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Acute kidney injury incidence, pathogenesis, and outcomes
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7 Acute Kidney Injury
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Acute Kidney Injury Incidence, Pathogenesis, and Outcomes AMIT LAHOTI AND SHELDON CHEN
Introduction Advances in therapy, risk stratification, and supportive care have improved survival of patients with cancer over the past 2 decades.1 Acute kidney injury (AKI) remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality.2,3 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.4 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.5 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 270
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.6 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.7 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.8 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.9 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.10 Depending on the
29 • Acute Kidney Injury Incidence, Pathogenesis, and Outcomes
case mix, AKI develops in 13% to 42% of critically ill patients with cancer, and 8% to 60% of these patients will require RRT.11 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%.11 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.12 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%.13 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.14 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 highrisk myelodysplastic syndrome undergoing induction chemotherapy, 36% of patients developed AKI as defined by the RIFLE classification.15 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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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-versushost 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.16 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.17
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.18 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.19 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.20–22
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.23 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.24 The authors note that the improved outcomes may also
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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.25 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 5 0.7) of cisplatin associated AKI.26 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.27 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.28 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/m2. 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.29,30 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.31 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.32 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.33
CANCER IMMUNOTHERAPY Oncologists have leveraged the ability of the immune system to eradicate cancer since the early 1980s. Interferonalpha 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.34,35 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%,36 the true incidence may be as high as 9.9% to 29%.37 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.
Outcomes Although outcomes after development of AKI have been studied extensively, results have been reported only sporadically in patients with cancer. At the University of Texas MD Anderson Cancer Center, over a 3-month period in 2006, approximately 3600 patients were prospectively analyzed.9
29 • Acute Kidney Injury Incidence, Pathogenesis, and Outcomes
Among patients admitted to the hospital, the incidence of AKI was 12%. In that group, 45% developed AKI within the first 2 days. The distribution of AKI by RIFLE criteria was risk (68%), injury (21%), and failure (11%). Dialysis was necessary in 4% of patients. The in-hospital mortality rate for the entire cohort was 4.6%. In those who developed AKI, the mortality rate was significantly higher (15.9%) than in those without AKI (2.7%; p , .001). Risk factors for mortality included leukemia, diabetes mellitus, hyponatremia, and transfer to the ICU. Rates of kidney recovery have not been studied in cancer patients per se, but have been studied extensively in many observational trials of AKI. Typically, kidney recovery is defined as a return of SCr to premorbid levels. Among the survivors of AKI, recovery was seen in 50% to 90%,38–45 even after severe AKI (dialysis requiring) in a critically ill population.46 Although the majority of survivors eventually recover some kidney function, recovery becomes less likely with more severe grades of AKI. In one study, patients with AKI in the Failure category of the RIFLE criteria had a significantly lower chance of recovery.47 The recovery rate may also be influenced by the modality of RRT. For those requiring RRT, kidney recovery was less frequent in patients treated with intermittent hemodialysis versus continuous RRT.44,48–50 The probability of kidney recovery after AKI is also affected by the kidney function at baseline. Patients with preexisting CKD, as compared with those with normal kidney function, have significantly lower recovery rate when they develop superimposed AKI.47 Of more recent concern is that a single episode of AKI, even if there is full kidney recovery, increases patients’ future risk of progressive CKD. Defined as a sustained reduction in estimated glomerular filtration rate to less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge, advanced CKD was independently associated with six variables: older age, female sex, higher baseline creatinine, albuminuria, AKI severity and higher creatinine at time of discharge.51
Summary AKI remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality. The etiology of AKI may be direct injury from the underlying malignancy, drug toxicity, related to stem cell transplant, or from treatment complications. Advances in immunotherapy and targeted therapy have also highlighted the nephrotoxic potential of many of these drugs. Patients with liquid tumors (leukemia, lymphoma, myeloma) have the highest incidence of AKI, especially in the critical care setting. Although AKI does tend to improve in survivors, renal recovery is less likely with more severe grade of AKI. Baseline CKD also confers an increased risk of AKI during cancer treatment. Although cancer itself is not a contraindication for starting 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.
