Journal

Correspondence

n engl j med 377;5 nejm.org August 3, 2017 499

Acute Kidney Injury in Patients with Cancer

To the Editor: Rosner and Perazella (May 4 is- sue)1 provide an overview of acute kidney injury in patients with cancer. Acute kidney injury jeop- ardizes the continuation of effective cancer treat- ment in a patient and limits the opportunity for inclusion in clinical trials. The review did not mention that diuretics are a major and underes- timated cause of nephrotoxicity.2 Diuretics are commonly used in daily practice, despite uncer- tainties about the benefits except in the context of fluid overload and cardiac dysfunction,3 and are frequently associated with the presence of the tumor lysis syndrome, sepsis,4 and hemodynamic instability.5

We assessed prognostic factors of modified major adverse kidney events at day 30 (MAKE30 — a composite of death, persistent renal failure, discontinuation of the most effective cancer treat- ment, and long-term dialysis) in 133 critically ill patients with cancer who were transferred to the intensive care unit and received renal-replace- ment therapy. A multivariate analysis confirmed that the usual risk factors for acute kidney injury — the tumor lysis syndrome (in patients receiv- ing first-line chemotherapy), use of vasopres- sors, and hepatic failure — were independently associated with the MAKE30 outcome, but di- uretic use was also independently associated with that combined outcome (Table 1).

Preventing acute kidney injury in critically ill patients with cancer is important. Weighing the risks and benefits of diuretic use in these pa- tients who commonly present with the tumor lysis syndrome, sepsis, and hemodynamic insta- bility seems to be crucial for short-term and long-term outcomes.

Colombe Saillard, M.D. Institut Paoli-Calmettes Marseille, France

Michael Darmon, M.D., Ph.D. Hôpital Nord Saint-Etienne, France

Djamel Mokart, M.D., Ph.D. Institut Paoli-Calmettes Marseille, France mokartd@ ipc . unicancer . fr

No potential conflict of interest relevant to this letter was re- ported.

1. Rosner MH, Perazella MA. Acute kidney injury in patients with cancer. N Engl J Med 2017; 376: 1770-81. 2. Pierson-Marchandise M, Gras V, Moragny J, et al. The drugs that mostly frequently induce acute kidney injury: a case–non- case study of a pharmacovigilance database. Br J Clin Pharmacol 2017; 83: 1341-9. 3. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006; 333: 420. 4. Honore PM, Jacobs R, Hendrickx I, et al. Prevention and treatment of sepsis-induced acute kidney injury: an update. Ann Intensive Care 2015; 5: 51. 5. Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the prevention and attenuation of acute kidney injury. Nat Rev Nephrol 2014; 10: 37-47. DOI: 10.1056/NEJMc1707248

To the Editor: In their review, Rosner and Pera- zella summarize various mechanisms of acute kid- ney injury in patients with cancer. As stated by the authors, some chemotherapeutic agents can pro- mote the development of thrombotic microangi- opathy.

Malignant conditions can also be the cause of secondary microangiopathy.1 The most common cancers associated with microangiopathies are gastric, breast, prostate, and lung cancers.2 In the case of prostate cancer, some patients are prone to having a presentation similar to that of the atypical hemolytic–uremic syndrome.3 Furthermore, in pa- tients who have a predisposition to complement dysregulation, cancer has been associated with the occurrence of the atypical hemolytic–uremic syndrome.4

Thus, acute kidney injury caused by micro-

Prognostic Factor Odds Ratio (95% CI) P Value

Diuretic use 3.2 (1.00–10.13) 0.04

Receiving first-line chemotherapy

3.7 (1.09–12.73) 0.03

Hepatic failure 3.6 (1.03–12.53) 0.04

Use of vasopressors 5.7 (1.90–17.31) 0.002

* CI denotes confidence interval.

Table 1. Independent Prognostic Factors Associated with Modified Major Adverse Kidney Events at Day 30 after Discharge from the Intensive Care Unit.*

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 377;5 nejm.org August 3, 2017500

angiopathy should not be seen only as a poten- tial complication of treatments in patients with cancer but also as a specific cancer-related injury. Although microangiopathy-related acute kidney injury caused by cancer is uncommon, early diag- nosis and recognition of this cancer-related injury is crucial, mainly to avoid immune-modulating therapies that are inappropriate in this context. Aliénor Dreyfus, M.D. Frederic M. Jacobs, M.D. Hôpital Antoine-Béclère Clamart, France frederic . jacobs@ abc . aphp . fr

No potential conflict of interest relevant to this letter was re- ported.

