InternalMed_Harrison

InternalMed_Harrison. Diagnostic Approach The cause of hypokalemia is usually evident from history, physical examination, and/or basic laboratory tests. The history should focus on medications (e.g., laxatives, diuretics, antibiotics), diet and dietary habits (e.g., licorice), and/or symptoms that suggest a particular cause (e.g., periodic weakness, diarrhea). The physical examination should pay particular attention to blood pressure, volume status, and signs suggestive of specific hypokalemic disorders, e.g., hyperthyroidism and Cushing’s syndrome. Initial laboratory evaluation should include electrolytes, BUN, creatinine, serum osmolality, Mg2+, Ca2+, a complete blood count, and urinary pH, osmolality, creatinine, and electrolytes (Fig. 63-7). The presence of a non–anion gap acidosis suggests a distal, hypokalemic renal tubular acidosis or diarrhea; calculation of the urinary anion gap can help differentiate these two diagnoses. Renal K+ excretion can be assessed with a 24-h urine collection; a 24-h K+


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InternalMed_Harrison. renal tubular acidosis or diarrhea; calculation of the urinary anion gap can help differentiate these two diagnoses. Renal K+ excretion can be assessed with a 24-h urine collection; a 24-h K+ excretion of <15 mmol is indicative of an extrarenal cause of hypokalemia (Fig. 63-7). If only a random, spot urine sample is available, serum and urine osmolality can be used to calculate the transtubular K+ gradient (TTKG), which should be <3 in the presence of hypokalemia (see also “Hyperkalemia”). Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/ mmol creatinine) is compatible with excessive renal K+ excretion. Urine Cl– is usually decreased in patients with hypokalemia from a nonreabsorbable anion, such as antibiotics or HCO3–. The most common causes of chronic hypokalemic alkalosis are surreptitious vomiting, diuretic abuse, and GS; these can be distinguished by the pattern of urinary electrolytes. Hypokalemic patients with vomiting due to bulimia will


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InternalMed_Harrison. hypokalemic alkalosis are surreptitious vomiting, diuretic abuse, and GS; these can be distinguished by the pattern of urinary electrolytes. Hypokalemic patients with vomiting due to bulimia will thus have a urinary Cl– <10 mmol/L; urine Na+, K+, and 307 Cl– are persistently elevated in GS, due to loss of function in the thiazide-sensitive Na+-Cl– cotransporter, but less elevated in diuretic abuse and with greater variability. Urine diuretic screens for loop diuretics and thiazides may be necessary to further exclude diuretic abuse.


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InternalMed_Harrison. Other tests, such as urinary Ca2+, thyroid function tests, and/or PRA and aldosterone levels, may also be appropriate in specific cases. A plasma aldosterone:PRA ratio of >50, due to suppression of circulating renin and an elevation of circulating aldosterone, is suggestive of hyperaldosteronism. Patients with hyperaldosteronism or apparent mineralocorticoid excess may require further testing, for example adrenal vein sampling (Chap. 406) or the clinically available testing for specific genetic causes (e.g., FH-I, SAME, Liddle’s syndrome). Patients with primary aldosteronism should thus be tested for the chimeric FH-I/GRA gene (see above) if they are younger than 20 years of age or have a family history of primary aldosteronism or stroke at a young age (<40 years). Preliminary differentiation of Liddle’s syndrome due to mutant ENaC channels from SAME due to mutant 11βHSD-2 (see above), both of which cause hypokalemia and hypertension with aldosterone suppression, can be made on a


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InternalMed_Harrison. of Liddle’s syndrome due to mutant ENaC channels from SAME due to mutant 11βHSD-2 (see above), both of which cause hypokalemia and hypertension with aldosterone suppression, can be made on a clinical basis and then confirmed by genetic analysis; patients with Liddle’s syndrome should respond to amiloride (ENaC inhibition) but not spironolactone, whereas patients with SAME will respond to spironolactone.


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InternalMed_Harrison. The goals of therapy in hypokalemia are to prevent life-threatening and/or serious chronic consequences, to replace the associated K+ deficit, and to correct the underlying cause and/or mitigate future hypokalemia. The urgency of therapy depends on the severity of hypokalemia, associated clinical factors (e.g., cardiac disease, digoxin therapy), and the rate of decline in serum K+. Patients with a prolonged QT interval and/or other risk factors for arrhythmia should be monitored by continuous cardiac telemetry during repletion. Urgent but cautious K+ replacement should be considered in patients with severe redistributive hypokalemia (plasma K+ concentration <2.5 mM) and/or when serious complications ensue; however, this approach has a risk of rebound hyperkalemia following acute resolution of the underlying cause. When excessive activity of the sympathetic nervous system is thought to play a dominant role in redistributive hypokalemia, as in TPP, theophylline overdose, and acute head


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InternalMed_Harrison. of the underlying cause. When excessive activity of the sympathetic nervous system is thought to play a dominant role in redistributive hypokalemia, as in TPP, theophylline overdose, and acute head injury, high-dose propranolol (3 mg/kg) should be considered; this nonspecific b-adrenergic blocker will correct hypokalemia without the risk of rebound hyperkalemia.


InternalMed_Harrison

InternalMed_Harrison. Oral replacement with K+-Cl– is the mainstay of therapy in hypokalemia. Potassium phosphate, oral or IV, may be appropriate in patients with combined hypokalemia and hypophosphatemia. Potassium bicarbonate or potassium citrate should be considered in patients with concomitant metabolic acidosis. Notably, hypomagnesemic patients are refractory to K+ replacement alone, such that concomitant Mg2+ deficiency should always be corrected with oral or intravenous repletion. The deficit of K+ and the rate of correction should be estimated as accurately as possible; renal function, medications, and comorbid conditions such as diabetes should also be considered, so as to gauge the risk of overcorrection. In the absence of abnormal K+ redistribution, the total deficit correlates with serum K+, such that serum K+ drops by approximately 0.27 mM for every 100-mmol reduction in total-body stores; loss of 400–800 mmol of total-body K+ results in a reduction in serum K+ by approximately 2.0 mM.


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InternalMed_Harrison. such that serum K+ drops by approximately 0.27 mM for every 100-mmol reduction in total-body stores; loss of 400–800 mmol of total-body K+ results in a reduction in serum K+ by approximately 2.0 mM. Notably, given the delay in redistributing potassium into intracellular compartments, this deficit must be replaced gradually over 24-48 h, with frequent monitoring of plasma K+ concentration to avoid transient overrepletion and transient hyperkalemia.


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InternalMed_Harrison. The use of intravenous administration should be limited to patients unable to use the enteral route or in the setting of severe complications (e.g., paralysis, arrhythmia). Intravenous K+-Cl– should always be administered in saline solutions, rather than dextrose, because the dextrose-induced increase in insulin can acutely


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Hypokalemia (Serum K+<3.5 mmol/l) <15 mmol/day OR <15 mmol/g Cr >15 mmol/g Cr OR >15 mmol/day Renal loss TTKG ˜ Distal K+ secretion ˜ Tubular flow -Osmotic diuresis BP and/or Volume Extrarenal loss/remote renal loss Metabolic acidosis -GI K+ loss Normal -Profuse sweating Metabolic alkalosis -Remote diuretic use -Remote vomiting or stomach drainage -Profuse sweating Non-reabsorbable anions other than HCO3 – -Hippurate -Penicillins Metabolic acidosis -Proximal RTA -Distal RTA -DKA -Amphotericin B -Acetazolamide Acid-base status Low OR normal Acid-base status Variable Aldosterone High Low High High Low High Normal Cortisol Renin Urine K+ Emergency? Pseudohypokalemia? Move to therapy History, physical examination & basic laboratory tests Clear evidence of transcellular shift No further workup Treat accordingly Clear evidence of low intake Treat accordingly and re-evaluate Yes Yes Yes Yes No No No No -Insulin excess -˜2-adrenergic


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InternalMed_Harrison. Clear evidence of transcellular shift No further workup Treat accordingly Clear evidence of low intake Treat accordingly and re-evaluate Yes Yes Yes Yes No No No No -Insulin excess -˜2-adrenergic agonists -FHPP -Hyperthyroidism -Barium intoxication -Theophylline -Chloroquine >4 >20 >0.20 <0.15 <10 <2 Metabolic alkalosis Urine Ca/Cr (molar ratio) -Vomiting -Chloride diarrhea Urine Cl– (mmol/l) -Loop diuretic -Bartter’s syndrome -Thiazide diuretic -Gitelman’s syndrome -RAS -RST -Malignant HTN -PA -FH-I -Cushing’s syndrome -Liddle’s syndrome -Licorice -SAME


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InternalMed_Harrison. FIguRE 63-7 The diagnostic approach to hypokalemia. See text for details. AME, apparent mineralocorticoid excess; BP, blood pressure; CCD, cortical collecting duct; DKA, diabetic ketoacidosis; FH-I, familial hyperaldosteronism type I; FHPP, familial hypokalemic periodic paralysis; GI, gastrointestinal; GRA, glucocorticoid remediable aldosteronism; HTN, hypertension; PA, primary aldosteronism; RAS, renal artery stenosis; RST, renin-secreting tumor; RTA, renal tubular acidosis; SAME, syndrome of apparent mineralocorticoid excess; TTKG, transtubular potassium gradient. (Used with permission from DB Mount, K Zandi-Nejad K: Disorders of potassium balance, in Brenner and Rector’s The Kidney, 8th ed, BM Brenner [ed]. Philadelphia, W.B. Saunders & Company, 2008, pp 547-587.) exacerbate hypokalemia. The peripheral intravenous dose is usually 20–40 mmol of K+-Cl– per liter; higher concentrations can cause localized pain from chemical phlebitis, irritation, and sclerosis. If hypokalemia is


InternalMed_Harrison

InternalMed_Harrison. The peripheral intravenous dose is usually 20–40 mmol of K+-Cl– per liter; higher concentrations can cause localized pain from chemical phlebitis, irritation, and sclerosis. If hypokalemia is severe (<2.5 mmol/L) and/or critically symptomatic, intravenous K+-Cl– can be administered through a central vein with cardiac monitoring in an intensive care setting, at rates of 10–20 mmol/h; higher rates should be reserved for acutely life-threatening complications. The absolute amount of administered K+ should be restricted (e.g., 20 mmol in 100 mL of saline solution) to prevent inadvertent infusion of a large dose. Femoral veins are preferable, because infusion through internal jugular or subclavian central lines can acutely increase the local concentration of K+ and affect cardiac conduction.


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InternalMed_Harrison. Strategies to minimize K+ losses should also be considered. These measures may include minimizing the dose of non-K+-sparing diuretics, restricting Na+ intake, and using clinically appropriate combinations of non-K+-sparing and K+-sparing medications (e.g., loop diuretics with angiotensin-converting enzyme inhibitors).


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InternalMed_Harrison. Hyperkalemia is defined as a plasma potassium level of 5.5 mM, occurring in up to 10% of hospitalized patients; severe hyperkalemia (>6.0 mM) occurs in approximately 1%, with a significantly increased risk of mortality. Although redistribution and reduced tissue uptake can acutely cause hyperkalemia, a decrease in renal K+ excretion is the most frequent underlying cause (Table 63-5). Excessive intake of K+ is a rare cause, given the adaptive capacity to increase renal secretion; however, dietary intake can have a major effect in susceptible patients, e.g., diabetics with hyporeninemic hypoaldosteronism and chronic kidney disease. Drugs that impact on the renin-angiotensin-aldosterone axis are also a major cause of hyperkalemia. CAuSES of HyPERKALEMiA I. Pseudohyperkalemia A. Cellular efflux; thrombocytosis, erythrocytosis, leukocytosis, in vitro hemolysis B. Hereditary defects in red cell membrane transport II. A. B.


