Article, Oncology

Acute kidney injury associated with tumor lysis syndrome: a paradigm shift

induced lysis of malignant cells in hematologic neoplasias and rapidly growing solid tumors. Large amounts of UA, phosphate, and potassium are released. Uric acid (UA) had the central role in the pathology of renal failure [1]. Because of its low renal clearance (5-8 mL/min in men), UA accumulates in plasma and in total body water. The renal excretion of UA increases linearly with increasing plasma levels up to 12 to 15 mg/dL. With higher plasma concentrations, the filtered load surmounts the tubular capacity for reabsorption and a steep increase of UA excretion results. Depending on Urine pH and volume, the excreted amount of UA can reach the limits of solubility resulting in crystal formation in distal tubules and collecting ducts with the risk of Acute kidney injury [2].

The prevention of TLS-induced AKI includes initiating prophylactic measures before and during chemotherapy, including hydration, alkalinization of the urine, and use of the xanthine oxidase inhibitor allopurinol, as well as the urate oxidase inhibitor rasburicase or its derivatives [3]. The problem with Urine alkalinization is the reduction of the solubility of calcium phosphate and precipitation of calcium phosphate crystals in renal tubules [2] In recent years, rasburicase, a recombinant urate oxidase, was approved for the treatment of TLS. Urate oxidase catalyzes the oxidation of UA to allantoin, which is 5 to 10 times more soluble than UA and is readily excreted. In several studies, rasburicase proved to be highly effective and reduced UA levels more rapidly when compared with allopurinol [4-6].

Acute phosphate nephropathy (APN) is a clinical pathologic entity characterized by acute and subsequent chronic renal failure. The pathophysiology of APN includes delivery of a large phosphate load to the distal nephron and precipitation of calcium phosphate in the distal tubule and collecting duct [7]. In 1984, Monballyu et al [8] described a case of transient acute renal failure due to tumor-lysis- induced severe phosphate load in a patient with Burkitt’s lymphoma. Since then, a few reports have been published, but more recently, the literature was focusing mainly on APN secondary to bowel preparation [7,9-11]. We think that wide use of rasburicase and urine alkalinization has resulted in a paradigm shift toward APN in TLS-induced

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AKI that is overlooked or underestimated. Herein, we report a case that developed recurrent AKI; the first AKI was secondary to spontaneous TLS-induced acute urate nephropathy, and second was chemotherapy-induced TLS APN. We claim that use of rasburicase and urine alkalinization unmasked the APN as a crucial cause of TLS-induced AKI.

Acute TLS is a Life-threatening complication of cancer therapy requiring prompt recognition and aggressive man-

agement. It occurs particularly in patients with lymphopro- liferative disease during potent myelosuppressive therapy [12]. The outcome of acute renal failure secondary to TLS is usually favorable [13-15].

It had been reported that hyperuricemia was the most common cause of acute renal failure as a complication of the TLS [8]. In recent years, rasburicase, a recombinant urate oxidase, was approved for the treatment of TLS. Rasburicase decreases UA by 86% 4 hours after administration [6]. The wide and early use of rasburicase has decreased the incidence and severity of TLS-induced AKI [16].

Table 1 Complete blood counts during the hospital stay of our patient

There is extremely high endogenous phosphorus load during TLS because the phosphorus content in lympho- blasts is much higher than in mature lymphocytes. In fact, cell content of several organic phosphorus fractions as well as of inorganic phosphorus may be 4 times greater in lymphoblasts. Once tubular transport mechanisms become saturated, serum phosphate levels rise. The first cases reported on TLS-induced APN were published in the late 70s and early 80s of the last century [8,17-20]. After that, most of the studies focused on the role of UA as the major cause of TLS-induced AKI [21-24]. More recently, after wide use of rasburicase, there was an increasing incidence of APN [25]. The mechanism of acute renal failure secondary to hyperphosphatemia may involve deposition of calcium phosphate complexes within the tubular lumen and renal interstitium [26]. Alkalinization may accelerate phosphate precipitation in the kidneys and, thereby, induce renal failure [27]. The administration of large volumes of fluid, therefore, remains the keystone in prevention of the TLS.

