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.

Hematopoietic stem cell transplant

HSCT is frequently complicated by AKI. Common causes include volume depletion, sepsis, and nephrotoxic antimicrobials. Risk factors for AKI that are rather unique to transplant include marrow infusion toxicity, graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome, thrombotic microangiopathy (TMA), and BK nephritis. The incidence of AKI is 10% after autologous SCT, 50% after reduced-intensity conditioning allogeneic transplant, and 73% after myeloablative allogeneic transplant. The median time to onset of AKI is 33 to 38 days after transplant. Patients that require RRT have a poor prognosis with a reported mortality of 55% to 100%. The greatest decline in kidney function tends to occur within the first year of HSCT and is associated with diabetes mellitus, hypertension, acute GVHD, and cytomegalovirus infection.

Multiple myeloma

AKI occurs in up to 40% of patients with MM during the course of their treatment and approximately 10% to 15% will require RRT. Median overall survival is worse for patients with AKI and decreases to 3.5 to 10 months for patients that require RRT. Although there are a variety of pathologic lesions that may be found on kidney biopsy, the most common etiologies include myeloma cast nephropathy (MCN), AL amyloidosis, and monoclonal immunoglobulin deposition disease (MIDD). Less commonly, plasma cells may cause AKI by direct renal infiltration. In one case series of 190 patients with MM who underwent renal biopsy, 33% had MCN, 22% had MIDD, and 21% had AL amyloidosis. However, there may have been some element of detection bias as not all patients with suspected MCN underwent renal biopsy. Autopsy studies have demonstrated MCN in 32% to 48% of patients who died with a diagnosis of MM.

Renal cell carcinoma

Radical nephrectomy is associated with up to a 33.7% risk of AKI and is a strong predictor or CKD at 1 year. In one study examining more than 250,000 patients who underwent nephrectomy over a 22-year period, AKI developed in 5.5% of patients. Radical nephrectomy was associated with a 20% increased risk of AKI versus partial nephrectomy in the multivariate analysis. Predictors of AKI included male sex, radical nephrectomy, older age, black race, CKD stage 3 or greater, and presence of comorbidities. AKI was found to be associated with greater morbidity, mortality, and hospital costs. Although there was a temporal increase in the incidence of AKI over time, this was attributed to the use of a more stringent definition of AKI and an aging population undergoing nephrectomy. A more contemporary analysis from the National Surgical Quality Improvement Program data set of patients undergoing nephrectomy from 2005 to 2011 revealed an incidence of 30-day AKI of only 1.8% within an average of 5.4 days after nephrectomy. The authors note that the improved outcomes may also reflect selection bias towards high-volume and private sector hospitals.

Chemotherapy

Cisplatin, a platinum-based alkylating agent that inhibits deoxyribonucleic acid (DNA) synthesis, is commonly used to treat solid tumors including sarcomas, small cell lung cancer, ovarian cancer, and germ cell tumors. Renal tubular toxicity generally occurs 7 to 10 days after administration and may lead to hyponatremia, hypomagnesemia, Fanconi syndrome, and AKI. The mechanism of injury may include formation of reactive oxygen molecules, activation of mitochondrial apoptotic pathways, and increased synthesis of tumor necrosis factor alpha. Approximately one-third of patients will experience AKI within days after treatment, and risk increases with repeated dosing. A recent study examined the incidence of AKI (rise in SCr of ≥ 0.3 mg/dL within 14 days of the first cycle of cisplatin) in 2118 patients, of which 13.6% developed AKI. A predictive model consisting of the patient’s age, cisplatin dose, hypertension, and serum albumin demonstrated good predictive capability (c statistic = 0.7) of cisplatin associated AKI.