InternalMed_Harrison

InternalMed_Harrison. CAuSES of HyPERKALEMiA I. Pseudohyperkalemia A. Cellular efflux; thrombocytosis, erythrocytosis, leukocytosis, in vitro hemolysis B. Hereditary defects in red cell membrane transport II. A. B. Hyperosmolality; radiocontrast, hypertonic dextrose, mannitol C. D. Digoxin and related glycosides (yellow oleander, foxglove, bufadienolide) E. F. Lysine, arginine, and ε-aminocaproic acid (structurally similar, positively charged) G. Succinylcholine; thermal trauma, neuromuscular injury, disuse atrophy, mucositis, or prolonged immobilization H. III. A. Inhibition of the renin-angiotensin-aldosterone axis; ↑ risk of hyperkalemia when used in combination 1. 2. Renin inhibitors; aliskiren (in combination with ACE inhibitors or angiotensin receptor blockers [ARBs]) 3. 4. Blockade of the mineralocorticoid receptor: spironolactone, eplerenone, drospirenone 5. Blockade of the epithelial sodium channel (ENaC): amiloride, triamterene, trimethoprim, pentamidine, nafamostat B.


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InternalMed_Harrison. Blockade of the epithelial sodium channel (ENaC): amiloride, triamterene, trimethoprim, pentamidine, nafamostat B. 1. 2. C. 1. Tubulointerstitial diseases: systemic lupus erythematosus (SLE), sickle cell anemia, obstructive uropathy 2. Diabetes, diabetic nephropathy 3. Drugs: nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX2) inhibitors, β-blockers, cyclosporine, tacrolimus 4. Chronic kidney disease, advanced age 5. Pseudohypoaldosteronism type II: defects in WNK1 or WNK4 kinases, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3) D. Renal resistance to mineralocorticoid 1. Tubulointerstitial diseases: SLE, amyloidosis, sickle cell anemia, obstructive uropathy, post–acute tubular necrosis 2. Hereditary: pseudohypoaldosteronism type I; defects in the mineralocorticoid receptor or the epithelial sodium channel (ENaC) E. 1. 2. 3. F. 1. Autoimmune: Addison’s disease, polyglandular endocrinopathy 2.


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InternalMed_Harrison. E. 1. 2. 3. F. 1. Autoimmune: Addison’s disease, polyglandular endocrinopathy 2. Infectious: HIV, cytomegalovirus, tuberculosis, disseminated fungal infection 3. Infiltrative: amyloidosis, malignancy, metastatic cancer 4. Drug-associated: heparin, low-molecular-weight heparin 5. Hereditary: adrenal hypoplasia congenita, congenital lipoid adrenal hyperplasia, aldosterone synthase deficiency 6. Adrenal hemorrhage or infarction, including in antiphospholipid syndrome


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InternalMed_Harrison. Pseudohyperkalemia Hyperkalemia should be distinguished from factitious hyperkalemia or “pseudohyperkalemia,” an artifactual increase in serum K+ due to the release of K+ during or after venipuncture. Pseudohyperkalemia can occur in the setting of excessive muscle activity during venipuncture (e.g., fist clenching), a marked increase in cellular elements (thrombocytosis, leukocytosis, and/or erythrocytosis) with in vitro efflux of K+, and acute anxiety during venipuncture with respiratory alkalosis and redistributive hyperkalemia. Cooling of blood following venipuncture is another cause, due to reduced cellular uptake; the converse is the increased uptake of K+ by cells at high ambient temperatures, leading to normal values for hyperkalemic patients and/or to spurious hypokalemia in normokalemic patients. Finally, there are multiple genetic subtypes of hereditary pseudohyperkalemia, caused by increases in the passive K+ permeability of erythrocytes. For example, causative mutations


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InternalMed_Harrison. patients. Finally, there are multiple genetic subtypes of hereditary pseudohyperkalemia, caused by increases in the passive K+ permeability of erythrocytes. For example, causative mutations have been described in the red cell anion exchanger (AE1, encoded by the SLC4A1 gene), leading to reduced red cell anion transport, hemolytic anemia, the acquisition of a novel AE1mediated K+ leak, and pseudohyperkalemia.


InternalMed_Harrison

InternalMed_Harrison. Redistribution and Hyperkalemia Several different mechanisms can induce an efflux of intracellular K+ and hyperkalemia. Acidemia is associated with cellular uptake of H+ and an associated efflux of K+; it is thought that this effective K+-H+ exchange serves to help maintain extracellular pH. Notably, this effect of acidosis is limited to non– anion gap causes of metabolic acidosis and, to a lesser extent, respiratory causes of acidosis; hyperkalemia due to an acidosis-induced shift of potassium from the cells into the ECF does not occur in the anion gap acidoses lactic acidosis and ketoacidosis. Hyperkalemia due to hypertonic mannitol, hypertonic saline, and intravenous immune globulin is generally attributed to a “solvent drag” effect, as water moves out of cells along the osmotic gradient. Diabetics are also prone to osmotic hyperkalemia in response to intravenous hypertonic glucose, when given without adequate insulin. Cationic amino acids, specifically lysine, arginine, and the


InternalMed_Harrison

InternalMed_Harrison. Diabetics are also prone to osmotic hyperkalemia in response to intravenous hypertonic glucose, when given without adequate insulin. Cationic amino acids, specifically lysine, arginine, and the structurally related drug epsilonaminocaproic acid, cause efflux of K+ and hyperkalemia, through an effective cation-K+ exchange of unknown identity and mechanism. Digoxin inhibits Na+/K+-ATPase and impairs the uptake of K+ by 310 skeletal muscle, such that digoxin overdose predictably results in hyperkalemia. Structurally related glycosides are found in specific plants (e.g., yellow oleander, foxglove) and in the cane toad, Bufo marinus (bufadienolide); ingestion of these substances and extracts thereof can also cause hyperkalemia. Finally, fluoride ions also inhibit Na+/K+-ATPase, such that fluoride poisoning is typically associated with hyperkalemia. Succinylcholine depolarizes muscle cells, causing an efflux of K+ through acetylcholine receptors (AChRs). The use of this agent is


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InternalMed_Harrison. that fluoride poisoning is typically associated with hyperkalemia. Succinylcholine depolarizes muscle cells, causing an efflux of K+ through acetylcholine receptors (AChRs). The use of this agent is contraindicated in patients who have sustained thermal trauma, neuromuscular injury, disuse atrophy, mucositis, or prolonged immobilization. These disorders share a marked increase and redistribution of AChRs at the plasma membrane of muscle cells; depolarization of these upregulated AChRs by succinylcholine leads to an exaggerated efflux of K+ through the receptor-associated cation channels, resulting in acute hyperkalemia.


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InternalMed_Harrison. Hyperkalemia Caused by Excess Intake or Tissue Necrosis Increased intake of even small amounts of K+ may provoke severe hyperkalemia in patients with predisposing factors; hence, an assessment of dietary intake is crucial. Foods rich in potassium include tomatoes, bananas, and citrus fruits; occult sources of K+, particularly K+-containing salt substitutes, may also contribute significantly. Iatrogenic causes include simple overreplacement with K+-Cl– or the administration of a potassium-containing medication (e.g., K+-penicillin) to a susceptible patient. Red cell transfusion is a well-described cause of hyperkalemia, typically in the setting of massive transfusions. Finally, severe tissue necrosis, as in acute tumor lysis syndrome and rhabdomyolysis, will predictably cause hyperkalemia from the release of intracellular K+.


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InternalMed_Harrison. Hypoaldosteronism and Hyperkalemia Aldosterone release from the adrenal gland may be reduced by hyporeninemic hypoaldosteronism, medications, primary hypoaldosteronism, or isolated deficiency of ACTH (secondary hypoaldosteronism). Primary hypoaldosteronism may be genetic or acquired (Chap. 406) but is commonly caused by autoimmunity, either in Addison’s disease or in the context of a polyglandular endocrinopathy. HIV has surpassed tuberculosis as the most important infectious cause of adrenal insufficiency. The adrenal involvement in HIV disease is usually subclinical; however, adrenal insufficiency may be precipitated by stress, drugs such as ketoconazole that inhibit steroidogenesis, or the acute withdrawal of steroid agents such as megestrol.


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InternalMed_Harrison. Hyporeninemic hypoaldosteronism is a very common predisposing factor in several overlapping subsets of hyperkalemic patients: diabetics, the elderly, and patients with renal insufficiency. Classically, patients should have suppressed PRA and aldosterone; approximately 50% have an associated acidosis, with a reduced renal excretion of NH4+, a positive urinary anion gap, and urine pH <5.5. Most patients are volume expanded, with secondary increases in circulating atrial natriuretic peptide (ANP) that inhibit both renal renin release and adrenal aldosterone release.


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InternalMed_Harrison. Renal Disease and Hyperkalemia Chronic kidney disease and end-stage kidney disease are very common causes of hyperkalemia, due to the associated deficit or absence of functioning nephrons. Hyperkalemia is more common in oliguric acute kidney injury; distal tubular flow rate and Na+ delivery are less limiting factors in nonoliguric patients. Hyperkalemia out of proportion to GFR can also be seen in the context of tubulointerstitial disease that affects the distal nephron, such as amyloidosis, sickle cell anemia, interstitial nephritis, and obstructive uropathy.


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InternalMed_Harrison. Hereditary renal causes of hyperkalemia have overlapping clinical features with hypoaldosteronism, hence the diagnostic label pseudohypoaldosteronism (PHA). PHA type I (PHA-I) has both an autosomal recessive and an autosomal dominant form. The autosomal dominant form is due to loss-of-function mutations in the MLR; the recessive form is caused by various combinations of mutations in the three subunits of ENaC, resulting in impaired Na+ channel activity in principal cells and other tissues. Patients with recessive PHA-I suffer from lifelong salt wasting, hypotension, and hyperkalemia, whereas the phenotype of autosomal dominant PHA-I due to MLR dysfunction improves in adulthood. PHA type II (PHA-II; also known as hereditary hypertension with hyperkalemia) is in every respect the mirror image of PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases GS caused by loss of function in NCC, the thiazide-sensitive Na+-Cl– cotransporter (see above); the clinical phenotype includes hypertension, hyperkalemia, hyperchloremic metabolic acidosis, suppressed PRA and aldosterone, hypercalciuria, and reduced bone density. PHA-II thus behaves like a gain of function in NCC, and treatment with thiazides results in resolution of the entire clinical phenotype. However, the NCC gene is not directly involved in PHA-II, which is caused by mutations in the WNK1 and WNK4 serine-threonine kinases or the upstream Kelch-like 3 (KLHL3) and Cullin 3 (CUL3), two components of an E3 ubiquitin ligase complex that regulates these kinases; these proteins collectively regulate NCC activity, with PHA-II-associated activation of the transporter.


