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Acute Kidney Injury in Patients With Cancer: A Review of Onconephrology

      Over the past 2 decades, significant research and advancements have been made in oncology and its therapeutics. Thanks to novel diagnostic methods, treatments, and supportive measures, patients with cancer live longer and have a better quality of life. However, an unforeseen consequence of this progress has been increasing medical complications, including acute kidney injury. The purpose of this review is to provide an overview of the epidemiology and most common causes of acute kidney injury in patients with cancer unrelated to oncological treatment.

      Graphical abstract

      Key Words

      • Acute kidney injury (AKI) is commonly experienced by patients with cancer, increasing morbidity, mortality, and health care costs.
      • AKI in patients with cancer may be secondary to hemodynamic derangements, thrombotic microangiopathy, renal parenchymal infiltrations, and obstructive nephropathy.
      • Knowledge of adverse kidney effects from conventional chemotherapy, target therapies, and immunotherapy is crucial in this rapidly evolving field.
      • More research is needed to clarify the utility of biomarkers in predicting AKI related to cancer treatment.
      Over the last 3 decades, advancements in the diagnosis, treatment, and supportive care of patients with cancer have yielded significant improvements in overall survival rates.
      • Lahoti A.
      • Chen S.
      29 - Acute kidney injury incidence, pathogenesis, and outcomes.
      Unfortunately, this improved survival has resulted in a higher rate of cancer-related complications, including chronic kidney disease (CKD) and acute kidney injury (AKI).
      • Rosner M.H.
      • Perazella M.A.
      Acute kidney injury in patients with cancer.
      AKI has been recognized as a highly prevalent complication of patients with cancer and a well-known risk factor for progression to CKD. Moreover, it is associated with an increased risk of morbidity and all-cause mortality.
      • Rosner M.H.
      • Perazella M.A.
      Acute kidney injury in patients with cancer.
      • 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.
      • Yang Y.
      • Li H.Y.
      • Zhou Q.
      • et al.
      Renal function and all-cause mortality risk among cancer patients.
      While the risks factors for developing AKI are similar to those of the general population, patients with cancer may develop AKI due to cancer per se or their treatment, adding an extra layer of complexity to their care (Fig 1).
      • Rosner M.H.
      • Perazella M.A.
      Acute kidney injury in patients with cancer.
      Additionally, from the patients' perspective, AKI is a vexing complication because it may lead to a longer hospital stay, decline in functional status, decreased quality of life, and prevention of further cancer treatment.
      Figure thumbnail gr1
      Figure 1Causes of AKI in patients with cancer. Ca+, hypercalcemia; HSCT, hematopoietic stem cell transplant; TLS, tumor lysis syndrome; TMA, thrombotic microangiopathy.