Alkylating agents, such as cyclophosphamide and ifosfamide, cause AKI by multiple mechanisms. Hemorrhagic cystitis may develop with both drugs, leading to obstruction from urinary blood clots. Chloracetaldehyde, a metabolite of ifosfamide, depletes cells of glutathione and other sulfhydryl compounds leading to the proximal tubule injury and AKI. Severe tubular injury may present as Fanconi syndrome, which generally resolves after stopping the drug. Risk of tubular injury is increased with cumulative dosing, younger age patients, and concurrent cisplatin therapy.

Antimetabolite drugs are commonly used to inhibit DNA synthesis. Methotrexate, an antifolate agent, and its metabolite, 7-hydroxymethotrexate, may precipitate as crystals, leading to intratubular obstruction. Risk is increased in patients with volume depletion, acidic urine, or doses in excess of 1 g/m ² . Methotrexate can also cause a transient decrease in glomerular filtration rate by inducing afferent arteriolar vasoconstriction. Therapy has largely focused on aggressive hydration and alkalinization of the urine to enhance solubility. Glucarpidase, which metabolizes methotrexate into inactive metabolites, was approved by the U.S. Food and Drug Administration in 2012 for the treatment of methotrexate toxicity.

Targeted therapy

Antivascular endothelial growth factor (anti-VEGF) therapy has been successfully used against a variety of tumor types to inhibit angiogenesis and cellular proliferation. VEGF and its receptors are abundantly expressed in the kidney and are vital for glomerular structure and function, repair mechanisms, and maintaining selective permeability of the glomerular basement membrane. Drugs that target the VEGF pathway often lead to hypertension, proteinuria, and less commonly AKI. Renal biopsies of patients with AKI or proteinuria in the setting of anti-VEGF therapy often demonstrate renal-limited TMA, although minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and interstitial nephritis have also been described. ^, Discontinuation of therapy generally leads to resolution of kidney side effects.

Other targeted therapies are also associated with AKI, although the true incidence is not entirely known for many of these drugs. Inhibitors of the mammalian target of rapamycin pathway may cause AKI, block tubular repair mechanisms, and induce proteinuria. In one study, 15% of patients with renal cell carcinoma developed AKI after everolimus treatment. Crizotinib, an inhibitor of anaplastic lymphoma kinase, may cause a reversible elevation in serum creatinine around 20% to 25%. Whether this is truly reflective of AKI or decreased tubular secretion of creatinine is unclear. v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, vemurafenib and dabrafenib, are commonly associated with tubulointerstitial nephritis that resolves with discontinuation of the drug.

Cancer immunotherapy

Oncologists have leveraged the ability of the immune system to eradicate cancer since the early 1980s. Interferon-alpha was used in chronic myelogenous leukemia, hairy cell leukemia, metastatic melanoma, and non-Hodgkin lymphoma to promote effector T cell-mediated responses. Podocyte injury may manifest as MCD or FSGS, whereas patients with endothelial damage may present with TMA. IL-2 has also been used to activate T-cells and natural killer cells in the treatment of metastatic renal cell carcinoma and metastatic melanoma. The majority of patients develop capillary leak syndrome and hypotension, leading to prerenal azotemia or ATN. ^, However, renal function tends to recover after discontinuation of therapy.

More recently, checkpoint inhibitors (CPI) have been used to activate T-cells via ligand binding to cytotoxic lymphocyte-associated antigen-4 receptor (ipilimumab), programmed cell death protein-1 (PD-1) ligand (atezolizumab), and PD-1 receptor (pembrolizumab and nivolumab). These receptors, which may be activated by tumor cells, negatively regulate T-cell activation and function. Although the overall incidence of CPI-related AKI during clinical trials was 2.2%, the true incidence may be as high as 9.9% to 29%. Renal biopsies generally reveal granulomatous interstitial nephritis, but cases of TMA have also been described. Chimeric antigen receptor (CAR) T-cell therapy uses T-cells modified with lentiviral vector to express receptors that target specific extracellular antigens. In cancer therapy, CAR T-cells may lead to cytokine release syndrome, which may cause AKI. The incidence of AKI is not completely known with these novel therapies.