Urinary alkalinization has been a long-standing modality used to facilitate uric acid excretion based on the initial work by Rieselbach et al. (1964) who showed that urinary alkalinization to a goal urine pH of 7.0 in addition to hyperhydration improved urinary excretion of uric acid. Although Conger and Falk (1977) later showed in a mouse model that urine alkalinization plays only a minor role in urate excretion as compared to hyperhydration, it remains unclear if this necessarily correlates with human physiology. The solubility of uric acid increases with increasing urine pH thereby making it easier for the kidneys to excrete excess uric acid; however, the solubility of calcium phosphate decreases as the pH increases leading to potential calcium phosphate precipitation in an increasingly alkaline environment (Howard et al. 2011). Therefore, theoretical concern exists regarding routine urinary alkalinization. In consensus guidelines, Coiffier et al. (2008) recommend against routine urine alkalinization, while Tosi et al. (2008) recommend urine alkalinization in low-risk patients, highlighting the lack of evidence to make firm uniform guidance. An update of the Tosi et al. (2008) Italian guidelines recommend against alkalinization even in low-risk patients (Pession et al. 2011).

Sodium bicarbonate is generally used as the additive to intravenous fluids with a goal urine pH of 7.0. It is unlikely that patients without risk of HU benefit from urinary alkalization; those with high tumor burdens and risk for TLS may benefit from urine alkalinization although data are lacking. Additionally, with the availability of rasburicase to rapidly degrade existing uric acid to a much more soluble byproduct, the risk of hyperuricemia and subsequent urate precipitation is almost nonexistent in settings with rasburicase availability thereby negating the need for alkalinization (Tosi et al. 2008; Howard et al. 2011). Patients with hyperphosphatemia should not be alkalinized due to the increased risk of calcium phosphate precipitation and availability of rasburicase to treat concomitant hyperuricemia, if present (Howard et al. 2011). In the patient with elevated uric acid or risk of hyperuricemia without hyperphosphatemia started on alkalinization, the alkalinization can be discontinued as the uric acid normalizes and the tumor burden decreases over the first few days of therapy (Table 3.3).

Allopurinol inhibits xanthine oxidase, an enzyme which converts hypoxanthine and xanthine to uric acid. Krakoff and Meyer (1965) and DeConti and Calabresi (1966) first showed that allopurinol effectively reduced serum uric acid levels without leading to significant accumulation of xanthine and hypoxanthine due to differential solubility products. Allopurinol has been noted to be quite safe and is extremely inexpensive. Xanthine nephropathy secondary to TLS and leading to AKI with concomitant allopurinol has been rarely reported in the literature (Band et al. 1970; Hande et al. 1981; Andreoli et al. 1986; Potter and Silvidi 1987; LaRosa et al. 2007). Andreoli et al. (1986) reported that although xanthine exceeded its solubility limit in 16 of 19 children with ALL receiving allopurinol, only 8 were noted to have precipitated xanthine in urine sediment and only half of those children developed AKI. They therefore theorized that additional factors are involved in the development of AKI during TLS. Xanthine nephropathy should be considered in the patient with AKI but appropriate TLS prophylaxis; in such cases allopurinol should be reduced or discontinued, xanthine levels should be drawn and patients should be tested for a defect in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme (LaRosa et al. 2007).

Drawbacks to allopurinol include a relatively slow onset of action (i.e., 24–72 h), the necessity of dose reduction in the setting of renal insufficiency and its inability to degrade preexisting uric acid (Howard et al. 2011). Intravenous allopurinol has been shown to be equally effective and safe as compared to oral allopurinol but comes at a much higher cost (2,000-fold) (Smalley et al. 2000; Feusner and Farber 2001; Patel et al. 2012). Prior to the advent of rasburicase, intravenous allopurinol was a potential option in patients unable to tolerate oral intake but is no longer available in Europe (Feusner and Farber 2001; Will and Tholouli 2011). Utilizing a single low dose of rasburicase, Patel et al. (2012) were able to extrapolate a significant cost savings over intravenous allopurinol. Consensus guidelines recommend allopurinol in low- and intermediate-risk patients (i.e., those patients not recommended to receive rasburicase) (Coiffier et al. 2008; Pession et al. 2011). Consensus guidelines recommend that patients who receive rasburicase should only have allopurinol initiated after rasburicase discontinuation in order to inhibit additional uric acid formation until the tumor burden is significantly decreased (i.e., usually 3–7 total days) (Coiffier et al. 2008; Tosi et al. 2008). Given the slow onset of action for allopurinol it may be more prudent to initiate allopurinol prior to this recommended time point. Similar to urine alkalinization, it is unclear if the addition of allopurinol is beneficial in patients with a low tumor burden and low risk of developing HU (Table 3.3) (Pession et al. 2011).

Rasburicase, recombinant urate oxidase, converts uric acid into allantoin, a five to ten times more soluble compound, in an extremely effective manner. Due to this fact, many studies have shown that rasburicase is efficacious in correcting HU in pediatric and adult patients (Pui et al. 2001; Patte et al. 2002; Bosly et al. 2003; Coiffier et al. 2003; Jeha et al. 2005; Pession et al. 2005; Shin et al. 2006; Kikuchi et al. 2009). Follow-up studies comparing efficacy of rasburicase and allopurinol naturally show that rasburicase is much more effective in rapidly and dramatically reducing the uric acid level although such studies fail to incorporate a clinically relevant endpoint (Goldman et al. 2001; Cortes et al. 2010). Many of these studies were supported by the pharmaceutical maker of rasburicase, including grant support, providing the drug, logistic support, editorial support, and data management, and some study authors had a financial stake in the pharmaceutical company (Goldman et al. 2001; Pui et al. 2001; Patte et al. 2002; Bosly et al. 2003; Coiffier et al. 2003; Jeha et al. 2005; Shin et al. 2006; Kikuchi et al. 2009; Cortes et al. 2010). Early studies also utilized higher doses of rasburicase (i.e., 0.15–0.2 mg/kg/day) and for a longer duration (up to 7 days) based on the recommendation of the manufacturer (and what was approved by the United States Food and Drug Administration [FDA]), rather than what is more rational based on the mechanism of the drug and underlying disease process (Pui et al. 2001; Patte et al. 2002; Bosly et al. 2003; Coiffier et al. 2003; Jeha et al. 2005; Pession et al. 2005; Shin et al. 2006; Kikuchi et al. 2009).