      Epidemiology of AKI in Patients with Cancer

      The epidemiology of AKI in patients with cancer has been described in 3 large population-based studies. The seminal study by Christiansen and colleagues sought to describe the rates of cancer-related AKI in 44,116 patients from Denmark, using RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria for defining AKI.
      • Christiansen C.F.
      • Johansen M.B.
      • Langeberg W.J.
      • Fryzek J.P.
      • Sorensen H.T.
      Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.
      The reported rates of AKI at 1 and 5 years after cancer diagnosis were 17.5% and 27%, respectively.
      • Christiansen C.F.
      • Johansen M.B.
      • Langeberg W.J.
      • Fryzek J.P.
      • Sorensen H.T.
      Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.
      Kitchlu and colleagues published a study including 163,071 patients with a new cancer diagnosis who commenced systemic chemotherapy in Ontario, Canada. For this purpose, the authors defined AKI as per KDIGO (Kidney Disease Improving Global Outcomes) criteria. They found an AKI rate of 27 per 1000 person-years, with an overall AKI incidence and a 5-year cumulative incidence of AKI needing kidney replacement therapy (KRT) of 9.3% and 0.8%, respectively.
      • Kitchlu A.
      • McArthur E.
      • Amir E.
      • et al.
      Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.
      Lastly, Cheng and colleagues described the incidence of AKI in patients with cancer in 136,756 hospitalized patients from China.
      • Cheng Y.
      • Nie S.
      • Li L.
      • et al.
      Epidemiology and outcomes of acute kidney injury in hospitalized cancer patients in China.
      Using the KDIGO criteria, they found an overall incidence of AKI of 7.5% (6% hospital-acquired and 1.5% community-acquired).
      • Cheng Y.
      • Nie S.
      • Li L.
      • et al.
      Epidemiology and outcomes of acute kidney injury in hospitalized cancer patients in China.
      In these 3 cohorts, the most common malignancies associated with AKI were hematological cancers—multiple myeloma (MM) and leukemia—kidney, bladder, and liver cancers. The patient-centric and cancer-specific risk factors are summed up in Table 1.
      Table 1Patient-Centric and Cancer-Specific Risk Factors Leading to AKI in Patients With Cancer
      • Christiansen C.F.
      • Johansen M.B.
      • Langeberg W.J.
      • Fryzek J.P.
      • Sorensen H.T.
      Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.
      ,
      • Kitchlu A.
      • McArthur E.
      • Amir E.
      • et al.
      Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.
      ,
      • Salahudeen A.K.
      • Doshi S.M.
      • Pawar T.
      • Nowshad G.
      • Lahoti A.
      • Shah P.
      Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center.
      ,
      • Kemlin D.
      • Biard L.
      • Kerhuel L.
      • et al.
      Acute kidney injury in critically ill patients with solid tumours.
      Patient-centric factors
      • Age > 65 years
      • Baseline chronic kidney disease
      • Diabetes mellitus
      • Hypertension
      • Concomitant treatment with renin-angiotensin receptor blockers, diuretics, and nonsteroidal anti-inflammatory agents.
      • Nephrotoxic antibiotic therapy
      • Electrolyte imbalance: hyponatremia.
      • ICU admission
      Cancer-specific factors
      • Renal cell carcinoma, after nephrectomy
      • Hematological malignancies (leukemia, multiple myeloma lymphomas)
      • Obstructive nephropathy
      • Hematopoietic stem cell transplant (HSCT)
      • Hypercalcemia of malignancy
      • Anticancer drugs nephrotoxicity
      • Paraneoplastic glomerular diseases
      • Tumor lysis syndrome
      • Neutropenic sepsis
      Table 2Key Differences Between Cancer-Associated and Drug-Induced TMA
      • George B.
      • Joy M.S.
      • Aleksunes L.M.
      Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy.
      ,
      • Lechner K.
      • Obermeier H.L.
      Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases.
      • Elliott M.A.
      • Letendre L.
      • Gastineau D.A.
      • Winters J.L.
      • Pruthi R.K.
      • Heit J.A.
      Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration.
      • Werner T.L.
      • Agarwal N.
      • Carney H.M.
      • Rodgers G.M.
      Management of cancer-associated thrombotic microangiopathy: what is the right approach?.
      • Lesesne J.B.
      • Rothschild N.
      • Erickson B.
      • et al.
      Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry.
      FeaturesCancer-Associated TMAChemotherapy-Induced TMA
      Metastatic disease90% have metastatic disease.May not be present.
      PhenotypeTTP in 6% of patients.The spectrum ranges from typical HUS to kidney-limited TMA.
      DIC15% of patients.Absent.
      Mean age56 years.40 years.
      Median duration of symptoms21 days.8 days.
      TherapyNo response to PLEX.Those with ADAMTS-13 deficiency especially respond to PLEX. Stopping the offending drug.
      Abbreviations: ADAMTS-13, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; PLEX, plasma exchange; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.
      Critically ill patients with cancer are highly susceptible to AKI, chiefly those admitted with septic shock, hematological malignancies, and exposed to nephrotoxins.
      • Benoit D.D.
      • Hoste E.A.
      Acute kidney injury in critically ill patients with cancer.
      • Lameire N.
      • Vanholder R.
      • Van Biesen W.
      • Benoit D.
      Acute kidney injury in critically ill cancer patients: an update.
      • Darmon M.
      • Ciroldi M.
      • Thiery G.
      • Schlemmer B.
      • Azoulay E.
      Clinical review: specific aspects of acute renal failure in cancer patients.
      • Soares M.
      • Salluh J.I.
      • Carvalho M.S.
      • Darmon M.
      • Rocco J.R.
      • Spector N.
      Prognosis of critically ill patients with cancer and acute renal dysfunction.
      Previous studies described an AKI incidence of 5% to 20% in critically ill patients with cancer.
      • Lameire N.
      • Van Biesen W.
      • Vanholder R.
      Acute renal problems in the critically ill cancer patient.
      However, Kitchlu and colleagues reported an increase in AKI from 18 to 52 per 1000 persons-years from 2007 to 2014, including AKI requiring KRT.
      • Kitchlu A.
      • McArthur E.
      • Amir E.
      • et al.
      Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.
      Currently, it is estimated that up to 40% of critically ill patients with cancer may need KRT.
      • Benoit D.D.
      • Hoste E.A.
      Acute kidney injury in critically ill patients with cancer.
      ,
      • Lameire N.
      • Vanholder R.
      • Van Biesen W.
      • Benoit D.
      Acute kidney injury in critically ill cancer patients: an update.
      The increasing necessity of KRT can, perhaps, be explained by a higher admission rate of patients with cancer to intensive care units, better supportive care, and better overall prognosis.
      • 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.
      • Peigne V.
      • Rusinova K.
      • Karlin L.
      • et al.
      Continued survival gains in recent years among critically ill myeloma patients.
      • Taccone F.S.
      • Artigas A.A.
      • Sprung C.L.
      • Moreno R.
      • Sakr Y.
      • Vincent J.L.
      Characteristics and outcomes of cancer patients in European ICUs.
      Notwithstanding, these observational data may present several biases due to the tendency to waive advanced life-sustaining treatments in patients with advanced cancer; hence, the real need for KRT may be underestimated.
      • Tanvetyanon T.
      • Leighton J.C.
      Life-sustaining treatments in patients who died of chronic congestive heart failure compared with metastatic cancer.

