Symptoms, Signs, and Laboratory Findings
The clinical presentation of patients with TLS is varied and depends on the extent of metabolic derangements present and type of end-organ damage caused by the released intracellular products. A heightened clinical suspicion for TLS should be maintained in those patients with known malignancies associated with high-risk features, especially following tumor reduction therapy.
Hyperkalemia (ie, potassium level >5 mEq/L) develops commonly in TLS and may be seen as early as 6 hours postchemotherapy. The predominant mechanism is a shift of large intracellular stores of potassium into the extracellular fluid (ECF) compartment as tumor cells lyse. In addition, a further shift of potassium out of viable tumor and host cells may occur if metabolic acidosis due to renal failure is present. Finally, the presence of chronic kidney disease prior to TLS and/or ARF developing as a result of TLS impairs renal clearance of this potassium load to the ECF, thereby exacerbating the severity of hyperkalemia and limiting the efficacy of attempts at medical management.
As the ratio of intracellular to extracellular potassium is important in the maintenance of the normal resting membrane potential, the symptoms associated with hyperkalemia most commonly reflect altered neuronal and muscular excitability. Mild elevations in serum potassium can manifest as lethargy, muscle weakness, muscle cramps, and paresthesias. Unfortunately, concomitant hypocalcemia often seen in TLS can further exacerbate the hyperkalemia-induced membrane excitability and neuromuscular symptoms. More progressive hyperkalemia is worrisome due to its effect on the cardiac conduction system, as can be seen during electrocardiogram (ECG) monitoring by peaked T waves, PR and QRS interval prolongation, various atrioventricular blocks, and eventual asystole and cardiac standstill.
In general, serum potassium levels >6.0 mEq/L associated with neuromuscular manifestations or ECG changes require immediate correction. However, one important caveat to consider is pseudohyperkalemia, which is frequently encountered in hematologic malignancies with significant elevations in white blood cell counts (ie, >100,000/mm3). The elevated potassium results from its release from leukocytes mechanically lysed during phlebotomy or as a result of shift following coagulation of blood within the vial. In such cases, the potassium levels returned by the laboratory, sometimes significantly elevated, do not reflect the level in vivo and are not associated with neuromuscular symptoms or ECG changes. By not using tourniquets and measuring plasma (instead of serum) values, potassium values that reliably reflect in vivo levels can be obtained.
Hypocalcemia and Hyperphosphatemia
Disturbances in calcium and phosphorus are common in TLS, and following cytoreductive therapy typically occur within 24–48 hours. The massive phosphorus load to the extracellular compartment as tumor cells lyse can overwhelm the maximal renal phosphaturic threshold thus leading to levels above 4.5 mg/dL, sometimes of great severity (ie, >15 mg/dL). Hypocalcemia, ie, a total calcium level <8.5 mg/dL corrected for albumin or an ionized calcium level <1.08 mmol/L, develops in the setting of hyperphosphatemia as calcium complexes with rising phosphorus levels. These calcium–phosphorus complexes are insoluble at physiologic conditions and precipitate in various tissues and can result in end-organ damage seen in TLS (ie, acute nephrocalcinosis). To a lesser degree, sustained hypocalcemia may also be a result of less 1,25-dihydroxyvitamin D3 (ie, calcitriol) synthesis.
Patients with TLS and disturbances of calcium and phosphorus typically manifest with neuromuscular signs or symptoms related to the hypocalcemia. In particular, patients can present with paresthesias, muscle cramps, tetany (eg, Chvostek's sign or carpopedal spasm), or seizures. Cardiac manifestations may also accompany significant hypocalcemia, most notably prolongation of the QT interval on ECG and depression of cardiac contractility leading to hypotension.
Uric acid is produced in hepatocytes as a byproduct of purine nucleotide catabolism [guanylic acid (GMP), inosinic acid (IMP), and adenylic acid (AMP)] (Figure 13–1). The rate-limiting and final reaction involves the conversion of xanthine to uric acid, driven by the enzyme xanthine oxidase. Further metabolism of uric acid in humans does not occur as the enzyme responsible for its conversion to allantoin, urate oxidase, was lost due to a nonsense mutation during human evolution. The major route of clearance of excessively produced uric acid is through the kidney. In the case of TLS a sudden load of purine nucleotides released from lysed tumor cells results in an acute rise in uric acid production that overwhelms the normal excretory capacity leading to a rise in serum uric acid levels above 7–8 mg/dL, with severe hyperuricemia >15 mg/dL being common. As will be discussed in the following section, the presenting clinical symptoms and signs of hyperuricemia associated with TLS are those associated with oliguria and ARF, which it can induce.
