Causes are outlined in Table 1-4; in most cases, hyperkalemia is due to decreased renal K+ excretion. However, increases in dietary K+ intake can have a major effect in susceptible pts, e.g., diabetics with hyporeninemic hypoaldosteronism and chronic kidney disease (CKD). Drugs that impact on the RAA axis are also a major cause of hyperkalemia.

TABLE 1-4: Causes of Hyperkalemia
  1. “Pseudo” hyperkalemia
    1. Cellular efflux: thrombocytosis, erythrocytosis, leukocytosis, in vitro hemolysis
    2. Hereditary defects in red cell membrane transport
  2. Intra- to extracellular shift
    1. Acidosis
    2. Hyperosmolality; radiocontrast, hypertonic dextrose, mannitol
    3. β-Adrenergic antagonists (noncardioselective agents)
    4. Digoxin and related glycosides (yellow oleander, foxglove, bufadienolide)
    5. Hyperkalemic periodic paralysis
    6. Lysine, arginine, and ε-aminocaproic acid (structurally similar, positively charged)
    7. Succinylcholine; thermal trauma, neuromuscular injury, disuse atrophy, mucositis, or prolonged immobilization
    8. Rapid tumor lysis
  3. Inadequate excretion
    1. Inhibition of the renin-angiotensin-aldosterone axis; ↑ risk of hyperkalemia when used in combination or at higher than recommended dosages
      1. ACE inhibitors
      2. Renin inhibitors: aliskiren (in combination with ACE inhibitors or ARBs)
      3. ARBs
      4. Blockade of the mineralocorticoid receptor: spironolactone, eplerenone, drospirenone
      5. Blockade of ENaC: amiloride, triamterene, trimethoprim, pentamidine, nafamostat
    2. Decreased distal delivery
      1. Congestive heart failure
      2. Volume depletion
    3. Hyporeninemic hypoaldosteronism
      1. Tubulointerstitial diseases: SLE, sickle cell anemia, obstructive uropathy
      2. Diabetes, diabetic nephropathy
      3. Drugs: nonsteroidal anti-inflammatory drugs, COX-2 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)
    4. 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 ENaCE. Advanced renal insufficiency with low GFR
    5. Advanced renal insufficiency with low GFR
      1. Chronic kidney disease
      2. End-stage renal disease
      3. Acute oliguric kidney injury
    6. Primary adrenal insufficiency
      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
Abbreviations: ARB, angiotensin receptor blocker; COX-2, cyclooxygenase 2; ENaC, epithelial Na+ channels.

The first priority in the management of hyperkalemia is to assess the need for emergency treatment (ECG changes and/or K+ ≥6.0 mM). This should be followed by a comprehensive workup to determine the cause (Fig. 1-3). History and physical examination should focus on medications (e.g., ACE inhibitors, NSAIDs, trimethoprim/sulfamethoxazole), diet and dietary supplements (e.g., salt substitute), risk factors for acute kidney failure, reduction in urine output, blood pressure, and volume status. Initial laboratory 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+] <20 meq/L suggests that distal Na+ delivery is a limiting factor in K+ excretion; volume repletion with 0.9% saline or treatment with furosemide may then be effective in reducing serum [K+] by increasing distal Na+ delivery. Serum and urine osmolality are required for calculation of the TTKG. The expected values of the TTKG are largely based on historic data: <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia.


The diagnostic approach to hyperkalemia. See text for details. ACEI, angiotensin-converting enzyme inhibitor; acute GN, acute glomerulonephritis; ARB, angiotensin II receptor blocker; ECV, effective circulatory volume; LMW heparin, low-molecular-weight heparin; PHA, pseudohypoaldosteronism; TTKG, transtubular potassium gradient. (Reprinted with permission from Mount DB, Zandi-Nejad K: Disorders of potassium balance. In: Brenner and Rector’s The Kidney, 8th ed, Brenner BM [ed]. Philadelphia, Saunders, 2008.)

There's more to see -- the rest of this topic is available only to subscribers.