urine cations). Chloride anion excretion contin- ues with ammonium cation excretion to maintain electrical Type 1 (Hypokalemic Distal) Renal Tubular Acidosis neutrality. In the context of increased urine NH,* production, In type 1 (hypokalemic distal) RTA, a distal tubular defect therefore, the urine anion gap will be negative (less than zero). results in impaired excretion of hydrogen ions by the distal A positive urine anion gap in a patient with acidemia suggests nephron (hence, low urine ammonium and positive urine the presence of a distal renal tubular acidosis. Proton secretion anion gap) with inability to acidify urine below a pH of 6.0. in the distal nephron generates NH,", and in distal renal tubular Serum bicarbonate may fall below 10 mEq/L (10 mmol/L) as acidosis there is a defect in this proton secretion. Therefore, levels fail to stabilize as is seen with type 2 (proximal) RTA; TABLE 11. Diagnostic Approach to Normal Anion Gap Metabolic Acidosis Diagnosis Urine Anion Gap (Uy, + Ux) — Uc Serum Potassium Urine pH | Ammonium chloride ingestion (acid load) Negative Normal <5.5 | Diarrhea and acidosis Negative Normal <5.5 Type 2 (proximal) RTA? Negative Decreased Variable

| Ammonium chloride ingestion (acid load) Negative Normal <5.5 | Diarrhea and acidosis Negative Normal <5.5 Type 2 (proximal) RTA? Negative Decreased Variable | Type 1 (hypokalemic distal) RTA Positive Decreased $515 Type 4 (hyperkalemic distal) RTA Positive Increased <5.5 RTA = renal tubular acidosis; Ug, = urine chloride; Ux = urine potassium; Uy, = urine sodium. *Type 2 (proximal) RTA is often associated with Fanconi or partial Fanconi syndrome (glycosuria, phosphaturia, aminoaciduria, hypouricemia). »Patients with type 2 (proximal) RTA have normal distal renal tubular function and can acidify the urine after the serum bicarbonate decreases to a point at which the filtered load of bicarbonate can be normally reabsorbed. 23

Acid-Base Disorders despite lower filtered bicarbonate, continued impairment in of consequent high urine pH (>6.0) and hypocitraturia, topira- acid excretion will worsen the acidosis. mate is associated with increased risk for calcium phosphate The most common causes include Sjogren syndrome and stones. Rare hereditary carbonic anhydrase deficiencies also other tubulointerstitial diseases, including reflux uropathy result in combined mixed RTA. and obstructive uropathy. Type 1 RTA can also be caused by medications such as amphotericin B and lithium and has been e In normal anion gap metabolic acidosis, a negative described in dysproteinemias, sickle cell disease, and Wilson urine anion gap identifies a nonrenal cause, whereas a disease. positive urine anion gap is associated with distal renal Urinary potassium wasting in the setting of diminished proton secretion underlies the development of hypokalemia. tubular acidoses.

