Acute Kidney Injury in the Cancer Patient G. Adam Campbell, Daniel Hu, and Mark D. Okusa Acute kidney injury (AKI) is a frequent and significant complication of cancer and cancer therapy. Cancer patients frequently encounter risk factors for AKI including older age, CKD, prerenal conditions, sepsis, exposure to nephrotoxins, and obstructive physiology. AKI can also be secondary to paraneoplastic conditions, including glomerulonephritis and microangiopathic processes. This complication can have significant consequences, including effects on patients’ ability to continue to receive therapy for their malignancy. This review will serve to summarize potential etiologies of AKI that present in patients with cancer as well as to highlight specific patient populations, such as the critically ill cancer patient. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Acute renal failure, AKI, Oncology, Nephrotoxins, Malignancy

Introduction and Epidemiology Acute kidney injury (AKI) is a significant complication in patients with cancer and is associated with high morbidity and mortality. Rates of AKI vary in cancer patients on the basis of several factors, including type of malignancy (either solid tumor or hematologic), severity of malignancy, associated complications such as critical illness, and types of supportive or interventional therapy given to the patient. The largest cohort study of Danish cancer patients documented the highest rates of AKI in patients with kidney cancers at 44%, myeloma at 33% and liver cancer at 31.8%.1 Patients with leukemia are also at high risk for AKI, with the Danish cohort study documenting a rate of 27.5%.1 Another study including patients with high-risk myelodysplastic syndrome to patients with acute myelogenous leukemia documented an AKI rate of 36% in a 537-patient study.2 Among critically ill cancer patients, the rate of AKI is between 12% and 49%, with 9% to 32% of patients requiring renal replacement therapy.3-6 These rates are higher in critically ill cancer patients than in other noncancer patient populations of similar severity of illness.3,7,8 In critically ill patients with cancer, AKI usually does not occur in isolation; rather, it occurs in the setting of multiple organ dysfunction. Among patients with cancer and critical illness who develop AKI, outcomes are worse than other populations.6,7,9 Mortality rates range from 72% to 85% when renal replacement therapy is needed.3 The most common cause of AKI in patients with critical illness is sepsis.10,11 In these patients with critical illness, AKI due

From Department of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA. Financial Disclosure: M.O. has affiliations with AM Pharma, American Physiological Society, PGX Health/Adenosine Therapeutics, LLC, and UVA Patent Office. The other authors declare that they have no relevant financial interests. Address correspondence to G. Adam Campbell, MD, Division of Nephrology, Box 800133, University of Virginia Health System, Charlottesville, VA 22908. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00


to medications or secondary to the malignancies is also seen.6 In a recent study of 200 patients with high-grade hematological malignancies and AKI, 68.5% had AKI according to the RIFLE criteria. Of all cases of AKI, 91.4% of these cases were due to 5 causes: hypoperfusion, tumor lysis syndrome, acute tubular necrosis (ATN), nephrotoxins and hemophagocytic lymphohistiocytosis.12 The outcomes of cancer patients with AKI are affected by several factors. Some cancer chemotherapeutic agents are cleared by the kidney. AKI alters the pharmacokinetics of these agents, which may lead to toxic levels. On the other hand, AKI requiring dialysis may lead to subtherapeutic levels of cancer drugs and potentially ineffective cancer treatment. In addition, dose-related adjustments of ancillary drugs, such as antibiotics and narcotics, may be necessary in patients with AKI. Toxic doses or inadequate doses may lead to adverse outcomes (Table 1). Thus, despite considerably improved chemotherapeutic agents, AKI may limit the efficacy of these improved agents. Kidney function should be closely monitored, and when possible, drugs with lower kidney toxicity or without kidney toxicity should be considered.13,14 A major limitation in patients receiving dialysis is that the information on the pharmacokinetics of drug distribution affected by dialysis is limited. Another major factor affecting the outcomes of cancer patients is frequent association between critical illness and multiorgan dysfunction. Mortality rates in patients with multiorgan dysfunction increase with the number of affected organs.15 In an observational study of 3591 critically ill patients requiring continuous renal replacement therapy, there was 90% and 100% mortality in patients with 4 and 5 dysfunctioning organs, respectively.15 Other factors contributing to poor outcomes in cancer patients with AKI include altered nutritional status and immunity and infections related to dialysis access. Some studies have documented a greater than 80% recovery of kidney function and 94% rate of dialysis independence if the cancer patient survives their critical illness.6 Certain patient characteristics, including age, performance status, and available critical illness severity scoring systems, may help identify patients who would benefit from more aggressive management.16-18

