Hyperkalemia

Etiology : Pseudohyperkalemia (In Vitro Release of Potassium From Cells)

  • Familial Pseudohyperkalemia
    • Genetics: autosomal dominant inheritance (maps to the 16q23–ter locus)
    • Mechanism: abnormally increased potassium permeability of the RBC membrane -> temperature-dependent loss of potassium from RBC’s when stored at room temperature
    • Clinical: characterized by hyperkalemia in whole blood stored at or below room temperature, without additional hematologic abnormalities
  • Phlebotomy-Related Cell Lysis
    • Mechanisms
      • Delay in Processing of Blood Sample: may result in red blood cell lysis
      • Excessive Vacuum with Very Small Gauge Needle During Phlebotomy: may result in red blood cell lysis
      • Prolonged Tourniquet Time or Fist-Clenching During Phlebotomy: may result in efflux of potassium from myocytes (fist-clenching during phlebotomy may increase potassium by as much as 1–2 mmol/L)
      • Transportation of Blood Samples in Pneumatic Tube System: may result in mechanical red blood cell lysis
  • Severe Leukocytosis (>70k)
    • Mechanism: due to potassium release from WBC in sample
    • Clinical: plasma, rather than serum, potassium should be measured: plasma potassium will be normal in these cases
  • Severe Polycythemia (Hct >55%)
    • Mechanism: due to potassium release from RBC in sample
    • Clinical: plasma, rather than serum, potassium should be measured: plasma potassium will be normal in these cases
  • Severe Thrombocytosis (>500k)
    • Mechanism: due to potassium release from platelets in sample
      • For every 100 x 10(9)/L of platelets, potassium increases approximately 0.07 to 0.15 mmol/L [MEDLINE]
    • Clinical: plasma, rather than serum, potassium should be measured: plasma potassium will be normal in these cases
  • Subset of Patients with “Leaky” Cell Membranes
    • Mechanism: these patients appear to be prone to hemolysis during phlebotomy

Etiology : Excessive Potassium Intake

  • Excessive IV/PO Potassium Chloride Replacement
    • Mechanism: may be iatrogenic (in the inpatient setting) or patient-related (in the outpatient setting)
  • Excessive Oral Salt Substitute Intake
    • Clinical: usually causes hyperkalemia only in the setting of impaired renal function
  • Lethal Injection
    • Mechanism: capital punishment technique uses lethal injection of potassium chloride
  • Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition, [[Total Parenteral Nutrition]])
    • Mechanism: with excessive potassium content (relative to patient’s renal function)

Etiology : Intracellular -> Extracellular Potassium Shift

Etiology : Impaired Renal Potassium Excretion

Decreased Distal Potassium Delivery

Renal Disease

Hypoaldosteronism (see Hypoaldosteronism, [[Hypoaldosteronism]])

