About 35 years ago, I encountered several children and adolescents with acute lymphoblastic leukemia or widespread non-Hodgkin lymphoma who presented with or who developed, upon initiation of therapy, severe renal and metabolic derangements. With two of my nephrology colleagues, I reviewed these patients' presentations, discussed the pathophysiology, and made therapeutic recommendations.[1] Over the next three decades, I have continued to see similar patients. I have shared my observations as senior author of the chapter “Tumor Lysis Syndrome” in all four editions of the textbook Abeloff's Clinical Oncology. I have carefully reread the 1977 review and the chapter on tumor lysis syndrome in the 2008 edition of the Abeloff textbook.[2] I am struck by the fact that very little has changed in the diagnosis and management of these patients in the past three decades.
Nonetheless, two things definitely have changed. First, the practice of alkalization of the urine with sodium bicarbonate(Drug information on sodium bicarbonate) or acetazolamide(Drug information on acetazolamide) to promote uric acid solublization and urinary excretion is no longer recommended. Systemic alkalization with bicarbonate leads to a decrease in ionized calcium. Both sodium bicarbonate and acetazolamide can decrease phosphate excretion, increase serum phosphate concentration, and promote precipitation of calcium phosphate(Drug information on calcium phosphate) salts, leading to metastatic calcifications—and potentially to nephrocalcinosis and obstructive uropathy that can result in permanent renal damage.
The second change is the availability of two new agents for the management of uric acid nephropathy. The first agent, the intravenous formulation of allopurinol(Drug information on allopurinol) (Alloprim), is useful for critically ill patients who cannot tolerate oral medications. Of greater import, the commercial availability of recombinant urate oxidase (rasburicase [Elitek]) has dramatically improved the management of impending and established urate nephropathy. While allopurinol is useful in preventing the formation of further uric acid from purine catabolism, it does not reduce preexisting uric acid, and 2 to 3 days of administration are required to see an effect. Rasburicase(Drug information on rasburicase) rapidly (within 4 hours) metabolizes preexisting uric acid to the much more soluble allantoin and can reverse established uric acid nephropathy in some patients. Although rasburicase is a very expensive agent, it may allow the earlier initiation of therapy and decrease the need for hemodialysis. Rasburicase is indicated for patients with significant spontaneous tumor lysis syndrome (TLS), those at high risk for severe tumor lysis (described below), those requiring urgent therapy, those who are difficult or impossible to hydrate adequately, and those in acute renal failure. [3] One dose of rasburicase is usually adequate and the need to redose should be individualized.
After reviewing the discussion of the management of tumor lysis syndrome in the review by Muslimani et al, I have several suggestions and additional management recommendations:
• It is very important to rapidly assess the patient to determine whether pretreatment tumor lysis is present or whether there is a high risk of significant tumor lysis developing. Risk factors include rapidly growing tumors; potentially chemotherapy-sensitive bulky tumors; urinary tract obstruction; enlarged kidneys; renal insufficiency at presentation; and pretherapy elevations of serum creatinine, potassium, uric acid, or lactate dehydrogenase and/or high white blood cell counts in acute leukemia.
• If possible, care for high-risk patients in an ICU or an oncology special care unit with continuous cardiac monitoring and hemodialysis capabilities.
• Establish reliable central venous access, weigh the patient twice daily on the same scale, carefully monitor intake and output, and alert your nephrologist and dialysis team.
• Start allopurinol immediately and assess for need for rasburicase administration. Whether to continue allopurinol in patients treated with rasburicase has not been definitively studied. The agents have different mechanisms for reducing uric acid load. Allopurinol prevents formation and rasburicase metabolizes already formed uric acid. Many clinicians will stop allopurinol when administering rasburicase and restart 24 hours later for ongoing TLS while others continue allopurinol.
• Hydrate at 2.5 to 3.0 L/m2/24 hours; decrease the rate if falling urine output is not responsive to loop diuretics and/or mannitol(Drug information on mannitol).
• Obtain comprehensive laboratory evaluations every 4 to 6 hours and continue monitoring for 48 to 72 hours after cytotoxic therapy has been initiated. Aggressive treatment of hyperkalemia with oral or rectal sodium polystyrene sulfonate(Drug information on sodium polystyrene sulfonate), and of hyperphosphatemia with aluminum hydroxide may avoid the need for hemodialysis.
• Initiate hemodialysis or hemofiltration early if the patient becomes oliguric; if the creatinine level is increasing; or if hyperkalemia, hyperphosphatemia, hypocalcemia, and/or azotemia is/are not responding to conventional measures.
• If possible, avoid any corticosteroid administration and delay initiation of cytotoxic therapy for 24 to 48 hours or until the patient is metabolically stable. Keep in mind that minimal therapy or potentially even stress with increased adrenal corticosteroid release can worsen or initiate tumor lysis.
• In my experience, relapsed disease results in TLS that is as severe as, or more severe, than TLS seen at initial diagnosis.
TLS is a medical emergency. The principles for the recognition and management of TLS are well established. Treatment is very effective if risk factors are recognized early and the patient is carefully, consistently, and compulsively monitored and treated aggressively to correct metabolic derangements.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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