Japanese Journal of Clinical Oncology Advance Access published March 17, 2015 Japanese Journal of Clinical Oncology, 2015, 1–12 doi: 10.1093/jjco/hyv035 Review Article
Review Article
Onco-nephrology: current concepts and future perspectives Yuichiro Kitai, Takeshi Matsubara, and Motoko Yanagita*
*For reprints and all correspondence: Motoko Yanagita, Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected] Received 23 December 2014; Accepted 17 February 2015
Abstract Onco-nephrology is a new and evolving subspecialized area in nephrology that deals with kidney diseases in cancer patients. As many newer cancer therapies emerge in the field of oncology, cancer patients are surviving longer than ever before. However, the benefits of the remarkable advances in cancer management have not been fully appreciated. Not only is cancer often associated with abnormalities that affect the kidney, but cancer therapy often leads to both acute and chronic kidney diseases. The development of cancer-associated kidney complications is associated with poor prognosis, whereas prompt recognition and treatment initiation are associated with improved outcomes in this population. Therefore, both nephrologists and oncologists should be familiar with the diagnosis and management of cancer-associated kidney complications. Another unique aspect of onco-nephrology is that significant improvements in predialysis and dialysis care in recent years have led to prolonged survival and a higher incidence of patients with chronic kidney disease suffering from cancer. Therefore, research is urgently needed to establish treatment for patients with chronic kidney disease. This update addresses the pathophysiology and treatment of various cancer-associated kidney complications, and highlights cancer treatment for patients with chronic kidney disease. Key words: onco-nephrology, cancer and the kidney, dialysis, thrombotic microangiopathy, therapeutic drug monitoring
Introduction Onco-nephrology, which has emerged as a new clinical entity in recent years, highlights the importance of the interaction between cancer and kidney disease. The nephrology–oncology connection is being emphasized more strongly than ever. This review focuses on two different aspects of this association, even though the term ‘onco-nephrology’ has broad meanings in the practice of renal medicine. First, improvement in cancer death rates due to more effective chemotherapeutic agents, including biologics and stem cell therapies, has led to an increase in the number of cancer survivors. Some survivors develop kidney complications due to cancer and its associated treatment that ultimately lead to chronic kidney disease (CKD). Therefore, nephrologists and oncologists should be knowledgeable about cancer-associated kidney complications, such as paraneoplastic glomerulopathies and chemotherapy-associated kidney diseases. It is also important to note that survival rates after acute kidney injury (AKI) are significantly
lower in cancer patients (1). Second, an increasing number of patients with CKD are diagnosed with cancer due to recent advances in predialysis and dialysis care. The coexistence of CKD with cancer reduces the likelihood that cancer patients will receive optimal anti-cancer therapy and supportive care. Formal data on renal or dialysis clearance for these agents are scarce, although most anti-cancer agents are eliminated through the kidneys. There is an urgent need to clarify the pharmacokinetics of drug distribution and the proper dose of anti-cancer agents. Thus, this review discusses two different aspects of onco-nephrology, ‘cancer-associated kidney complications’ and ‘cancer treatment for patients with CKD.’
AKI in cancer patients AKI is probably the most common form of kidney disease for which a nephrologist would be consulted in a hospitalized cancer patient.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
1
Downloaded from http://jjco.oxfordjournals.org/ at University of California, San Francisco on March 24, 2015
Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
2
Onco-nephrology
Table 1. Etiologies of acute renal injury in cancer patients (2)
AKI may occur as a consequence of the cancer itself, its treatment, or associated severe complications. The largest cohort study of Danish cancer patients documented increased risks of AKI in this population, defined as having a >50% increase in creatinine level, with 1- and 5-year risks of 17.5 and 27.0%, respectively (3). Another study reported that AKI conferred a 6-month mortality of as high as 73% in critically ill cancer patients (4). An increased incidence of AKI in cancer patients is not surprising given the effects of cancer and anti-cancer therapy on several factors that cause AKI. Although the causes of AKI in cancer patients are often multifactorial, it is clinically useful to categorize the causes of AKI as prerenal, intrinsic and postrenal etiologies (Table 1) (5). Details related to the disease state associated with chemotherapy are discussed in ‘Chemotherapy-associated Kidney Diseases.’