      Patient Outcomes in AKI in a Patient with Cancer

      The notion that prognosis of critically ill patients with cancer are ominous and, therefore, advanced care (including KRT) should be withheld has been challenged by several studies.
      • Berghmans T.
      • Meert A.P.
      • Markiewicz E.
      • Sculier J.P.
      Continuous venovenous haemofiltration in cancer patients with renal failure: a single-centre experience.
      ,
      • Benoit D.D.
      • Hoste E.A.
      • Depuydt P.O.
      • 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.
      In a Sepsis Occurrence in Critically Ill Patients (SOAP) sub-study, the overall mortality of all cancer patients was similar to that in the noncancer population, with a 27% hospital mortality rate. However, in the subgroup analysis of patients with more than three failing organs, more than 75% of patients with cancer died, compared with 50% of patients without cancer.
      • Taccone F.S.
      • Artigas A.A.
      • Sprung C.L.
      • Moreno R.
      • Sakr Y.
      • Vincent J.L.
      Characteristics and outcomes of cancer patients in European ICUs.
      One could argue that advanced cancer should not be an absolute contraindication for providing acute KRT.
      • Darmon M.
      • Thiery G.
      • Ciroldi M.
      • Porcher R.
      • Schlemmer B.
      • Azoulay E.
      Should dialysis be offered to cancer patients with acute kidney injury?.
      The ethical concerns surrounding KRT in patients with cancer are discussed separately in detail in the upcoming article "Palliative Care for Patients with Cancer and Kidney Disease" (to be published in Advances in Chronic Kidney Disease, volume 29, Part 2 of this collection).
      The literature on the long-term kidney prognosis of patients with cancer complicated by AKI is scarce. In their study, Christiansen and colleagues reported that 5.1% of patients with cancer-related AKI needed KRT within a year of AKI diagnosis, and only 0.8% progressed to end-stage kidney disease.
      • Christiansen C.F.
      • Johansen M.B.
      • Langeberg W.J.
      • Fryzek J.P.
      • Sorensen H.T.
      Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.
      Similarly, Soares and colleagues described that 6% of critically ill patients with cancer-related AKI progressed to end-stage kidney disease.
      • Soares M.
      • Salluh J.I.
      • Carvalho M.S.
      • Darmon M.
      • Rocco J.R.
      • Spector N.
      Prognosis of critically ill patients with cancer and acute renal dysfunction.

      Hemodynamic Acute Kidney Injury

      Hemodynamic, also deemed prerenal, AKI is the most frequent subtype of AKI in cancer patients. Up to 60%-80% of patients diagnosed with cancer will experience anorexia, nausea, and vomiting in the course of their disease, making them susceptible to volume contraction and, therefore, AKI.
      • O’Reilly M.
      • Mellotte G.
      • Ryan B.
      • O’Connor A.
      Gastrointestinal side effects of cancer treatments.
      These symptoms are highly prevalent after standard chemotherapy and radiotherapy.
      • Berk L.
      • Rana S.
      Hypovolemia and dehydration in the oncology patient.
      In addition, novel oncological treatments, such as immune checkpoint inhibitors, have also been associated with severe colitis and adrenal insufficiency leading to hypovolemia.
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint Blockade.
      A carefully obtained medical history and a thorough volume status assessment are paramount in evaluating these patients. Investigations should include a complete serum and urine electrolytes panel, along with serum calcium, phosphate, and creatinine. Examination of the urine sediment searching for data indicating acute tubular injury is strongly encouraged. Moreover, the use of point-of-care ultrasound has been gaining popularity among physicians to enhance physical examination and perform a more accurate evaluation of the volume status of patients.
      • Velez J.C.Q.
      • Petkovich B.
      • Karakala N.
      • Huggins J.T.
      Point-of-Care echocardiography unveils misclassification of acute kidney injury as hepatorenal syndrome.
      ,
      • Beaubien-Souligny W.
      • Denault A.
      • Robillard P.
      • Desjardins G.
      The role of point-of-care ultrasound monitoring in cardiac surgical patients with acute kidney injury.