Advances in Chronic Kidney Disease, Vol 21, No 1 (January), 2014: pp 64-71

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obstruction and ureteral obstruction. The most common solid organ malignancies causing obstructive processes include bladder, prostate, uterus, and cervix malignancies. Ureteral obstruction can also occur in these settings, as well as because of external compression from retroperitoneal lymphadenopathy. Diagnosis of obstructive uropathy may be difficult, and the diagnosis should always be suspected in patients with cancer. Anuria, flank pain, a palpable mass, or a palpable bladder should raise suspicion for the diagnosis of obstruction. However partial obstruction may lead to AKI without anuria. Laboratory Etiologies of AKI tests demonstrating hyperkalemia with a nonanion gap AKI seen in cancer patients can be categorized as having metabolic acidosis is suggestive of a renal tubular acidoprerenal, intrarenal, or postrenal etiologies (Table 2).19 sis associated with obstruction.22 These patients are at increased risk for AKI because of Postrenal AKI is associated with a bland urine sediseveral factors related to older age, preexisting CKD, asment, which may contain crystals or blood. Diagnosis of sociated comorbidities, and coexisting drug therapies obstructive uropathy can be confirmed through diagnostic (Table 3). imaging. Imaging can be performed by ultrasound or computed tomography (CT) scan and most commonly will Prerenal AKI show hydronephrosis and/or hydroureter. The utility of Prerenal AKI is frequently seen in cancer patient poultrasound relates to its diagnostic yield in high-risk papulations. In these patients, tients, rapid diagnosis, simprerenal AKI may be due to plicity, noninvasiveness, CLINICAL SUMMARY true intravascular volume and cost-effectiveness.23 CT depletion, such as in the scans have the benefit of be AKI is common in patients with cancer, with overall rates setting of sepsis, vomiting, ing able to better visualize and etiologies varying greatly based on the type of cancer or diarrhea.6 In some cases other pelvic organs.24 Oband other comorbidities. medications may lead to mustructive AKI can present  Drug-induced AKI can be seen with therapeutic agents used cositis and reduced oral in the absence of hydroin treatment of cancer, contrast agents, and drugs used in intake, which can lead to prenephrosis or hydroureter in the treatment of the patient’s co-morbid illnesses. renal AKI. In septic patients, the setting of retroperitoneal  AKI in the critically ill cancer patient is most commonly hypotension and vasodilafibrosis, in early obstruction caused by sepsis, with prognosis affected by the patient’s tion due to sepsis or pharmaas a result of the malignancy overall clinical status. cological interventions using itself, or as a complication of vasoconstrictors, such as nortreatment of malignancy. epinephrine or vasopressin, Radiation therapy of the may lead to hypoperfusion and prerenal AKI. Prerenal abdomen and pelvis can lead to retroperitoneal azotemia can also be seen in the setting of complications fibrosis. Treatment of obstructive AKI involves relief of of malignancies, such as sinusoidal obstruction disease.17 obstruction by percutaneous nephrostomy or stenting. Hypercalcemia, which is seen in 20% to 30% of malignanRecovery depends on the severity and duration of cies, can lead to a prerenal state because of the effects of obstruction. hypercalcemia inducing kidney vasoconstriction as well as volume depletion from natriuresis and diuresis.20 Intrinsic Kidney Disease Finally, medications such as diuretics, angiotensinIntrinsic causes of AKI in cancer patients include primary converting enzyme inhibitors, angiotensin receptor glomerular disease, ATN due to toxins or ischemia, infilblockers, or nonsteroidal anti-inflammatory agents used trative processes, and microangiopathic processes.16,19,21 for the malignancy or other medical conditions, such as These disease states may be secondary to either the hypertension or congestive heart failure, can lead to prereprimary disease process or its treatment. It is nal AKI. Consideration should be given to the riskimportant to consider the patient’s malignancy and benefits of continuing these medications in patients with any chemotherapeutic agents the patient has received 21 cancer who are at risk for prerenal AKI. when forming the patient’s differential diagnosis.

This review serves to summarize the different causes of AKI in cancer patients and to highlight several concerns specific to this patient population, including disease-related complications and nephrotoxicity with chemotherapy agents. We will avoid or minimize discussions related to myeloma-associated kidney disease, hematopoietic stem cell transplant-associated kidney disease, and tubulointerstitial lesions associated with cancer chemotherapy because these areas are covered in detail in other articles in this issue.

Postrenal AKI and Obstruction Postrenal AKI due to obstructive processes is seen more commonly in malignancies than in the general population.19 Postrenal AKI is commonly due to bladder outlet

Glomerulonephritis Glomerular processes seen in malignancies include antineutrophil cytoplasmic antibody (ANCA) vasculitis,


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Table 1. Effect of AKI on Outcomes of Cancer Patients 1. Inadequate cancer therapy a. Type of chemotherapy (allogenic/autologous transplantation) b. Optimal dose of chemotherapy 2. AKI-related mortality in critically ill patients a. Multiorgan dysfunction b. Intensive-care-associated high mortality 3. Inadequate concomitant drugs a. Toxic doses of drugs b. Inadequate dose of drugs due to increased clearance by dialysis Abbreviation: AKI, acute kidney injury.