Prerenal causes Prerenal AKI is frequently seen in cancer patients. In these patients, prerenal AKI may be due to true intravascular volume depletion, such as in the setting of vomiting, diarrhea or sepsis. AKI due to volume depletion related to cancer treatment-associated malnutrition is often encountered in clinical practice. In sepsis, hypotension and vasodilation due to sepsis or pharmacological interventions using vasoconstrictors, such as norepinephrine or vasopressin, also lead to hypoperfusion and prerenal AKI. Medications such as diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or non-steroidal anti-inflammatory drugs (NSAIDs) used for the malignancy or other medical conditions, can lead to prerenal AKI. Clinicians should consider whether continuing these medications confers benefits in cancer patients who are at risk for prerenal AKI. Other well-known etiologies associated with prerenal AKI are described below. Hypercalcemia Hypercalcemia, seen in 20–30% of cancer patients at some time during the course of their disease, can lead to a prerenal state due to renal vasoconstriction as well as volume depletion from natriuresis and diuresis (6). There are three known mechanisms of cancer-associated hypercalcemia. Most commonly, tumors synthesize and secrete parathyroid hormone (PTH)-like substances, specifically parathyroid hormone-related protein (PTHrP), which increase bone turnover and the release of calcium stores. Squamous-cell carcinomas of the lung, cervix and
Hepatic sinusoidal obstruction syndrome Hepatic sinusoidal obstruction syndrome (SOS) is a complication of hematopoietic cell transplantation (HCT), and is considered to be caused by acute radiochemotherapy-induced damage to sinusoidal endothelial cells and hepatocytes in Zone 3 of the liver acinus (the area surrounding the central veins), subsequent sinusoidal thrombosis and portal hypertension. Clinically, SOS begins as a fluid-retentive state with low urinary sodium that leads to peripheral edema and weight gain, and elevated serum bilirubin within the first few days after HCT (19). A recent review of 135 studies performed between 1979 and October 2007 reported that the overall mean incidence of SOS was 13.7% (20). SOS occurs less commonly in myeloablative autologous HCT compared with myeloablative allogenic HCT, probably due to the absence of methotrexate (21,22). In non-myeloablative regimens, the frequency of SOS is essentially non-existent, probably due to less intensive radiochemotherapy (23). A transvenous approach that allows both biopsy and hepatic venous pressure measurements is the most accurate diagnostic test. A hepatic venous pressure gradient >10 mmHg is highly specific for SOS (24). More than 70% of patients with SOS will recover spontaneously with supportive treatment alone, including management of sodium and water balance, preservation of renal blood flow and repeated paracenteses for ascites to relieve abdominal discomfort (25). Unfortunately, there are still no satisfactory therapies for severe cases, although a recent randomized controlled trial (RCT) of 149 patients with severe SOS showed that defibrotide, a single-stranded oligodeoxyribonucleotide with antithrombotic and profibrinolytic properties, conferred a 46% complete response rate,
Downloaded from http://jjco.oxfordjournals.org/ at University of California, San Francisco on March 24, 2015
A. Prerenal Extracellular fluid depletion ( poor food intake, vomiting, diarrhea), hypercalcemia, hepatic sinusoidal occlusive syndrome and drugs (calcineurin inhibitors, non-steroidal anti-inflammatory drugs) B. Intrinsic B-1. Glomerular Membranous nephropathy, minimal-change disease, focal segmental glomerulonephritis, membranoproliferative glomerulonephritis and amyloidosis B-2. Tubulointerstitial Acute tubular necrosis, lymphomatous infiltration of the kidney, cast nephropathy (multiple myeloma) and uric acid nephropathy (tumor lysis syndrome) B-3. Vascular Thrombotic microangiopathy C. Postrenal Extrarenal obstruction ( primary disease, retroperitoneal lymphadenopathy, retroperitoneal fibrosis)
esophagus as well as certain lymphomas, renal cell carcinoma and adenocarcinomas of the breast, prostate and ovary have been reported to cause hypercalcemia via PTHrP release (7). Second, in patients with substantial tumor burden metastatic to bone, the local effects of the tumor can directly facilitate osteolysis and calcium mobilization. This mechanism is most commonly noted in patients with metastatic breast and lung carcinomas as well as in patients with extensive multiple myeloma (MM) (8,9). Third, less commonly, the activation of vitamin D by the tumor itself, commonly seen in Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (10). 