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InternalMed_Harrison. Medication-Associated Hyperkalemia Most medications associated with hyperkalemia cause inhibition of some component of the reninangiotensin-aldosterone axis. ACE inhibitors, angiotensin receptor blockers, renin inhibitors, and MLRs are predictable and common causes of hyperkalemia, particularly when prescribed in combination. The oral contraceptive agent Yasmin-28 contains the progestin drospirenone, which inhibits the MLR and can cause hyperkalemia in susceptible patients. Cyclosporine, tacrolimus, NSAIDs, and cyclooxygenase 2 (COX2) inhibitors cause hyperkalemia by multiple mechanisms, but share the ability to cause hyporeninemic hypoaldosteronism. Notably, most drugs that affect the renin-angiotensin-aldosterone axis also block the local adrenal response to hyperkalemia, thus attenuating the direct stimulation of aldosterone release by increased plasma K+ concentration.


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InternalMed_Harrison. Inhibition of apical ENaC activity in the distal nephron by amiloride and other K+-sparing diuretics results in hyperkalemia, often with a voltage-dependent hyperchloremic acidosis and/or hypovolemic hyponatremia. Amiloride is structurally similar to the antibiotics trimethoprim (TMP) and pentamidine, which also block ENaC; risk factors for TMP-associated hyperkalemia include the administered dose, renal insufficiency, and hyporeninemic hypoaldosteronism. Indirect inhibition of ENaC at the plasma membrane is also a cause of drug-associated hyperkalemia; nafamostat, a protease inhibitor used in some countries for the management of pancreatitis, inhibits aldosteroneinduced renal proteases that activate ENaC by proteolytic cleavage.


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InternalMed_Harrison. Clinical Features Hyperkalemia is a medical emergency due to its effects on the heart. Cardiac arrhythmias associated with hyperkalemia include sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and asystole. Mild increases in extracellular K+ affect the repolarization phase of the cardiac action potential, resulting in changes in T-wave morphology; further increase in plasma K+ concentration depresses intracardiac conduction, with progressive prolongation of the PR and QRS intervals. Severe hyperkalemia results in loss of the P wave and a progressive widening of the QRS complex; development of a sine-wave sinoventricular rhythm suggests impending ventricular fibrillation or asystole. Hyperkalemia can also cause a type I Brugada pattern in the electrocardiogram (ECG), with a pseudo–right bundle branch block and persistent coved ST segment elevation in at least two precordial leads. This hyperkalemic Brugada’s sign occurs


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InternalMed_Harrison. pattern in the electrocardiogram (ECG), with a pseudo–right bundle branch block and persistent coved ST segment elevation in at least two precordial leads. This hyperkalemic Brugada’s sign occurs in critically ill patients with severe hyperkalemia and can be differentiated from genetic Brugada’s syndrome by an absence of P waves, marked QRS widening, and an abnormal QRS axis. Classically, the electrocardiographic manifestations in hyperkalemia progress from tall peaked T waves (5.5–6.5 mM), to a loss of P waves (6.5–7.5 mM) to a widened QRS complex (7.0–8.0 mM), and, ultimately, a to a sine wave pattern (>8.0 mM). However, these changes are notoriously insensitive, particularly in patients with chronic kidney disease or end-stage renal disease.


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InternalMed_Harrison. Hyperkalemia from a variety of causes can also present with ascending paralysis, denoted secondary hyperkalemic paralysis to differentiate it from familial hyperkalemic periodic paralysis (HYPP). The presentation may include diaphragmatic paralysis and respiratory failure. Patients with familial HYPP develop myopathic weakness during hyperkalemia induced by increased K+ intake or rest after heavy exercise. Depolarization of skeletal muscle by hyperkalemia unmasks an inactivation defect in skeletal Na+ channel; autosomal dominant mutations in the SCN4A gene encoding this channel are the predominant cause.


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InternalMed_Harrison. Within the kidney, hyperkalemia has negative effects on the ability to excrete an acid load, such that hyperkalemia per se can contribute to metabolic acidosis. This defect appears to be due in part to competition between K+ and NH4+ for reabsorption by the TALH and subsequent countercurrent multiplication, ultimately reducing the medullary gradient for NH3/NH4 excretion by the distal nephron. Regardless of the underlying mechanism, restoration of normokalemia can, in many instances, correct hyperkalemic metabolic acidosis.


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InternalMed_Harrison. Diagnostic Approach The first priority in the management of hyperkalemia is to assess the need for emergency treatment, followed by a comprehensive workup to determine the cause (Fig. 63-8). History and physical examination should focus on medications, diet and dietary supplements, risk factors for kidney failure, reduction in urine output, blood pressure, and volume status. Initial laboratory 311 tests should include electrolytes, BUN, creatinine, serum osmolality, Mg2+ and Ca2+, a complete blood count, and urinary pH, osmolality, creatinine, and electrolytes. A urine Na+ concentration of <20 mM indicates that distal Na+ delivery is a limiting factor in K+ excretion; volume repletion with 0.9% saline or treatment with furosemide may be effective in reducing plasma K+ concentration. Serum and urine osmolality are required for calculation of the transtubular K+ gradient (TTKG) (Fig. 63-8). The expected values of the TTKG are largely based on historical data, and are <3 in the presence


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InternalMed_Harrison. and urine osmolality are required for calculation of the transtubular K+ gradient (TTKG) (Fig. 63-8). The expected values of the TTKG are largely based on historical data, and are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia.


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InternalMed_Harrison. CHAPTER 63 Fluid and Electrolyte Disturbances Hyperkalemia(Serum K+ ˜5.5 mmol/l) History, physical examination & basic laboratory tests Decreased urinary K+ excretion (<40 mmol/day) Urine electrolytes TTKG Evidence of increased potassium load Urine Na+ <25 mmol/L Reduced tubular flow Reduced distal K+ secretion (GFR >20 ml/min) Advanced kidney failure (GFR ˜20 ml/min) Reduced ECV TTKG <8 (Tubular resistance) TTKG ˜8 Low aldosterone Renin 9°-Fludrocortisone Treat accordingly and re-evaluate Pseudohyperkalemia? Evidence of transcellular shift No further actionK+ ˜6.0 or ECG changes Emergency therapy Yes Yes Decreased distal Na+ delivery Yes Treat accordingly and re-evaluate -Hypertonicity (e.g., mannitol) -Hyperglycemia -Succinylcholine -˛-aminocaproic acid -Digoxin -˝-blockers -Metabolic acidosis (non-organic) -Arginine or lysine infusion -Hyperkalemic periodic paralysis -˙Insulin -Exercise Yes No No No No >8 <5 High Low Drugs -Amiloride -Spironolactone -Triamterene -Trimethoprim


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InternalMed_Harrison. acidosis (non-organic) -Arginine or lysine infusion -Hyperkalemic periodic paralysis -˙Insulin -Exercise Yes No No No No >8 <5 High Low Drugs -Amiloride -Spironolactone -Triamterene -Trimethoprim -Pentamidine -Eplerenone -Drospirenone -Calcineurin inhibitors Other causes -Tubulointerstitial diseases -Urinary tract obstruction -PHA type I -PHA type II -Sickle cell disease -Renal transplant -SLE -Primary adrenal insufficiency -Isolated aldosterone deficiency -Heparin/ LMW heparin -ACE-I / ARB -Ketoconazole -Diabetes mellitus -Acute GN -Tubulointerstitial diseases -PHA type II -NSAIDs -˝-Blockers FIguRE 63-8 The diagnostic approach to hyperkalemia. See text for details. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angioten-sin II receptor blocker; CCD, cortical collecting duct; ECG, electrocardiogram; ECV, effective circulatory volume; GFR, glomerular filtration rate; GN, glomerulonephritis; HIV, human immunodeficiency virus; LMW heparin, low-molecular-weight heparin; NSAIDs,


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InternalMed_Harrison. electrocardiogram; ECV, effective circulatory volume; GFR, glomerular filtration rate; GN, glomerulonephritis; HIV, human immunodeficiency virus; LMW heparin, low-molecular-weight heparin; NSAIDs, nonsteroidal anti-inflammatory drugs; PHA, pseudohypoaldosteronism; SLE, systemic lupus erythematosus; TTKG, transtubular potassium gradient. (Used with permission from DB Mount, K Zandi-Nejad K: Disorders of potassium balance, in Brenner and Rector’s The Kidney, 8th ed, BM Brenner [ed]. Philadelphia, W.B. Saunders & Company, 2008, pp 547-587.)


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InternalMed_Harrison. Electrocardiographic manifestations of hyperkalemia should be considered a medical emergency and treated urgently. However, patients with significant hyperkalemia (plasma K+ concentration ≥6.5 mM) in the absence of ECG changes should also be aggressively managed, given the limitations of ECG changes as a predictor of cardiac toxicity. Urgent management of hyperkalemia includes admission to the hospital, continuous cardiac monitoring, and immediate treatment. The treatment of hyperkalemia is divided into three stages: 1.


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InternalMed_Harrison. Immediate antagonism of the cardiac effects of hyperkalemia. Intravenous calcium serves to protect the heart, whereas other measures are taken to correct hyperkalemia. Calcium raises the action potential threshold and reduces excitability, without changing the resting membrane potential. By restoring the difference between resting and threshold potentials, calcium reverses the depolarization blockade due to hyperkalemia. The recommended dose is 10 mL of 10% calcium gluconate (3–4 mL of calcium chloride), infused intravenously over 2–3 min with cardiac monitoring. The effect of the infusion starts in 1–3 min and lasts 30–60 min; the dose should be repeated if there is no change in ECG findings or if they recur after initial improvement. Hypercalcemia potentiates the cardiac toxicity of digoxin; hence, intravenous calcium should be used with extreme caution in patients taking this medication; if judged necessary, 10 mL of 10% calcium gluconate can be added to 100 mL of 5% dextrose in


InternalMed_Harrison

InternalMed_Harrison. hence, intravenous calcium should be used with extreme caution in patients taking this medication; if judged necessary, 10 mL of 10% calcium gluconate can be added to 100 mL of 5% dextrose in water and infused over 20–30 min to avoid acute hypercalcemia.


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InternalMed_Harrison. 2. Rapid reduction in plasma K+ concentration by redistribution into cells. Insulin lowers plasma K+ concentration by shifting K+ into cells. The recommended dose is 10 units of intravenous regular insulin followed immediately by 50 mL of 50% dextrose (D50W, 25 g of glucose total); the effect begins in 10–20 min, peaks at 30–60 min, and lasts for 4–6 h. Bolus D50W without insulin is never appropriate, given the risk of acutely worsening hyperkalemia due to the osmotic effect of hypertonic glucose. Hypoglycemia is common with insulin plus glucose; hence, this should be followed by an infusion of 10% dextrose at 50–75 mL/h, with close monitoring of plasma glucose concentration. In hyperkalemic patients with glucose concentrations of ≥200–250 mg/dL, insulin should be administered without glucose, again with close monitoring of glucose concentrations.


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InternalMed_Harrison. β2-agonists, most commonly albuterol, are effective but underused agents for the acute management of hyperkalemia. Albuterol and insulin with glucose have an additive effect on plasma K+ concentration; however, ~20% of patients with end-stage renal disease (ESRD) are resistant to the effect of β2-agonists; hence, these drugs should not be used without insulin. The recommended dose for inhaled albuterol is 10–20 mg of nebulized albuterol in 4 mL of normal saline, inhaled over 10 min; the effect starts at about 30 min, reaches its peak at about 90 min, and lasts for 2–6 h. Hyperglycemia is a side effect, along with tachycardia. β2-Agonists should be used with caution in hyperkalemic patients with known cardiac disease.


