GU and Electrolyte Toxicities

L. Bressler
November, 1997

I. TUMOR LYSIS SYNDROME

Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia,

hyperphosphatemia and hypocalcemia. It is due to the rapid release of the

intracellular contents of tumor cells. Tumor lysis syndrome is seen with large

tumor burdens with high growth fractions that are very sensitive to chemotherapy.

Examples include high-grade lymphomas and leukemias with high leukocyte

counts. Tumor lysis syndrome is seen less often with solid tumors. It can be treated/prevented with HYDRATION, ALLOPURINOL 300-900 mg/day, and URINARY ALKALINIZATION to pH > 7. (This can be achieved with 50-lOO mEq sodium bicarbonate per liter of fluid, with subsequent adjustment based on urine pH.)

Dialysis may be required.

  1. HYPERURICEMIA results from the action of xanthine oxidase on hypoxanthine and xanthine. It can lead to URATE NEPHROPATHY with resultant renal failure.
  2. HYPERKALEMIA associated with tumor lysis syndrome can lead to ARRHYTHMIAS. It can be treated with KAYEXALATE.
  3. HYPERPHOSPHATEMIA can also lead to renal failure.
  4. HYPOCALCEMIA results from hyperphosphatemia. It can lead to MUSCLE CRAMPS, ARRHYTHMIAS, or TETANY. Hypocalcemia may be treated with CALCIUM GLUCONATE.

 

II. STERILE HEMORRHAGIC CYSTITIS

It is seen with cyclophosphamide and ifosfamide. It is thought to be due to an alkylating metabolite, acrolein.

Hemorrhagic cystitis has been seen after single high doses or prolonged low doses. Patients may be asymptomatic or they may present with symptoms of cystitis (eg. burning, frequency). Hematuria may be microscopic (detectable only on urinalysis) or gross . The potential danger accompanying hemorrhagic cystitis is BLOOD LOSS. HYDRATION is commonly employed to prevent hemorrhagic cystitis from cyclophosphamide. When possible, the drug should be given early in the day, followed by hydration and FREQUENT VOIDING (eg. every few hours). MESNA is always given with ifosfamide (and it may be used with cyclophosphamide) to prevent hemorrhagic cystitis. MESNA provides a substrate for acrolein to alkylate.

III. HYPOMAGNESEMIA FROM CISPLATIN is a common electrolyte abnormality.

Magnesium falls in many patients who receive cisplatin. Unless it is very low (eg.< 1) or accompanied by hypocalcemia, hypomagnesemia is usually asymptomatic. Although magnesium replacement is frequently undertaken, it is of questionable value in the absence of other electrolyte abnormalities. Urinary magnesium loss is increased and frequently continues even after cisplatin therapy is stopped. Thus administered magnesium may simply be lost in the urine. It has been suggested that treatment is only necessary in patients who have other electrolyte abnormalities, or who are symptomatic.

IV. HYPONATREMIA FROM CYCLOPHOSPHAMIDE

It has been seen following high doses (eg. usually after doses of > 50mg/kg). It is characterized by a decrease in urine output occurring 6 to 8 hours after drug administration, weight gain, increase in urine osmoiality and decrease in serum osmolality. The syndrome, resembling SIADH, is generally self-limiting. Furosemide can be given to preserve urine output and prevent symptomatic hyponatremia; potassium would be required to prevent hypokalemia. (Note that the possibility of this syndrome does not preclude the hydration suggested above to prevent hemorrhagic cystitis. The latter is much more common, and the former has been reported primarily after high doses.)

V. CISPLATIN NEPHROTOXICITY -

In the past, nephrotoxicity secondary to tubular damage, was the dose-limiting toxicity of cisplatin. Increases in BUN and creatinine, and decreases in CrCl may be seen shortly after cisplatin therapy. Usually, with doses < 100mg/m2 , nephrotoxicity is mild and reversible. It is no longer the dose-limiting toxicity, as it may be prevented or minimized by the use of hydration immediately before and following drug administration. Mannitol has also been used to ensure diuresis and prevent nephrotoxicity, as has furosemide. Caution should be taken so as not to dehydrate patients if diuresis is greater than hydration.

Hypertonic saline has been used to prevent nephrotoxicity from higher doses of cisplatin (eg. 40mg/m2/day x 5 days).

DDTC (diethyldithiocarbamate), a heavy metal chelator, has also been used as an investigational agent to prevent cisplatin nephrotoxicity.

Amifostine, a recently marketed protectant, is reported to decrease the nephrotoxicity (as well as some other toxicities) of cisplatin or other alkylators. Its exact place in therapy remains to be determined. Currently it is approved for use with cisplatin in advanced ovarian or non-small cell lung cancer. Frequent monitoring for hypotension is required and amifostine can worsen the nausea and vomiting seen with cisplatin.

VI. Nephrotoxicity

It has been associated with HIGH DOSE METHOTREXATE. High dose usually refers to doses > 1 gm/m2 and is given in conjunction with leucovorin. Nephrotoxicity is thought to be due to precipitation of the metabolite of methotrexate in an acidic urine, leading to renal tubular injury. Acute renal failure due to obstruction can result. Further, elimination of methotrexate will be inhibited, leading to severe toxicity. Nephrotoxicity can be prevented with hydration (eg. 3L/m2 x 24 hours) and urinary alkalinization to maintain urine pH >= 6.5.

 

VII. MITOMYCIN

It has been associated with renal failure due to a hemolytic-uremic syndrome. There is no consistently effective treatment, although recovery has been seen after temporary dialysis.

 

VIII. STREPTOZOCIN

It is a nitrosourea derivative, is also associated with renal failure. The earliest sign is hypophosphatemia, and the most frequent sign is proteinuria. Urinalyses should precede each dose of streptozocin. If the drug is stopped early (ie. when mild proteinuria is the only abnormality), toxicity is reversible. If the drug is continued, increases in BUN and creatinine can follow, and nephrotoxicity can be irreversible.

 

IX.

Renal failure is associated with nitrosoureas (BCNU, CCNU). Azotemia and increases in creatinine have been seen following prolonged use and high cumulative doses (eg. 1200 mg/m2). Most reports are in children treated for brain tumors.

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