despite lower filtered bicarbonate, continued impairment in of consequent high urine pH (>6.0) and hypocitraturia, topira- acid excretion will worsen the acidosis. mate is associated with increased risk for calcium phosphate The most common causes include Sjogren syndrome and stones. Rare hereditary carbonic anhydrase deficiencies also other tubulointerstitial diseases, including reflux uropathy result in combined mixed RTA. and obstructive uropathy. Type 1 RTA can also be caused by medications such as amphotericin B and lithium and has been e In normal anion gap metabolic acidosis, a negative described in dysproteinemias, sickle cell disease, and Wilson urine anion gap identifies a nonrenal cause, whereas a disease. positive urine anion gap is associated with distal renal Urinary potassium wasting in the setting of diminished proton secretion underlies the development of hypokalemia. tubular acidoses. Hypercalciuria and hyperphosphatemia are frequent in e In type 2 (proximal) renal tubular acidosis, failure of the untreated type 1 RTA because of increased calcium and phos- proximal tubule to adequately absorb filtered bicarbo- phate release from bone due to buffering of acid. Reduced nate causes bicarbonate loss; treatment consists of tubular calcium resorption in the context of acidosis exacer- alkali replacement and a thiazide diuretic. bates hypercalciuria. Increased proximal reabsorption of cit- ¢ In type 1 (hypokalemic distal) renal tubular acidosis, rate in the context of acidosis and hypokalemia causes impaired distal hydrogen ion excretion causes citrate hypocitraturia. Citrate usually inhibits calcium crystallization; reabsorption and increases the risk for nephrocalcino- therefore, hypocitraturia, in addition to hypercalciuria, sis; treatment consists of potassium citrate. increases the risk for calcium phosphate stones and ¢ In type 4 (hyperkalemic distal) renal tubular acidosis, nephrocalcinosis. aldosterone deficiency or resistance causes hyper- Treatment consists of potassium citrate (citrate is metabo- kalemia and decreased NH,* excretion; treatment lized to bicarbonate), with the dose titrated to response. includes correction of the underlying cause and treat- ment of hyperkalemia. Type 4 (Hyperkalemic Distal) Renal Tubular Acidosis Type 4 (hyperkalemic distal) RTA is caused by aldosterone defi- ciency or resistance. Primary adrenal insufficiency (Addison disease) may cause aldosterone deficiency. Hyporeninemic Metabolic Alkalosis hypoaldosteronism is a more common cause and may occur in Metabolic alkalosis results either from a loss of acid or from the presence of various kidney diseases, most often diabetic administration or retention of bicarbonate (alkali). Metabolic kidney disease. Aldosterone resistance can occur in those with alkalosis occurs in two phases: a generation phase in which tubulointerstitial disease, including urinary obstruction, sickle the primary disorder (such as vomiting or the accumulation of cell disease, medullary cystic kidney disease, and kidney alkali) occurs, and a maintenance phase in which typical renal transplant rejection. Drug-induced type 4 RTA can be caused compensatory excretion of excess bicarbonate is ineffective. by numerous drugs that reduce aldosterone production, The generation phase usually involves the gastrointestinal (GI) including ACE inhibitors, angiotensin receptor blockers, tract (in vomiting-induced acid loss) or the kidney (typically a direct renin inhibitors, heparin, and cyclooxygenase-2 mineralocorticoid effect, either primary or in response to inhibitors. intravascular volume depletion, with resulting sodium and Type 4 RTA is associated with a positive urine anion gap bicarbonate retention at the expense of acid and potassium but a urine pH <S.5 (see Table 11). Hyperkalemia decreases secretion). Conditions that contribute to maintenance of met- NH; production (and therefore NH,*), resulting in a positive abolic alkalosis include volume contraction, ineffective arterial urine anion gap. Even if the distal nephron is able to decrease blood volume (e.g., in cirrhosis or heart failure), hypokalemia, urine pH appropriately, reduced NH,* excretion will lead to chloride depletion, hyperaldosteronism, and decreased glo- insufficient acid excretion, generating a metabolic acidosis. merular filtration. Treatment is focused on correcting the underlying cause Symptoms of metabolic alkalosis are usually related to the if possible; offending medications should be discontinued underlying disorder. Coexisting hypokalemia markedly when identified. Because many patients are also hypertensive increases the risk for cardiac arrhythmias. Severe metabolic and volume expanded, thiazide or loop diuretics may help alkalosis (serum bicarbonate >50 mEq/L [50 mmol/L]) can increase serum bicarbonate and decrease serum potassium. cause hypocalcemia, hypoventilation, and hypoxemia, with Fludrocortisone can be used to replace mineralocorticoids in seizures, delirium, and stupor. hyporeninemic hypoaldosteronism in those without hyper- Thorough history and physical examination, including tension or heart failure. assessment of blood pressure and volume status, are essential to identifying the likely cause (Figure 11). Laboratory evalua- Mixed Forms of Renal Tubular Acidosis tion is based on urine chloride rather than urine sodium. Topiramate may cause mixed RTA through inhibition of car- The most common causes of metabolic alkalosis are asso- bonic anhydrase in both proximal and distal tubules. Because ciated with chloride depletion: vomiting, nasogastric suction,