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InternalMed_Harrison. Intravenous bicarbonate has no role in the acute treatment of hyperkalemia, but may slowly attenuate hyperkalemia with sustained administration over several hours. It should not be given repeatedly as a hypertonic intravenous bolus of undiluted ampules, given the risk of associated hypernatremia, but should instead be infused in an isotonic or hypotonic fluid (e.g., 150 mEqu in 1 L of D5W). In patients with metabolic acidosis, a delayed drop in plasma K+ concentration can be seen after 4–6 h of isotonic bicarbonate infusion. 3. Removal of potassium. This is typically accomplished using cation exchange resins, diuretics, and/or dialysis. The cation exchange resin sodium polystyrene sulfonate (SPS) exchanges Na+ for K+ in the gastrointestinal tract and increases the fecal excretion of K+; alternative calcium-based resins, when available, may


InternalMed_Harrison

InternalMed_Harrison. Part 2 Cardinal Manifestations and Presentation of Diseases be more appropriate in patients with an increased ECFV. The recommended dose of SPS is 15–30 g of powder, almost always given in a premade suspension with 33% sorbitol. The effect of SPS on plasma K+ concentration is slow; the full effect may take up to 24 h and usually requires repeated doses every 4–6 h. Intestinal necrosis, typically of the colon or ileum, is a rare but usually fatal complication of SPS. Intestinal necrosis is more common in patients administered SPS via enema and/or in patients with reduced intestinal motility (e.g., in the postoperative state or after treatment with opioids). The coadministration of SPS with sorbitol appears to increase the risk of intestinal necrosis; however, this complication can also occur with SPS alone. If SPS without sorbitol is not available, clinicians must consider whether treatment with SPS in sorbitol is absolutely necessary. The low but real risk of intestinal necrosis with


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InternalMed_Harrison. with SPS alone. If SPS without sorbitol is not available, clinicians must consider whether treatment with SPS in sorbitol is absolutely necessary. The low but real risk of intestinal necrosis with SPS, which can sometimes be the only available or appropriate therapy for the removal of potassium, must be weighed against the delayed onset of efficacy. Whenever possible, alternative therapies for the acute management of hyperkalemia (i.e., aggressive redistributive therapy, isotonic bicarbonate infusion, diuretics, and/or hemodialysis) should be used instead of SPS.


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InternalMed_Harrison. Therapy with intravenous saline may be beneficial in hypovolemic patients with oliguria and decreased distal delivery of Na+, with the associated reductions in renal K+ excretion. Loop and thiazide diuretics can be used to reduce plasma K+ concentration in volume-replete or hypervolemic patients with sufficient renal function for a diuretic response; this may need to be combined with intravenous saline or isotonic bicarbonate to achieve or maintain euvolemia.


InternalMed_Harrison

InternalMed_Harrison. Hemodialysis is the most effective and reliable method to reduce plasma K+ concentration; peritoneal dialysis is considerably less effective. Patients with acute kidney injury require temporary, urgent venous access for hemodialysis, with the attendant risks; in contrast, patients with ESRD or advanced chronic kidney disease may have a preexisting venous access. The amount of K+ removed during hemodialysis depends on the relative distribution of K+ between ICF and ECF (potentially affected by prior therapy for hyperkalemia), the type and surface area of the dialyzer used, dialysate and blood flow rates, dialysate flow rate, dialysis duration, and the plasma-to-dialysate K+ gradient. Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples David B. Mount, Thomas D. DuBose, Jr. CASE 1 64e


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InternalMed_Harrison. Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples David B. Mount, Thomas D. DuBose, Jr. CASE 1 64e A 23-year-old woman was admitted with a 3-day history of fever, cough productive of blood-tinged sputum, confusion, and orthostasis. Past medical history included type 1 diabetes mellitus. A physical examination in the emergency department indicated postural hypo-tension, tachycardia, and Kussmaul respiration. The breath was noted to smell of “acetone.” Examination of the thorax suggested consolidation in the right lower lobe. Sodium 130 meq/L Potassium 5.0 meq/L Chloride 96 meq/L CO2 14 meq/L Blood urea nitrogen (BUN) 20 mg/dL Creatinine 1.3 mg/dL Glucose 450 mg/dL Pneumonic infiltrate, right lower lobe The diagnosis of the acid-base disorder should proceed in a stepwise fashion: 1. The normal anion gap (AG) is 8–10 meq/L, but in this case, the AG is elevated (20 meq/L). Therefore, the change in AG (ΔAG) = ~10 meq/L. 2.


InternalMed_Harrison

InternalMed_Harrison. The normal anion gap (AG) is 8–10 meq/L, but in this case, the AG is elevated (20 meq/L). Therefore, the change in AG (ΔAG) = ~10 meq/L. 2. Compare the ΔAG and the Δ[HCO3−]. In this case, the ΔAG, as noted above, is 10, and the Δ[HCO3−] (25 – 14) is 11. Therefore, the increment in the AG is approximately equal to the decrement in bicarbonate. 3. Estimate the respiratory compensatory response. In this case, the predicted Paco2 for an [HCO3−] of 14 should be approximately 29 mmHg. This value is obtained by adding 15 to the measured [HCO3−] (15 + 14 = 29) or by calculating the predicted Paco2 from the Winter equation: 1.5 × [HCO3−] + 8. In either case, the predicted value for Paco2 of 29 is significantly higher than the measured value of 24. Therefore, the prevailing Paco2 exceeds the range for compensation alone and is too low, indicating a superimposed respiratory alkalosis. 4.


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InternalMed_Harrison. 4. Therefore, this patient has a mixed acid-base disturbance with two components: (a) high AG acidosis secondary to ketoacidosis and (b) respiratory alkalosis (which was secondary to community-acquired pneumonia in this case). The latter resulted in an additional compo-64e-1 nent of hyperventilation that exceeded the compensatory response driven by metabolic acidosis, explaining the normal pH. The finding of respiratory alkalosis in the setting of a high AG acidosis suggests another cause of the respiratory component. Respiratory alkalosis frequently accompanies community-acquired pneumonia. The clinical features in this case include hyperglycemia, hypovolemia, ketoacidosis, central nervous system (CNS) signs of confusion, and superimposed pneumonia. This clinical scenario is consistent with diabetic ketoacidosis (DKA) developing in a patient with known type 1 diabetes mellitus. Infections in DKA are common and may be a precipitating feature in the development of ketoacidosis.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of DKA is usually not challenging but should be considered in all patients with an elevated AG and metabolic acidosis. Hyperglycemia and ketonemia (positive acetoacetate at a dilution of 1:8 or greater) are sufficient criteria for diagnosis in patients with type 1 diabetes mellitus. The Δ[HCO3−] should approximate the increase in the plasma AG (ΔAG), but this equality can be modified by several factors. For example, the ΔAG will often decrease with IV hydration, as glomerular filtration increases and ketones are excreted into the urine. The decrement in plasma sodium is the result of hyperglycemia, which induces the movement of water into the extracellular compartment from the intracellular compartment of cells that require insulin for the transport of glucose. Additionally, a natriuresis occurs in response to an osmotic diuresis associated with hyperglycemia. Moreover, in patients with DKA, thirst is very common and water ingestion often continues. The plasma potassium


InternalMed_Harrison

InternalMed_Harrison. a natriuresis occurs in response to an osmotic diuresis associated with hyperglycemia. Moreover, in patients with DKA, thirst is very common and water ingestion often continues. The plasma potassium concentration is usually mildly elevated, but in the face of acidosis, and as a result of the ongoing osmotic diuresis, a significant total-body deficit of potassium is almost always present. Recognition of the total-body deficit of potassium is critically important. The inclusion of potassium replacement in the therapeutic regimen at the appropriate time and with the appropriate indications (see below) is essential. Volume depletion is a very common finding in DKA and is a pivotal component in the pathogenesis of the disorder.


InternalMed_Harrison

InternalMed_Harrison. Patients with DKA often have a sustained and significant deficit of sodium, potassium, water, bicarbonate, and phosphate. The general approach to treatment requires attention to all of these abnormalities. Successful treatment of DKA involves a stepwise approach, as follows: 1. Replace extracellular fluid (ECF) volume deficits. Because most patients present with actual or relative hypotension and, at times, impending shock, the initial fluid administered should be 0.9% NaCl infused rapidly until the systolic blood pressure is >100 mmHg or until 2–3 L cumulatively have been administered. During the initial 2–3 h of infusion of saline, the decline in blood glucose can be accounted for by dilution and increased renal excretion. Glucose should be added to the infusion as D5 normal saline (NS) or D5 0.45% NS once the plasma glucose declines to 230 mg/dL or below. 2.


InternalMed_Harrison

InternalMed_Harrison. 2. Abate the production of ketoacids. Regular insulin is required during DKA as an initial bolus of 0.1 U/kg body weight (BW) IV, followed immediately by a continuous infusion of 0.1 U/kg BW per hour in NS. The effectiveness of IV insulin (not subcutaneous) can be tracked by observing the decline in plasma ketones. Because the increment in the AG above the normal value of 10 meq/L represents accumulated ketoacids in DKA, the disappearance of ketoacid anions is reflected by the narrowing and eventual correction of the AG. Typically, the plasma AG returns to normal within 8–12 h. 3. Replace potassium deficits. Although patients with DKA often have hyperkalemia due to insulin deficiency, they are usually severely K+ depleted. KCl (20 meq/L) should be added to each liter of IV fluids when urine output is established and insulin has been administered. 4.


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InternalMed_Harrison. 4. Correct the metabolic acidosis. The plasma bicarbonate concentration will usually not increase for several hours because of dilution from administered IV NaCl. The plasma [HCO−] approaches 18 meq/L once ketoacidosis disappears. Sodium bicarbonate therapy is often not recommended or necessary and is contraindicated CHAPTER 64e Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples 64e-2 for children. Bicarbonate is administered to adults with DKA for extreme acidemia (pH <7.1); for elderly patients (>70 years old), a threshold pH of 7.20 is recommended. Sodium bicarbonate, if administered, should only be given in small amounts. Because ketoacids are metabolized in response to insulin therapy, bicarbonate will be added to the ECF as ketoacids are converted. Overshoot alkalosis may occur from the combination of exogenously administered sodium bicarbonate plus metabolic production of bicarbonate. 5.


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InternalMed_Harrison. 5. Phosphate. In the first 6–8 h of therapy, it may be necessary to infuse potassium with phosphate because of the unmasking of phosphate depletion during combined insulin and glucose therapy. The latter drives phosphate into the cell. Therefore, in patients with DKA, the plasma phosphate level should be followed closely, but phosphate should never be replaced empirically. Phosphate should be administered to patients with a declining plasma phosphate once the phosphate level declines into the low-normal level. Therapy is advisable in the form of potassium phosphate at a rate of 6 mmol/h. 6. Always seek underlying factors, such as infection, myocardial infarction, pancreatitis, cessation of insulin therapy, or other events, responsible for initiating DKA. The case presented here is illustrative of this common scenario. 7.