membrano-proliferative glomerulonephritis, and thrombotic microangiopathy (TMA).25 A case-control study of 200 consecutive patients with ANCA vasculitis showed a relative risk of malignancy of 6 compared with an age- and gender-matched general population and a disease control group comprising patients with systemic lupus erythematosus or Henoch-Schonlein purpura.25 These results were also confirmed in further studies suggesting an association of malignancy and ANCA vasculitis.26,27 Thus, patients with ANCA-associated vasculitis have an increased risk of preceding or concurrent malignancy. Case reports also exist for membrano-proliferative glomerulonephritis in malignancies.19 TMA, either thrombotic thrombocytopenia purpura or hemolytic uremic syndrome, is seen in malignant conditions and in response to treatment regimens. The most common malignancies associated with TMA include gastric, breast, lung, prostate, and pancreas cancer; 5.7% of patients with metastatic cancers have TMA.19,28 Gastric cancer is the most common malignancy seen with TMA; it is responsible for over half of malignancy-associated TMA. Breast and lung cancers are noted to be the next most frequently observed malignancies associated with TMA.19,29 Chemotherapeutic agents associated with TMA include mitomycin C, bleomycin, cisplatin, and 5-flouro-uracil.19

Ischemic ATN Ischemic ATN in cancer patients may be related to severe dehydration, hypotension, or sepsis, in which prerenal conditions lead to ATN.16 Patients with malignancies are predisposed to contrast nephropathy due to risk factors that include older age, CKD, congestive heart failure, dehydration, coexisting exposure to nephrotoxins, or sepsis. Contrast agent toxicity and other nephrotoxins will be discussed in further detail in a later section.

Nephrotoxins: Medications and Contrast Agents

Table 2. Etiologies of Acute Kidney Injury in Cancer Patients 1. Prerenal a. Effective intravascular volume depletion i. Vomiting, diarrhea, anemia, sepsis b. Sinusoidal obstructive disease c. Hypercalcemia 2. Intrarenal a. Glomerular i. Membranous nephropathy ii. Minimal change disease iii. Focal and segmental glomerulonephritis iv. Antineutrophil cytoplasmic antibody v. Thrombotic microangiopathy vi. Membrano-proliferative glomerulonephritis b. Acute tubular necrosis c. Tumor lysis syndrome d. Myeloma cast nephropathy e. Kidney cell cancer with nephrectomy 3. Nephrotoxic agents a. Gemcitibine b. Cisplatin c. Methotrexate d. Bevacizumab e. Interferon-a f. Ifosphamide g. Contrast media 4. Postrenal a. Obstruction b. Retroperitoneal fibrosis

metastatic disease, and hypercalcemia. In a retrospective analysis of 398 cancer patients treated with bisphosphonate, 16 (4%) developed AKI.30 The risk factors seen in this study in these patients included concomitant nephrotoxin usage (nonsteroidal anti-inflammatory drugs, cisplatin), worsening performance status, and urologic malignancy.30 The mechanism of damage includes ATN as well as collapsing focal and segmental glomerular sclerosis (FSGS) when seen with significant proteinuria.31 There have also been rare case reports of minimal change disease with pamidronate.31,32 In the process of approval for clinical use, zoledronic acid had changes to dose and infusion time made out of concern for kidney toxicity. Documented risk of AKI with zolendronic acid ranges between 9% and 24%.33 When a 25% decline in creatinine clearance is used as defining AKI, the rate of AKI reaches 42% to 54%.33 Bisphosphonates can be dose adjusted for preexisting kidney insufficiency, and in a study of 220 patients (36 with baseline impaired kidney function), there was a similar incidence of AKI in patients with creatinine clearance of 30-60 mL/minute receiving renally adjusted zolendronic acid (19.4%) compared with patients with creatinine clearance greater than 60 mL/minute receiving full-dose zoledronic acid (20.7%).33

Bisphophonates Bisphosphonates are widely prescribed and highly effective at limiting bone loss, and they are commonly used in the treatment of cancer patients with myeloma, skeletal

Cisplatin Cisplatin, a platinum-based alkylating agent, is used in the treatment of many malignancies, including solid

Cancer-Associated AKI

Table 3. Patient Risk Factors for Acute Kidney Injury in Cancer Patients 1. Advanced age 2. Preexisting CKD 3. Medical comorbidities a. Diabetes b. Congestive heart failure c. Hypertension d. Renal artery stenosis 4. Coexisting drug therapy a. Diuretics b. Nonsteroidal anti-inflammatory drugs c. Renin-angiotensin-mediated drugs