Hypercalciuria and hyperphosphatemia are frequent in e In type 2 (proximal) renal tubular acidosis, failure of the untreated type 1 RTA because of increased calcium and phos- proximal tubule to adequately absorb filtered bicarbo- phate release from bone due to buffering of acid. Reduced nate causes bicarbonate loss; treatment consists of tubular calcium resorption in the context of acidosis exacer- alkali replacement and a thiazide diuretic. bates hypercalciuria. Increased proximal reabsorption of cit- ¢ In type 1 (hypokalemic distal) renal tubular acidosis, rate in the context of acidosis and hypokalemia causes impaired distal hydrogen ion excretion causes citrate hypocitraturia. Citrate usually inhibits calcium crystallization; reabsorption and increases the risk for nephrocalcino- therefore, hypocitraturia, in addition to hypercalciuria, sis; treatment consists of potassium citrate. increases the risk for calcium phosphate stones and ¢ In type 4 (hyperkalemic distal) renal tubular acidosis, nephrocalcinosis. aldosterone deficiency or resistance causes hyper- Treatment consists of potassium citrate (citrate is metabo- kalemia and decreased NH,* excretion; treatment lized to bicarbonate), with the dose titrated to response. includes correction of the underlying cause and treat- ment of hyperkalemia. Type 4 (Hyperkalemic Distal) Renal Tubular Acidosis Type 4 (hyperkalemic distal) RTA is caused by aldosterone defi- ciency or resistance. Primary adrenal insufficiency (Addison disease) may cause aldosterone deficiency. Hyporeninemic Metabolic Alkalosis hypoaldosteronism is a more common cause and may occur in Metabolic alkalosis results either from a loss of acid or from the presence of various kidney diseases, most often diabetic administration or retention of bicarbonate (alkali). Metabolic kidney disease. Aldosterone resistance can occur in those with alkalosis occurs in two phases: a generation phase in which tubulointerstitial disease, including urinary obstruction, sickle the primary disorder (such as vomiting or the accumulation of cell disease, medullary cystic kidney disease, and kidney alkali) occurs, and a maintenance phase in which typical renal transplant rejection. Drug-induced type 4 RTA can be caused compensatory excretion of excess bicarbonate is ineffective. by numerous drugs that reduce aldosterone production, The generation phase usually involves the gastrointestinal (GI) including ACE inhibitors, angiotensin receptor blockers, tract (in vomiting-induced acid loss) or the kidney (typically a direct renin inhibitors, heparin, and cyclooxygenase-2 mineralocorticoid effect, either primary or in response to inhibitors. intravascular volume depletion, with resulting sodium and Type 4 RTA is associated with a positive urine anion gap bicarbonate retention at the expense of acid and potassium but a urine pH <S.5 (see Table 11). Hyperkalemia decreases secretion). Conditions that contribute to maintenance of met- NH; production (and therefore NH,*), resulting in a positive abolic alkalosis include volume contraction, ineffective arterial urine anion gap. Even if the distal nephron is able to decrease blood volume (e.g., in cirrhosis or heart failure), hypokalemia, urine pH appropriately, reduced NH,* excretion will lead to chloride depletion, hyperaldosteronism, and decreased glo- insufficient acid excretion, generating a metabolic acidosis. merular filtration. Treatment is focused on correcting the underlying cause Symptoms of metabolic alkalosis are usually related to the if possible; offending medications should be discontinued underlying disorder. Coexisting hypokalemia markedly when identified. Because many patients are also hypertensive increases the risk for cardiac arrhythmias. Severe metabolic and volume expanded, thiazide or loop diuretics may help alkalosis (serum bicarbonate >50 mEq/L [50 mmol/L]) can increase serum bicarbonate and decrease serum potassium. cause hypocalcemia, hypoventilation, and hypoxemia, with Fludrocortisone can be used to replace mineralocorticoids in seizures, delirium, and stupor. hyporeninemic hypoaldosteronism in those without hyper- Thorough history and physical examination, including tension or heart failure. assessment of blood pressure and volume status, are essential to identifying the likely cause (Figure 11). Laboratory evalua- Mixed Forms of Renal Tubular Acidosis tion is based on urine chloride rather than urine sodium. Topiramate may cause mixed RTA through inhibition of car- The most common causes of metabolic alkalosis are asso- bonic anhydrase in both proximal and distal tubules. Because ciated with chloride depletion: vomiting, nasogastric suction, 24

