Cancer and the Kidney: The Growth of Onco-nephrology

Abstract

Onco-nephrology is a rapidly growing area of nephrology that has recently garnered increased attention by specialty societies, such as the American Society of Nephrology and National Kidney Foundation, as well as several prominent journals.1Berns J.S. Rosner M.H. Onco-nephrology: What the nephrologist needs to know about cancer and the kidney.Clin J Am Soc Nephrol. 2012; 7: 1691Crossref PubMed Scopus (15) Google Scholar, 2Humphreys B.D. Onco-nephrology: Kidney disease in the cancer patient: Introduction.Semin Nephrol. 2010; 30: 531-533Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 3Humphreys B.D. Sanders P.W. Cancer and the kidney.Nephrol Self Assess Program. 2013; 12: 3-64Google Scholar, 4Salahudeen A.K. Bonventre J.V. Onconephrology: the latest frontier in the war against kidney disease.J Am Soc Nephrol. 2013; 24: 26-30Crossref PubMed Scopus (52) Google Scholar, 5American Society of Nephrology. OncoNephrology forum. Available at: http://www.asn-online.org/about/committees/committee.aspx?panel1/4 OncoNeph. Accessed August 16, 2013.Google Scholar Many of us during our nephrology fellowship training and in earlier years of practice encountered cancer patients with various kidney-related insults, including acute kidney injury (AKI), tumor lysis syndrome (TLS), hypercalcemia, lactic acidosis, and other electrolyte and acid-base disturbances. However, for the most part, these cases only made up a small percentage of our consult list. Over time, particularly in the last 10 to 15 years, this trend has changed dramatically. Now, when we attend on the nephrology consult and/or critical care nephrology services, oncology patients make up a significant number of the patients we see for kidney-related problems. Why is there an increase in the number of patients with kidney disease? Clearly, the incidence rates for many malignancies remain high.6National Cancer Institute. Surveillance Epidemiology and End Results: SEER stat fact sheets: All sites. Available at: http://seer.cancer.gov/statfacts/html/all.html. Accessed August 16, 2013.Google Scholar Improvement in the 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 of whom develop acute or chronic kidney diseases due to their malignancy and/or its associated treatment.7National Cancer Institute: Find cancer statistics. Available at: www.cancer.gov/statistics/find. Accessed August 16, 2013.Google Scholar The kidneys may be directly or indirectly injured by the cancer or one of the growing numbers of therapeutic agents that extend lives, but at the cost of causing acute or chronic kidney disease. Patients may also develop multiorgan illness requiring intensive care unit care and kidney replacement therapy. When this type of critical illness occurs in the setting of far advanced malignancy, it raises questions about the appropriateness of aggressive care in “futile situations” and the role of palliation. Thus, care for oncology patients has become more specialized and complicated, requiring collaboration among nephrologists, oncologists, intensivists, and palliative care specialists. The remarkable advances in cancer management present new opportunities and complex challenges for the oncology and nephrology communities. It is essential for nephrologists to be informed and actively involved in certain facets of cancer care. A better understanding of the rapidly evolving field of cancer biology and its therapy is required for nephrologists to become a valuable member of the cancer care team and to provide the best nephrology care possible. In this issue of Advances in Chronic Kidney Disease, the rapidly growing area of onco-nephrology is addressed by several outstanding contributions by experts in the field. This issue covers some of the clinically relevant topics in onco-nephrology. Drs. Rosner and Dalkin cover the various electrolyte disturbances associated with cancer. They point out how these metabolic abnormalities develop as a direct result of the underlying malignancy or the therapy used to treat and manage the patients. Hyponatremia is the most common disorder, results by various mechanisms, and may be associated with untoward outcomes. Other cancer-related electrolyte disturbances include hypo- and hyperkalemia, hypophosphatemia, and hypercalcemia. An interesting cause of hypophosphatemia is fibroblast growth factor-23, a phosphaturic factor produced by certain tumors. Hypercalcemia of malignancy is a fascinating disorder that can be due to production of parathyroid-hormone-related peptide, vitamin D, or various cytokines produced locally by bone metastases. Rosner and Dalkin review therapies that focus on electrolyte management, supportive care, and tumor eradication/debulking. TLS remains a potentially life-threatening complication for patients with several malignancies, in particular leukemias and lymphomas, which have large tumor burdens and enhanced chemosensitivity. Drs. Wilson and Berns review the challenges associated with treatment and the recent advances in management of TLS. They define this oncologic emergency in terms of laboratory