tumors and lymphoma. Renal tubules are the primary kidney site of toxicity.24 Cisplatin nephrotoxicity is seen in up to 30% of patients and is generally seen between 7 and 10 days of dosing.24 These changes can be permanent in nature, with chronic tubulointerstitial fibrosis and tuCisplatin nephrotoxicity bular dysfunction.34,35 manifesting as tubulopathies can present with Fanconi syndrome, proteinuria, phosphate wasting, and sodium wasting.34 Mechanisms of toxicity with cisplatin include activation of intrinsic and mitochondrial apoptotic pathways, an increase in reactive oxygen species, and an increase in tumor necrosis factor-a.34-36 Distal tubule toxicity is manifested with decreased expression of aquaporin 2 and loss of concentrating ability.37 Preventative strategies have been studied extensively in vitro and in vivo with limited success, and few approaches have reached clinical human investigation.35 In a study of 157 patients treated for testicular germ cell cancer, 72% received chemotherapy with cisplatin as part of their regimen. New-onset CKD as defined by an estimated glomerular filtration rate (eGFR) of less than 60 by the Modification of Diet in Renal Disease equation was noted in 19 patients (12.1%), all in the chemotherapy group. This risk was only statistically significant in patients receiving 3 cycles (13.8% of patients receiving 3 cycles developed CKD) and 4 or more cycles (20.9% of patients receiving 4 or more cycles developed CKD).38

Methotrexate The dihydrofolate reductase inhibitor methotrexate is extensively used in breast and ovarian cancers, lymphomas, and leukemias. Methotrexate nephrotoxicity is due to precipitation of methotrexate and its metabolites in the renal tubules. Because methotrexate and its metabolites are renally excreted, development of AKI can further lead to toxic levels of the drug. Methotrexate nephrotoxicity is characterized by oliguric AKI, and it is often associated with other end-organ effects of methotrexate.24 Risk of AKI is dose dependent and seen most commonly with high-dose therapy.34 Risk of methotrexate-induced AKI is noted when levels exceed 15 mmol/L at 24 hours, 1.5 mmol/L at 48 hours, and 0.5


mmol/L at 72 hours.3 Other risk factors include volume depletion, underlying CKD, and acidic urine.34 Rates of AKI range between 1.8% and 12% in published studies.34,39 Prevention strategies include supportive care, hydration, use of intravenous fluids, and alkalinization of the urine.34,39 Leucovorin, either with or without thymidine, may also be helpful to minimize the toxic effects of methotrexate.40 Glucarbidase, carboxypeptidase G2, is a therapeutic option in the setting of toxic methotrexate levels and can be used in the setting of AKI.34,41 Hemodialysis can be used, but with some limitations given the large volume of distribution of methotrexate and rebound of methotrexate levels after therapy.34,39

Ifosfamide Ifosfamide is an alkylating agent used for the treatment of solid tumors including sarcoma, testicular cancer, and lymphoma. In addition to AKI, tubulopathies are also seen with ifosfamide, manifested by nephrogenic diabetes insipidus and Fanconi syndrome (glycosuria, aminoaciduria, and proteinuria).34 Ifosfamide also causes direct tubular toxicity, and the mechanism is through a metabolite of ifosfamide, chloroacetaldehyde. Chloroacetaldehyde damage leads to depletion of glutathione and sulfhydryl compounds and is most noticeable in the proximal tubule.24 Kidney toxicity is seen at greater rates with patients with prior ifosfamide or cyclophosphamide exposure and preexisting kidney insufficiency. Hydration and treatment with Mesna, a cytoprotective drug that may act as an antioxidant, can be used to prevent toxicities relating to hemorrhagic cystitis, but it does not have a significant effect on nephrotoxicity.24,34

Gemcitabine and Bevacizumab Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, and gemcitabine, a pyrimidine antagonist, have been associated with AKI manifesting as TMA.42 With bevacizumab, proteinuria and hypertension were also associated with the development of TMA. In a case series of 6 patients with AKI on bevacizumab, all of which had TMA by biopsy, improvement was noted in AKI when bevacizumab was discontinued. Data using a VEGF knockout mouse suggested that decreased glomerular VEGF would lead to a similar pattern of damage seen with TMA.42 Gemcitibine also has been associated with AKI presenting as TMA, frequently in association with hypertension. Risk of TMA with gemcitabine appears to be dose dependent and is increased in patients with prior therapy with mitomycin-C.34 In 2 of the largest series of patients with TMA from gemcitabine, 2 of 8 patients and 7 of 29 patients, respectively, developed ESRD.43,44 The primary treatment is withdrawal of gemcitabine. Plasma exchange has been used in