Acid-Base Disorders | Metabolic alkalosis | Vv | Assess blood pressure and volume status | Vv Vv v e ECF increased Blood pressure and ¢ Blood pressure and ECF increased ¢ Blood pressure usually low ECF normal to decreased ¢ Urine sodium and chloride >15 ¢ Urine sodium and chloride <15 mEq/L (15 mmol/L) mEq/L (15 mmol/L) due to (saline-resistant) decreased EABV y ¢ Heart failure v y © Cirrhosis Urine chloride level * Renin-secreting tumor ¢ Nephrotic syndrome L ¢ Malignant hypertension ¢ Renovascular hypertension A e’ ¢ Primary hyperaldosteronism ¢ Exogenous mineralocorticoid <15 mEq/L (15 mmol/L) >15 mEq/L (15 mmol/L) ¢ Glucocorticoid-remediable hyperaldosteronism (saline-responsive) | ¢ Syndromes of apparent mineralocorticoid excess:

y ¢ Heart failure v y © Cirrhosis Urine chloride level * Renin-secreting tumor ¢ Nephrotic syndrome L ¢ Malignant hypertension ¢ Renovascular hypertension A e’ ¢ Primary hyperaldosteronism ¢ Exogenous mineralocorticoid <15 mEq/L (15 mmol/L) >15 mEq/L (15 mmol/L) ¢ Glucocorticoid-remediable hyperaldosteronism (saline-responsive) | ¢ Syndromes of apparent mineralocorticoid excess: . Glycyrrhetinic acid (licorice; chewing tobacco) Familial syndrome of apparent mineralocorticoid Urine sodium level excess (11-B-HSD deficiency) ¢ Active diuretic use Increased nonaldosterone mineralocorticoid | ¢ Hypokalemia receptor agonist (congenital adrenal hyperplasia; i y ¢ Hypomagnesemia Cushing syndrome; ¢ Bartter syndrome deoxycorticosterone-producing tumor; ¢ Gitelman syndrome 5-a-reductase deficiency) <15 mEq/L (15 mmol/L) >15 mEq/L (15 mmol/L) ¢ Aminoglycoside Ectopic ACTH syndrome

. Glycyrrhetinic acid (licorice; chewing tobacco) Familial syndrome of apparent mineralocorticoid Urine sodium level excess (11-B-HSD deficiency) ¢ Active diuretic use Increased nonaldosterone mineralocorticoid | ¢ Hypokalemia receptor agonist (congenital adrenal hyperplasia; i y ¢ Hypomagnesemia Cushing syndrome; ¢ Bartter syndrome deoxycorticosterone-producing tumor; ¢ Gitelman syndrome 5-a-reductase deficiency) <15 mEq/L (15 mmol/L) >15 mEq/L (15 mmol/L) ¢ Aminoglycoside Ectopic ACTH syndrome | toxicity Liddle syndrome v © Remote diuretic use © Vomiting (generation e Vomiting (maintenance phase: slight reduction phase: marked decreased in ECF volume) ECF volume) © High-dose penicillin ¢ Post-hypercapnic metabolic alkalosis FIGURE 11. Assessment of metabolic alkalosis. ACTH = adrenocorticotropic hormone; EABV = effective arterial blood volume; ECF = extracellular fluid; HSD = hydroxysteroid dehydrogenase.