and clinical TLS, on the basis of the Cairo–Bishop criteria, and provide a lucid review of the pathophysiology of this disorder. The clinical manifestations of TLS, including metabolic abnormalities and AKI, are discussed as are the preventive and therapeutic strategies that are available. In particular, the authors provide guidance on the utility and role of intravenous fluids, xanthine oxidase inhibitors such as allopurinol and febuxostat, rasburicase, and renal replacement therapy (RRT) in preventing and treating TLS, while recognizing the lack of evidence in many of these areas. Drs. Luciano and Brewster tackle the issue of lymphoma and leukemia-associated kidney disease. Both of these cancers frequently infiltrate the kidneys without affecting kidney function, but they may also cause clinically severe AKI or CKD. They point out that AKI results from routine causes (volume depletion, acute tubular necrosis [ATN], and obstruction), but it also results from lesions specific to these hematologic malignancies. The authors review the various glomerular lesions that develop with these forms of cancer. Hematologic malignancies also cause various electrolyte disturbances, such as hypercalcemia, type B lactic acidosis, hypophosphatemia, and abnormalities in potassium homeostasis from lysozyme-induced tubular injury. The authors discuss their diagnosis and management in current times. Myeloma-related kidney disease remains a common problem that nephrologists face. Drs. Leung and Nasr expertly cover a topic that they have had much experience with at the Mayo Clinic. The authors adeptly review the mechanism of paraprotein-associated kidney injury and the numerous light-chain-related lesions seen with myeloma as well as their clinical manifestations. The authors discuss the common lesions such as myeloma cast nephropathy, AL amyloidosis, and monoclonal immunoglobulin (light and heavy chain) deposition disease as well the occurrence of Fanconi syndrome with light-chain deposition disease. The authors also touch on immunotactoid glomerulonephritis (GN) and the less well-understood lesion monoclonal gammopathy-related membranoproliferative GN. Preventive and therapeutic strategies, including chemotherapeutic agents, plasmapheresis, and high-cutoff hemodialysis, are also reviewed for the reader, providing an up-to-date guide for the management of patients with multiple myeloma. Glomerular diseases complicate various cancers, including several solid and hematologic malignancies. Dr. Jhaveri and colleagues provide a thorough overview of these lesions. Most commonly, membranous GN occurs in connection with several solid tumors and in the setting of hematopoietic stem cell transplantation (HSCT). Minimal change lesion develops as a complication of Hodgkin's and non-Hodgkin's lymphoma. Membranoproliferative GN complicates numerous cancers, in particular chronic hematologic malignancies such as chronic lymphocytic leukemia. Chemotherapeutic agents can also cause various forms of glomerular pathology. The authors discuss clinical presentation, diagnosis, and management of this interesting group of patients. Chemotherapeutic agents are a common cause of acute and chronic kidney injury in cancer patients. Drs. Shirali and Perazella review the various tubulointerstitial injury patterns that develop during and after chemotherapy. After reviewing the various factors that increase risk for kidney injury after these drugs, they review examples of medications that cause AKI from acute tubular injury/necrosis, isolated tubulopathies, crystal nephropathy, and chronic interstitial nephritis. Cisplatin is a classic nephrotoxin that causes acute tubular injury/necrosis, various tubulopathies, and CKD. Cetuximab is recognized to cause kidney magnesium wasting, whereas methotrexate is associated with AKI via direct tubular toxicity and the unique mechanism of crystal deposition within the distal nephron. Less commonly, acute interstitial nephritis may occur with some drugs, whereas others may promote CKD by causing chronic tubulointerstitial injury. Identification of patients at risk and use of preventive strategies, when possible, is required. In certain instances of chemotherapy-associated nephrotoxicity, directed therapy is useful, but supportive care and RRT are most often used. Drs. Campbell, Hu, and Okusa highlight the importance of AKI as a frequent and serious complication of cancer and its therapy. They describe risk factors such as the prerenal condition, sepsis, and nephrotoxin exposure. The various causes of AKI in patients with malignancy are also reviewed, including the all too common prerenal AKI, various intrinsic forms of kidney injury, and postrenal AKI. Among the intrinsic kidney diseases, the authors touch on glomerular injury, ischemic ATN, various forms of chemotherapeutic drug-induced kidney injury, TLS, and myeloma and lymphoma-related kidney disease. The authors also review the causes of AKI in the critically ill patient admitted to the intensive care unit, noting the high morbidity and mortality that occur in this group of patients. Difficult decisions regarding