Acute renal failure (ARF) can be one of the many complications associated with malignancy and, unfortunately, often harbors a worse prognosis for the afflicted patient. Insult to the kidneys can occur for a variety of reasons in the oncologic patient. This article focuses on several of these etiologies, such as tumor lysis syndrome (TLS) and thrombotic microangiopathy (TMA), which are unique threats faced by the oncologic patient.
Acute renal failure (ARF) can be one of the many complications associated with malignancy and, unfortunately, often harbors a worse prognosis for the afflicted patient. Insult to the kidneys can occur for a variety of reasons in the oncologic patient. The kidneys are susceptible to injury from malignant infiltration, damage by metabolites of malignant cells, nephrotoxic drugs including chemotherapeutic agents, tumor lysis syndrome (TLS), radiation, septicemia associated with immune suppression, cast nephropathy, complications of bone marrow transplant (BMT), and autoimmune phenomena. This article focuses on several of these etiologies, such as TLS and thrombotic microangiopathy (TMA), which are unique threats faced by the oncologic patient. Therapeutic and diagnostic drug-induced nephrotoxicity, although common in all disease states, is also briefly reviewed. Nephrotoxic complications of chemotherapeutic agents warrant a separate discussion and are reviewed elsewhere in this issue.
Epidemiology
It is difficult to quantify the extent of renal complications associated with malignancy, as renal dysfunction can be present before the identification of malignancy, coincide with the diagnosis of malignancy, or be a secondary or tertiary effect of treatment. Several studies have examined the occurrence of renal failure in patients with specific malignancies, such as leukemia, lymphoma, and multiple myeloma. About 20% to 40% of newly diagnosed multiple myeloma patients have evidence of renal impairment. Renal failure in lymphoma and leukemia is also well described. The incidence of renal complications in leukemia patients undergoing chemotherapy has been reported to be 30% or greater. Patients undergoing BMT for leukemia have a 50% risk of renal complications. Unfortunately, the presence of ARF is also an independent risk factor for a poor prognosis. A reasonable approach to these patients in the emergency department (ED) is to consider prerenal, renal, and postrenal etiologies, since more than 1 type of azotemia may be present (listed in Table 1 ).
| Prerenal Failure | Renal (Intrinsic) Failure | Postrenal Failure |
|---|---|---|
|
|
|
Prerenal azotemia
Prerenal azotemia is commonly encountered in cancer patients and can be due to multiple mechanisms, including poor oral intake, early satiety, vomiting, and diarrhea. Elderly cancer patients are particularly prone to dehydration, which should be corrected promptly to minimize further renal injury.
Prerenal azotemia
Prerenal azotemia is commonly encountered in cancer patients and can be due to multiple mechanisms, including poor oral intake, early satiety, vomiting, and diarrhea. Elderly cancer patients are particularly prone to dehydration, which should be corrected promptly to minimize further renal injury.
Renal azotemia
Malignant Infiltration
Malignant infiltration of the kidneys is very common in leukemia and lymphoma. Fortunately, the presence of malignancy-related infiltration does not always coincide with renal dysfunction, and severe infiltration is rare. Leukemic or lymphoma infiltration of the kidneys can present with a variety of signs and symptoms, varying from mild proteinuria to florid ARF. The only way to diagnose infiltration is by renal biopsy; thus, in the emergent evaluation of malignancy-associated renal failure, it is important to exclude more easily identifiable causes for the dysfunction. Once identified, infiltration of the kidney is addressed by aggressively treating the primary malignancy with chemotherapy.