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InternalMed_Harrison. 7. Volume overexpansion with IV fluid administration is not uncommon and contributes to the development of hyperchloremic acidosis during the later stages of treatment of DKA. Volume overexpansion should be avoided. A 25-year-old man with a 6-year history of HIV-AIDS complicated recently by Pneumocystis jiroveci pneumonia (PCP) was treated with intravenous trimethoprim-sulfamethoxazole (20 mg trimethoprim/kg per day). On day 4 of treatment, the following laboratory data were PART 2 Cardinal Manifestations and Presentation of Diseases H2O AQP-2AQP-3, 4 H2O


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 64e-1 Water, sodium, potassium, ammonia, and proton transport in principal cells (PC) and adjacent type A intercalated cells (A-IC). Water is absorbed down the osmotic gradient by principal cells, through the apical aquaporin-2 (AQP-2) and basolateral aquaporin-3 (AQP-3) and aquaporin-4 (AQP-4) channels. The absorption of Na+ via the amiloride-sensitive epithelial sodium channel (ENaC) generates a lumen-negative potential difference, which drives K+ excretion through the apical secretory K+ channel, ROMK (renal outer medullary K+ channel), and/or the flow-dependent maxi-K channel. Transepithelial ammonia (NH3) transport and proton transport occur in adjacent type A intercalated cells, via apical and basolateral ammonia channels and apical H+-ATPase pumps, respectively; NH4+ is ultimately excreted in the urine, in the defense of systemic pH. Electrogenic proton secretion by type A intercalated cells is also affected by the lumen-negative potential difference generated by the


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InternalMed_Harrison. excreted in the urine, in the defense of systemic pH. Electrogenic proton secretion by type A intercalated cells is also affected by the lumen-negative potential difference generated by the adjacent principal cells, such that reduction of this lumen-negative electrical gradient can reduce H+ excretion. Type A intercalated cells also reabsorb filtered K+ in potassium-deficient states, via apical H+/K+-ATPase.


InternalMed_Harrison

InternalMed_Harrison. hyperkalemia and metabolic acidosis is not uncommon in this setting. H+ secretion via apical H+-ATPase pumps in adjacent type A intercalated cells (Fig. 64e-1) is also electrogenic, such that the reduction in the lumen-negative potential difference due to trimethoprim inhibits distal H+ secretion; this is often referred to as a “voltage defect” form of dRTA. Systemic hyperkalemia also suppresses renal ammoniagenesis, ammonium excretion, and, thus, acid excretion; i.e., hyperkalemia per se has multiple effects on urinary acidification.


InternalMed_Harrison

InternalMed_Harrison. The inhibitory effect of trimethoprim on K+ and H+ secretion in the cortical collecting tubule follows a dose-response relationship, and therefore, the higher doses of this agent used in HIV/AIDS patients with PCP or in deep tissue infections with methicillin-resistant Staphylococcus aureus (MRSA) result in a higher prevalence of hyperkalemia and acidosis. Conventional does of trimethoprim can also induce hyperkalemia and/or acidosis in predisposed patients, in particular the elderly, patients with renal insufficiency, and/or those with baseline hyporeninemic hypoaldosteronism. One means by which to assess the role of the kidney in the development of hyperkalemia is to calculate, from a spot urine and coincident plasma sample, the transtubular potassium gradient (TTKG). The TTKG is calculated as (Posmol ). The expected values of the TTKG are <3 in the presence of hypokalemia (see also Case 7 and Case 8) and >7–8 in the presence of hyperkalemia.


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InternalMed_Harrison. obtained: 135 60 6.5 15 110 43 15 0 7.30 5.5 14 — 0.9 — 268 270 What caused the hyperkalemia and metabolic acidosis in this patient? What other medications may be associated with a similar presentation? How does one use the urine electrolyte data to determine if the hyperkalemia is of renal origin or due to a shift from the cell to the extracellular compartment?


InternalMed_Harrison

InternalMed_Harrison. Hyperkalemia occurs in 15–20% of hospitalized patients with HIV/ AIDS. The usual causes are either adrenal insufficiency, the syndrome of hyporeninemic hypoaldosteronism, or one of several drugs, including trimethoprim, pentamidine, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, spironolactone, and eplerenone. Trimethoprim is usually given in combination with sulfamethoxazole or dapsone for PCP and, on average, increases the plasma K+ concentration by about 1 meq/L; however, the hyperkalemia may be severe. Trimethoprim is structurally and chemically related to amiloride and triamterene and, in this way, may function as a potassium-sparing diuretic. This effect results in inhibition of the epithelial sodium channel (ENaC) in the principal cell of the collecting duct. By blocking the Na+ channel, K+ secretion is also inhibited; K+ secretion is dependent on the lumen-negative potential difference generated by Na+


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InternalMed_Harrison. (ENaC) in the principal cell of the collecting duct. By blocking the Na+ channel, K+ secretion is also inhibited; K+ secretion is dependent on the lumen-negative potential difference generated by Na+ entry through the ENaC (Fig. 64e-1).


InternalMed_Harrison

InternalMed_Harrison. Trimethoprim is associated with a non-AG acidosis that parallels development of hyperkalemia such that the co-occurrence of In this case, the value for the TTKG of approximately 2 indicates that renal excretion of potassium is abnormally low for the prevailing hyperkalemia. Therefore, the inappropriately low TTKG indicates that the hyperkalemia is of renal tubular origin.


InternalMed_Harrison

InternalMed_Harrison. Knowledge of the factors controlling potassium secretion by the cortical collecting tubule principal cell can be helpful in understanding the basis for treatment of the hyperkalemia, especially if discontinuing the offending agent is not a reasonable clinical option. Potassium secretion is encouraged by a higher urine flow rate, increased distal delivery of sodium, distal delivery of a poorly reabsorbed anion (such as bicarbonate), and/or administration of a loop diuretic. Therefore, the approach to treatment in this patient should include intravenous 0.9% NaCl to expand the ECF and deliver more Na+ and Cl− to the cortical collecting tubule. In addition, because the trimethoprim molecule must be protonated to inhibit ENaC, alkalinization of the renal tubule fluid enhances distal tubular K+ secretion. As an alternative to inducing bicarbonaturia to assist in potassium secretion, a carbonic anhydrase inhibitor may be administered to induce a kaliuresis. However, in the case presented


InternalMed_Harrison

InternalMed_Harrison. K+ secretion. As an alternative to inducing bicarbonaturia to assist in potassium secretion, a carbonic anhydrase inhibitor may be administered to induce a kaliuresis. However, in the case presented here, for acetazolamide to be effective, the non-AG metabolic acidosis in this patient would first need to be corrected; Acetazolamide would, thus, require the coadministration of intravenous sodium bicarbonate for maximal benefit. Finally, systemic hyperkalemia directly suppresses renal ammoniagenesis, ammonium excretion, and, thus, acid excretion. Correcting the hyperkalemia with a potassium-binding resin (Kayexalate) is sometimes appropriate in these patients; the subsequent decline in the plasma K+ concentration will also increase urinary ammonium excretion, helping correct the acidosis.


InternalMed_Harrison

InternalMed_Harrison. A 63-year-old man was admitted to the intensive care unit (ICU) with a severe aspiration pneumonia. Past medical history included schizophrenia, for which he required institutional care; treatment had included neuroleptics and intermittent lithium, the latter restarted 6 months before admission. The patient was treated with antibiotics and intubated for several days, with the development of polyuria (3–5 L/d), hypernatremia, and acute renal insufficiency; the peak plasma Na+ concentration was 156 meq/L, and peak creatinine was 2.6 mg/dL. Urine osmolality was measured once and reported as 157 mOsm/kg, with a coincident plasma osmolality of 318 mOsm/kg. Lithium was stopped on admission to the ICU. On physical examination, the patient was alert, extubated, and thirsty. Weight was 97.5 kg. Urine output for the previous 24 h had been 3.4 L, with an IV intake of 2 L/d of D5W.


InternalMed_Harrison

InternalMed_Harrison. On physical examination, the patient was alert, extubated, and thirsty. Weight was 97.5 kg. Urine output for the previous 24 h had been 3.4 L, with an IV intake of 2 L/d of D5W. After 3 days of intravenous hydration, a water deprivation test was performed. A single dose of 2 μg IV desmopressin (DDAVP) was given at 9 h (+9): Why did the patient develop hypernatremia, polyuria, and acute renal insufficiency? What does the water deprivation test demonstrate? What is the underlying pathophysiology of this patient’s hypernatremic syndrome?


InternalMed_Harrison

InternalMed_Harrison. This patient became polyuric after admission to the ICU with severe pneumonia, developing significant hypernatremia and acute renal insufficiency. Polyuria can result from either an osmotic diuresis or a water diuresis. An osmotic diuresis can be caused by excessive excretion of Na+-Cl−, mannitol, glucose, and/or urea, with a daily solute excretion of >750–1000 mOsm/d (>15 mOsm/kg body water per day). In this case, however, the patient was excreting large volumes of very hypotonic urine, with a urine osmolality that was substantially lower than that of plasma; this, by definition, was a water diuresis, resulting in inappropriate excretion of free water and hypernatremia. The appropriate response to hypernatremia and a plasma osmolality >295 mOsm/kg is an increase in circulating vasopressin (AVP) and the excretion of low volumes (<500 mL/d) of maximally concentrated urine, i.e., urine with osmolality >800 mOsm/kg. This patient’s response to hypernatremia was clearly inappropriate, due


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InternalMed_Harrison. (AVP) and the excretion of low volumes (<500 mL/d) of maximally concentrated urine, i.e., urine with osmolality >800 mOsm/kg. This patient’s response to hypernatremia was clearly inappropriate, due to either a loss of circulating AVP (central diabetes insipidus [CDI]) or renal resistance to AVP (nephrogenic diabetes insipidus [NDI]). Ongoing loss of free water was sufficiently severe in this patient that absolute hypovolemia ensued, despite the fact that approximately two-thirds of the excreted water was derived from the intracellular fluid compartment rather than the ECF compartment. Hypovolemia led to an acute decrease in the glomerular filtration rate (GFR), i.e., acute renal insufficiency, with gradual improvement following hydration (see below).


InternalMed_Harrison

InternalMed_Harrison. Following the correction of hypernatremia and acute renal insufficiency with appropriate hydration (see below), the patient was subjected to a water deprivation test followed by administration of DDAVP. This test helps determine whether an inappropriate water diuresis is caused by CDI or NDI. The patient was water restricted beginning in the early morning, with careful monitoring of vital signs and urine output; overnight water deprivation of patients with diabetes insipidus is unsafe and clinically inappropriate, given the potential for severe hypernatremia. The plasma Na+ concentration, which is more accurate and more immediately available than plasma osmolality, was monitored hourly during water deprivation. A baseline AVP sample was drawn at the beginning of the test, with a second sample drawn once the plasma Na+ reached 148–150 meq/L. At this point, a single 2-μg dose of the V2 AVP receptor agonist DDAVP was administered. An alternative approach would have been to measure AVP


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InternalMed_Harrison. sample drawn once the plasma Na+ reached 148–150 meq/L. At this point, a single 2-μg dose of the V2 AVP receptor agonist DDAVP was administered. An alternative approach would have been to measure AVP and administer DDAVP when the patient was initially hypernatremic; however, it would have been less safe to administer DDAVP in the setting of renal impairment because clearance of DDAVP is renal dependent.


