Abstract
Onco-nephrology is a growing subspecialty in the field of nephrology. It is essential for clinicians to have a better understanding of kidney complications of cancer and its treatment and the implications of chronic kidney disease (CKD) in patients with cancer. Although patients with malignancy can develop kidney diseases similar to other acutely and chronically ill patients, they are also at risk for unique renal syndromes because of either the cancer itself or its treatment. Understanding these unique disorders is a prerequisite to providing outstanding clinical care. In addition, because patients now have improved survival owing to advances in cancer treatment, the prevalence of CKD has also increased. Providing expert advice on the impact of CKD on patient survival, drug response, toxicity, and clearance, and clinical study eligibility are important considerations in the field of onco-nephrology. Finally, patients with advanced malignancy can develop severe acute kidney injury with multiple organ dysfunction syndrome. In these cases, the onco-nephrologist is essential to discussions about end-of-life issues and the appropriateness of initiating kidney replacement therapies.
Keywords
onco-nephrology, acute kidney injury, chemotherapy, thrombotic microangiopathy, stem cell transplantation, paraneoplastic glomerulonephritis
Onco-nephrology is a growing field within nephrology, with many malignancies and their treatments affecting the kidneys and kidney disease impacting the management of many malignancies. Although patients with malignancy can develop kidney diseases similar to other acutely and chronically ill patients, they are also at risk for unique kidney syndromes because of either the cancer itself or its treatment. Understanding these unique disorders is a prerequisite to providing outstanding clinical care. In addition, because patient survival has improved owing to advances in cancer treatment, chronic kidney disease (CKD) prevalence has also increased. Providing expert advice on the impact of CKD on patient survival; drug response, toxicity, and clearance; and clinical study eligibility are important considerations in onco-nephrology. Finally, patients with advanced malignancy can develop severe acute kidney injury (AKI) with multiple organ dysfunction syndrome. In these cases, the nephrologist is an essential partner in discussions about end-of-life issues and the appropriateness of initiating kidney replacement therapies.
This chapter provides an overview of kidney diseases either caused by cancer or its treatment, including AKI, CKD, electrolyte abnormalities, glomerular diseases, tumor lysis syndrome (TLS), and anticancer drug nephrotoxicity. Multiple myeloma, amyloidosis, and other dysproteinemias are discussed in Chapter 28 .
Acute Kidney Injury
In hospitalized cancer patients, AKI is associated with increased morbidity, mortality, length of stay, and costs. In a northern Denmark study with a 1.2 million population in the catchment area, incident cancer was found in 44,116 patients. The 1-year and 5-year risk of AKI in this population was 17.5% and 27.5%, respectively. The incidence of AKI was highest for kidney cancer (44%), multiple myeloma (33%), liver cancer (32%), and acute leukemia (28%).
Among critically ill patients, 20% have underlying malignancy with overall prognosis strongly dependent on the admitting diagnosis and the type of cancer. Patients with solid tumors have lower mortality (56%) than those with hematologic malignancies (67%). In the Sepsis Occurrence in Critically Ill Patients (SOAP) study, in the subset of patients with more than three failing organs, over 75% of patients with cancer died; this compares to 50% of those without cancer. In a retrospective analysis of 1009 critically ill patients with hematologic malignancies, Darmon and colleagues reported an AKI incidence of 66.5%. After adjustment, factors associated with AKI development were older age, history of hypertension, TLS, multiple myeloma, exposure to nephrotoxins, and sequential organ failure assessment (SOFA) score.
The etiology of AKI in cancer patients is quite varied and is often multifactorial. Causes vary from those common to all hospitalized patients such as exposure to various nephrotoxins (antibiotics and radiocontrast), sepsis, and volume depletion, and factors unique to the underlying malignancy or its treatment. Table 27.1 provides a comprehensive list of causes of AKI.
| Prerenal |
|
| Intrinsic kidney | Acute tubular necrosis
Tubulointerstitial nephritis
Vascular/thrombotic microangiopathy
|
| Postkidney/obstruction | Intrarenal
Extrarenal
|
Chemotherapeutic Agents
Chemotherapeutic agents can cause a variety of kidney manifestations including AKI, tubulointerstitial nephritis (TIN), acid-base and electrolyte disturbances, hypertension, proteinuria/nephrotic syndrome, and thrombotic microangiopathy (TMA). One challenge for clinicians is the vast array of new agents with unique mechanisms of action; given potentially unknown adverse kidney effects, a great degree of vigilance is needed.