whether or not to provide RRT and other aspects of care are often required in critically ill patients with cancer and kidney disease. Drs. Scherer and Swidler discuss the important details that underlie the decision-making process in this complicated group of patients and use clinical scenarios to highlight the challenges. A comprehensive discussion of overall prognosis and options for treatment for the malignant condition as well as the underlying kidney injury is absolutely required to make appropriate dialysis decisions. The authors note that such discussions require the careful integration of information about both of these disease processes. Prognostication for patients and their families utilizes an examination of patient performance and functional status, comorbidities, level of nutrition, and frailty. What proves to be critically important in reaching a decision about the approach to care is the shared decision-making model. The authors review how this model can help the health-care team effectively communicate prognosis and treatment options while gaining an understanding the patient's personal goals, and ultimately formulating a plan consistent with the patient's preferences. Drs. Haas and Nathanson address the topic of hereditary kidney cancer syndromes, a rapidly evolving area that often requires the expertise, clinical assessment, and guidance of a knowledgeable nephrologist. The authors review 10 genetic syndromes that are associated with increased risk of various types of kidney cancer. Examples include those that are familiar to the reader, such as von Hippel Lindau disease and tuberous sclerosis complex, and those less commonly encountered (hereditary papillary renal cancer, Birt-Hogg-Dube syndrome, and BAP1 mutant disease). The genetic mutations and aberrant gene products that are involved in these disorders are reviewed. Clinical manifestations, potential screening, and therapeutic options are also discussed, including data from clinical trials. HSCT is being increasingly used to treat cancer and other disorders. Dr. Sawinski provides an overview of this therapy and how the conditioning regimen used and other aspects of the transplant process may injure the kidneys. The kidney effects of HCST are varied and include acute and chronic kidney disease, one which confer excess morbidity and mortality. AKI is most often due to prerenal AKI and ATN, but HCST-related injuries, including TLS, hepatic sinusoidal syndrome, and BK virus nephropathy must be considered in the differential diagnosis. The causes of CKD in these patients are not always as clear, but include graft versus host disease, radiation nephritis, calcineurin-inhibitor nephrotoxicity, and thrombotic microangiopathy. As Dr. Sawinski points out, patients who progress to ESRD do poorly on chronic maintenance dialysis; however, kidney transplantation remains a reasonably good kidney replacement option for many patients. Cancer is a frequent complication noted in transplant patients, occurring at a younger age than the general population. Drs. Asch and Bia review the malignancies commonly observed in the immunosuppressed host and the higher risk in those associated with an oncogenic virus. Based on published guidelines, the authors discuss when cancer screening in post-transplant recipients is appropriate and situations when screening offers no improvement in quality of life or survival. Finally, they provide very practical recommendations for cancer therapy, in particular when immunosuppression reduction is appropriate. Lastly, Drs. Chang, Finelli, Berns, and Rosner discuss the evolving landscape of the care of patients with renal cell cancer (RCC). A large number of patients with RCC either have a reduced glomerular filtration rate at baseline or are found to have undiagnosed renal disease in the surgical pathology specimen. Surgeons have approached the issue of post-surgical CKD by focusing their efforts on nephron sparing surgery in order to preserve function. However, this article points out that nephrologists and pathologists must take a more active role in the care of patients with RCC. Thus, improving outcomes in this group of patients will require close collaboration among nephrologists, surgeons, and pathologists. We hope that this compilation of articles covering various aspects of the nephrology-oncology connection provides Advances in Chronic Kidney Disease readers with the building blocks upon which further information can be added as technology advances. We believe that nephrologists must be well prepared to care for patients with cancer and its associated kidney complications. This approach is sensible, as the renal manifestations of cancer have many unique features, and these conditions often require specialized approaches to manage fluid, electrolyte, and acid-base disturbances as well as acute and chronic kidney injury. The ever-evolving field of cancer therapy demands a comprehensive team approach with the nephrologist as one of the critically important care providers. As such, it is essential for nephrologists to develop expertise in the practice of onco-nephrology.