1α-hydroxylase, which converts 25-hydroxyvitamin D to activated vitamin D, calcitriol, is considered to be highly expressed in neoplastic tissues. Patients presenting with hypercalcemia are usually volume-depleted and a resultant reduced glomerular filtration rate (GFR) can further exacerbate the hypercalcemia. The activation of the calcium sensing receptor in the thick ascending limb of the loop of the Henle and collecting duct leads to decreased reabsorption of sodium, chloride and water (11). The mainstay of therapy is intravenous hydration with an aim to increase kidney clearance of calcium. The routine use of loop diuretics in this setting cannot be recommended, and their use should be restricted to patients who develop fluid overload after vigorous hydration. To block the mobilization of calcium from bone, antiresorptive therapy with bisphosphonates is generally mandatory. Randomized clinical trials have demonstrated the efficacy of bisphosphonates in the treatment of hypercalcemia (12–14). However, kidney complications such as focal segmental glomerulosclerosis (FSGS), minimal-change disease (MCD) and acute tubular necrosis (ATN) have been reported (15–17). An alternative antiresorptive agent, denosumab, is a monoclonal antibody directed against RANKL. Denosumab is not cleared by the kidneys, and hence does not require dosing adjustments for renal insufficiency. For patients with tumor-induced hypercalcemia resulting from excess 1α-hydroxylase, corticosteroid therapy may be beneficial (18).
Jpn J Clin Oncol, 2015 defined as total serum bilirubin
Review Article
Onco-nephrology: current concepts and future perspectives Yuichiro Kitai, Takeshi Matsubara, and Motoko Yanagita*
*For reprints and all correspondence: Motoko Yanagita, Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected] Received 23 December 2014; Accepted 17 February 2015
Abstract Onco-nephrology is a new and evolving subspecialized area in nephrology that deals with kidney diseases in cancer patients. As many newer cancer therapies emerge in the field of oncology, cancer patients are surviving longer than ever before. However, the benefits of the remarkable advances in cancer management have not been fully appreciated. Not only is cancer often associated with abnormalities that affect the kidney, but cancer therapy often leads to both acute and chronic kidney diseases. The development of cancer-associated kidney complications is associated with poor prognosis, whereas prompt recognition and treatment initiation are associated with improved outcomes in this population. Therefore, both nephrologists and oncologists should be familiar with the diagnosis and management of cancer-associated kidney complications. Another unique aspect of onco-nephrology is that significant improvements in predialysis and dialysis care in recent years have led to prolonged survival and a higher incidence of patients with chronic kidney disease suffering from cancer. Therefore, research is urgently needed to establish treatment for patients with chronic kidney disease. This update addresses the pathophysiology and treatment of various cancer-associated kidney complications, and highlights cancer treatment for patients with chronic kidney disease. Key words: onco-nephrology, cancer and the kidney, dialysis, thrombotic microangiopathy, therapeutic drug monitoring
Introduction Onco-nephrology, which has emerged as a new clinical entity in recent years, highlights the importance of the interaction between cancer and kidney disease. The nephrology–oncology connection is being emphasized more strongly than ever. This review focuses on two different aspects of this association, even though the term ‘onco-nephrology’ has broad meanings in the practice of renal medicine. First, improvement in cancer death rates due to more effective chemotherapeutic agents, including biologics and stem cell therapies, has led to an increase in the number of cancer survivors. Some survivors develop kidney complications due to cancer and its associated treatment that ultimately lead to chronic kidney disease (CKD). Therefore, nephrologists and oncologists should be knowledgeable about cancer-associated kidney complications, such as paraneoplastic glomerulopathies and chemotherapy-associated kidney diseases. It is also important to note that survival rates after acute kidney injury (AKI) are significantly
lower in cancer patients (1). Second, an increasing number of patients with CKD are diagnosed with cancer due to recent advances in predialysis and dialysis care. The coexistence of CKD with cancer reduces the likelihood that cancer patients will receive optimal anti-cancer therapy and supportive care. Formal data on renal or dialysis clearance for these agents are scarce, although most anti-cancer agents are eliminated through the kidneys. There is an urgent need to clarify the pharmacokinetics of drug distribution and the proper dose of anti-cancer agents. Thus, this review discusses two different aspects of onco-nephrology, ‘cancer-associated kidney complications’ and ‘cancer treatment for patients with CKD.’