1. Morton JM, George JN. Microangiopathic hemolytic anemia and thrombocytopenia in patients with cancer. J Oncol Pract 2016; 12: 523-30. 2. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemo- lytic uraemic syndrome. Lancet 2017 February 25 (Epub ahead of print). 3. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 re- ported cases. Medicine (Baltimore) 2012; 91: 195-205. 4. Favre GA, Touzot M, Fremeaux-Bacchi V, et al. Malignancy and thrombotic microangiopathy or atypical haemolytic and uraemic syndrome? Br J Haematol 2014; 166: 802-5.

DOI: 10.1056/NEJMc1707248

The authors reply: We thank Saillard et al. for their observations on the risk of diuretics in crit- ically ill patients with cancer who either have or are at risk for acute kidney injury. Their observa- tions are in line with those from observational studies that caution about the risk of adverse out- comes with the use of diuretics in patients with acute kidney injury.1 In the few prospective trials that have examined the use of diuretics in pa- tients with acute kidney injury, these agents were shown to be either ineffective or detrimental in the prevention and treatment of the condition, with no effect on the duration of acute kidney injury or prevention of the need for dialysis.1 However, di- uretics have an important role in the manage- ment of volume overload in patients with or with- out acute kidney injury. For instance, a higher positive fluid balance was associated with worse outcomes, and diuretic use was associated with a higher rate of survival.2 Furthermore, in a second- ary analysis of data from patients with acute kid- ney injury in the Fluid and Catheter Treatment Trial, furosemide dose administered after the de- velopment of acute kidney injury improved fluid

balance, and this improvement was associated with a lower mortality.3 Thus, diuretics should be used cautiously in patients with acute kidney in- jury who have clear indications for reduction of volume overload. For the specific group of pa- tients with both cancer and acute kidney injury, individualized therapeutic decisions should be made that weigh the risks and benefits of diuret- ics, with clear goals of the therapy and cessation of the diuretic if these goals are not being met.

Dreyfus and Jacobs raise the point that vari- ous cancers are associated with the development of thrombotic microangiopathy in the absence of exposure to chemotherapeutic drugs. We agree that certain malignant conditions, in par- ticular mucin-producing adenocarcinomas, are a more common cause of this form of acute kid- ney injury.4 However, cancer as a direct cause of thrombotic microangiopathy is less common than thrombotic microangiopathy induced by chemotherapy.4 A feature of this less-common cause of thrombotic microangiopathy is that 90% of patients in whom cancer-related throm- botic microangiopathy develops have metastatic disease, whereas chemotherapeutic agents often cause thrombotic microangiopathy despite mini- mally detectable or no detectable cancer.4 Fur- thermore, up to 15% of patients with metastatic cancer–related thrombotic microangiopathy fre- quently have disseminated intravascular coagu- lation,5 which is absent in patients with the drug-induced form. Another distinguishing fea- ture is that patients with cancer-related throm- botic microangiopathy have a leukoerythroblastic blood smear and higher serum lactate dehydroge- nase levels than patients who have chemotherapy- associated thrombotic microangiopathy.4,5 It has been speculated that direct vascular endothelial injury (with release of large von Willebrand fac- tor multimers) from the mucin produced by these malignant conditions, as well as circulat- ing tumor cells and tumor emboli, cause throm- botic microangiopathy in this context.4,5

Mitchell H. Rosner, M.D. University of Virginia Health System Charlottesville, VA mhr9r@ virginia . edu

Mark A. Perazella, M.D. Yale University School of Medicine New Haven, CT

Since publication of their article, the authors report no fur- ther potential conflict of interest.

n engl j med 377;5 nejm.org August 3, 2017 501

notices

1. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006; 333: 420-5. 2. Teixeira C, Garzotto F, Piccinni P, et al. Fluid balance and urine volume are independent predictors of mortality in acute kidney injury. Crit Care 2013; 17: R14. 3. Grams ME, Estrella MM, Coresh J, Brower RG, Liu KD. Fluid balance, diuretic use, and mortality in acute kidney injury. Clin J Am Soc Nephrol 2011; 6: 966-73. 4. Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis 2015; 66: 857-68. 5. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 re- ported cases. Medicine (Baltimore) 2012; 91: 195-205. DOI: 10.1056/NEJMc1707248 Correspondence Copyright © 2017 Massachusetts Medical Society.

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