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Understanding Tumor Lysis Syndrome Lara Zafrani1,2*, Emmanuel Canet3 and Michael Darmon1

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Understanding Tumor Lysis Syndrome Lara Zafrani1,2*, Emmanuel Canet3 and Michael Darmon1 Intensive Care Med (2019) 45:1608–1611 https://doi.org/10.1007/s00134-019-05768-x UNDERSTANDING THE DISEASE Understanding tumor lysis syndrome Lara Zafrani1,2*, Emmanuel Canet3 and Michael Darmon1 © 2019 Springer-Verlag GmbH Germany, part of Springer Nature Tumor lysis syndrome (TLS) is a life-threatening condi- Current defnitions of TLS follow the classifca- tion in patients with extensive and chemosensitive malig- tion developed by Cairo and Bishop [6]. Accordingly, nancies. It usually occurs as a consequence of antican- laboratory TLS refers to the occurrence of metabolic cer treatments, although it can also arise spontaneously disturbances (hyperkalemia, hyperphosphatemia, hyper- (in up to a third of TLS cases) [1, 2]. TLS results from uricemia, and hypocalcemia) within the three days prior the rapid destruction of malignant cells, whose intracel- to or the seven days following the administration of lular content (ions, proteins, and metabolites) is conse- cancer chemotherapy, while clinical TLS refers to the quently released into the extracellular space. Potassium, presence of clinical manifestations (cardiac, renal, or calcium, phosphates, and deoxyribonucleic acid (DNA), neurological) in a patient with laboratory TLS. However, which are present in high concentrations in malignant despite these defnitions, TLS is not a straightforward cells, are released into the extracellular space, leading diagnosis, for several reasons. First of all, uremic syn- to hyperkalemia, hyperphosphatemia, and subsequent drome resulting from other causes may mimic TLS. In hypocalcemia. DNA catabolism leads to the release of this setting, electrolytic abnormalities kinetic (i.e increase adenosine and guanosine, which are converted into xan- of phosphatemia, kaliemia and lacticodehydrogenase lev- thine and then uric acid. TLS occurs when renal clear- els) may help in diferentiating TLS-induced AKI from ance is insufcient to handle this metabolite release. Te AKI due to other etiologies. Indeed, in TLS, hyperphos- above-described metabolic disturbances may contribute phatemia and hyperkalemia precede the appearance of to the development of acute kidney injury (AKI), thereby AKI; furthermore, intracellular levels of phosphorus in further decreasing metabolite clearance and increasing tumor cells are four times higher than the levels found TLS symptoms and consequences. Te formation of uric in normal cells. A rapid course of hyperphosphatemia, acid crystals in the renal tubules has been described as which parallels the rapid increase of lactico-dehydroge- the main mechanism underlying AKI, other causes being nase and hyperuricemia, will suggest that TLS is involved calcium-phosphate deposition and crystal-independent in the mechanism of AKI. It is also necessary to be aware pathways involving systemic infammatory responses that TLS may be present prior to the detection of cancer, (Fig. 1) [3]. or conversely that its onset may be delayed in patients Because TLS-induced AKI decreases the chances of receiving targeted therapies or immunotherapies [7]. chemotherapy being optimally efective, it reduces the Early recognition of patients at high risk of TLS is nec- likelihood of achieving complete remission of the under- essary in order to allow adequate monitoring and initia- lying malignancy and is associated with high mortality tion of preventive measures. High-risk patients usually rates [2, 4, 5]. Although kidney is the main afected organ have a high-grade hematological malignancy (acute leu- during TLS, systemic infammatory response mimicking kemia or high-grade lymphoma) and a large tumor bur- sepsis and multiple organ failure may occur [3]. den (hyperleukocytosis or bulky disease) [8]. However, an increasing rate of TLS has been described in indolent tumors (solid tumors, chronic lymphoid leukemia and myeloma) treated with targeted therapies [7]. Despite *Correspondence: [email protected] routine urate oxidase therapy, TLS may develop in up to 1 Medical Intensive Care Unit, Hopital Saint Louis, Assistance des Hôpitaux two-thirds of high-risk patients, leading to AKI in half of de Paris, Paris University, Paris, France Full author information is available at the end of the article them [2]. 