In patients with malignant lymphomas, prevention of AKI due to excessive phosphate load mandate the routine determination of serum phosphate and an awareness of phosphaturia during chemotherapy. If these values do rise during treatment and serum UA and uricosuria can be kept under control, routine alkalinization of the urine should be

Fig. 1 The patient’s serum creatinine, uric acid, calcium and phosphate levels during the course of treatment. The graph shows 2 episodes of AKI, first was associated with hyperurecemia and second was associated with hyperphosphatemia.

abandoned. If extremely elevated values of phosphatemia and phosphaturia are encountered, preventive treatment with hemodialysis or hemofiltration should be considered. From the limited experience published so far, it appears that recovery from renal failure is rapid when dialysis is started early. The contribution of oral treatment with aluminum hydroxide to control the exaggerated phosphate load may also help in patient’s management.

In our patient, serum UA and Creatinine levels were elevated initially but returned to normal after treatment with allopurinol, rasburicase, and extracellular Volume expansion and urine alkalinization before chemotherapy was started. Serum UA remained within normal limits after institution of chemotherapy. On the day before the occurrence of second AKI, the 24-hour urate excretion was normal. Uric acid nephropathy, therefore, could not be considered as the cause of second AKI in this patient. Serum phosphate levels and phosphaturia, on the other hand, were extremely elevated shortly after the start of chemotherapy. It seems logical, therefore, to ascribe the AKI to the enormous phosphate load that was the consequence of tumor lysis. The rapid recovery of renal function after normalization of serum phosphate by medication and frequent hemodialysis also favors this diagnosis. Hemodialysis is primarily supportive in acute renal failure and should be provided until there is evidence of renal recovery. However, in cases where further chemotherapy is administered, hemodialysis contributes to further phosphate clearance and prevention of further Renal damage.

Renal biopsy is not routinely indicated in the manage- ment of TLS with renal failure because the presumptive histologic diagnosis is acute tubular necrosis. However, in the context of progressive hematologic disease or continu- ing renal dysfunction, a renal biopsy may be indicated. A renal biopsy helps exclude other differential diagnoses such as an acute interstitial nephritis. It also yields important prognostic information about the kidney with regard to any background damage and, hence, the likelihood of renal recovery. We could not justify the risk of renal biopsy in our patient in view of severe thrombocytopenia and rapid recovery, and in addition, we did not feel it would change the patient’s management.

We highlight this interesting case of TLS that had 2 distinct biochemical aberrations with equally distinct mechanisms of injury. With the increasing use of rasburi- case in hematologic malignancies, it is expected that the incidence of TLS secondary to hyperuricemia will decrease and presentations of normouricemic TLS will be more frequently encountered. In this setting of pretreatment with rasburicase, calcium phosphate precipitation is probably a major cause of renal damage in TLS and alkalization should be withheld [28]. In TLS with renal failure, early renal replacement therapy is indicated, although as illustrated, the outcomes may be variable. Renal biopsy should be considered in cases where renal function fails to improve as anticipated.