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Key Points n n
n
Acute kidney injury occurs commonly in cancer patients. Acute kidney injury results from both etiologies common to all hospitalized patients and causes unique to patients with cancer because of the underlying cancer or its treatment. Newer biological and immunoregulatory chemotherapeutic agents are associated with unique mechanisms of kidney injury.
References 2. Samuels J, Ng CS, Nates J, et al. Small increases in serum creatinine are associated with prolonged ICU stay and increased hospital mortality in critically ill patients with cancer. Support Care Cancer. 2011;19(10):1527-1532. 3. Lahoti A, Nates JL, Wakefield CD, Price KJ, Salahudeen AK. Costs and outcomes of acute kidney injury in critically ill patients with cancer. J Support Oncol. 2011;9(4):149-155. 4. Perazella MA. Renal vulnerability to drug toxicity. Clin J Am Soc Nephrol. 2009;4(7):1275-1283. 8. Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP, Sørensen HT. Incidence of acute kidney injury in cancer patients: a Danish populationbased cohort study. Eur J Intern Med. 2011;22(4):399-406. 9. Salahudeen AK, Doshi SM, Pawar T, Nowshad G, Lahoti A, Shah P. Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center. Clin J Am Soc Nephrol. 2013;8(3):347-354. 11. Benoit DD, Hoste EA. Acute kidney injury in critically ill patients with cancer. Crit Care Clin. 2010;26(1):151-179. 12. van Vliet M, Verburg IW, van den Boogaard M, et al. Trends in admission prevalence, illness severity and survival of haematological patients treated in Dutch intensive care units. Intensive Care Med. 2014;40(9):1275-1284. 13. Kemlin D, Biard L, Kerhuel L, et al. Acute kidney injury in critically ill patients with solid tumours. Nephrol Dial Transplant. 2018;33(11): 1997-2005. 14. Darmon M, Vincent F, Canet E, et al. Acute kidney injury in critically ill patients with haematological malignancies: results of a multicentre cohort study from the Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie. Nephrol Dial Transplant. 2015;30(12): 2006-2013. 15. 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. 16. Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-2267. 17. Hingorani S, Pao E, Stevenson P, et al. Changes in glomerular filtration rate and impact on long-term survival among adults after hematopoietic cell transplantation: a prospective cohort study. Clin J Am Soc Nephrol. 2018;13(6):866-873. 18. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010; 28(33):4976-4984. 23. Schmid M, Krishna N, Ravi P, et al. Trends of acute kidney injury after radical or partial nephrectomy for renal cell carcinoma. Urol Oncol. 2016;34(7):293.e1-293.e10. 24. Schmid M, Abd-El-Barr AE, Gandaglia G, et al. Predictors of 30-day acute kidney injury following radical and partial nephrectomy for renal cell carcinoma. Urol Oncol. 2014;32(8):1259-1266. 25. 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. 29. Izzedine H, Escudier B, Lhomme C, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine (Baltimore). 2014;93(24): 333-339.
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32. Porta C, Cosmai L, Gallieni M, Pedrazzoli P, Malberti F. Renal effects of targeted anticancer therapies. Nat Rev Nephrol. 2015;11(6):354-370. 37. Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017;45(2):160-169.