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Interferon-a (IFN-a) is used in the treatment of malignancies. Manifestations of kidney injury seen with IFN-a include glomerular and podocyte injury. This is most commonly manifested as minimal change disease or FSGS. Minimal change disease was documented in 8 patients in case reports summarized by Markowitz and colleagues.45 All 8 cases were complicated by nephroticrange proteinuria with 2 of the 8 patients developing AKI. Discontinuation of IFN-a, with the addition of steroids in some of the cases, led to clinical remission in all of the patients.45 The histologic variance of FSGS seen with IFN-a includes collapsing FSGS frequently with nephrotic syndrome. Potential mechanisms for damage include alteration to podocyte cellular proliferation and metabolism or increased podocyte oxidative capacity. Treatment includes discontinuation of IFN-a, but resolution is not universally seen. Other treatment options include steroids or cyclophosphamide for FSGS seen with IFN-a, but these are not reported as being particularly effective.34,45

higher preoperative eGFR.56 The decreased incidence of AKI seen in patients with large kidney cell cancers was postulated to be the result of compensatory hypertrophy in the contralateral kidney before nephrectomy, an adaptation that would have occurred to a lesser degree in patients with small kidney cell cancers.56 Partial nephrectomy can also be performed for patients with suitable primary lesions. In a study assessing AKI in patients undergoing partial nephrectomy, 70 of 362 patients (19%) developed AKI within 30 days of surgery, which was a lower rate of AKI than seen in comparable studies of patients undergoing radical nephrectomy. Factors associated with increased risk of AKI included an increase in warm ischemia time, a decrease in the amount of remaining kidney tissue, and decreased preoperative glomerular filtration rate.57 In a study by Kang and colleagues, 32 patients undergoing partial nephrectomy were compared to 92 patients undergoing radical nephrectomy. Although this study was focused on kidney function 1 year after surgery, it should be noted that the rate of progression to CKD, as defined as a GFR less than 60 mL/minute, was 6.3% in the partial nephrectomy group and 68.5% in the radical nephrectomy group.58 Consideration should be given for partial nephrectomy when this is an option.

Contrast Media

Tumor Lysis Syndrome

Contrast-induced nephropathy (CIN), which occurs most commonly after CT examinations with iodinated contrast media, is seen in patients with malignancies. CKD, a risk factor for CIN, is prevalent in cancer patients.46,47 Other risk factors for CIN that are common in cancer patients include dehydration and concomitant use of nephrotoxins, including chemotherapy agents. Rates of CIN range between 1% and 5%.46,48,49 Given the risks of CIN in cancer patients, preventative strategies should be used, including volume expansion with isotonic saline or sodium bicarbonate.50-53 Consideration should also be given to the use of N-acetylcysteine and/or bicarbonate in these patients, but the supportive data for their use are controversial.50,54 Furthermore, consideration of alternative imaging modalities, which do not require contrast agent, should also be considered if clinically appropriate.46,55

Tumor lysis syndrome is seen in the setting of rapid cellular turnover of large or fast-growing malignancies and after chemotherapy. Notable findings with tumor lysis syndrome include hypocalcemia, hyperkalemia, hyperphosphatemia, hyperuricemia, and AKI. The primary mechanism of kidney injury includes urate and phosphate nephropathy. Urate nephropathy occurs because of intratubular obstruction and direct toxicity.19,59,60 Phosphate nephropathy is due to direct toxicity or calcium phosphate deposition.19,61 Patients can receive prophylactic therapy to prevent tumor lysis syndrome, including hydration and the use of allopurinol.62 A rare complication of allopurinol usage is xanthine deposition.14,19 Rasburicase may be used to decrease incidence of tumor lysis.63,64 Rasburicase may be effective after onset of AKI.62 In patients in which medical therapy is ineffective or excessive phosphate load leads to nephrotoxicity, hemodialysis can be used.65

patients with TMA from gemcitabine but with limited success.34,43


Kidney Cancers: Radical and Partial Nephrectomy Nephrectomy for treatment of kidney cell cancer is associated with AKI. In a retrospective study of 519 adults undergoing radical nephrectomy with preoperative eGFR greater than 60 mL/minute, 175 (33.7%) patients developed AKI. This was associated with a 4.24% increase in risk of developing CKD 1 year after nephrectomy.56 Risk factors for development of AKI in patients after radical nephrectomy that were identified in 1 study’s multivariate analysis included advanced age, being male, increased body mass index, smaller cancer size, and

Lymphomatous Infiltration Infiltration of the kidney by hematological malignancies, lymphoma, or leukemia19 and solid tumor malignancies such as lung, gastric, and breast cancer do not commonly lead to AKI.19,66 The diagnosis of lymphomatous infiltration is often unsuspected. In a published series of kidney biopsies in which the diagnosis of kidney lymphoma was made, 55 cases were reviewed and lymphoma was considered among preprocedure di-