      Acute Kidney Injury Due to Cancer

      Cancer-Associated Thrombotic Microangiopathy

      Cancer-associated thrombotic microangiopathy (TMA) is a disorder characterized by microvascular thrombosis, thrombocytopenia, and end-organ ischemia.
      • Pisoni R.
      • Ruggenenti P.
      • Remuzzi G.
      Drug-induced thrombotic microangiopathy: incidence, prevention and management.
      One of the earliest reported studies on TMA in patients with cancer was published in 1972 from Germany, showing that 5.7% of patients with metastatic cancer have TMA. Gastric carcinoma tops the list (50%), followed by breast and lung carcinoma.
      • Lohrmann H.P.
      • Adam W.
      • Heymer B.
      • Kubanek B.
      Microangiopathic hemolytic anemia in metastatic carcinoma. Report of eight cases.
      In an oncological setting, one difficult task is to differentiate between cancer-associated and drug-induced TMA. Table 2 outlines some key differences between the 2 processes. This topic will be dealt with in greater detail in the upcoming article "Thrombotic Microangiopathy Syndromes: Common Ground and Distinct Frontiers" (to be published in Advances in Chronic Kidney Disease, volume 29, Part 2 of this collection).

      Obstructive Nephropathy

      Obstructive nephropathy can happen due to intratubular or extra-renal obstruction. Intratubular obstruction occurs because of intratubular precipitations of crystals or casts (ie, uric acid, light chain casts, drug-induced crystals as in high-dose methotrexate therapy); it is commonly seen in lymphoproliferative malignancies. Extra-renal obstruction commonly occurs in advanced prostatic or urothelial cancers, metastatic diseases, postradiation therapy (immediately due to blood clots or later due to fibrosis involving the ureteral orifices), and in BK virus infection. Nondilated obstructive uropathy is a frequently missed and underreported entity.
      • Kocurek J.N.
      • Orihuela E.
      • Saltzstein D.R.
      Non-dilated obstructive uropathy and renal failure as a result of carcinoma of the intrapelvic area.
      Although nondilated obstructive nephropathy is not a very common phenomenon in the general population, it is commonly encountered in oncology settings, with 60% of the patients having an intrapelvic malignancy.
      • Kocurek J.N.
      • Orihuela E.
      • Saltzstein D.R.
      Non-dilated obstructive uropathy and renal failure as a result of carcinoma of the intrapelvic area.
      Possible causes for the nondilatation of the upper urinary tract can be encasement of the ureter with tumor or fibrous tissue (Ormond's disease), abnormal ureteral peristalsis, ureteral edema, or coexisting severe volume depletion.
      • Rascoff J.H.
      • Golden R.A.
      • Spinowitz B.S.
      • Charytan C.
      Nondilated obstructive nephropathy.
      • Lalli A.F.
      Retroperitoneal fibrosis and inapparent obstructive uropathy.
      • Curry N.S.
      • Gobien R.P.
      • Schabel S.I.
      Minimal-dilatation obstructive nephropathy.
      Acute-onset obstruction can lead to abdominal pain and hematuria; however, urine output may be preserved unless there is complete bilateral obstruction. Regardless of the mechanism, urinary tract ultrasound is usually the first imaging modality performed when clinically suspected. Computed tomography or magnetic resonance imaging can also be used. Once the diagnosis has been established, a urinary catheter, percutaneous nephrostomy, or ureteral stenting may be used to bypass the obstruction until definite management is possible. A multidisciplinary decision-making process is highly recommended in cases with advanced malignancy.