Decreased Aldosterone Synthesis

  • Inherited Disorders
    • Congenital Isolated Hypoaldosteronism
      • 21 Hydroxylase Deficiency
      • Other Defects
    • Pseudohypoaldosteronism Type 2 (Gordon’s Syndrome)
      • Physiology: defects in WKNK1 or WNK4 kinases
      • Clinical
        • Familial Hypertension (see Hypertension, [[Hypertension]])
        • Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])
        • Low or Low-Normal Plasma Renin Activity and Aldosterone Level
        • Metabolic Acidosis
        • Normal Renal Function
  • Hyporeninemic Hypoaldosteronism
    • General Comments
      • Hyporeninemic hypoaldosteronism is characterized by a combination of decreased renin release and an intra-adrenal defect -> these result in decreased systemic and intra-adrenal angiotensin II synthesis -> results in decreased aldosterone secretion
        • The intra-adrenal defect may be related to the local renin-angiotensin system: this is supported by the fact that angiotensin II produced locally within the adrenal gland may stimulate the release of aldosterone
        • Many of these patients may also have decreased aldosterone responsiveness, since they require a higher mineralocorticoid dose for physiologic replacement
    • Advanced Age
    • Drug-Induced Hyporeninemic Hypoaldosteronism
      • Beta Blockers (see β-Adrenergic Receptor Antagonists, [[β-Adrenergic Receptor Antagonists]])
      • Calcineurin Inhibitors (see Calcineurin Inhibitors, [[Calcineurin Inhibitors]])
        • Physiology: due to decreased secretion of aldosterone and decreased responsiveness to aldosterone (likely due to decreased mineralocorticoid receptor expression)
        • Cyclosporine A (see Cyclosporine A, [[Cyclosporine A]])
        • Tacrolimus (see Tacrolimus, [[Tacrolimus]])
      • Non-Steroidal Anti-Inflammatory Drug (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]])
        • Physiology: dose-dependent COX-inhibition -> decreased renal prostaglandin synthesis -> since PGI2 stimulates the juxtaglomerular cells in the kidney to release renin, this results in decreased renal renin secretion
        • Additionally, impaired angiotensin II-induced release of aldosterone may occur
        • NSAID-induced decrease in glomerular filtration rate may also contribute to the development of hyperkalemia
    • Intrinsic Renal Disease
      • Acute Glomerulonephritis with Volume Expansion (see Acute Glomerulonephritis, [[Acute Glomerulonephritis]])
        • Treatment: responds to mineralocorticoid replacement
        • Prognosis: recovery of renal function (typically within 1-2 wks) leads to resolution of hyperkalemia
      • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): with chronic interstitial nephritis
      • Diabetic Nephropathy (see Diabetes Mellitus, [[Diabetes Mellitus]]): accounts for 50% of cases of hyporeninemic hypoaldosteronism
  • Drugs
    • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]])
      • Physiology: impair the conversion of angiotensin I to angiotensin II systemically (and possibly within the adrenal zona glomerulosa) -> since the normal stimulatory effect of hyperkalemia on aldosterone release may be mediated in part by the adrenal generation of angiotensin II, ACE inhibitors can decrease both angiotensin II-mediated and potassium-mediated aldosterone release
        • In contrast to ARB’s and renin inhibitors, ACE inhibitors increase renin levels
      • Captopril (Capoten) (see Captopril, [[Captopril]])
      • Enalapril (Vasotec, Enalaprilat) (see Enalapril, [[Enalapril]])
      • Fosinopril (Monopril) (see Fosinopril, [[Fosinopril]])
      • Lisinopril (Zestril) (see Lisinopril, [[Lisinopril]])
      • Moexipril (Univasc) (see Moexipril, [[Moexipril]])
      • Perindopril (Coversyl, Coversum, Preterax, Aceon) (see Perindopril, [[Perindopril]])
      • Quinapril (Accupril) (see Quinapril, [[Quinapril]])
      • Ramipril (Altace) (see Ramipril, [[Ramipril]])
      • Trandolapril (Mavik) (see Trandolapril, [[Trandolapril]])
    • Angiotensin II Receptor Blockers (see Angiotensin II Receptor Blockers, [[Angiotensin II Receptor Blockers]])
      • Physiology: block angiotensin II activity at its receptor
      • Candesartan (Atacand) (see Candesartan, [[Candesartan]])
      • Fimasartan (Kanarb) (see Fimasartan, [[Fimasartan]])
      • Irbesartan (Avapro, Aprovel, Karvea) (see Irbesartan, [[Irbesartan]])
      • Losartan (Cozaar) (see Losartan, [[Losartan]])
      • Olmesartan (Benicar, Olmecip) (see Olmesartan, [[Olmesartan]])
      • Telmisartan (Micardis) (see Telmisartan, [[Telmisartan]])
      • Valsartan (Diovan) (see Valsartan, [[Valsartan]])
    • Heparins
      • Physiology: heparins have a direct toxic effect on the adrenal zona glomerulosa cells (this may be mediated by a decrease in the number and affinity of adrenal angiotensin II receptors)
        • May occur even with the low doses of heparin used for deep venous thrombosis prophylaxis
      • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
      • Heparin (see Heparin, [[Heparin]])
    • Renin Inhibitors
      • Physiology: directly inhibit renin activity
      • Aliskiren (Tekturna, Rasilez) (see Aliskiren, [[Aliskiren]]): renin inhibitor (may cause hyperkalemia when used in combination with ACE inhibitors or ARB’s)
  • Other
    • Severe Illness
      • Physiology: decreased adrenal aldosterone synthesis (perhaps complicated by volume expansion)
        • Additionally, stress-induced ACTH hypersecretion may decrease aldosterone synthesis by diverting substrate to the synthesis of cortisol
    • Primary Adrenal Insufficiency (see Adrenal Insufficiency, [[Adrenal Insufficiency]])
      • Physiology: decreased cortisol and aldosterone
        • Note: in contrast, pituitary disease does not result in hypoaldosteronism, since corticotropin (ACTH) does not play a major role in the regulation of aldosterone release