InternalMed_Harrison

InternalMed_Harrison. The patient’s water deprivation test was consistent with NDI, with an AVP level within the normal range in the setting of hypernatremia (i.e., no evidence of CDI) and an inappropriately low urine osmolality that failed to increase by >50% or >150 mOsm/kg after both water deprivation and the administration of DDAVP. This defect would be considered compatible with complete NDI; patients with partial NDI can achieve urine osmolalities of 500–600 mOsm/kg after DDAVP treatment but will not maximally concentrate their urine to 800 mOsm/kg or higher.


InternalMed_Harrison

InternalMed_Harrison. NDI has a number of genetic and acquired causes, which all share interference with some aspect of the renal concentrating mechanism. For example, loss-of-function mutations in the V2 AVP receptor cause X-linked NDI. This patient suffered from NDI due to lithium therapy, perhaps the most common cause of NDI in adult medicine. Lithium causes NDI via direct inhibition of renal glycogen synthase kinase-3 (GSK3), a kinase thought to be the pharmacologic target of lithium in psychiatric disease; renal GSK3 is required for the response of principal cells to AVP. Lithium also induces the expression of cyclooxygenase-2 (COX2) in the renal medulla; COX2-derived prostaglandins inhibit AVP-stimulated salt transport by the thick ascending limb and AVP-stimulated water transport by the collecting duct, thereby


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InternalMed_Harrison. CHAPTER 64e Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples 64e-4 exacerbating lithium-associated polyuria. The entry of lithium through the amiloride-sensitive Na+ channel ENaC (Fig. 64e-1) is required for the effect of the drug on principal cells, such that combined therapy with lithium and amiloride can mitigate lithium-associated NDI. However, lithium causes chronic tubulointerstitial scarring and chronic kidney disease after prolonged therapy, such that patients may have a persistent NDI long after stopping the drug, with a reduced therapeutic benefit from amiloride. Notably, this particular patient had been treated intermittently for several years with lithium, with the development of chronic kidney disease (baseline creatinine of 1.3–1.4) and NDI that persisted after stopping the drug. How should this patient be treated? What are the major pitfalls of therapy?


InternalMed_Harrison

InternalMed_Harrison. How should this patient be treated? What are the major pitfalls of therapy? This patient developed severe hypernatremia due to a water diuresis from lithium-associated NDI. Treatment of hypernatremia must include both replacement of the existing free water deficit and daily replacement of ongoing free water loss. The first step is to estimate total-body water (TBW), typically estimated as 50% of the body weight in women and 60% in men. The free water deficit is then calculated as ([Na+ − 140]/140) × TBW. In this patient, the free water deficit was 4.2 L at a weight of 97.5 kg and plasma Na+ concentration of 150 meq/L. This free water deficit should be replaced slowly over 48–72 h to avoid increasing the plasma Na+ concentration by >10 meq/L per 24 h. A common mistake is to replace this deficit while neglecting to replace ongoing losses of free water, such that plasma Na+ concentration either fails to correct or, in fact, increases.


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InternalMed_Harrison. Ongoing losses of free water can be estimated using the equation for electrolyte-free water clearance: PART 2 Cardinal Manifestations and Presentation of Diseases where V is urinary volume, UNa is urinary [Na+], UK is urinary [K+], and PNa is plasma [Na+].


InternalMed_Harrison

InternalMed_Harrison. For this patient, the CeH2O was 2.5 L/d when initially evaluated, i.e., with urine Na+ and K+ concentrations of 34 and 5.2 meq/L, plasma Na+ concentration of 150 meq/L, and a urinary volume of 3.4 L. Therefore, the patient was given 2.5 L of D5W over the first 24 h to replace ongoing free water losses, along with 2.1 L of D5W to replace half his free water deficit. Daily random urine electrolytes and urinary volume measurement can be used to monitor CeH2O and adjust daily fluid administration in this manner, while following plasma Na+ concentration. Physicians often calculate the free water deficit to guide therapy of hypernatremia, providing half the deficit in the first 24 h. This approach can be adequate in patients who do not have significant ongoing losses of free water, e.g., with hypernatremia due to decreased free water intake. This case illustrates how free water requirements can be grossly underestimated in hypernatremic patients if ongoing, daily free water losses are not


InternalMed_Harrison

InternalMed_Harrison. hypernatremia due to decreased free water intake. This case illustrates how free water requirements can be grossly underestimated in hypernatremic patients if ongoing, daily free water losses are not taken into account.


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InternalMed_Harrison. A 78-year-old man was admitted with pneumonia and hyponatremia. Plasma Na+ concentration was initially 129 meq/L, decreasing within 3 days to 118–120 meq/L despite fluid restriction to 1 L/d. A chest computed tomography (CT) revealed a right 2.8 × 1.6 cm infrahilar mass and postobstructive pneumonia. The patient was an active smoker. Past medical history was notable for laryngeal carcinoma treated 15 years prior with radiation therapy, renal cell carcinoma, peripheral vascular disease, and hypothyroidism. On review of systems, he denied headache, nausea, and vomiting. He had chronic hip pain, managed with acetaminophen with codeine. Other medications included cilostazol, amoxicillin/clavulanate, digoxin, diltiazem, and thyroxine. He was euvolemic on examination, with no lymphadenopathy and a normal chest examination. Na+ 120 K+ 4.3 Cl− 89 HCO3− 23 BUN 8 Creat 1.0 Glu 93 Alb 3.1 Ca 8.9 Phos 2.8 Mg 2.0 Plasma osm 248 mOsm/kg Cortisol 25 μg/dL TSH 2.6 Uric acid 2.7 mg/dL


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InternalMed_Harrison. Na+ 120 K+ 4.3 Cl− 89 HCO3− 23 BUN 8 Creat 1.0 Glu 93 Alb 3.1 Ca 8.9 Phos 2.8 Mg 2.0 Plasma osm 248 mOsm/kg Cortisol 25 μg/dL TSH 2.6 Uric acid 2.7 mg/dL Urine: Na+ 97 K+ 22 Cl− 86 Osm 597 The patient was treated with furosemide, 20 mg PO bid, and salt tablets. The plasma Na+ concentration increased to 129 meq/L with this therapy; however, the patient developed orthostatic hypotension and dizziness. He was started on demeclocycline, 600 mg PO in the morning and 300 mg in the evening, just before discharge from hospital. Plasma Na+ concentration increased to 140 meq/L with a BUN of 23 and creatinine of 1.4, at which point demeclocycline was reduced to 300 mg PO bid. Bronchoscopic biopsy eventually showed small-cell lung cancer; the patient declined chemotherapy and was admitted to hospice. What factors contributed to this patient’s hyponatremia? What are the therapeutic options?


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InternalMed_Harrison. This patient developed hyponatremia in the context of a central lung mass and postobstructive pneumonia. He was clinically euvolemic, with a generous urine Na+ concentration and low plasma uric acid concentration. He was euthyroid, with no evidence of pituitary dysfunction or secondary adrenal insufficiency. The clinical presentation is consistent with the syndrome of inappropriate antidiuresis (SIAD). Although pneumonia was a potential contributor to the SIAD, it was notable that the plasma Na+ concentration decreased despite a clinical response to antibiotics. It was suspected that this patient had SIAD due to small-cell lung cancer, with a central lung mass on chest CT and a significant smoking history. There was a history of laryngeal cancer and renal cancer but with no evidence of recurrent disease; these malignancies were not considered contributory to his SIAD. Biopsy of the lung mass ultimately confirmed the diagnosis of small-cell lung cancer, which is responsible for ~75% of


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InternalMed_Harrison. disease; these malignancies were not considered contributory to his SIAD. Biopsy of the lung mass ultimately confirmed the diagnosis of small-cell lung cancer, which is responsible for ~75% of malignancy-associated SIAD; ~10% of patients with this neuroendocrine tumor will have a plasma Na+ concentration of <130 meq/L at presentation. The patient had no other “nonosmotic” stimuli for an increase in AVP, with no medications associated with SIAD and minimal pain or nausea.


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InternalMed_Harrison. The patient had no symptoms attributable to hyponatremia but was judged at risk for worsening hyponatremia from severe SIAD. Persistent, chronic hyponatremia (duration >48 h) results in an efflux of organic osmolytes (creatine, betaine, glutamate, myoinositol, and taurine) from brain cells; this response reduces intracellular osmolality and the osmotic gradient favoring water entry. This cellular response does not fully protect patients from symptoms, which can include vomiting, nausea, confusion, and seizures, usually at plasma Na+ concentration <125 meq/L. Even patients who are judged “asymptomatic” can manifest subtle gait and cognitive defects that reverse with correction of hyponatremia. Chronic hyponatremia also increases the risk of bony fractures due to an increased risk of falls and to a hyponatremia-associated reduction in bone density. Therefore, every attempt should be made to correct plasma Na+ concentration safely in patients with chronic hyponatremia. This is


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InternalMed_Harrison. of falls and to a hyponatremia-associated reduction in bone density. Therefore, every attempt should be made to correct plasma Na+ concentration safely in patients with chronic hyponatremia. This is particularly true in malignancy-associated SIAD, where it can take weeks to months for a tissue diagnosis and the subsequent reduction in AVP following initiation of chemotherapy, radiotherapy, and/or surgery.


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InternalMed_Harrison. What are the therapeutic options in SIAD? Water deprivation, a cornerstone of therapy for SIAD, had little effect on the plasma Na+ concentration in this patient. The urine:plasma electrolyte ratio (urinary [Na+] + [K+]/plasma [Na+]) can be used to estimate electrolyte-free water excretion and the required degree of water restriction; patients with a ratio of >1 should be more aggressively restricted (<500 mL/d), those with a ratio of ~1 should be restricted to 500–700 mL/d, and those with a ratio <1 should be restricted to <1 L/d. This patient had a urine:plasma electrolyte ratio of 1 and predictably did not respond to a moderate water restriction of ~1 L/d. A more aggressive water restriction would have theoretically been successful; however, this can be very difficult for patients with SIAD to tolerate, given that their thirst is also inappropriately stimulated.


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InternalMed_Harrison. Combined therapy with furosemide and salt tablets can often increase the plasma Na+ concentration in SIAD; furosemide reduces maximal urinary concentrating ability by inhibiting the countercurrent mechanism, whereas the salt tablets mitigate diuretic-associated NaCl loss and amplify the ability to excrete free water by increasing urinary solute excretion. This regimen is not always successful and requires careful titration of salt tablets to avoid volume depletion; indeed, in this particular patient, the plasma Na+ concentration remained <130 meq/L and the patient became orthostatic. The principal cell toxin, demeclocycline, is an alternative oral agent in SIAD. Treatment with demeclocycline was very successful in this patient, with an increase in plasma Na+ concentration to 140 meq/L. However, demeclocycline can be natriuretic, leading to a prerenal decrease in GFR. Demeclocycline has also been implicated in nephrotoxic injury, particularly in patients with cirrhosis and chronic


InternalMed_Harrison

InternalMed_Harrison. However, demeclocycline can be natriuretic, leading to a prerenal decrease in GFR. Demeclocycline has also been implicated in nephrotoxic injury, particularly in patients with cirrhosis and chronic liver disease, in whom the drug accumulates. Notably, this particular patient developed a significant but stable decrease in GFR while on demeclocycline, necessitating a reduction in the administered dose.