Cancer-Associated AKI

agnosis in only 10 of these cases.67 Thus, this diagnosis should be considered and appropriate treatment may lead to resolution of the kidney failure.19,68 AKI in the Critically Ill Patient The severity of illness in cancer patients relates to sepsis and multiorgan failure, the cancer itself, or a consequence of treatment. Sepsis is the most common cause of AKI seen in patients with cancer.6,16,69 The need for some form of renal replacement therapy for treatment of AKI in critically ill cancer patients has ranged in published studies to be between 8% and 59%, with a higher incidence of renal replacement therapy noted in the setting of sepsis and septic shock.4,6 However, the mortality in these patients has improved with advances in care rendered in intensive care units (ICUs) within the last decade.16,69 A recent cohort study of 773 patients (15% with cancer) was unable to document an independent association with cancer and mortality in patients that required renal replacement therapy.70 These findings have led some authors to support the use of renal replacement therapy in select patients with cancer, although the broad application of this therapy for critically ill cancer patients remains a subject of debate.16-18,69,70 In reviewing the epidemiology of AKI in cancer patients, several factors must be considered. The documented rate of AKI in studies and reviews ranges between 13% and 42%. Subgroup analysis showed the highest rates to be in patients with septic shock and patients with myeloma.16 Data from a cohort study performed from 1997 to 2002 showed outcomes including ICU mortality, in-hospital mortality, and 6-month survival to be worse in patients with cancer compared with those without cancer.7,16 When these data were adjusted for duration of hospital stay before the patient required intensive care or were adjusted for severity of illness, 6-month survival was no longer affected by the presence of cancer.7,16 Other cohort studies have failed to associate the presence of cancer with mortality in multivariate analysis.9,16,17,70 These data suggest that other characteristics of the critical illness have more bearing on survival and should be considered. It is noteworthy that 1 study showed a 6-month mortality of cancer patients with AKI of 33% without additional organ system dysfunction that increased to 65%, 80%, and 93% with an increase in organ system of 1, 2, and 3 additional organ systems, respectively. Other factors in this study associated with increased mortality included age greater than 60 years, uncontrolled cancer, and poor performance status.18 In patients with AKI from sepsis with cancer, survival rates are similar in patients with cancer and ICU patients in general.16,71 When considering cancer patients with AKI, it is important not only to consider survival, but also dialysis dependence. Published data on recovery of kidney function after AKI


in critically ill cancer patients varies but can be favorable. In a study conducted from 2000 to 2004, 82% of patients reached a level of complete recovery and only 6% of patients required chronic dialysis.16,18 Another singlecenter cohort study from 2002 to 2005 found rates of ESRD after AKI of 21% and 22% at discharge and after 6 months, respectively.16,17 An additional cohort with lower rates of recovery (34% complete recovery and 25% partial recovery) underscores the need for further study and multicenter prospective studies.16,17 Until further data are available, current studies suggest that consideration of renal replacement therapy in select individuals is appropriate. Factors such as additional organ system involvement, age, performance status, and other critical-illness-related scoring systems, such as Acute Physiology and Chronic Health Evaluation II (APACHE II) or Simplified Acute Physiology Score II (SAPS II), should be considered in assessing the patient as a reasonable candidate for further aggressive ICU management including renal replacement therapy.16-18 A team-based approach with nephrologists, oncologists, and critical care physicians working together should be considered to best identify the select patients who would most benefit from renal replacement therapy.

Conclusion Cancer patients with AKI present a unique set of challenges to the treatment team and their nephrology care providers. Thorough evaluation to assess for general and cancer-related etiologies can assist in forming a treatment plan that best addresses the patient’s kidney and oncologic issues. It is important to consider that in certain circumstances treatment of the malignancy can lead to further kidney complications including AKI. This change in kidney function can necessitate adjustment in their oncologic care such as chemotherapy options, options for diagnostic evaluation, and other supportive care. Given the overall prognosis and kidney prognosis in some of these conditions, including critically ill cancer patients, aggressive care and support of these patients should be considered.

References 1. Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP, Sorensen HT. Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study. Eur J Intern Med. 2011;22(4):399-406. 2. Lahoti A, Kantarjian H, Salahudeen AK, et al. Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Cancer. 2010; 116(17):4063-4068. 3. Darmon M, Ciroldi M, Thiery G, Schlemmer B, Azoulay E. Clinical review: specific aspects of acute renal failure in cancer patients. Crit Care. 2006;10(2):211. 4. Joannidis M, Metnitz PG. Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin. 2005;21(2):239-249.