44. Goldberg R, Dennen P. Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis. 2008;15(3):297-307. 51. James MT, Pannu N, Hemmelgarn BR, et al. Derivation and external validation of prediction models for advanced chronic kidney disease following acute kidney injury. JAMA. 2017;318(18):1787-1797. A full list of references is available at Expertconsult.com
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References 1. Brenner H. Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet. 2002; 360(9340):1131-1135. 2. Samuels J, Ng CS, Nates J, et al. Small increases in serum creatinine are associated with prolonged ICU stay and increased hospital mortality in critically ill patients with cancer. Support Care Cancer. 2011;19(10):1527-1532. 3. Lahoti A, Nates JL, Wakefield CD, Price KJ, Salahudeen AK. Costs and outcomes of acute kidney injury in critically ill patients with cancer. J Support Oncol. 2011;9(4):149-155. 4. Perazella MA. Renal vulnerability to drug toxicity. Clin J Am Soc Nephrol. 2009;4(7):1275-1283. 5. Darmon M, Thiery G, Ciroldi M, Porcher R, Schlemmer B, Azoulay É. Should dialysis be offered to cancer patients with acute kidney injury? Intensive Care Med. 2007;33(5):765-772. 6. Zhang Z, Lu B, Sheng X, Jin N. Cystatin C in prediction of acute kidney injury: a systemic review and meta-analysis. Am J Kidney Dis. 2011;58(3):356-365. 7. Bárdi E, Bobok I, Oláh AV, Oláh E, Kappelmayer J, Kiss C. Cystatin C is a suitable marker of glomerular function in children with cancer. Pediatr Nephrol. 2004;19(10):1145-1147. 8. Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP, Sørensen HT. Incidence of acute kidney injury in cancer patients: a Danish populationbased cohort study. Eur J Intern Med. 2011;22(4):399-406. 9. Salahudeen AK, Doshi SM, Pawar T, Nowshad G, Lahoti A, Shah P. Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center. Clin J Am Soc Nephrol. 2013;8(3):347-354. 10. Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411-1423. 11. Benoit DD, Hoste EA. Acute kidney injury in critically ill patients with cancer. Crit Care Clin. 2010;26(1):151-179. 12. van Vliet M, Verburg IW, van den Boogaard M, et al. Trends in admission prevalence, illness severity and survival of haematological patients treated in Dutch intensive care units. Intensive Care Med. 2014;40(9):1275-1284. 13. Kemlin D, Biard L, Kerhuel L, et al. Acute kidney injury in critically ill patients with solid tumours. Nephrol Dial Transplant. 2018;33(11): 1997-2005. 14. Darmon M, Vincent F, Canet E, et al. Acute kidney injury in critically ill patients with haematological malignancies: results of a multicentre cohort study from the Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie. Nephrol Dial Transplant. 2015;30(12): 2006-2013. 15. 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. 16. Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-2267. 17. Hingorani S, Pao E, Stevenson P, et al. Changes in glomerular filtration rate and impact on long-term survival among adults after hematopoietic cell transplantation: a prospective cohort study. Clin J Am Soc Nephrol. 2018;13(6):866-873. 18. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010; 28(33):4976-4984. 19. Nasr SH, Valeri AM, Sethi S, et al. Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies. Am J Kidney Dis. 2012;59(6):786-794. 20. Iványi B. Frequency of light chain deposition nephropathy relative to renal amyloidosis and Bence Jones cast nephropathy in a necropsy study of patients with myeloma. Arch Pathol Lab Med. 1990; 114(9):986-987. 21. Kapadia SB. Multiple myeloma: a clinicopathologic study of 62 consecutively autopsied cases. Medicine (Baltimore). 1980;59(5):380-392. 22. Oshima K, Kanda Y, Nannya Y, et al. Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma. Am J Hematol. 2001;67(1):1-5. 23. Schmid M, Krishna N, Ravi P, et al. Trends of acute kidney injury after radical or partial nephrectomy for renal cell carcinoma. Urol Oncol. 2016;34(7):293.e1-293.e10.