Purine catabolism metabolic pathway.
Azotemia and Acute Renal Failure
As stated earlier, a common and potentially serious complication of TLS is acute renal failure. Usually presenting as oliguria associated with a progressive rise in serum creatinine and urea nitrogen, the etiology of ARF is multifactorial. A major mechanism is acute uric acid nephropathy. With a pKa of 5.5, urate is soluble as the ionized form in the blood at a physiologic pH of 7. However, in the distal nephron where the glomerular effluent is acidified to a pH <5.5, under appropriate conditions urate can become protonated and precipitate, especially in the setting of low urine flow rates. When the uric acid load is high enough, such precipitation can lead to intratubular crystal formation and obstruction of urine flow. As a result of this obstruction, the glomerular filtration rate (GFR) drops and clinical ARF ensues. Although rare, the intratubular obstruction can be severe enough to cause collecting system dilation as evidenced by bilateral hydronephrosis on renal ultrasound. Another likely mechanism leading to ARF with TLS is acute nephrocalcinosis. As stated earlier, the precipitous rise in serum phosphorus levels results in the acute formation of calcium–phosphorus complexes, which deposit in tissues. In the kidney this deposition results in tubular toxicity and interstitial inflammation, which further exacerbate the reduction in GFR.
Patients with ARF associated with TLS can present along a spectrum of severity, from asymptomatic azotemia to severe anuria with uremia and volume overload. Particular attention should be paid to volume status (ie, depletion or overload) and electrolyte anomalies (especially potassium and calcium) as disturbances of these can be immediately life threatening and dictate the initial plan of therapy.
Although most often identified in the appropriate clinical setting with compatible laboratory findings, other studies may assist the clinician in the diagnosis of TLS and guide appropriate therapy.
As alluded to earlier, a serious yet treatable complication of TLS is hyperkalemia with associated cardiac conduction defects and arrhythmias. All patients with TLS and laboratory evidence of hyperkalemia should have an ECG performed. Attention should particularly be focused on changes typically indicative of elevated serum potassium levels on cardiac myocyte conduction: T wave peaking, prolongation of the PR and QRS complex, flattened or absent P waves, and atrioventricular blocks or ventricular arrhythmias. The presence of any of these dictates the immediate need for intervention to stabilize the myocardium and lower the serum potassium level.
As part of an initial evaluation of patients with ARF due to TLS the urinalysis (UA) is indispensable in guiding the clinician to the correct diagnosis. Although their presence does not firmly rule in or their absence rule out TLS, uric acid crystals may be seen on microscopic examination of the urine sediment. These appear as rhomboid or rosette-shaped crystals of yellow or brown color under light microscopy. Other aspects of the UA can aid the clinician during the evaluation of ARF, and, although not specific for TLS, provide useful information. These include an elevated specific gravity indicative of a concentrated urine from concomitant volume depletion, microscopic hematuria, and minimal if any proteinuria in the absence of other renal disease.
As described above, a major pathophysiologic mechanism of ARF associated with TLS is obstruction of tubular fluid flow by uric acid crystal formation. Although rare, bilateral hydronephrosis has been reported due to presumed extensive tubular obstruction. However, a renal ultrasound can also provide valuable information to help differentiate ARF from TLS from other causes in patients with known malignancies, most notably obstructive uropathy from extrinsic compression of ureters by solid tumors.
Urine Uric Acid/Creatinine Ratio
Although quite sensitive, elevated serum uric acid levels in the setting of ARF are not specific for TLS. Although rarely extremely high, mild to moderate elevations in serum uric acid levels can be seen in ARF from various causes due to impaired renal clearance of normally produced quantities of uric acid as GFR falls. In these cases the uric acid found in the urine results mostly from tubular secretion. Thus the sum total of uric acid excreted is less than normal. This is in contrast to uric acid nephropathy associated with TLS where uric acid production and excretion are greatly increased. Despite the presence of impaired GFR, as long as anuria is not present the net amount of uric acid excreted is higher than the basal state. As such, by measuring the concentration of uric acid in the urine and dividing this value by the urine creatinine concentration to control for the degree of urinary concentration, it is possible to help differentiate ARF due to TLS from other causes. While one study reported that a urinary uric acid/creatinine ratio of >1 was specific for cases of ARF associated with TLS, and a ratio <0.6–0.75 was found in cases of ARF due to other causes, the utility of the urine uric acid/creatinine ratio has not been confirmed in other studies.