Aldosterone Resistance

  • Inherited Disorders
    • Pseudohypoaldosteronism Type 1
      • Subtypes
        • Autosomal Recessive Pseudohypoaldosteronism Type 1
        • Autosomal Dominant/Sporadic Pseudohypoaldosteronism Type 1
      • Physiology: resistance to action of aldosterone
  • Drugs
    • Aldosterone Antagonists: antagonize the activity of aldosterone on the collecting tubule cells by competition for the aldosterone receptor
      • Drospirenone (Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, Angeliq) (see Drospirenone, [[Drospirenone]]): synthetic hormone used in birth control pills
      • Eplerenone (Inspra) (see Eplerenone, [[Eplerenone]])
      • Spironolactone (Aldactone) (see Spironolactone, [[Spironolactone]])
    • Epithelial Sodium Channel (ENaC) Antagonists (see Epithelial Sodium Channel Antagonists, [[Epithelial Sodium Channel Antagonists]]): these agents act to close sodium channels on the luminal membrane of cells in the collecting tubule (collecting tubule is the site of action of aldosterone)
  • Other
    • Tubulointerstitial Renal Disease: defect in sodium reabsorption by distal tubule

Diagnosis

  • Transtubular K Gradient
    • Transtubular K Gradient= (Urine K/Plasm K)/(Urine Osm/Plasma Osm)
      • TTKG>8: normal aldosterone effect
      • TTKG<2: hypoaldo/aldosterone resistance of tubule
      • TTKG assumes urine Na >20and urine Osm >300
  • Urine K/Na Ratio
    • Urine K/Na Ratio = Urine K/Urine Na
      • Ratio <1: impaired aldosterone effect
      • Ratio >1: normal aldosterone effect

Clinical Manifestations

Cardiovascular Manifestations

Atrioventricular Heart Blocks

Bradycardia (see Bradycardia, [[Bradycardia]])

  • May Occur

Cardiac Arrest (see Cardiac Arrest, [[Cardiac Arrest]])

  • May Occur

EKG Changes

  • Peaked T-Waves -> Widened QRS and T-Waves

Gastrointestinal Manifestations

  • Hypoactive Bowel Sounds/Ileus (see Ileus, [[Ileus]])

Neurologic Manifestations

  • Depression (see Depression, [[Depression]])
  • Fatigue (see Fatigue, [[Fatigue]])
  • Flaccid Paralysis (see xxxx, [[xxxx]])
  • Hyporeflexia (see Hyporeflexia, [[Hyporeflexia]])
  • Muscle Weakness

Pulmonary Manifestations

Other Manifestations

  • xxxxx
  • xxxxx
  • xxxxx
  • xxxxx

Treatment

Insulin (see Insulin, [[Insulin]])

  • Administration: 5-10 U regular insulin IV + 1 amp D50 IV
  • Mechanism: drives potassium into cells
  • Onset: decreases potassium by 1-2 within 30-60 min
  • Duration: hours

Calcium

  • Agents
  • Indication: fastest treatment for cardiac toxicity (although has no effect on potassium levels)
  • Administration: 1 am calcium chloride IV
  • Mechanism: counteract potassium effect on neuromuscular membranes
  • Onset: immediate
  • Duration: transient

Sodium Bicarbonate (see Sodium Bicarbonate, [[Sodium Bicarbonate]])

  • Indication: useful even in absence of acidosis
  • Administration: 1 amp sodium bicarb IV
  • Mechanism: drives potassium into cells
  • Onset: 1 hr
  • Duration: hours
  • Adverse Effects: there is some concern that bicarbonate may decrease intracellular calcium levels, which may increase risk of arrhythmias

Hypertonic Saline (see Hypertonic Saline, [[Hypertonic Saline]])

  • Indication: useful for cardiac toxicity in cases with coexistent hyponatremia (due to dilution of plasma K and antagonization of neuromuscular toxicity)

Kayexelate (Sodium Polystyrene) (see Kayexelate, [[Kayexelate]])

  • Administration: PO or retention enema
  • Mechanism: binds intestinal K -> enhanced GI potassium excretion
  • Onset: 50g enema decreases K by 0.5-2.0 mEq within 1 hr

Albuterol (see Albuterol, [[Albuterol]])

  • Administration: unit dose via neubilizer
  • Mechanism: drives potassium into cells
  • Adverse Effects: sinus tachycardia, etc

References

  • Effect of bicarbonate administration on plasma potassium in dialysis patients: interactions with insulin and albuterol. Am J Kidney Dis. 1996 Oct;28(4):508-14 [MEDLINE]
  • A case of pseudohyperkalaemia and thrombocytosis. Ann Acad Med Singapore. 1998 May;27(3):442-3 [MEDLINE]
  • Acute hyperkalemia associated with intravenous epsilon-aminocaproic acid therapy. Am J Kidney Dis. 1999 Apr;33(4):782-5 [MEDLINE]
  • Fludrocortisone for the treatment of heparin-induced hyperkalemia. Ann Pharmacother. 2000 May;34(5):606-10 [MEDLINE]
  • An unusual case of pseudohyperkalaemia. Nephrol. Dial. Transplant. (2003) 18 (8): 1657-1659 [MEDLINE]