24. Schmid M, Abd-El-Barr AE, Gandaglia G, et al. Predictors of 30-day acute kidney injury following radical and partial nephrectomy for renal cell carcinoma. Urol Oncol. 2014;32(8):1259-1266. 25. 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. 26. Motwani SS, McMahon GM, Humphreys BD, Partridge AH, Waikar SS, Curhan GC. Development and validation of a risk prediction model for acute kidney injury after the first course of cisplatin. J Clin Oncol. 2018;36(7):682-688. 27. Patzer L, Hernando N, Ziegler U, Beck-Schimmer B, Biber J, Murer H. Ifosfamide metabolites CAA, 4-OH-Ifo and Ifo-mustard reduce apical phosphate transport by changing NaPi-IIa in OK cells. Kidney Int. 2006;70(10):1725-1734. 28. Oberlin O, Fawaz O, Rey A, et al. Long-term evaluation of ifosfamiderelated nephrotoxicity in children. J Clin Oncol. 2009;27(32):5350-5355. 29. Izzedine H, Escudier B, Lhomme C, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine (Baltimore). 2014;93(24): 333-339. 30. Usui J, Glezerman IG, Salvatore SP, Chandran CB, Flombaum CD, Seshan SV. Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature. Hum Pathol. 2014;45(9):1918-1927. 31. Ha SH, Park JH, Jang HR, et al. Increased risk of everolimus-associated acute kidney injury in cancer patients with impaired kidney function. BMC Cancer. 2014;14:906. 32. Porta C, Cosmai L, Gallieni M, Pedrazzoli P, Malberti F. Renal effects of targeted anticancer therapies. Nat Rev Nephrol. 2015;11(6): 354-370. 33. Jhaveri KD, Sakhiya V, Fishbane S. Nephrotoxicity of the BRAF inhibitors vemurafenib and dabrafenib. JAMA Oncol. 2015;1(8):11331134. 34. Shalmi CL, Dutcher JP, Feinfeld DA, et al. Acute renal dysfunction during interleukin-2 treatment: suggestion of an intrinsic renal lesion. J Clin Oncol. 1990;8(11):1839-1846. 35. Belldegrun A, Webb DE, Austin HA III, et al. Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer. Ann Intern Med. 1987;106(6):817-822. 36. Cortazar FB, Marrone KA, Troxell ML, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90(3):638-647. 37. Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017;45(2):160-169. 38. Liaño F, Felipe C, Tenorio MT, et al. Long-term outcome of acute tubular necrosis: a contribution to its natural history. Kidney Int. 2007;71(7):679-686. 39. Schiffl H. Renal recovery from acute tubular necrosis requiring renal replacement therapy: a prospective study in critically ill patients. Nephrol Dial Transplant. 2006;21(5):1248-1252. 40. Leacche M, Rawn JD, Mihaljevic T, et al. Outcomes in patients with normal serum creatinine and with artificial renal support for acute renal failure developing after coronary artery bypass grafting. Am J Cardiol. 2004;93(3):353-356. 41. Korkeila M, Ruokonen E, Takala J. Costs of care, long-term prognosis and quality of life in patients requiring renal replacement therapy during intensive care. Intensive Care Med. 2000;26(12): 1824-1831. 42. Morgera S, Kraft AK, Siebert G, Luft FC, Neumayer HH. Long-term outcomes in acute renal failure patients treated with continuous renal replacement therapies. Am J Kidney Dis. 2002;40(2):275-279. 43. Doyle JF, Forni LG. Acute kidney injury: short-term and long-term effects. Crit Care. 2016;20(1):188. 44. Goldberg R, Dennen P. Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis. 2008;15(3):297-307. 45. Salmanullah M, Sawyer R, Hise MK. The effects of acute renal failure on long-term renal function. Ren Fail. 2003;25(2):267-276. 46. 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): R700-R709. 47. Ali T, Khan I, Simpson W, et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol. 2007;18(4):1292-1298.
274.e2 48. Jacka MJ, Ivancinova X, Gibney RT. Continuous renal replacement therapy improves renal recovery from acute renal failure. Can J Anaesth. 2005;52(3):327-332. 49. Bell M, Swing, Granath F, Schön S, Ekbom A, Martling CR. Continuous renal replacement therapy is associated with less chronic renal failure than intermittent haemodialysis after acute renal failure. Intensive Care Med. 2007;33(5):773-780.
50. Mehta RL, McDonald B, Gabbai FB, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int. 2001;60(3):1154-1163. 51. James MT, Pannu N, Hemmelgarn BR, et al. Derivation and external validation of prediction models for advanced chronic kidney disease following acute kidney injury. JAMA. 2017;318(18):1787-1797.
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Abstract Acute kidney injury (AKI) remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality. The etiology of AKI may be direct injury from the underlying malignancy, drug toxicity, related to stem cell transplant, or from treatment complications. Advances in immunotherapy and targeted therapy have also highlighted the nephrotoxic potential of many of these drugs. Patients with liquid tumors (leukemia, lymphoma, myeloma) have the highest incidence of AKI, especially in the critical care setting. Although AKI does tend to improve in survivors, renal recovery is less likely with more severe grade of AKI. Baseline chronic kidney disease also confers
an increased risk of AKI during cancer treatment. 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.