Tumor Lysis Syndrome
TLS is a metabolic emergency secondary to the breakdown of a large tumor burden with release of intracellular contents into the extracellular space and systemic circulation. Factors that contribute to TLS are the type of malignancy, its responsiveness to chemotherapy, rapidity of cell turnover, and tumor burden. It is clinically defined by the triad of hyperuricemia, hyperphosphatemia, and hyperkalemia, whereas elevated serum lactate dehydrogenase (LDH) levels, hypocalcemia, and ARF are secondary findings. Although the potassium and phosphate are primarily derived from cytoplasmic contents, the uric acid is a product of nucleic acid breakdown. Hypocalcemia is secondary to calcium downregulation in the setting of hyperphosphatemia. TLS can occur spontaneously, but it is more commonly seen following the initiation of chemotherapy. Cancers such as acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), Burkitt’s lymphoma, and large solid tumors are more prone to TLS after the initiation of chemotherapy. Spontaneous TLS has been described in AML and ALL and is usually associated with marked hyperuricemia in the absence of hyperphosphatemia. It is thought that in spontaneous TLS, the released phosphorus is reutilized by new cancer cells.
TLS usually appears within 1 to 5 days of a chemotherapy session. Symptoms are nonspecific and include nausea, vomiting, fatigue, and weakness. Altered mental status, cardiac dysrhythmias, autonomic instability, and ARF are common findings on presentation. A recent study by Montesinos and colleagues evaluated predisposing factors in an attempt to develop a predictive model for TLS in patients with AML. In this study of 772 adults, 130 (17%) developed TLS. Multivariate analysis showed that pretreatment LDH levels above laboratory normal values, creatinine (Cr) >1.4 mg/dL, uric acid >7.5 mg/dL, and white blood cell counts >25 × 10(9)/L were independent risk factors for TLS. Prechemotherapy laboratory evaluation should be performed to assess the risk for development of TLS and to assist in the decision to initiate prophylactic therapy in high-risk patients.
The goal of therapy and prophylaxis ( Table 2 ) is to promote excretion of metabolic products, to prevent renal failure, and decrease uric acid production. The mainstay of therapy to date has been hydration or hyperhydration. Two to 4 times maintenance hydration with normal saline or isotonic sodium bicarbonate solutions to assist with urine alkalinization is generally recommended. Urine alkalinization with sodium bicarbonate to a goal pH between 7.0 and 8.0 may prevent precipitation of uric acid in the renal tubules; however, there are no experimental studies confirming any benefit to urine alkalinization. One study that compared urine alkalinization to hydration alone showed hydration to be just as effective in minimizing uric acid precipitation. Furthermore, alkalinization may encourage deposition of calcium phosphate in organs of patients with existing hyperphosphatemia. Current recommendations are to alkalinize urine with a bicarbonate solution only in patients with existing metabolic acidosis. Alkalinization should continue until uric acid ceases to climb and is closer to a normal reference range of 2.0 to 8.0; however, reference ranges differ for males, females, and pediatric versus adult populations. If bicarbonate alkalinization fails to achieve a urine pH greater than 7.0, intravenous (IV) acetazolamide may be given to well-hydrated patients to decrease bicarbonate reabsorption in the proximal renal tubules. Bicarbonate therapy should be discontinued once uric acid levels normalize, if serum bicarbonate is greater than 30 mEq/L, or if urine pH is more than 8.0. It is also important to simultaneously manage other symptomatic electrolyte abnormalities, such as hyperkalemia and hypocalcemia.
| Drug | Dosing | Mechanism |
|---|---|---|
| Acetazolamide | Oral: 5 mg/kg/dose repeated 2-3 times during 24 h | Inhibits carbonic anhydrase, increased renal excretion of sodium, potassium, bicarbonate, and water. Urine alkalization decreases urate crystal precipitation. |
| Allopurinol |
| Xanthine analog; competitively inhibits xanthine oxidase, blocks the metabolism of hypoxanthine and xanthine to uric acid. Decreases the formation of new uric acid. Reduce dosage by 50% in the setting of renal insufficiency. |
| Rasburicase |
| Catalyzes oxidation of uric acid to allantoin, which is more water soluble than uric acid and easily excreted. |
| Aluminum hydroxide | 50–150 mg/kg/d divided every 4–6 h | Binds phosphate and bile salts to form an insoluble compound. Reduces serum phosphate levels. Risk of aluminum toxicity limits its use in renal failure. |
| Mannitol | 0.5–1 g IV bolus | Increases the osmotic pressure of glomerular filtrate, preventing reabsorption of water and electrolytes and increasing urinary output. Increases phosphate excretion. |
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