1609 Fig. 1 Mechanisms of TLS-induced multi-organ failure. Tumour cells release intracellular potassium, phosphate and Deoxy-ribo-Nucleic Acid (DNA) into the extracellular space. Potassium may induce cardiac arrhythmia. Phos- phate and calcium may precipitate together and induce nephrocalcinosis. DNA is metabolised into adenosine and guanosine, which are converted into xanthine and then uric acid. Uric-acid crystal formation in the renal tubules has been described as the main mechanism of AKI. Tese metabolic disturbances may lead to AKI. Moreover, AKI increases hyperkalaemia, hyperphosphatemia and hyperuricemia. Crystal independent mechanisms of AKI and multi-organ failure are poorly understood and may involve other metabolites and cytokines secreted by tumour cells. Hydration maintains a high urinary output to enhance uric acid and phosphate clearance. Renal replacement therapy may be efective in controlling the metabolic disturbances and preventing AKI. Allopurinol, a structural isomer of hypoxanthine inhibits the conversion of xanthine to uric acid. Rasburicase is a recombinant urate oxidase that converts uric acid into allantoin, carbon dioxide, and hydrogen peroxide Prevention and treatment of TLS volume expansion carries a risk of fuid overload with the Hydration attendant clinical consequences. Careful attention should Extracellular fuid volume expansion with saline (3L/ be paid to elderly patients with underlying chronic m2 per day) is the cornerstone of TLS prevention and heart or kidney disease. Urinary alkalinization is poorly treatment [1, 9]. Te theoretical rationale for aggressive efcient [10], increases the risk of calcium-phosphate intravenous hydration is that this approach will dilute nephropathy, and is therefore no longer recommended the intracellular components that are released into the [9]. blood, increase urinary output, and preserve renal func- tion. However, in the absence of obvious volume deple- Diuretics tion, the concept that intravenous hydration can prevent, or reduce the severity of AKI, or accelerate renal recovery Te use of diuretics has been advocated by some authors is not demonstrated by robust clinical data. Moreover, in order to enhance urinary fow rate and decrease the risk of crystal precipitation [1]. However, this approach 1610 has never been specifcally studied and the hemodynamic optimal timing for initiating RRT in TLS-induced AKI changes associated with diuretics may compromise kid- is unknown. A stepped wedge cluster randomized con- ney function in these patients. trolled trial on the benefts of prophylactic RRT in high- risk patients might provide guidance for intensivists with Hypouricemic agents regard to the management of these patients. Allopurinol, a structural isomer of hypoxanthine, inhib- Te role of the intensivist in the management of high- its the conversion of xanthine to uric acid. It is the drug risk patients is primordial. Chemotherapy can be safely of choice for prophylaxis in patients with low/intermedi- administered in the ICU, and hematological patients at ate risk of TLS, but it may be less efective than rasbur- high risk of complications, including TLS, should prefer- icase in patients with hyperuricemia and already formed ably be admitted before the onset of organ failure. Close urate crystals [8, 9, 11]. Rasburicase is a recombinant monitoring of TLS patients includes measurement of urate oxidase that converts uric acid into a hydrosoluble serum potassium, calcium, phosphate, urea, creatinine, compound: allantoin. Rasburicase is contraindicated in and uric acid, at least every 6 h [8]. Close collaboration patients with glucose-6-phosphate dehydrogenase def- between intensivists, oncologists, and hematologists ciency, as it may induce severe methemoglobinemia and is also of primordial importance. Indeed, in high-risk hemolytic anemia. Rasburicase is efective in decreasing patients, one should discuss diferent “debulking” strate- uric acid concentrations within four hours [11], but no gies; in acute myeloid leukemia with high white blood cell study has shown it to impact on AKI prevention, the need count, for example, a possible strategy might be to gradu- for renal replacement therapy (RRT), or mortality. British ally escalate doses of chemotherapy or oral hydroxyurea guidelines recommend a dose of 0.2 mg/kg of rasburicase in order to gradually lower the white blood cell count [9]. However, a fxed dose of 3 mg in a single administra- prior to intensive chemotherapy, with a view to avoiding tion followed by close monitoring has been proven safe massive release of intracellular content [16]. and efcient [12]. Tese same guidelines recommend the In conclusion, TLS may lead to AKI and multiple use of rasburicase in established TLS and for preven- organ failure. Te pathophysiology of TLS-induced AKI tion in high-risk patients and intermediate-risk patients includes both crystal-dependent and crystal-independent with hyperuricemia [9]. Te possible role of febuxostat, mechanisms that are currently poorly understood. ‘Pre- another oxidase inhibitor, remains to be defned. ventive’ ICU admission of high-risk patients would allow better management of electrolyte disturbances, hydra- Prevention of nephrocalcinosis tion, and anticancer therapeutic strategies, as well as Knowledge of the role of
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