The adverse kidney effects of chemotherapy can be classified by the primary site of injury. For example, these include injury to the endothelium (hypertension and TMA), visceral podocyte (proteinuria and nephrotic syndrome), renal tubules (AKI), and tubulointerstitium (renal tubular acidosis, Fanconi syndrome, and electrolyte wasting). A list of anticancer agents and their known associated kidney effects are found in Table 27.2 . The nephrotoxic effects of specific anticancer drugs are reviewed in Chapter 35 .
| Chemotherapy and Miscellaneous | Kidney Effects |
|---|---|
| Cisplatin |
|
| Ifosfamide |
|
| Methotrexate | Acute kidney injury (crystalline nephropathy) |
| Pamidronate |
|
| Calcineurin inhibitors |
|
| Biologic Agents | |
| Interferon-α |
|
| Interleukin-2 |
|
| Targeted Therapies | |
| Antivascular endothelial growth factor (e.g., bevacizumab, sorafenib) |
|
| Epidermal growth factor blockade (e.g., cetuximab, erlotinib) | Renal magnesium wasting |
| Check point inhibitors (e.g., nivolumab, ipilimumab) | Acute tubulointerstitial nephritis |
Tumor Lysis Syndrome
TLS is defined by laboratory (any two of hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia) and clinical (one of three among AKI, seizures, arrhythmias, and death) criteria. TLS complicated by AKI often is a dramatic presentation. It is characterized by the development of hyperphosphatemia, hypocalcemia, hyperuricemia, and hyperkalemia of varying severity. TLS can occur spontaneously during the rapid growth phase of malignancies, such as bulky lymphoblastomas and Burkitt and non-Burkitt lymphomas that have extremely rapid cell turnover rates, or when cytotoxic chemotherapy induces lysis of malignant cells in patients with large tumor burdens.
The pathophysiology of AKI associated with TLS classically is attributed to two main factors: preexisting volume depletion and the precipitation of uric acid and calcium phosphate complexes in the renal tubules and tubulointerstitium. There is also a major contribution from a “cytokine release syndrome” associated with tumor cell lysis. This leads to kidney underperfusion and AKI. Volume depletion is multifactorial and may reflect anorexia, nausea and vomiting from the malignancy or its treatment, and increased insensible losses from fever or tachypnea.
Hyperuricemia may develop despite allopurinol prophylaxis in patients with spontaneous TLS or after therapy in very chemosensitive malignancies. Excess serum uric acid is filtered into the tubular space. In general, uric acid is nearly completely ionized at physiologic pH, but it becomes progressively more insoluble in the acidic environment of the renal tubules. Precipitation of uric acid causes intratubular obstruction, while hyperuricemia may also lead to increased renal vascular resistance and decreased glomerular filtration rate (GFR). In addition, a granulomatous reaction to intraluminal uric acid crystals and necrosis of tubular epithelium may occur, resulting in inflammation and further kidney injury. Hyperphosphatemia and hypocalcemia also occur in TLS. In patients who develop AKI but do not develop hyperuricemia, kidney injury has been attributed to metastatic intrarenal calcification or acute nephrocalcinosis. Tumor lysis with release of inorganic phosphate may promote both kidney and systemic metastatic calcification, which is complicated by acute hypocalcemia.
Optimal management of TLS can reduce the risk of AKI and of development of symptomatic electrolyte abnormalities. Key management components include ensuring a high urine output with intravenous fluids, reducing uric acid levels, and controlling serum phosphate levels. It is recommended that urine output be maintained at a rate of 200 mL/hour by infusion of isotonic crystalloid solutions. In the absence of significant hypervolemia, use of loop diuretics should be avoided because they acidify the urine and can lead to volume depletion. A consensus statement on the treatment of TLS was published by the American Society of Clinical Oncology in 2008. In patients at low risk to develop TLS, allopurinol is administered to inhibit uric acid formation. Through its metabolite oxypurinol, allopurinol inhibits xanthine oxidase and thereby blocks the conversion of hypoxanthine and xanthine to uric acid. During massive tumor lysis, excessive uric acid production with increased uric acid excretion by the kidneys may occur despite allopurinol administration, making intravenous hydration necessary to prevent AKI. Because allopurinol and its metabolites are excreted by the kidneys, the starting dose should be lower in those with low GFR. Other limitations to allopurinol use include hypersensitivity reaction, drug interactions, and delayed time to lowering uric acid levels.
In the past, because uric acid is very soluble at physiologic pH, sodium bicarbonate was often added to intravenous fluids to achieve a urinary pH greater than 6.5. However, this therapy is no longer recommended for several reasons. First, systemic alkalosis from alkali administration can aggravate hypocalcemia, resulting in tetany and seizures. Second, an alkaline urine pH markedly decreases the urinary solubility of calcium phosphate, thereby promoting development of acute nephrocalcinosis from intratubular calcium-phosphate crystals.
Patients at high risk for TLS can be treated with rasburicase (recombinant urate oxidase). Risk factors for TLS include bulky lymphadenopathy, elevated lactate dehydrogenase (LDH) (>2× normal), increased white blood cell count (>25,000/mm 3 ), baseline creatinine greater than 1.4 mg/dL, and baseline uric acid greater than 7.5 mg/dL. Rasburicase converts uric acid to water-soluble allantoin, thereby decreasing serum uric acid levels and urinary uric acid excretion. Importantly, use of rasburicase obviates the need for urinary alkalinization and its complications. However, high urine flow rates achieved with normal saline are important given the probability of preexisting volume depletion and its consequences. Rasburicase treatment should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency, because hydrogen peroxide, a breakdown product of uric acid, can cause methemoglobinemia and, in severe cases, hemolytic anemia. Management of TLS is outlined in Fig. 27.1 .