AKI in cancer patients AKI is probably the most common form of kidney disease for which a nephrologist would be consulted in a hospitalized cancer patient.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
1
Downloaded from http://jjco.oxfordjournals.org/ at University of California, San Francisco on March 24, 2015
Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
2
Onco-nephrology
Table 1. Etiologies of acute renal injury in cancer patients (2)
AKI may occur as a consequence of the cancer itself, its treatment, or associated severe complications. The largest cohort study of Danish cancer patients documented increased risks of AKI in this population, defined as having a >50% increase in creatinine level, with 1- and 5-year risks of 17.5 and 27.0%, respectively (3). Another study reported that AKI conferred a 6-month mortality of as high as 73% in critically ill cancer patients (4). An increased incidence of AKI in cancer patients is not surprising given the effects of cancer and anti-cancer therapy on several factors that cause AKI. Although the causes of AKI in cancer patients are often multifactorial, it is clinically useful to categorize the causes of AKI as prerenal, intrinsic and postrenal etiologies (Table 1) (5). Details related to the disease state associated with chemotherapy are discussed in ‘Chemotherapy-associated Kidney Diseases.’
Prerenal causes Prerenal AKI is frequently seen in cancer patients. In these patients, prerenal AKI may be due to true intravascular volume depletion, such as in the setting of vomiting, diarrhea or sepsis. AKI due to volume depletion related to cancer treatment-associated malnutrition is often encountered in clinical practice. In sepsis, hypotension and vasodilation due to sepsis or pharmacological interventions using vasoconstrictors, such as norepinephrine or vasopressin, also lead to hypoperfusion and prerenal AKI. Medications such as diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or non-steroidal anti-inflammatory drugs (NSAIDs) used for the malignancy or other medical conditions, can lead to prerenal AKI. Clinicians should consider whether continuing these medications confers benefits in cancer patients who are at risk for prerenal AKI. Other well-known etiologies associated with prerenal AKI are described below. Hypercalcemia Hypercalcemia, seen in 20–30% of cancer patients at some time during the course of their disease, can lead to a prerenal state due to renal vasoconstriction as well as volume depletion from natriuresis and diuresis (6). There are three known mechanisms of cancer-associated hypercalcemia. Most commonly, tumors synthesize and secrete parathyroid hormone (PTH)-like substances, specifically parathyroid hormone-related protein (PTHrP), which increase bone turnover and the release of calcium stores. Squamous-cell carcinomas of the lung, cervix and
Hepatic sinusoidal obstruction syndrome Hepatic sinusoidal obstruction syndrome (SOS) is a complication of hematopoietic cell transplantation (HCT), and is considered to be caused by acute radiochemotherapy-induced damage to sinusoidal endothelial cells and hepatocytes in Zone 3 of the liver acinus (the area surrounding the central veins), subsequent sinusoidal thrombosis and portal hypertension. Clinically, SOS begins as a fluid-retentive state with low urinary sodium that leads to peripheral edema and weight gain, and elevated serum bilirubin within the first few days after HCT (19). A recent review of 135 studies performed between 1979 and October 2007 reported that the overall mean incidence of SOS was 13.7% (20). SOS occurs less commonly in myeloablative autologous HCT compared with myeloablative allogenic HCT, probably due to the absence of methotrexate (21,22). In non-myeloablative regimens, the frequency of SOS is essentially non-existent, probably due to less