      Acute Kidney Injury from Cancer Infiltration and Metastatic Disease

      Direct parenchymal involvement is one of the less frequent causes of AKI. Lymphomas and leukemias are commonly associated with kidney infiltration, with 6%-60% in autopsy studies.
      • Xiao J.C.
      • Walz-Mattmuller R.
      • Ruck P.
      • Horny H.P.
      • Kaiserling E.
      Renal involvement in myeloproliferative and lymphoproliferative disorders. A study of autopsy cases.
      The diagnosis is usually incidental; however, AKI, new-onset proteinuria, and hematuria are features of lymphomatous invasion of the kidneys, found in about 1% of cases with lymphoma.
      • Lommatzsch S.E.
      • Bellizzi A.M.
      • Cathro H.P.
      • Rosner M.H.
      Acute renal failure caused by renal infiltration by hematolymphoid malignancy.
      Tornroth and colleagues showed that interstitial and glomerular infiltration were the most common pathological phenotypes, present in 87% and 45% of patients, respectively.
      • Törnroth T.
      • Heiro M.
      • Marcussen N.
      • Franssila K.
      Lymphomas diagnosed by percutaneous kidney biopsy.
      Kidney imaging in these cases shows bulky and enlarged kidneys. Moreover, demonstration of lymphomatous invasion of the kidneys may prompt initiation of chemotherapy even in indolent cancers such as chronic lymphocytic leukemia.
      Certain cancers are prone to metastasize to the kidneys, most commonly malignant melanoma and lung, breast, and gastric carcinoma.
      • Darmon M.
      • Ciroldi M.
      • Thiery G.
      • Schlemmer B.
      • Azoulay E.
      Clinical review: specific aspects of acute renal failure in cancer patients.
      Usually, this condition presents as bilateral, small, multifocal parenchymal nodules although single exophytic lesions have been reported. These metastases usually occur in the setting of massive tumor burden and portend a dismal prognosis.
      AKI from infiltrative cancers may result from parenchymal compression, which leads to disruption of the glomerular, tubulointerstitial, and microvascular architecture. Most cases are subclinical; however, patients may present with hypertension due to upregulation of the renin-angiotensin axis, flank pain, and hematuria. This topic will be discussed in-depth in an upcoming article titled "Hematological Malignancies and the Kidney" (to be published in Advances in Chronic Kidney Disease, volume 29, Part 2 of this collection).

      AKI Due to Paraproteinemia

      Multiple myeloma is the most common cause of paraproteinemia encountered in clinical practice. The incidence of AKI in patients with MM is 20% to 50%, with cast nephropathy being the most common etiology.
      • Eleutherakis-Papaiakovou V.
      • Bamias A.
      • Gika D.
      • et al.
      Renal failure in multiple myeloma: incidence, correlations, and prognostic significance.
      ,
      • Rajkumar S.V.
      • Dimopoulos M.A.
      • Palumbo A.
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      Cast nephropathy develops when the free light chains, filtered by the glomerulus, binds to Tamm Horsfall protein in the thick ascending loop of Henle, leading to intraluminal obstruction. Histological examination demonstrates interstitial inflammation and intraluminal, fractured casts.
      • Sanders P.W.
      • Booker B.B.
      Pathobiology of cast nephropathy from human Bence Jones proteins.
      The diagnosis is made by quantitative assessment of free light chain along with serum and urine protein electrophoresis. AKI can happen in other forms of monoclonal gammopathies, not only in MM. The largest published series on kidney biopsy in Waldenstrom macroglobulinemia and other IgM monoclonal gammopathies from Mayo Clinic identified monoclonal Ig-related amyloidosis as the most common kidney lesion in 33%, followed by cryoglobulinemic glomerulonephritis G in 28% of the total cases.
      • Higgins L.
      • Nasr S.H.
      • Said S.M.
      • et al.
      Kidney involvement of patients with Waldenstrom macroglobulinemia and other IgM-Producing B cell lymphoproliferative disorders.
      Figure 2 shows various ways in which paraproteinemia and its therapeutics can affect various compartments of the nephron. This topic will be exhaustively reviewed in an upcoming article titled "Monoclonal Gammopathy-Related Kidney Diseases" (to be published in Advances in Chronic Kidney Disease, volume 29, Part 2 of this collection).
      Figure thumbnail gr2
      Figure 2Causes of AKI in paraproteinemia and compartment of nephron affected. AH, amyloid heavy chains; AL, amyloid light chains; ALH, ascending loop of Henle; BRAF, B-Raf gene; Ca+2, hypercalcemia; DCT, distal convoluted tubule; FGN, fibrillary GN; FSGS, focal segmental glomerulosclerosis; GD, glomerular disease; ICI, immune checkpoint inhibitors; ITGN, immunotactoid GN; LCDD, light-chain deposition disease; MCN, minimal change nephropathy; MPGN, membranoproliferative GN; mTORi, mammalian target of rapamycin inhibitor; PCT, proximal convoluted tubule; PGNMIDD, proliferative GN with monoclonal immunoglobulin deposition disease; TLS, tumor lysis syndrome; TMA, thrombotic microangiopathy.