v © Remote diuretic use © Vomiting (generation e Vomiting (maintenance phase: slight reduction phase: marked decreased in ECF volume) ECF volume) © High-dose penicillin ¢ Post-hypercapnic metabolic alkalosis FIGURE 11. Assessment of metabolic alkalosis. ACTH = adrenocorticotropic hormone; EABV = effective arterial blood volume; ECF = extracellular fluid; HSD = hydroxysteroid dehydrogenase. and diuretic use. Although upper GI losses are far more com- bicarbonate retention manifested by edema; treatment is tai- mon, lower GI chloride-secretory diarrheas (villous ade- lored to improving effective arterial blood volume and diuresis. noma, congenital chloridorrhea) can rarely cause chloride Mineralocorticoid excess presents with a high urine depletion with bicarbonate retention. A “contraction alkalo- chloride (>15 mEq/L [15 mmol/L]) with elevated blood pres- sis” results from loss of extracellular fluid containing low sure and hypokalemia without volume overload (saline- amounts of bicarbonate, leaving a contracted extracellular resistant metabolic alkalosis). The lack of an overt increase in volume containing a constant amount of existing circulating extravascular volume is often described as “aldosterone bicarbonate. escape”: After initial sodium retention, sodium balance is In patients with low urine chloride (<15 mEq/L attained through spontaneous diuresis that returns vascular [15 mmol/L]), normal/low intravascular volume, and normal/ volume toward normal. Mineralocorticoid excess is treated low extracellular volume, treatment consists of saline admin- with potassium repletion and treatment of the underlying istration plus repletion of potassium (saline-responsive meta- condition. bolic alkalosis) while addressing the primary cause of Rarely, patients may have clinical features consistent with the alkalosis. In contrast, those with a low urine chloride saline-responsive metabolic alkalosis but with a urine chloride (<15 mEq/L [15 mmol/L]) and normal/low intravascular volume of >15 mEq/L (15 mmol/L); ongoing diuretic use can present but with an increased extravascular volume (heart failure, cir- this way. Two autosomal recessive genetic conditions, Bartter rthosis) have secondary hyperaldosteronism with sodium and and Gitelman syndromes, result in disordered renal sodium

and diuretic use. Although upper GI losses are far more com- bicarbonate retention manifested by edema; treatment is tai- mon, lower GI chloride-secretory diarrheas (villous ade- lored to improving effective arterial blood volume and diuresis. noma, congenital chloridorrhea) can rarely cause chloride Mineralocorticoid excess presents with a high urine depletion with bicarbonate retention. A “contraction alkalo- chloride (>15 mEq/L [15 mmol/L]) with elevated blood pres- sis” results from loss of extracellular fluid containing low sure and hypokalemia without volume overload (saline- amounts of bicarbonate, leaving a contracted extracellular resistant metabolic alkalosis). The lack of an overt increase in volume containing a constant amount of existing circulating extravascular volume is often described as “aldosterone bicarbonate. escape”: After initial sodium retention, sodium balance is In patients with low urine chloride (<15 mEq/L attained through spontaneous diuresis that returns vascular [15 mmol/L]), normal/low intravascular volume, and normal/ volume toward normal. Mineralocorticoid excess is treated low extracellular volume, treatment consists of saline admin- with potassium repletion and treatment of the underlying istration plus repletion of potassium (saline-responsive meta- condition. bolic alkalosis) while addressing the primary cause of Rarely, patients may have clinical features consistent with the alkalosis. In contrast, those with a low urine chloride saline-responsive metabolic alkalosis but with a urine chloride (<15 mEq/L [15 mmol/L]) and normal/low intravascular volume of >15 mEq/L (15 mmol/L); ongoing diuretic use can present but with an increased extravascular volume (heart failure, cir- this way. Two autosomal recessive genetic conditions, Bartter rthosis) have secondary hyperaldosteronism with sodium and and Gitelman syndromes, result in disordered renal sodium 25