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InternalMed_Harrison. A major advance in the management of hyponatremia was the clinical development of AVP antagonists (vaptans). These agents inhibit the effect of AVP on renal V2 receptors, resulting in the excretion of electrolyte-free water and correction of hyponatremia. The specific indications for these agents are not as yet clear, despite U.S. Food and Drug Administration (FDA) approval for the management of both euvolemic and hypervolemic hyponatremia. It is, however, anticipated that the vaptans will have an increasing role in the management of SIAD and other causes of hyponatremia. Indeed, if this particular patient had continued with active therapy for his cancer, substitution of demeclocycline with oral tolvaptan (a V2-specific oral vaptan) would have been the next appropriate step, given the development of renal insufficiency with demeclocycline. As with other measures to correct hyponatremia (e.g., hypertonic saline, demeclocycline), the vaptans have the potential to “overcorrect” plasma


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InternalMed_Harrison. of renal insufficiency with demeclocycline. As with other measures to correct hyponatremia (e.g., hypertonic saline, demeclocycline), the vaptans have the potential to “overcorrect” plasma Na+ concentration (a rise of >8–10 meq/L per 24 h or 18 meq/L per 18 h), thus increasing the risk for osmotic demyelination (see Case 5). Therefore, the plasma Na+ concentration should be monitored closely during the initiation of therapy with these agents. In addition, long-term use of tolvaptan has been associated with abnormalities in liver function tests; hence, use of this agent should be restricted to only 1–2 months.


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InternalMed_Harrison. A 76-year-old woman presented with a several-month history of diarrhea, with marked worsening over the 2–3 weeks before admission (up to 12 stools a day). Review of systems was negative for fever, orthostatic dizziness, nausea and vomiting, or headache. Past medical history included hypertension, kidney stones, and hypercholesterolemia; medications included atenolol, spironolactone, and lovastatin. She also reliably consumed >2 L of liquid per day in management of the nephrolithiasis. The patient received 1 L of saline over the first 5 h of her hospital admission. On examination at hour 6, the heart rate was 72 sitting and 90 standing, and blood pressure was 105/50 mmHg lying and standing. Her jugular venous pressure (JVP) was indistinct with no peripheral edema. On abdominal examination, the patient had a slight increase in bowel sounds but a nontender abdomen and no organomegaly.


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InternalMed_Harrison. The plasma Na+ concentration on admission was 113 meq/L, with a creatinine of 2.35 (Table 64e-1). At hospital hour 7, the plasma Na+ concentration was 120 meq/L, potassium 5.4 meq/L, chloride 90 64e-5 meq/L, bicarbonate 22 meq/L, BUN 32 mg/dL, creatinine 2.02 mg/dL, glucose 89 mg/dL, total protein 5.0, and albumin 1.9. The hematocrit was 33.9, white count 7.6, and platelets 405. A morning cortisol was 19.5, with thyroid-stimulating hormone (TSH) of 1.7. The patient was treated with 1 μg of intravenous DDAVP, along with 75 mL/h of intravenous half-normal saline. After the plasma Na+ concentration dropped to 116 meq/L, intravenous fluid was switched to normal saline at the same infusion rate. The subsequent results are shown in Table 64e-1.


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InternalMed_Harrison. This patient presented with hypovolemic hyponatremia and a “prerenal” reduction in GFR, with an increase in serum creatinine. She had experienced diarrhea for some time and manifested an orthostatic tachycardia after a liter of normal saline. As expected for hypovolemic hyponatremia, the urine Na+ concentration was <20 meq/L in the absence of congestive heart failure or other causes of hypervolemic hyponatremia, and she responded to saline hydration with an increase in plasma Na+ concentration and a decrease in creatinine.


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InternalMed_Harrison. The initial hypovolemia increased the sensitivity of this patient’s AVP response to osmolality, both decreasing the osmotic threshold for AVP release and increasing the slope of the osmolality response curve. AVP has a half-life of only 10–20 min; therefore, the acute increase in intravascular volume after a liter of intravenous saline led to a rapid reduction in circulating AVP. The ensuing water diuresis is the primary explanation for the rapid increase in plasma Na+ concentration in the first 7 h of her hospitalization.


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InternalMed_Harrison. The key concern in this case was the evident chronicity of the patient’s hyponatremia, with several weeks of diarrhea followed by 2–3 days of acute exacerbation. This patient was judged to have chronic hyponatremia, i.e., with a suspected duration of >48 h; as such, she would be predisposed to osmotic demyelination were she to undergo too rapid a correction in her plasma Na+ concentration, i.e., by >8–10 meq/L in 24 h or 18 meq/L in 48 h. At presentation, she had no symptoms that one would typically attribute to acute hyponatremia, and the plasma Na+ concentration had already increased by a sufficient amount to protect from cerebral edema; however, she had corrected by 1 meq/L per hour within the first 7 h of admission, consistent with impending overcorrection. To reduce or halt the increase in plasma Na+ concentration, the patient received 1 μg of intravenous DDAVP along with intravenous free water. Given the hypovolemia and resolving acute renal insufficiency, a decision was made to


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InternalMed_Harrison. in plasma Na+ concentration, the patient received 1 μg of intravenous DDAVP along with intravenous free water. Given the hypovolemia and resolving acute renal insufficiency, a decision was made to administer half-normal saline as a source of free water, rather than D5W; this was switched to normal saline when plasma Na+ concentration acutely dropped to 117 meq/L (Table 64e-1).


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InternalMed_Harrison. Overcorrection of chronic hyponatremia is a major risk factor for the development of osmotic demyelination syndrome (ODS). Animal studies show a neurologic and survival benefit in ODS of “re-lowering” plasma Na+ concentration with DDAVP and free water administration; this approach is demonstrably safe in patients with hyponatremia, with no evident risk of seizure or other sequelae. This combination can be used to prevent an overcorrection or to re-lower plasma Na+ concentration in patients who have already overcorrected. DDAVP is required because in most of these patients endogenous AVP levels have plummeted, resulting in a free water diuresis; the administration of free water alone has minimal effect in this setting, given the relative absence of circulating AVP. An alternative approach in patients who present with severe hyponatremia is to treat them


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InternalMed_Harrison. CHAPTER 64e Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples ity, coadministering hypertonic saline to increase slowly the plasma Na+ con- centration in a more controlled fashion.


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InternalMed_Harrison. Creatinine (mg/dL) 1.2 2.35 2.10 2.02 1.97 1.79 1.53 1.20 1.13 days after DDAVP administration. It is 64e-6 conceivable that residual hypovolemic hyponatremia attenuated the recovery of the plasma Na+ concentration. Alternatively, attenuated recovery was due to persistent effects of the single dose of DDAVP. Of note, although the plasma half-life of DDAVP is only 1–2 h, pharmacodynamic studies indicate a much more prolonged effect on urine output and/or urine osmolality. One final consideration is the effect of the patient’s initial renal dysfunction on the pharmacokinetics and pharmacodynamics of the administered DDAVP, which is renally excreted; DDAVP should be administered with caution for the reinduction of hyponatremia in patients with chronic kidney disease or acute renal dysfunction. A 44-year-old woman was referred from a local hospital after presenting with flaccid paralysis. Severe hypokalemia was documented (2.0 meq/L), and an infusion containing KCl was initiated.


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InternalMed_Harrison. A 44-year-old woman was referred from a local hospital after presenting with flaccid paralysis. Severe hypokalemia was documented (2.0 meq/L), and an infusion containing KCl was initiated. PART 2 Cardinal Manifestations and Presentation of Diseases Sodium 140 meq/L Potassium 2.6 meq/L Chloride 115 meq/L Bicarbonate 15 meq/L Anion gap 10 meq/L BUN 22 mg/dL Creatinine 1.4 mg/dL pH 7.32 U PaCO2 30 mmHg HCO3− 15 meq/L Rheumatoid factor positive, anti-Ro/SS-A positive, and anti-La/SS-B positive pH = 6.0, normal sediment without white or red blood cell casts and no bacteria. The urine protein-to-creatinine ratio was 0.150 g/g. Urinary electrolyte values were: Na+ 35, K+ 40, Cl− 18 meq/L. Therefore, the urine anion gap was positive, indicating low urine NH4+ excretion.


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InternalMed_Harrison. The diagnosis in this case is classic hypokalemic dRTA from Sjögren’s syndrome. This patient presented with a non-AG metabolic acidosis. The urine AG was positive, indicating an abnormally low excretion of ammonium in the face of systemic acidosis. The urine pH was inappropriately alkaline, yet there was no evidence of hypercalciuria, nephrocalcinosis, or bone disease. The patient was subsequently shown to exhibit hyperglobulinemia. These findings, taken together, indicate that the cause of this patient’s hypokalemia and non-AG metabolic acidosis was a renal tubular abnormality. The hypokalemia and abnormally low excretion of ammonium, as estimated by the urine AG, in the absence of glycosuria, phosphaturia, or aminoaciduria (Fanconi’s syndrome), defines the entity of classic distal renal tubular acidosis (dRTA), also known as type 1 RTA. Because of the hyperglobulinemia, additional serology was obtained, providing evidence for the diagnosis of primary Sjögren’s syndrome. Furthermore,


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InternalMed_Harrison. tubular acidosis (dRTA), also known as type 1 RTA. Because of the hyperglobulinemia, additional serology was obtained, providing evidence for the diagnosis of primary Sjögren’s syndrome. Furthermore, additional history indicated a 5-year history of xerostomia and keratoconjunctivitis sicca but without synovitis, arthritis, or rash.


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InternalMed_Harrison. Classic dRTA occurs frequently in patients with Sjögren’s syndrome and is a result of an immunologic attack on the collecting tubule, causing failure of the H+-ATPase to be inserted into the apical membrane of type A intercalated cells. Sjögren’s syndrome is one of the best-documented acquired causes of classic dRTA. The loss of H+-ATPase function also occurs with certain inherited forms of classic dRTA. There was no family history in the present case, and other family members were not affected. A number of autoantibodies have been associated with Sjögren’s syndrome; it is likely that these autoantibodies prevent trafficking or function of the H+-ATPase in the type A intercalated cell of the collecting tubule. Although proximal RTA has also been reported in patients with Sjögren’s syndrome, it is much less frequent, and there were no features of proximal tubule dysfunction (Fanconi’s syndrome) in this patient. The hypokalemia is due to secondary hyperaldosteronism from volume


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InternalMed_Harrison. syndrome, it is much less frequent, and there were no features of proximal tubule dysfunction (Fanconi’s syndrome) in this patient. The hypokalemia is due to secondary hyperaldosteronism from volume depletion.


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InternalMed_Harrison. The long-term renal prognosis for patients with classic dRTA due to Sjögren’s syndrome has not been established. Nevertheless, the metabolic acidosis and the hypokalemia respond to alkali replacement with either sodium citrate solution (Shohl’s solution) or sodium bicarbonate tablets. Obviously, potassium deficits must be replaced initially, but potassium replacement is usually not required in dRTA patients long term because sodium bicarbonate (or citrate) therapy expands volume and corrects the secondary hyperaldosteronism. A consequence of the interstitial infiltrate seen in patients with Sjögren’s syndrome and classic dRTA is progression of chronic kidney disease. Cytotoxic therapy plus glucocorticoids has been the mainstay of therapy in Sjögren’s syndrome for many years, although B lymphocyte infiltration in salivary gland tissue subsides and urinary acidification improves after treatment with rituximab.