Amr El-Husseini Alberto Sabucedo Jorge Lamarche Craig Courville Alfredo Peguero

James A. Haley Veterans Hospital USF Division of Nephrology and Hypertension

University of South Florida Tampa, FL 33612, USA

E-mail address: [email protected] doi:10.1016/j.ajem.2010.12.029


  1. Bosly A, Sonet A, Pinkerton CR, McCowage G, Bron D, Sanz MA, et al. Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study. Cancer 2003;98:1048-54.
  2. Hummel M, Reiter S, Adam K, Hehlmann R, Buchheidt D. Effective treatment and prophylaxis of hyperuricemia and impaired renal function in Tumor lysis syndrome with low doses of rasburicase. Eur J Haematol 2008;80(4):331-6.
  3. Shimada M, Johnson RJ, May Jr WS, Lingegowda V, Sood P, Nakagawa T, et al. A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome. Nephrol Dial Transplant 2009; 24(10):2960-4.
  4. Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate- use trial. Leukemia 2001;15:1505-9.
  5. Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 2001;19:697-704.
  6. Goldman SC, Holcenberg JS, Finklestein JZ, Hutchinson R, Kreissman S, Johnson FL, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998-3003.
  7. Markowitz GS, Perazella MA. Acute phosphate nephropathy. Kidney Int 2009;76(10):1027-34.
  8. Monballyu J, Zachee P, Verberckmoes R, Boogaerts MA. Transient acute renal failure due to tumor-lysis-induced severe phosphate load in a patient with Burkitt’s lymphoma. Clin Nephrol 1984;22(1): 47-50.
  9. Abcar A, Hever A, Momi JS, Sim JJ. Acute phosphate nephropathy. Perm J 2009;13(3):48-50.
  10. Rocuts AK, Waikar SS, Alexander MP, Rennke HG, Singh AK. Acute phosphate nephropathy. Kidney Int 2009;75(9):987-91.
  11. Sica DA, Carl D, Zfass AM. Acute phosphate nephropathy–an emerging issue. Am J Gastroenterol 2007;102(9):1844-7.
  12. Lin CJ, Chen HH, Hsieh RK, Chen YC, Wu CJ. Acute tumor lysis syndrome in a hemodialysis patient with diffuse large B cell lymphoma. Med Oncol 2009;26(1):93-5.
  13. Arrambide K, Toto RD. The tumor lysis syndrome. Semin NephroL 1993;13:273-80.
  14. Haller CH, Dhadly M. The tumour lysis syndrome. Ann Int Med 1991;


  1. Razis E, et al. Incidence and treatment of tumor lysis syndrome in patients with acute leukaemia. Acta Haematol 1994;91:171-4.
  2. Ho VQ, Wetzstein GA, Patterson SG, Bradbury R. Abbreviated rasburicase dosing for the prevention and treatment of hyperuricemia

in adults at risk for tumor lysis syndrome. Support Cancer Ther 2006;3 (3):178-82.

  1. Cadman EC, Lunberg WB, Bertino JR. Hyperphosphatermia and hypocalcemia accompanying rapid cell lysis in a patient with Burkitt’s lymphoma and Burkitt cell leukemia. Am J Med 1977;62 (2):283-90.
  2. Ettinger DS, Harker WG, Gerry HW, Sanders RC, Saral R. Hyperphosphatemia, hypocalcemia, and transient renal failure. Results of cytotoxic treatment of acute lymphoblastic leukemia. JAMA 1978; 239(23):2472-4.
  3. Kanfer A, Richet G, Roland J, Chatelet F. Extreme hyperpho- sphataemia causing acute anuric nephrocalcinosis in lymphosarcoma. Br Med J 1979;1:1320.
  4. Boles JM, Dutel JL, Briere J, Mialon P, Robasckiewicz M, Garre M, et al. Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia. Cancer 1984;53 (11):2425-9.
  5. Wolf G, Hegewisch-Becker S, Hossfeld DK, Stahl RA. Hyperuri- cemia and renal insufficiency associated with Malignant disease: urate oxidase as an efficient therapy? Am J Kidney Dis 1999;34 (5):E20.
  6. Mahmoud HH, Leverger G, Patte C, Harvey E, Lascombes F. Advances in the management of malignancy-associated hyperuricaemia. Br J Cancer 1998;77(Suppl 4):18-20.
  7. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 1993;94(2):133-9.
  8. O’Connor NT, Prentice HG, Hoffbrand AV. Prevention of urate nephropathy in the tumour lysis syndrome. Clin Lab Haematol 1989; 11(2):97-100.
  9. Mukherjee E, Mukherji D, Jayawardene SA, Kon SP. Tumor lysis syndrome and acute renal failure–an increasing spectrum of presentations. Clin Nephrol 2007;68(3):186-9.
  10. Boles JM, Dutel JL, Briere J, Mialon P, Robasckiewicz M, Garre M, et al. Acute renal failure caused by extreme hyperphosphataemia after chemotherapy of an acute lymphoblastic leukaemia. Cancer 1984;53: 2425-9.
  11. Veenstra J, Krediet RT, Somers R, Arisz L. Tumour lysis syndrome and acute renal failure in Burkitt’s lymphoma. Description of 2 cases and a review of the literature on prevention and management. Neth J Med 1994;45(5):211-6.
  12. Van den Berg H, Reintsema AM. Renal tubular damage in rasburicase: risks of alkalinisation. Ann Oncol 2004;15(1):175-6.