Keywords Acute kidney injury, cancer, immunotherapy, critical care, targeted therapy
7 Acute Kidney Injury
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Acute Kidney Injury Incidence, Pathogenesis, and Outcomes AMIT LAHOTI AND SHELDON CHEN
Introduction Advances in therapy, risk stratification, and supportive care have improved survival of patients with cancer over the past 2 decades.1 Acute kidney injury (AKI) remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality.2,3 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.4 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.5 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 270
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.6 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.7 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.8 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.9 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.10 Depending on the
29 • Acute Kidney Injury Incidence, Pathogenesis, and Outcomes
case mix, AKI develops in 13% to 42% of critically ill patients with cancer, and 8% to 60% of these patients will require RRT.11 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%.11 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.12 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%.13 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.14 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 highrisk myelodysplastic syndrome undergoing induction chemotherapy, 36% of patients developed AKI as defined by the RIFLE classification.15 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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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-versushost 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.16 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.17
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.18 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.19 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.20–22
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.23 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.24 The authors note that the improved outcomes may also
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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.25 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 5 0.7) of cisplatin associated AKI.26 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.27 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.28 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/m2. 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.29,30 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.31 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.32 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.33
CANCER IMMUNOTHERAPY Oncologists have leveraged the ability of the immune system to eradicate cancer since the early 1980s. Interferonalpha 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.34,35 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%,36 the true incidence may be as high as 9.9% to 29%.37 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.
Outcomes Although outcomes after development of AKI have been studied extensively, results have been reported only sporadically in patients with cancer. At the University of Texas MD Anderson Cancer Center, over a 3-month period in 2006, approximately 3600 patients were prospectively analyzed.9
29 • Acute Kidney Injury Incidence, Pathogenesis, and Outcomes
Among patients admitted to the hospital, the incidence of AKI was 12%. In that group, 45% developed AKI within the first 2 days. The distribution of AKI by RIFLE criteria was risk (68%), injury (21%), and failure (11%). Dialysis was necessary in 4% of patients. The in-hospital mortality rate for the entire cohort was 4.6%. In those who developed AKI, the mortality rate was significantly higher (15.9%) than in those without AKI (2.7%; p , .001). Risk factors for mortality included leukemia, diabetes mellitus, hyponatremia, and transfer to the ICU. Rates of kidney recovery have not been studied in cancer patients per se, but have been studied extensively in many observational trials of AKI. Typically, kidney recovery is defined as a return of SCr to premorbid levels. Among the survivors of AKI, recovery was seen in 50% to 90%,38–45 even after severe AKI (dialysis requiring) in a critically ill population.46 Although the majority of survivors eventually recover some kidney function, recovery becomes less likely with more severe grades of AKI. In one study, patients with AKI in the Failure category of the RIFLE criteria had a significantly lower chance of recovery.47 The recovery rate may also be influenced by the modality of RRT. For those requiring RRT, kidney recovery was less frequent in patients treated with intermittent hemodialysis versus continuous RRT.44,48–50 The probability of kidney recovery after AKI is also affected by the kidney function at baseline. Patients with preexisting CKD, as compared with those with normal kidney function, have significantly lower recovery rate when they develop superimposed AKI.47 Of more recent concern is that a single episode of AKI, even if there is full kidney recovery, increases patients’ future risk of progressive CKD. Defined as a sustained reduction in estimated glomerular filtration rate to less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge, advanced CKD was independently associated with six variables: older age, female sex, higher baseline creatinine, albuminuria, AKI severity and higher creatinine at time of discharge.51
Summary AKI remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality. The etiology of AKI may be direct injury from the underlying malignancy, drug toxicity, related to stem cell transplant, or from treatment complications. Advances in immunotherapy and targeted therapy have also highlighted the nephrotoxic potential of many of these drugs. Patients with liquid tumors (leukemia, lymphoma, myeloma) have the highest incidence of AKI, especially in the critical care setting. Although AKI does tend to improve in survivors, renal recovery is less likely with more severe grade of AKI. Baseline CKD also confers an increased risk of AKI during cancer treatment. Although cancer itself is not a contraindication for starting 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.