Campbell et al

5. Lameire N, Van Biesen W, Vanholder R. The changing epidemiology of acute renal failure. Nat Clin Pract Nephrol. 2006;2(7):364-377. 6. Lameire N, Van Biesen W, Vanholder R. Acute renal problems in the critically ill cancer patient. Curr Opin Crit Care. 2008;14(6): 635-646. 7. Benoit DD, Hoste EA, Depuydt PO, et al. Outcome in critically ill medical patients treated with renal replacement therapy for acute renal failure: comparison between patients with and those without haematological malignancies. Nephrol Dial Transplant. 2005;20(3): 552-558. 8. Darmon M, Thiery G, Ciroldi M, et al. Intensive care in patients with newly diagnosed malignancies and a need for cancer chemotherapy. Crit Care Med. 2005;33(11):2488-2493. 9. Bagshaw SM, Laupland KB, Doig CJ, et al. Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care. 2005;9(6):R700R709. 10. Bagshaw SM, Uchino S, Bellomo R, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2(3):431-439. 11. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. J Am Med Assoc. 2005;294(7):813-818. 12. Canet E, Zafrani L, Lambert J, et al. Acute kidney injury in patients with newly diagnosed high-grade hematological malignancies: impact on remission and survival. PLoS One. 2013;8(2):e55870. 13. Aapro M, Launay-Vacher V. Importance of monitoring renal function in patients with cancer. Cancer Treat Rev. 2012;38(3):235-240. 14. Launay-Vacher V, Spano JP, Janus N, et al. Renal insufficiency and anticancer drugs in elderly cancer patients: a subgroup analysis of the IRMA study. Crit Rev Oncology Hematol. 2009;70(2):124-133. 15. Schwilk B, Wiedeck H, Stein B, Reinelt H, Treiber H, Bothner U. Epidemiology of acute renal failure and outcome of haemodiafiltration in intensive care. Intensive Care Med. 1997;23(12):1204-1211. 16. Benoit DD, Hoste EA. Acute kidney injury in critically ill patients with cancer. Crit Care Clin. 2010;26(1):151-179. 17. Darmon M, Thiery G, Ciroldi M, Porcher R, Schlemmer B, Azoulay E. Should dialysis be offered to cancer patients with acute kidney injury? Intensive Care Med. 2007;33(5):765-772. 18. Soares M, Salluh JI, Carvalho MS, Darmon M, Rocco JR, Spector N. Prognosis of critically ill patients with cancer and acute renal dysfunction. J Clin Oncol. 2006;24(24):4003-4010. 19. Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated with cancer and its treatment: an update. J Am Soc Nephrol. 2005;16(1):151-161. 20. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373-379. 21. Lam AQ, Humphreys BD. Onco-nephrology: AKI in the cancer patient. Clin J Am Soc Nephrol. 2012;7(10):1692-1700. 22. Batlle D. Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med. 1981;304(7):373-380. 23. Licurse A, Kim MC, Dziura J, et al. Renal ultrasonography in the evaluation of acute kidney injury: developing a risk stratification framework. Arch Intern Med. 2010;170(21):1900-1907. 24. Denker B, Robles-Osorio ML, Sabath E. Recent advances in diagnosis and treatment of acute kidney injury in patients with cancer. Eur J Intern Med. 2011;22(4):348-354. 25. Pankhurst T, Savage CO, Gordon C, Harper L. Malignancy is increased in ANCA-associated vasculitis. Rheumatology (Oxford). 2004;43(12):1532-1535. 26. Edgar JD, Rooney DP, McNamee P, McNeill TA. An association between ANCA positive renal disease and malignancy. Clin Nephrol. 1993;40(1):22-25. 27. Knight A, Askling J, Ekbom A. Cancer incidence in a populationbased cohort of patients with Wegener’s granulomatosis. Int J Cancer. 2002;100(1):82-85.

28. Lohrmann HP, Adam W, Heymer B, Kubanek B. Microangiopathic hemolytic anemia in metastatic carcinoma. Report of eight cases. Ann Intern Med. 1973;79(3):368-375. 29. Antman KH, Skarin AT, Mayer RJ, Hargreaves HK, Canellos GP. Microangiopathic hemolytic anemia and cancer: a review. Medicine (Baltimore). 1979;58(5):377-384. 30. Bonomi M, Nortilli R, Molino A, et al. Renal toxicity and osteonecrosis of the jaw in cancer patients treated with bisphosphonates: a long-term retrospective analysis. Med Oncol. 2010;27(2):224-229. 31. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385-1393. 32. Barri YM, Munshi NC, Sukumalchantra S, et al. Podocyte injury associated glomerulopathies induced by pamidronate. Kidney Int. 2004;65(2):634-641. 33. Shah SR, Jean GW, Keisner SV, Ussery SM, Dowell JE. Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid. Support Care Cancer. 2012;20(1):87-93. 34. Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents. Clin J Am Soc Nephrol. 2012;7(10):1713-1721. 35. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008;73(9):994-1007. 36. Jiang M, Wang CY, Huang S, Yang T, Dong Z. Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway. Am J Physiol Renal Physiol. 2009;296(5):F983-F993. 37. Kim SW, Lee JU, Nah MY, et al. Cisplatin decreases the abundance of aquaporin water channels in rat kidney. J Am Soc Nephrol. 2001;12(5):875-882. 38. Suer E, Mermerkaya M, Gulpinar O, et al. Does the number of cycles of cisplatin based chemotherapy have any effect on renal function in patients with testicular germ cell tumor? J Urol. 2013. In press. Available online June 11, 2013. 10.1016/j.juro.2013.06. 009. [Epub ahead of print, June 11, 2013]. 39. Perazella MA. Crystal-induced acute renal failure. Am J Med. 1999;106(4):459-465. 40. Abelson HT, Fosburg MT, Beardsley GP, et al. Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oncol. 1983;1(3):208-216. 41. Patterson DM, Lee SM. Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther. 2010;10(1): 105-111. 42. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11): 1129-1136. 43. Humphreys BD, Sharman JP, Henderson JM, et al. Gemcitabineassociated thrombotic microangiopathy. Cancer. 2004;100(12): 2664-2670. 44. Glezerman I, Kris MG, Miller V, Seshan S, Flombaum CD. Gemcitabine nephrotoxicity and hemolytic uremic syndrome: report of 29 cases from a single institution. Clin Nephrol. 2009;71(2):130-139. 45. Markowitz GS, Nasr SH, Stokes MB, D’Agati VD. Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010;5(4): 607-615. 46. Heiken JP. Contrast safety in the cancer patient: preventing contrast-induced nephropathy. Cancer Imaging. 2008;8(Spec No A): S124-S127. 47. Launay-Vacher V, Oudard S, Janus N, et al. Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study. Cancer. 2007;110(6):1376-1384. 48. Thomsen HS, Morcos SK, Erley CM, et al. The ACTIVE Trial: comparison of the effects on renal function of iomeprol-400 and iodixanol-320 in patients with chronic kidney disease undergoing abdominal computed tomography. Invest Radiol. 2008;43(3): 170-178.

