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Acute kidney injury incidence, pathogenesis, and outcomes
Introduction
Advances in therapy, risk stratification, and supportive care have improved survival of patients with cancer over the past 2 decades. Acute kidney injury (AKI) remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality. , In addition, AKI may also lead to decreased functional status, decreased quality of life, and exclusion from further cancer therapy or trials. The etiology of AKI may be direct injury from the underlying malignancy (e.g., lymphomatous infiltration), drug toxicity (e.g., acute tubular necrosis [ATN]), related to stem cell transplant, or from treatment complications (e.g., tumor lysis syndrome). Patient related risk factors for AKI include older age, female sex, underlying chronic kidney disease (CKD), diabetes mellitus, volume depletion, and renal hypoperfusion. Advances in immunotherapy and targeted therapy have also highlighted the nephrotoxic potential of many of these drugs. Although cancer itself is not a contraindication for starting renal replacement therapy (RRT), the benefits of RRT must be weighed against the overall prognosis of the patient and quality of life. A multidisciplinary discussion between the patient, nephrologist, oncologist, intensivist, and palliative care physician is often necessary to make an informed clinical decision.
Diagnosis
The use of an arbitrary cut-off value of serum creatinine (SCr) for AKI is discouraged because many factors determine a patient’s “baseline” creatinine level. Muscle mass, protein intake, volume expansion, and medications all affect SCr levels independent of kidney function. Therefore increases in SCr relative to baseline level are more reflective of AKI. Uniform definitions of AKI, such as RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage renal disease [ESRD]) classification, Acute Kidney Injury Network, and the Kidney Disease: Improving Global Outcome, have facilitated the cross-comparison of studies by staging AKI by: (1) relative increases in SCr compared with baseline; or (2) progressive decline in urine output.
Cystatin C, a cysteine protease inhibitor produced by all nucleated cells, is freely filtered by the glomerulus and is neither secreted nor reabsorbed by the tubules. It is almost completely catabolized by the proximal tubular cells. In one particular metaanalysis of 13 studies, cystatin C had a sensitivity and specificity of 0.84 and 0.82, respectively, and an area under the receiver operating characteristic curve of 0.96 to predict AKI. Given that cystatin C is a marker of inflammation, levels correlate with cigarette smoking, steroid use, and C-reactive protein levels. Recent studies have not found a correlation with tumor burden. Given the significant increase in cost with cystatin C versus creatinine measurement, it has not been widely adopted for use in clinical practice.
Novel urinary biomarkers of renal injury, which potentially have better ability in detecting the onset and severity of AKI, are under active investigation. Potential candidate markers include inflammatory biomarkers (NGAL, interleukin [IL]-6, and IL-18), cell injury biomarkers (KIM-1, L-FABP, NHE-3, and netrin 1), and cell cycle markers (TIMP-2 and IGFBP-7). Although some studies have demonstrated benefit of urinary biomarkers for early detection of AKI after chemotherapy, other studies have demonstrated poor diagnostic performance. In addition, no studies have demonstrated improved patient outcomes with earlier detection. At this time, routine use of these newer biomarkers of kidney injury cannot be recommended.
Incidence
The incidence of AKI in cancer varies widely depending on the case mix studied. A large Danish study examined a cohort of 1.2 million people over a 7-year period, of which there were 37,267 incident cases of cancer. As defined by the RIFLE classification, the 1-year risk for the “risk,” “injury,” and “failure” categories were 17.5%, 8.8%, and 4.5%, respectively. Corresponding 5-year risks for AKI were 27.0%, 14.6%, and 7.6%, respectively. The incidence of AKI was highest in patients with renal cell cancer (44%), multiple myeloma (MM) (33%), liver cancer (32%), and leukemia (28%). Among patients that developed AKI, 5.1% required dialysis within 1 year. In one large single center observational study of 3558 patients, 12% of patients developed AKI after admission. Patients with AKI had increased length of stay, hospital costs, and mortality.
Critically ill patients with cancer
Patients with cancer comprise approximately 20% of all intensive care unit (ICU) admissions. Depending on the case mix, AKI develops in 13% to 42% of critically ill patients with cancer, and 8% to 60% of these patients will require RRT. The need for dialysis is more common in critically ill patients with cancer versus those without cancer. The incidence of RRT for AKI in patients with cancer admitted to the ICU ranges from 9% to 33% and entails a short-term mortality rate of more than 66%. This is likely an underestimate of the actual severity of AKI in this population, given that many patients with cancer choose to forgo life-sustaining treatments. The higher incidence of AKI and RRT in this subgroup of patients is related to a higher incidence of severe sepsis, hypertension, exposure to nephrotoxic antimicrobials and chemotherapy, preexisting CKD, and tumor lysis syndrome. This is especially true for patients with hematologic malignancies who have bone marrow suppression from chemotherapy or complications from hematopoietic stem cell transplantation (HSCT). In the Dutch National Intensive Care Evaluation database, AKI occurred in 19.4% of critically ill patients with hematologic malignancies versus 11% in patients with solid tumors. In addition, Taccone and colleagues reported an increased incidence of RRT in critically ill patients with hematologic malignancies versus patients with solid tumors (21.7% vs. 8%). In a multicenter study of 1753 patients with hematologic tumors who were admitted to the ICU with acute respiratory failure, the incidence of AKI was 33.9%, and 16.3% of patients received RRT. In a single center study of 204 critically ill patients with solid tumors, the incidence of AKI was 59%. Main causes in this study were sepsis (80%), hypovolemia (40%), and urinary outflow tract obstruction (17%). RRT was required in 12% of patients with an associated hospital mortality of 39%.
Leukemia and lymphoma
AKI may occur in up to 60% of patients with hematologic malignancies at any time during the disease course. Common etiologies include septic and nephrotoxic ATN, hypoperfusion from third spacing and volume depletion, tumor lysis syndrome, and malignant obstruction from lymph nodes. Although leukemic or lymphomatous infiltration of the kidneys may be seen in up to 60% of patients at autopsy, this is an uncommon cause of AKI. Other less common causes of AKI in this subset of patients include hemophagocytic lymphohistiocytosis, vascular occlusion from hyperleukostasis, lysozymuria with direct tubular injury, and intratubular obstruction from medications (e.g., methotrexate). In a single center study looking at 537 patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy, 36% of patients developed AKI as defined by the RIFLE classification. Eight-week mortality was 3.8%, 13.6%, 19.6%, and 61.7% for the non-AKI, risk, injury, and failure categories, respectively. Predictors of AKI in this study were age older than 55 years, mechanical ventilation, vasopressors, intravenous diuretics, administration of vancomycin or amphotericin, and low serum albumin.
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