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Onco-Nephrology: Tumor Lysis Syndrome

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Onco-Nephrology: Tumor Lysis Syndrome Onco-Nephrology: Tumor Lysis Syndrome F. Perry Wilson and Jeffrey S. Berns Summary Tumor lysis syndrome (TLS) describes the clinical and laboratory sequelae that result from the rapid release of intracellular contents of dying cancer cells. It is characterized by the release of potassium, phosphorous, and nucleic acids from cancer cells into the blood stream, with the potential to cause hyperkalemia; hyperphospha- temia and secondary hypocalcemia; hyperuricemia; AKI; and, should usual homeostatic mechanisms fail, death. TLS most commonly follows treatment of hematologic malignancies, such as acute lymphocytic or lymphoblastic Perelman School of Medicine at the leukemia, acute myeloid leukemia, and Burkitt lymphoma, but also occurs after treatment of other bulky or rapidly University of growing tumors, particularly if the patient is highly sensitive to the effects of cytotoxic chemotherapy. Prevention Pennsylvania, and treatment depend on prompt recognition of patients at risk, volume repletion, allopurinol, rasburicase Hospitalofthe (a novel recombinant urate oxidase), and, when indicated, dialysis. University of – Pennsylvania, Clin J Am Soc Nephrol 7: 1730 1739, 2012. doi: 10.2215/CJN.03150312 Philadelphia, Pennsylvania Introduction within a 24-hour period. This complicated time limi- Correspondence: Tumor lysis syndrome (TLS) describes the clinical and tation requires defining TLS according to a future Dr. Jeffrey S. Berns, laboratory sequelae that result from the rapid release event (the administration of chemotherapy) and Perelman School of Medicine at the of intracellular contents of dying cancer cells. It is the does not provide a framework for the diagnosis of University of single most common oncologic emergency and a spontaneous TLS (14). These definitions continue to Pennsylvania, frequent source of inpatient consultation for nephrol- be debated (2). From a nephrologic perspective, de- Hospitalofthe ogists (1). TLS is characterized by the release of po- fining AKI on the basis of a creatinine value .1.5 University of tassium, phosphorous, and nucleic acids from cancer Pennsylvania, 3400 times the upper limit of normal for patient age and Spruce Street, 1 cells into the blood stream, with the potential to cause sex is not typical and does not clearly distinguish Founders Pavilion, hyperkalemia; hyperphosphatemia and secondary CKD from AKI. It would seem appropriate to rede- Philadelphia, PA hypocalcemia; hyperuricemia;AKI;and,should fine the renal criteria for clinical TLS to an absolute 19104. Email: bernsj@ usual homeostatic mechanisms fail, death. TLS most 0.3-mg/dl increase or relative 50% increase in creati- uphs.upenn.edu commonly follows treatment of hematologic malig- nine over established baseline to be more closely nancies, such as acute lymphocytic or lymphoblastic aligned with commonly used AKI criteria (15). This leukemia, acute myeloid leukemia, and Burkitt lym- more sensitive definition would potentially identify pa- phoma, but also occurs after treatment of other bulky tients with TLS earlier, allowing for more rapid inter- or rapidly growing tumors, particularly if highly sensi- vention and perhaps improved outcomes. Use of tive to the effects of cytotoxic chemotherapy (2–4). TLS urinary and serum biomarkers may in the future allow has been reported after treatment with conventional diagnosis and treatment of very early TLS-associated chemotherapy, dexamethasone (5), and newer agents AKI but has not yet been studied. such as bortezomib (6,7), thalidomide (8,9), and rituximab (10); radiation therapy of radio-sensitive solid tumors (11); and total-body irradiation (12). Pathophysiology The clinical and laboratory complications of TLS are Definitions: The Cairo-Bishop Criteria due to release of intracellular contents into the extra- Although no classification scheme for TLS is uni- cellular space, overwhelming homeostatic mechanisms. fi formly accepted, that of Cairo and Bishop is often Although the electrolyte complications have signi - used (13). The lack of universal definitions for diag- cant morbid potential, the liberation of nucleic acids nosis has made the analysis of studies examining TLS plays a major role in the AKI seen in TLS (16). as an exposure or outcome complicated because of heterogeneity. The Cairo-Bishop definitions of “labo- Uric Acid ratory TLS” and “clinical TLS” are shown in Table 1. Following the release of intracellular nucleic acids, Clinical TLS requires the presence of laboratory TLS adenine and guanine are metabolized to xanthine, in addition to evidence of renal, cardiac, or neuro- which is broken down by xanthine oxidase to uric logic dysfunction. The Cairo-Bishop classification re- acid. This process