      Acute Kidney Injury Resulting from Treatment of Cancer

      AKI Due to Therapeutic Agents

      Conventional chemotherapeutic agents can injure virtually all compartments of the nephron (tubules, interstitium, vasculature, and glomerulus), leading to AKI due to various mechanisms. Similarly, targeted agents such as bevacizumab (Avastin) and novel immunotherapies can lead to a syndrome consisting of AKI, proteinuria, and hypertension. Figure 3 shows the various onco-therapeutic drugs and their site of action on the nephron leading to AKI. Supplemental Table 1 summarizes various medications used in cancer treatment that cause AKI.
      • Cosmai L.
      • Porta C.
      • Foramitti M.
      • et al.
      Preventive strategies for acute kidney injury in cancer patients.
      • Chiruvella V.
      • Annamaraju P.
      • Guddati A.K.
      Management of nephrotoxicity of chemotherapy and targeted agents: 2020.
      • Malyszko J.
      • Kozlowska K.
      • Kozlowski L.
      • Malyszko J.
      Nephrotoxicity of anticancer treatment.
      • Perazella M.A.
      • Moeckel G.W.
      Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy.
      • Santos M.L.C.
      • de Brito B.B.
      • da Silva F.A.F.
      • Botelho A.
      • de Melo F.F.
      Nephrotoxicity in cancer treatment: an overview.
      This topic is dealt with in detail in 3 articles in this issue: "Conventional Chemotherapy Nephrotoxicity" (pp 402-414), "Nephrotoxicity From Molecularly Targeted Chemotherapeutic Agents" (pp 415-428), and "Immunotherapy-Related Acute Kidney Injury" (pp 429-437).
      Figure thumbnail gr3
      Figure 3Oncotherapeutic drugs and their site of action on the nephron leading to AKI. BRAFi, v-Raf murine sarcoma viral oncogene homologue B inhibitor; ICPI, immune checkpoint inhibitor; IL-2, interleukin 2; mTORi, mammalian target of rapamycin inhibitor; TKI, tyrosine kinase inhibitor; TLS, tumor lysis syndrome; VEGFi, vascular endothelial growth factor inhibitor; VEGFRi, vascular endothelial growth factor receptor inhibitor.

      AKI in the Setting of Hematopoietic Stem Cell Transplant

      AKI in the context of hematopoietic stem cell transplant (HSCT) is usually defined as a doubling of baseline serum creatinine or a decline in estimated glomerular filtration rate (eGFR) of at least 50% within the first 100 days after engraftment.
      • Ando M.
      • Mori J.
      • Ohashi K.
      • et al.
      A comparative assessment of the RIFLE, AKIN and conventional criteria for acute kidney injury after hematopoietic SCT.
      AKI occurs in 12%-21% of patients undergoing autologous HSCT and depends on the type of conditioning used before HSCT. Myeloablative and reduced-intensity conditioning are associated with 35%-56% and 7%-46% incidence of AKI, respectively.
      • Ando M.
      • Mori J.
      • Ohashi K.
      • et al.
      A comparative assessment of the RIFLE, AKIN and conventional criteria for acute kidney injury after hematopoietic SCT.
      • Lopes J.A.
      • Jorge S.
      • Silva S.
      • et al.
      Acute renal failure following myeloablative autologous and allogeneic hematopoietic cell transplantation.
      • Kersting S.
      • Dorp S.V.
      • Theobald M.
      • Verdonck L.F.
      Acute renal failure after nonmyeloablative stem cell transplantation in adults.
      KRT requirement in autologous HSCT, myeloablative allogenic HSCT, and reduced-intensity conditioning is 7%, 20%-33%, and 4%, respectively.
      • Kersting S.
      • Dorp S.V.
      • Theobald M.
      • Verdonck L.F.
      Acute renal failure after nonmyeloablative stem cell transplantation in adults.
      ,
      • Satwani P.
      • Bavishi S.
      • Jin Z.
      • et al.
      Risk factors associated with kidney injury and the impact of kidney injury on overall survival in pediatric recipients following allogeneic stem cell transplant.
      Unfortunately, among patients who require KRT, the mortality is exceedingly high (55%-100%). This topic will be discussed in more detail in an upcoming article titled "Kidney Disease Following Hematopoietic Cell Transplantation" (to be published in Advances in Chronic Kidney Disease, volume 29, Part 2 of this collection).