Cancer-Associated AKI

49. Barrett BJ, Katzberg RW, Thomsen HS, et al. Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol. Invest Radiol. 2006;41(11):815-821. 50. Brar SS, Hiremath S, Dangas G, Mehran R, Brar SK, Leon MB. Sodium bicarbonate for the prevention of contrast induced-acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(10):1584-1592. 51. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994;331(21):1416-1420. 52. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrastinduced nephropathy with sodium bicarbonate: a randomized controlled trial. J Am Med Assoc. 2004;291(19):2328-2334. 53. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Kidney Int Suppl. 2012;2:1-138. 54. Berwanger O. Acetylcysteine for prevention of renal outcomes of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation. 2011;124(11):1250-1259. 55. Weisbord SD, Palevsky PM. Strategies for the prevention of contrast-induced acute kidney injury. Curr Opin Nephrol Hypertens. 2010;19(6):539-549. 56. Cho A, Lee JE, Kwon GY, et al. Post-operative acute kidney injury in patients with renal cell carcinoma is a potent risk factor for newonset chronic kidney disease after radical nephrectomy. Nephrol Dial Transplant. 2011;26(11):3496-3501. 57. Thompson RH, Lane BR, Lohse CM, et al. Renal function after partial nephrectomy: effect of warm ischemia relative to quantity and quality of preserved kidney. Urology. 2012;79(2):356-360. 58. Kang SH, Rhew HY, Kim TS. Changes in renal function after laparoscopic partial nephrectomy: comparison with laparoscopic radical nephrectomy. Korean J Urol. 2013;54(1):22-25. 59. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis. 1999;33(2):225-234.


60. Jerome KR, Corey L. The danger within. N Engl J Med. 2004;350(4): 411-412. 61. Boles JM, Dutel JL, Briere J, et al. Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia. Cancer. 1984;53(11):2425-2429. 62. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127(1):3-11. 63. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001;97(10):2998-3003. 64. Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin’s lymphoma: results of the GRAAL1 (Groupe d’Etude des Lymphomes de l’Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol. 2003;21(23):4402-4406. 65. El-Husseini A, Sabucedo A, Lamarche J, Courville C, Peguero A. Acute kidney injury associated with tumor lysis syndrome: a paradigm shift. Am J Emerg Med. 2012;30(2):390.e3-390.e6. 66. Manning EC, Belenko MI, Frauenhoffer EE, Ahsan N. Acute renal failure secondary to solid tumor renal metastases: case report and review of the literature. Am J Kidney Dis. 1996;27(2):284-291. 67. Tornroth T, Heiro M, Marcussen N, Franssila K. Lymphomas diagnosed by percutaneous kidney biopsy. Am J Kidney Dis. 2003;42(5):960-971. 68. Obrador GT, Price B, O’Meara Y, Salant DJ. Acute renal failure due to lymphomatous infiltration of the kidneys. J Am Soc Nephrol. 1997;8(8):1348-1354. 69. Pene F, Soares M. Can we still refuse ICU admission of patients with hematological malignancies? Intensive Care Med. 2008;34(5): 790-792. 70. Maccariello E, Valente C, Nogueira L, et al. Outcomes of cancer and non-cancer patients with acute kidney injury and need of renal replacement therapy admitted to general intensive care units. Nephrol Dial Transplant. 2011;26(2):537-543. 71. Pene F, Percheron S, Lemiale V, et al. Temporal changes in management and outcome of septic shock in patients with malignancies in the intensive care unit. Crit Care Med. 2008;36(3):690-696.

Acute kidney injury in the cancer patient.

Acute kidney injury (AKI) is a frequent and significant complication of cancer and cancer therapy. Cancer patients frequently encounter risk factors f...
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