intensive radiochemotherapy (23). A transvenous approach that allows both biopsy and hepatic venous pressure measurements is the most accurate diagnostic test. A hepatic venous pressure gradient >10 mmHg is highly specific for SOS (24). More than 70% of patients with SOS will recover spontaneously with supportive treatment alone, including management of sodium and water balance, preservation of renal blood flow and repeated paracenteses for ascites to relieve abdominal discomfort (25). Unfortunately, there are still no satisfactory therapies for severe cases, although a recent randomized controlled trial (RCT) of 149 patients with severe SOS showed that defibrotide, a single-stranded oligodeoxyribonucleotide with antithrombotic and profibrinolytic properties, conferred a 46% complete response rate,
Downloaded from http://jjco.oxfordjournals.org/ at University of California, San Francisco on March 24, 2015
A. Prerenal Extracellular fluid depletion ( poor food intake, vomiting, diarrhea), hypercalcemia, hepatic sinusoidal occlusive syndrome and drugs (calcineurin inhibitors, non-steroidal anti-inflammatory drugs) B. Intrinsic B-1. Glomerular Membranous nephropathy, minimal-change disease, focal segmental glomerulonephritis, membranoproliferative glomerulonephritis and amyloidosis B-2. Tubulointerstitial Acute tubular necrosis, lymphomatous infiltration of the kidney, cast nephropathy (multiple myeloma) and uric acid nephropathy (tumor lysis syndrome) B-3. Vascular Thrombotic microangiopathy C. Postrenal Extrarenal obstruction ( primary disease, retroperitoneal lymphadenopathy, retroperitoneal fibrosis)
esophagus as well as certain lymphomas, renal cell carcinoma and adenocarcinomas of the breast, prostate and ovary have been reported to cause hypercalcemia via PTHrP release (7). Second, in patients with substantial tumor burden metastatic to bone, the local effects of the tumor can directly facilitate osteolysis and calcium mobilization. This mechanism is most commonly noted in patients with metastatic breast and lung carcinomas as well as in patients with extensive multiple myeloma (MM) (8,9). Third, less commonly, the activation of vitamin D by the tumor itself, commonly seen in Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (10). 1α-hydroxylase, which converts 25-hydroxyvitamin D to activated vitamin D, calcitriol, is considered to be highly expressed in neoplastic tissues. Patients presenting with hypercalcemia are usually volume-depleted and a resultant reduced glomerular filtration rate (GFR) can further exacerbate the hypercalcemia. The activation of the calcium sensing receptor in the thick ascending limb of the loop of the Henle and collecting duct leads to decreased reabsorption of sodium, chloride and water (11). The mainstay of therapy is intravenous hydration with an aim to increase kidney clearance of calcium. The routine use of loop diuretics in this setting cannot be recommended, and their use should be restricted to patients who develop fluid overload after vigorous hydration. To block the mobilization of calcium from bone, antiresorptive therapy with bisphosphonates is generally mandatory. Randomized clinical trials have demonstrated the efficacy of bisphosphonates in the treatment of hypercalcemia (12–14). However, kidney complications such as focal segmental glomerulosclerosis (FSGS), minimal-change disease (MCD) and acute tubular necrosis (ATN) have been reported (15–17). An alternative antiresorptive agent, denosumab, is a monoclonal antibody directed against RANKL. Denosumab is not cleared by the kidneys, and hence does not require dosing adjustments for renal insufficiency. For patients with tumor-induced hypercalcemia resulting from excess 1α-hydroxylase, corticosteroid therapy may be beneficial (18).
Jpn J Clin Oncol, 2015 defined as total serum bilirubin