      Kidney Cancer Surgery and AKI

      Surgical resection of kidney cancer is associated with AKI in 40%-60% of patients.
      • Schmid M.
      • Abd-El-Barr A.E.
      • Gandaglia G.
      • et al.
      Predictors of 30-day acute kidney injury following radical and partial nephrectomy for renal cell carcinoma.
      Irrespective of cancer stage (localized or metastatic), patients undergoing radical nephrectomy are at increased risk of AKI.
      • Massari F.
      • Di Nunno V.
      • Gatto L.
      • et al.
      Should CARMENA really change our Attitude towards cytoreductive nephrectomy in metastatic renal cell carcinoma? A systematic review and meta-analysis evaluating cytoreductive nephrectomy in the era of targeted therapy.
      Current standard of care emphasizes preoperative assessment of patients undergoing nephrectomy and estimation of eGFR and albuminuria. Partial nephrectomy, usually is a nephron-sparing procedure, is also associated with AKI depending on the sacrificed amount of nonneoplastic renal tissue.
      • Klingler M.J.
      • Babitz S.K.
      • Kutikov A.
      • et al.
      Assessment of volume preservation performed before or after partial nephrectomy accurately predicts postoperative renal function: results from a prospective multicenter study.
      The occurrence of AKI has future implications on developing CKD. A study conducted on the Veteran Administration data identified that among patients with preoperative eGFR ≥ 30 mL/min per 1.73 m2, the incidence of CKD stage 4 or higher after radical or partial nephrectomy was 7.9%. Compared with radical nephrectomy, partial nephrectomy was associated with a marked reduction in the incidence of clinically significant CKD and with enhanced survival.
      • Leppert J.T.
      • Lamberts R.W.
      • Thomas I.C.
      • et al.
      Incident CKD after radical or partial nephrectomy.
      This topic will be discussed in detail in 2 separate manuscripts titled "Oncosurgery-related Acute Kidney Injury" (to be published in Advances in Chronic Kidney Disease, volume 29, Part 2 of this collection) and "Renal Cell Cancer and Chronic Kidney Disease" (pp 460-468) in this issue.

      Metabolic Disturbances Leading to AKI in Patients with Cancer

      Hypercalcemia is seen more commonly in patients who have metastatic disease with bone involvement, most commonly in MM, squamous cell lung cancer, breast, renal cell carcinoma, and lymphomas.
      • Abudayyeh A.
      Onconephrology: an evolving field.
      ,
      • Body J.J.
      Hypercalcemia of malignancy.
      The two mechanisms of hypercalcemia include local osteolytic metastatic lesions and humoral hypercalcemia due to tumor cells secreting parathyroid hormone-related peptides. Both mechanisms cause an increase in bone resorption.
      • Stewart A.F.
      Clinical practice. Hypercalcemia associated with cancer.
      Hypercalcemia can cause pre-renal azotemia, renal vasoconstriction, and intratubular calcium deposition.
      • Mussap M.
      • Merlini G.
      Pathogenesis of renal failure in multiple myeloma: any role of contrast media?.
      ,
      • Lameire N.
      • Van Biesen W.
      • Vanholder R.
      Electrolyte disturbances and acute kidney injury in patients with cancer.
      One of the most important mechanisms is fewer aquaporin-2 channels in the collecting tubule due to calcium deposition in the medulla causing tubulointerstitial injury. This injury results in the kidney's inability to concentrate urine, leading to polyuria and volume depletion.
      • Earm J.H.
      • Christensen B.M.
      • Frokiaer J.
      • et al.
      Decreased aquaporin-2 expression and apical plasma membrane delivery in kidney collecting ducts of polyuric hypercalcemic rats.
      Moreover, hypercalcemia activates the calcium sensor located in the thick ascending loop of Henle, causing a furosemide-like effect worsening hypovolemia.
      • Toka H.R.
      • Al-Romaih K.
      • Koshy J.M.
      • et al.
      Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.
      ,
      • Hebert S.C.
      Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney.
      Therapy for malignancy associated with hypercalcemia requires aggressive intravenous hydration, intravenous bisphosphonates, and calcitonin.
      • Zagzag J.
      • Hu M.I.
      • Fisher S.B.
      • Perrier N.D.
      Hypercalcemia and cancer: differential diagnosis and treatment.
      This topic is dealt with in more detail in a separate chapter titled "Disorders of Divalent Ions (Magnesium, Calcium, and Phosphorous) in Patients With Cancer" (pp 447-459) in this issue.
      Tumor lysis syndrome (TLS) is an oncological emergency seen in patients with a high tumor burden or after cancer therapies causing rapid cancer cell breakdown.
      • Howard S.C.
      • Jones D.P.
      • Pui C.H.
      The tumor lysis syndrome.
      Usually, TLS is associated with high-grade lymphomas, specifically Burkitt Lymphoma and T cell acute lymphoblastic leukemia.
      • Gupta A.
      • Moore J.A.
      Tumor lysis syndrome.
      Biochemical hallmark of TLS is hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and varying degree of AKI resulting from precipitation of calcium phosphate and uric acid crystals in the tubular lumen.
      • Howard S.C.
      • Jones D.P.
      • Pui C.H.
      The tumor lysis syndrome.
      During TLS, there is a release of inflammatory mediators leading to vasoconstriction and autoregulatory defects of renal blood flow, causing renal tissue hypoxia and endothelial injury. The Cairo Bishop Criteria is used for the diagnosis and grading of TLS. However, these criteria cannot be applied to spontaneous TLS.
      • Cairo M.S.
      • Bishop M.
      Tumour lysis syndrome: new therapeutic strategies and classification.
      Prevention of AKI requires early detection of TLS and treatment with aggressive hydration, urate-lowering agents such as rasburicase, and, in certain instances, KRT. A separate article in this issue titled "Tumor Lysis Syndrome" (pp 438-446) discusses this topic in much more detail.