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InternalMed_Harrison. A 32-year-old man was admitted to the hospital with weakness and hypokalemia. The patient had been very healthy until 2 months previously when he developed intermittent leg weakness. His review of systems was otherwise negative. He denied drug or laxative abuse and was on no medications. Past medical history was unremarkable, with no history of neuromuscular disease. Family history was notable for a sister with thyroid disease. Physical examination was notable only for reduced deep tendon reflexes. Sodium 139 143 meq/L Potassium 2.0 3.8 meq/L Chloride 105 107 meq/L Bicarbonate 26 29 meq/L BUN 11 16 mg/dL Creatinine 0.6 1.0 mg/dL Calcium 8.8 8.8 mg/dL Phosphate 1.2 mg/dL Albumin 3.8 meq/L TSH 0.08 μIU/L (normal 0.2–5.39) Free T4 41 pmol/L (normal 10–27)


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InternalMed_Harrison. This patient developed hypokalemia due to a redistribution of potassium between the intracellular and extracellular compartments; this pathophysiology was readily apparent following calculation of the TTKG. The TTKG is calculated as (P × U )/(P × U ). The expected values for the TTKG are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia (see also Case 2 and Case 8). Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/mmol creatinine) is compatible with excessive renal K+ excretion. In this case, the calculated TTKG was 2.5, consistent with appropriate renal conservation of K+ and a nonrenal cause for hypokalemia. In the absence of significant gastrointestinal loss of K+, the patient was diagnosed with a “redistributive” subtype of hypokalemia.


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InternalMed_Harrison. More than 98% of total-body potassium is intracellular; regulated buffering of extracellular K+ by this large intracellular pool plays a crucial role in the maintenance of a stable plasma K+ concentration. Clinically, changes in the exchange and distribution of intraand extracellular K+ can cause significant hypoor hyperkalemia. Insulin, β2-adrenergic activity, thyroid hormone, and alkalosis promote cellular uptake of K+ by multiple interrelated mechanisms, leading to hypokalemia. In particular, alterations in the activity of the endogenous sympathetic nervous system can cause hypokalemia in several settings, including alcohol withdrawal, hyperthyroidism, acute myocardial infarction, and severe head injury.


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InternalMed_Harrison. Weakness is common in severe hypokalemia; hypokalemia causes hyperpolarization of muscle, thereby impairing the capacity to depolarize and contract. In this particular patient, Graves’ disease caused hyperthyroidism and hypokalemic paralysis (thyrotoxic periodic paralysis [TPP]). TPP develops more frequently in patients of Asian or Hispanic origin. This predisposition has been linked to genetic variation in Kir2.6, a muscle-specific, thyroid hormone–induced K+ channel; however, the pathophysiologic mechanisms that link dysfunction of this ion channel to TPP have yet to be elucidated. The hypokalemia in TPP is attributed to both direct and indirect activation of the Na+/ K+-ATPase by thyroid hormone, resulting in increased uptake of K+ by muscle and other tissues. Thyroid hormone induces expression of multiple subunits of the Na+/K+-ATPase in skeletal muscle, increasing the capacity for uptake of K+; hyperthyroid increases in β-adrenergic activity are also thought to play an important


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InternalMed_Harrison. of multiple subunits of the Na+/K+-ATPase in skeletal muscle, increasing the capacity for uptake of K+; hyperthyroid increases in β-adrenergic activity are also thought to play an important role in TPP.


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InternalMed_Harrison. Clinically, patients with TPP present with weakness of the extremities and limb girdle, with paralytic episodes that occur most frequently between 1 and 6 am. Precipitants of weakness include high carbohydrate loads and strenuous exercise. Signs and symptoms of hyperthyroidism are not always present, often leading to delays in diagnosis. Hypokalemia is often profound and usually accompanied by redistributive hypophosphatemia, as in this case. A TTKG of <2–3 separates patients with TPP from those with hypokalemia due to renal potassium wasting, who will have TTKG values that are >4. This distinction is of considerable importance for therapy; patients with large potassium deficits require aggressive repletion with K+-Cl−, which has a significant risk of rebound hyperkalemia in TPP and related disorders.


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InternalMed_Harrison. Ultimately, definitive therapy for TPP requires treatment of the associated hyperthyroidism. In the short term, however, potassium replacement is necessary to hasten muscle recovery and prevent cardiac arrhythmias. The average recovery time of an acute attack is reduced by ~50% in patients treated with intravenous K+-Cl− at a rate of 10 meq/h; however, this incurs a significant risk of rebound hyperkalemia, with up to 70% developing a plasma K+ concentration of >5.0 meq/L. This potential for rebound hyperkalemia is a general problem in the management of all causes of redistributive hypokalemia, resulting in the need to distinguish these patients accurately and rapidly from those with a large K+ deficit due to renal or extrarenal loss of K+. An attractive alternative to K+-Cl− replacement in TPP is treatment with high-dose propranolol (3 mg/kg), which rapidly reverses the associated hypokalemia, hypophosphatemia, and paralysis. Notably, rebound hyperkalemia is not associated with this


InternalMed_Harrison

InternalMed_Harrison. in TPP is treatment with high-dose propranolol (3 mg/kg), which rapidly reverses the associated hypokalemia, hypophosphatemia, and paralysis. Notably, rebound hyperkalemia is not associated with this treatment.


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InternalMed_Harrison. A 66-year-old man was admitted to hospital with a plasma K+ concentration of 1.7 meq/L and profound weakness. The patient had noted progressive weakness over several days, to the point that he was unable to rise from bed. Past medical history was notable for small-cell lung cancer with metastases to brain, liver, and adrenals. The patient had been treated with one cycle of cisplatin/etoposide 1 year before this admission, which was complicated by acute kidney injury (peak creatinine of 5, with residual chronic kidney disease), and three subsequent cycles of cyclophosphamide/doxorubicin/vincristine, in addition to 15 treatments with whole-brain radiation. On physical examination, the patient was jaundiced. Blood pressure was 130/70 mmHg, increasing to 160/98 mmHg after 1 L of saline, with a JVP at 8 cm. There was generalized muscle weakness. Potassium 3.7 1.7 3.5 meq/L 7.47 Creatinine 2.8 2.9 2.3 mg/dL Magnesium 1.3 1.6 2.4 mg/dL Albumin 3.4 2.8 2.3 Total bilirubin 0.65 5.19 5.5


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InternalMed_Harrison. Potassium 3.7 1.7 3.5 meq/L 7.47 Creatinine 2.8 2.9 2.3 mg/dL Magnesium 1.3 1.6 2.4 mg/dL Albumin 3.4 2.8 2.3 Total bilirubin 0.65 5.19 5.5 Abbreviations: ACTH, adrenocorticotropic hormone; HD2, hospital day 2; PTA, prior to admission. The patient’s hospital course was complicated by acute respiratory failure attributed to pulmonary embolism; he died 2 weeks after admission. Why was this patient hypokalemic? Why was he weak? Why did he have an alkalosis? This patient suffered from metastatic small-cell lung cancer, which was persistent despite several rounds of chemotherapy and radiotherapy. He presented with profound hypokalemia, alkalosis, hypertension, severe weakness, jaundice, and worsening liver function tests.


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InternalMed_Harrison. With respect to the hypokalemia, there was no evident cause of nonrenal potassium loss, e.g., diarrhea. The urinary TTKG was 11.7, at a plasma K+ concentration of 1.7 meq/L; this TTKG value is consistent with inappropriate renal K+ secretion, despite severe hypokalemia. The TTKG is calculated as (P × U )/(P × U ). The expected values for the TTKG are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia (see also Case 2 and Case 6).


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InternalMed_Harrison. The patient had several explanations for excessive renal loss of potassium. First, he had had a history of cisplatin-associated acute kidney injury, with residual chronic kidney disease. Cisplatin can cause persistent renal tubular defects, with prominent hypokalemia and hypomagnesemia; however, this patient had not previously required potassium or magnesium repletion, suggesting that cisplatin-associated renal tubular defects did not play a major role in this presentation with severe hypokalemia. Second, he was hypomagnesemic on presentation, suggesting total-body magnesium depletion. Magnesium depletion has inhibitory effects on muscle Na+/K+-ATPase activity, reducing influx into muscle cells and causing a secondary increase in K+ excretion. Magnesium depletion also increases K+ secretion by the distal nephron; this is attributed to a reduction in the magnesium-dependent, intracellular block of K+ efflux through the secretory K+ channel of principal cells (ROMK, Fig. 64e-1).


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InternalMed_Harrison. secretion by the distal nephron; this is attributed to a reduction in the magnesium-dependent, intracellular block of K+ efflux through the secretory K+ channel of principal cells (ROMK, Fig. 64e-1). Clinically, hypomagnesemic patients are


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InternalMed_Harrison. CHAPTER 64e Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples 64e-8 refractory to K+ replacement in the absence of Mg2+ repletion. Again, however, this patient had not previously developed significant hypokalemia, despite periodic hypomagnesemia, such that other factors must have caused the severe hypokalemia. The associated hypertension in this case suggested an increase in mineralocorticoid activity, causing increased activity of ENaC channels in principal cells, NaCl retention, hypertension, and hypokalemia. The increase in ENaC-mediated Na+ transport in principal cells would have led to an increase in the lumen-negative potential difference in the connecting tubule and cortical collecting duct, driving an increase in K+ secretion through apical K+ channels (Fig. 64e-1). This explanation is compatible with the very high TTKG, i.e., an increase in K+ excretion that is inappropriate for the plasma K+ concentration. What caused an increase in mineralocorticoid


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InternalMed_Harrison. 64e-1). This explanation is compatible with the very high TTKG, i.e., an increase in K+ excretion that is inappropriate for the plasma K+ concentration. What caused an increase in mineralocorticoid activity in this patient? The patient had bilateral adrenal metastases, indicating that primary hyperaldosteronism was unlikely. The clinical presentation (hypokalemia, hypertension, and alkalosis) and the history of small-cell lung cancer suggested Cushing’s syndrome, with a massive increase in circulating glucocorticoids, in response to ectopic adrenocorticotropic hormone (ACTH) secretion by his small-cell lung cancer tumor. Confirmation of this diagnosis was provided by a very high plasma cortisol level, high ACTH level, and increased urinary cortisol (see the laboratory data above). Why would an increase in circulating cortisol cause an apparent increase in mineralocorticoid activity? Cortisol and aldosterone have equal affinity for the mineralocorticoid receptor (MLR); thus, cortisol


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InternalMed_Harrison. an increase in circulating cortisol cause an apparent increase in mineralocorticoid activity? Cortisol and aldosterone have equal affinity for the mineralocorticoid receptor (MLR); thus, cortisol has mineralocorticoid-like activity; however, cells in the aldosteronesensitive distal nephron (the distal convoluted tubule [DCT]), connecting tubule (CNT), and collecting duct are protected from circulating cortisol by the enzyme 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2), which converts cortisol to cortisone (Fig. 64e-2); cortisone has minimal affinity for the MLR. Activation of the MLR causes activation of the basolateral Na+/K+-ATPase, activation of the thiazide-sensitive Na+-Cl− cotransporter in the DCT, and activation of apical ENaC


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases