Setting: hospital ward
CC: “I feel weak since my chemotherapy.”
VS: BP:112/72 mm Hg; P: 88 beats/minute; T: 100.2°F; R: 16 breaths/minute
HPI: A 32-year-old woman admitted for combination chemotherapy for non-Hodgkin lymphoma (NHL) is in the hospital the night after the administration of the medications. She had IV fluids started the morning of the chemotherapy. She received cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone. She is now feeling severe muscle weakness.
PMHX: stage IV lymphoma with widespread disease including bone marrow
Medications:
IV NS
Allopurinol
Allopurinol
• Inhibits xanthine oxidase
• Inhibits production of uric acid
PE:
General: weak and tired
Neurological: normal, no focal deficits
Musculoskeletal: decreased motor strength in all four extremities
Allopurinol is a hypoxanthine analog.
Initial Orders:
CHEM-20
UA
Uric acid level
IV saline
Continue allopurinol
ECG
Phosphate and magnesium levels
Hydration and allopurinol are standard before chemotherapy to prevent tumor lysis syndrome.
Move the case forward the shortest amount of time to get the potassium level. The single most important thing is to exclude a dangerous level of hyperkalemia and cardiac toxicity from it.
Report:
Potassium 6.8 mEq/dL
UA: normal
Uric acid level: elevated
ECG: widening of QRS, flat T wave
Phosphate: elevated
Hyperkalemia + ECG Changes = Calcium Chloride (or Gluconate) IV
• Calcium protects the heart from hyperkalemia.
• Calcium raises the threshold at which depolarization occurs.
What is the mechanism of a high phosphate level?
a. Muscle breakdown
b. Release from lymphocytes
c. Binding with potassium
d. Renal failure
Answer a. Muscle breakdown
Phosphate is released from intracellular storage. There is no direct effect of potassium on phosphate. Although renal failure is associated with high phosphate level from the inability to excrete it, this could not happen in just 1 day. Even if uric acid were to cause renal failure, it would not become evident on the same day.
• If the patient is allergic to allopurinol, use febuxostat.
• Febuxostat is a xanthine oxidase inhibitor.
Immediately after the hyperkalemia and ECG abnormalities are discovered, the patient is given calcium chloride, glucose, and insulin. Move the clock forward and recheck the potassium level. The potassium level should start to improve within 30 minutes.
Insulin stimulates Na+/K+-ATPase to drive potassium into cells.
How does hyperkalemia cause muscle weakness?
a. It inhibits acetylcholine release at the neuromuscular junction.
b. It prevents repolarization.
c. It interferes with the actin-myosin interaction.
d. It blocks calcium release from SERCA.
Answer b. It prevents repolarization.
Repolarization is based on potassium being extruded from cells to lower the cell to a negative polarity. In other words, the positively charged potassium ion (K+) has to leave the cell so that it can go back to its resting membrane potential, which is −70 to −90. If the blood level of potassium is markedly increased, the potassium cannot leave the cell. In fact, potassium can go backwards into the cell through the ungated potassium channels.
Increased Blood K = K Cannot Leave Cells
K Cannot Leave Cells = No Repolarization
No Repolarization = No Depolarization
All This = Muscle Becomes Weak and Patient Dies of Arrhythmia
Several hours later, the potassium level has been normalized and the muscle weakness has resolved. Repeat chemistry shows the creatinine level rises from 0.8 to 1.5 mg/dL. Uric acid is still up. Six hours later, despite fluids and allopurinol, the creatinine goes to 1.7 mg/dL.
What is the mechanism of uric acid’s damaging effect on the kidney?
a. Tubular damage
b. Vasoconstriction of afferent arteriole
c. Interference with TAL Na+/K+/2Cl– pumps
d. Vasa recta toxicity
e. Glomerular damage
Answer a. Tubular damage
Uric acid causes acute tubular necrosis. Uric acid and oxalic acid are two forms of crystals that both damage the kidney. You can see the crystals on a urinalysis. You must lose more than 50% of renal function before the creatinine will even begin to rise. When allopurinol damages the kidney, it is from allergic interstitial nephritis.
Diagnosing Etiology of Renal Failure
• Allopurinol: Hansel stain for eosinophils
• Uric acid: urine crystals
Report:
UA: no WBCs, uric acid crystals seen
Hansel stain (urine eosinophils): negative
As hydration and allopurinol have not been able to control the uric acid−induced renal failure, you add rasburicase. The following day, the uric acid level normalizes. BUN and creatinine levels come back down to normal 2 days later. Allopurinol and febuxostat do not decrease uric acid levels once it is formed. They only prevent formation.
Rasburicase dissolves uric acid into allantoin.
Allantoin benignly goes out through the kidneys.
Rasburicase “melts” uric acid. It is a uricase!
Increasing urate oxidase!
Case Summary:
Tumor lysis syndrome is a known entity after chemotherapy, particularly for lymphoma. Prevention with hydration and either rasburicase or allopurinol is standard. Rasburicase may be better than allopurinol and that is the lesson learned from this case. Elevations in potassium, phosphate, and uric acid levels are well known. There is no clear benefit of routine urinary alkalinization.