and the relative solubilities of the quires an increase in electrolyte markers to occur molecules involved are displayed in Figure 1. In most between 3 days before and 7 days after initiation of animals, uric acid is metabolized to the highly soluble chemotherapy, with two markers being abnormal allantoin by urate oxidase. Humans and many other 1730 Copyright © 2012 by the American Society of Nephrology www.cjasn.org Vol 7 October, 2012 Clin J Am Soc Nephrol 7: 1730–1739, October, 2012 Tumor Lysis Syndrome, Wilson and Berns 1731 resistance beyond the peritubular capillaries was in- Table 1. Cairo-Bishop classification of tumor lysis syndrome in creased by more than three-fold. These findings demon- adults strated that acute uric acid nephropathy is related not only to tubular obstruction but also to marked hemody- Laboratory TLS Clinical TLS namic changes in multiple renal vessels. Even at soluble Uric acid: $8.0 AKI (defined as creatinine concentrations, uric acid may predispose to renal ische- mg/dl .1.53 the upper limit mia. Uric acid can scavenge bioavailable nitric oxide, lead- of normal for patient ing to vasoconstriction (19). Vascular smooth muscle cells age and sex) exposed to dissolved uric acid release the inflammatory $ Potassium: 6.0 Cardiac arrhythmia cytokines monocyte chemotactic protein-1, TNF-a,and mEq/dl other vasoactive mediators, leading to chemotaxis of Phosphorus: $4.6 Seizure, tetany, or other white cells and further inflammatory injury (20). Finally, mg/dl symptomatic hypocalcemia Calcium: #7.0 uric acid may inhibit proximal tubule cell proliferation, mg/dl prolonging the duration of kidney injury (21). Potassium Patients must meet more than two of four laboratory criteria in The intracellular concentration of potassium is as high the same 24-hour period within 3 days before to 7 days after chemotherapy initiation. A .25% increase from “baseline” 120 mEq/L (22,23). In the case of hematologic malignan- laboratory values is also acceptable (13). Other causes of AKI cies, much of the 2.6 kg of bone marrow in the average (e.g., nephrotoxin exposure, obstruction) should be excluded. human may be replaced by malignant cells. The rapid lib- TLS, tumor lysis syndrome. eration of potassium into the extracellular fluid will lead to severe hyperkalemia if it exceeds the normal homeostatic uptake of potassium into liver and muscle cells. In the primates lack this enzyme, making less soluble uric acid setting of CKD or AKI, renal clearance of potassium is the final end product of adenine and guanine metabolism. reduced, increasing the severity of hyperkalemia (24). Hy- Uric acid impairs kidney function via crystal-dependent perkalemia can lead to weakness and death via cardiac and crystal-independent mechanisms, with crystal-dependent arrhythmia. processes generally considered to be more important (17). An acid urine pH favors production of poorly soluble uric Phosphorous and Calcium acid over the more soluble urate, increasing the risk for TLS can rapidly liberate a large volume of intracellular precipitation of intratubular uric acid crystals. Conger phosphate. Hyperphosphatemia is less common in cases of and Falk evaluated uric acid nephropathy in a rat model, spontaneous TLS than in typical TLS, presumably because demonstrating marked increases in proximal and distal of the rapid uptake of extracellular phosphate by the remain- tubular pressures in rats given exogenous uric acid loads ing highly active residual tumor cells in the former condition along with a uricase inhibitor (18). In addition, peritubular (25–28). Hyperphosphatemia in patients with TLS will be capillary pressures were increased two-fold, and vascular further exacerbated by any associated AKI. Figure 1. | Metabolism of purine nucleic acids. In humans and apes, the end product is uric acid. Allopurinol inhibits metabolism of xanthine to uric acid. Recombinant urate oxidase catalyzes the metabolism of uric acid into the more soluble allantoin (55,94,95). Solubilities at a pH of 7 are shown in parentheses. 1732 Clinical Journal of the American Society of Nephrology The primary toxicity of hyperphosphatemia is the sec- medulloblastoma, hepatoblastoma, breast carcinoma, non– ondary hypocalcemia that results from chelation of calcium small-cell lung cancer, vulvar carcinoma, thymoma, ovarian by phosphate anions. Hypocalcemia can lead to cardiac ar- carcinoma, colorectal carcinoma, gastric carcinoma, mela- rhythmias, seizures, tetany, and death. Interestingly, pro- noma, hepatocellular carcinoma, and sarcoma (35). longed hypocalcemia has been described even after resolution Although a recommendation to include routine measure- of hyperphosphatemia in TLS, presumably due to a deficiency ment of serum uric acid, potassium, calcium, or phospho- of 1,25-vitamin D (29). rus during treatment of solid malignancies
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