      Biomarkers and Cancer-Related AKI: Are We There yet?

      Considerable research has been carried out in the field of AKI regarding the utility of biomarkers, resulting in a better understanding of the pathophysiology and precision management of AKI. However, the literature supporting the use of biomarkers in evaluating AKI in patients with cancer is scarce. In patients with cancer, biomarkers aimed at early prediction of AKI have been studied almost exclusively in the context of cisplatin administration.
      Urine cystatin C (CyC) and urinary neutrophil gelatinase-associated lipocalin (NGAL) have been used to identify patients at risk for AKI before cisplatin therapy. One study showed that maximum urine CyC was an independent predictor of AKI and that pre-cisplatin urinary NGAL and peak urine CyC levels could identify patients prone to developing AKI. Hence, these biomarkers could potentially help in the individualization of cisplatin therapy.
      • Jelinek M.J.
      • Lee S.M.
      • Wyche Okpareke A.
      • et al.
      Predicting acute renal injury in cancer patients receiving cisplatin using urinary neutrophil gelatinase-associated lipocalin and cystatin C.
      An observational study from Japan compared the urinary excretion of biomarkers: N-acetyl-beta-D-glucosaminidase, kidney injury molecule-1, and NGAL between cisplatin and non-cisplatin-based chemotherapy. All the biomarkers were significantly elevated at day 5 after receiving cisplatin-based chemotherapy and were more sensitive than serum creatinine.
      • Maeda A.
      • Ando H.
      • Ura T.
      • et al.
      Differences in urinary renal failure biomarkers in cancer patients initially treated with cisplatin.
      Similarly, a single-center study showed kidney injury molecule-1 had the highest percentage of increase over the course of AKI compared to other urinary biomarkers such as NGAL and CyC.
      • Abdelsalam M.
      • Elmorsy E.
      • Abdelwahab H.
      • et al.
      Urinary biomarkers for early detection of platinum based drugs induced nephrotoxicity.
      Other urinary biomarkers such as beta-2 microglobulin, calbindin, monocyte chemotactic protein-1, and trefoil factor-3 show a distinct pattern of elevation in a time-dependent manner after administration of cisplatin.
      • George B.
      • Joy M.S.
      • Aleksunes L.M.
      Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy.
      In an analysis of 34 patients (70% of which had solid tumors) admitted to an oncologic ICU, AKI risk score was calculated as the product of tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7). A cutoff value > 0.3 was used to predict progression to moderate to severe AKI. In all, 74% of patients were classified as high risk of progression, of which 80% developed stage 2/3 AKI within 24 hours.
      • Mehta S.
      • Pastores S.M.
      • Kostelecky N.
      • et al.
      Urine Biomarkers TIMP-2 and IGFBP7 Early Predict Acute Kidney Injury in Cancer Patients in the ICU.
      To summarize, the lack of randomized trials and paucity of validation studies limited the implementation of urinary biomarkers in predicting AKI in an onconephrology setup. In addition, the time-dependent dynamic response, cutoff values, and range for the biomarker assays need to be validated in patients with cancer.

      Conclusions and Future Directives

      With the advent of advances in cancer treatment, there was a demonstrable increase in the survival of patients who have cancer. However, along with these advancements, the incidence of AKI has increased. Patients with cancer who sustain AKI present challenges in prognosis and planning of further treatment. It is essential to identify patients at risk of developing these adverse kidney outcomes so that their treatment can be individualized. Advances in supportive care, including KRT, have improved outcomes in critically ill patients with cancer; however, a multidisciplinary approach is needed to determine which patients can benefit from KRT. Moreover, a broad outlook needs to be maintained to identify possible causes of AKI in patients with cancer to provide appropriate supportive care. Finally, a multidisciplinary approach incorporating an oncologist, nephrologist, and pharmacist is paramount in onconephrology.

      Supplementary Data

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