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Key Points n n
n
Acute kidney injury occurs commonly in cancer patients. Acute kidney injury results from both etiologies common to all hospitalized patients and causes unique to patients with cancer because of the underlying cancer or its treatment. Newer biological and immunoregulatory chemotherapeutic agents are associated with unique mechanisms of kidney injury.
References 2. Samuels J, Ng CS, Nates J, et al. Small increases in serum creatinine are associated with prolonged ICU stay and increased hospital mortality in critically ill patients with cancer. Support Care Cancer. 2011;19(10):1527-1532. 3. Lahoti A, Nates JL, Wakefield CD, Price KJ, Salahudeen AK. Costs and outcomes of acute kidney injury in critically ill patients with cancer. J Support Oncol. 2011;9(4):149-155. 4. Perazella MA. Renal vulnerability to drug toxicity. Clin J Am Soc Nephrol. 2009;4(7):1275-1283. 8. Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP, Sørensen HT. Incidence of acute kidney injury in cancer patients: a Danish populationbased cohort study. Eur J Intern Med. 2011;22(4):399-406. 9. Salahudeen AK, Doshi SM, Pawar T, Nowshad G, Lahoti A, Shah P. Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center. Clin J Am Soc Nephrol. 2013;8(3):347-354. 11. Benoit DD, Hoste EA. Acute kidney injury in critically ill patients with cancer. Crit Care Clin. 2010;26(1):151-179. 12. van Vliet M, Verburg IW, van den Boogaard M, et al. Trends in admission prevalence, illness severity and survival of haematological patients treated in Dutch intensive care units. Intensive Care Med. 2014;40(9):1275-1284. 13. Kemlin D, Biard L, Kerhuel L, et al. Acute kidney injury in critically ill patients with solid tumours. Nephrol Dial Transplant. 2018;33(11): 1997-2005. 14. Darmon M, Vincent F, Canet E, et al. Acute kidney injury in critically ill patients with haematological malignancies: results of a multicentre cohort study from the Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie. Nephrol Dial Transplant. 2015;30(12): 2006-2013. 15. 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. 16. Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-2267. 17. Hingorani S, Pao E, Stevenson P, et al. Changes in glomerular filtration rate and impact on long-term survival among adults after hematopoietic cell transplantation: a prospective cohort study. Clin J Am Soc Nephrol. 2018;13(6):866-873. 18. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010; 28(33):4976-4984. 23. Schmid M, Krishna N, Ravi P, et al. Trends of acute kidney injury after radical or partial nephrectomy for renal cell carcinoma. Urol Oncol. 2016;34(7):293.e1-293.e10. 24. Schmid M, Abd-El-Barr AE, Gandaglia G, et al. Predictors of 30-day acute kidney injury following radical and partial nephrectomy for renal cell carcinoma. Urol Oncol. 2014;32(8):1259-1266. 25. 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. 29. Izzedine H, Escudier B, Lhomme C, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine (Baltimore). 2014;93(24): 333-339.
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32. Porta C, Cosmai L, Gallieni M, Pedrazzoli P, Malberti F. Renal effects of targeted anticancer therapies. Nat Rev Nephrol. 2015;11(6):354-370. 37. Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017;45(2):160-169.
44. Goldberg R, Dennen P. Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis. 2008;15(3):297-307. 51. James MT, Pannu N, Hemmelgarn BR, et al. Derivation and external validation of prediction models for advanced chronic kidney disease following acute kidney injury. JAMA. 2017;318(18):1787-1797. A full list of references is available at Expertconsult.com
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Abstract Acute kidney injury (AKI) remains a common complication of cancer treatment and entails increased length of stay, cost, and mortality. The etiology of AKI may be direct injury from the underlying malignancy, drug toxicity, related to stem cell transplant, or from treatment complications. Advances in immunotherapy and targeted therapy have also highlighted the nephrotoxic potential of many of these drugs. Patients with liquid tumors (leukemia, lymphoma, myeloma) have the highest incidence of AKI, especially in the critical care setting. Although AKI does tend to improve in survivors, renal recovery is less likely with more severe grade of AKI. Baseline chronic kidney disease also confers
an increased risk of AKI during cancer treatment. 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.
Keywords Acute kidney injury, cancer, immunotherapy, critical care, targeted therapy