Correction from The New England Journal of Medicine — The Tumor Lysis Syndrome. Correspondence from The New England Journal of Medicine — The Tumor Lysis Syndrome. N Engl J Med. May 12;(19) doi: /NEJMra The tumor lysis syndrome. Howard SC(1), Jones DP, Pui CH. Author information.
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Tumor lysis syndrome is an oncometabolic emergency resulting from rapid cell death. Tumor lysis syndrome can occur as a consequence of tumor targeted therapy or spontaneously. Clinicians should stratify every hospitalized cancer patient and especially those receiving chemotherapy for the risk of tumor lysis syndrome. Several aspects of prevention include adequate hydration, use of uric acid syndrkme therapies, use of phosphate binders and minimization of potassium intake.
Patients at high risk for the development of tumor lysis syndrome should be monitored in the intensive care unit. Established tumor lysis syndrome should be treated in the intensive care unit by aggressive hydration, possible use of loop diuretics, possible use of phosphate binders, use of uric acid lowering agents and dialysis in refractory cases. Tumor lysis syndrome TLS is characterized by a massive tumor lyeis death leading to the development of nemm derangements and target organ dysfunction.
TLS can occur as a result of cancer treatment or spontaneously.
Acute Kidney Injury in Patients with Cancer | NEJM Resident
Blood cancers constitute the vast majority of TLS cases because of the sensitivity to therapy and rapid division rates. Solid cancers comprise the minority of cases and are usually advanced nejk complicated by TLS.
Prophylaxis is the mainstay of management and should be routinely implemented in high and intermediate risk patients. Management of established TLS includes intravenous hydration, urate lowering therapies, management of hyperkalemia and hemodialysis in refractory cases. These cancers differ in their cellular origin, pathogenesis, clinical presentation, and management.
Furthermore, cancer has been found by the Centers for Disease Control and Prevention to be the second leading cause of death among United States residents in [ 1 ]. Thus, because of the high prevalence of malignant neoplasms, it is essential that clinicians are aware of the major complications of cancer itself and its management.
Furthermore, it is likely that physicians will manage a greater number of cancer patients in future in the future, due to the improved survival rates of patients with cancer, ageing and growing population.
Tumor lysis syndrome TLS is a major oncometabolic entity requiring emergent recognition and management. TLS comprises a clinicolaboratory derangement of cellular metabolism, which can lead to severe renal impairment, cardiac arrhythmias, seizures, and death[ 2 ]. Cellular death mediated lydis treatment targeted at cancer chemotherapy or another pharmacological antitumor intervention, embolization of tumor or radiation therapy or lsyis cellular death in rapidly dividing cancer cells which is known as spontaneous TLS leads to an efflux of cellular material rich in potassium, phosphorus, and uric acid into the bloodstream.
However, serum calcium levels typically decrease in patients with TLS because of its binding to excess phosphorus. These key metabolic derangements mediate the acute impairment of renal function, cardiac arrhythmogenicity, central nervous system toxicity, and ultimately death.
The most widely used diagnostic criteria are those proposed by Cairo et al[ 2 ] in It is necessary to note that laboratory TLS is defined as the presence of at least two or more biochemical variables within the 3 d before chemotherapy or 7 d after chemotherapy in syndrpme face of adequate hydration and use of uric acid lowering agent.
Clinical TLS is defined as the presence of at least one clinical criterion that is not believed to be attributable to the chemotherapy agent[ 2 ]. However, our group has recently mentioned that this definition is imperfect since radiation therapy may lead to TLS as well, and TLS can occur spontaneously in rapidly proliferating and bulky malignancies[ 34 ].
Adapted from Cairo et al[ 2 ]. Activities of daily living; HF: Upper limits of normal. This manuscript summarizes the current state knowledge on TLS for clinicians involved in the care of critically ill patients: The search terms were: The reference lists of the identified articles were further screened for potentially relevant articles that could have been overlooked by an electronic search.
The search methodology was adapted from the scientific search guidelines published in [ 5 ]. The basic understanding of the pathogenesis of TLS lies in the fact that cells and cancer cells in particular are rich in potassium, phosphorus, and uric acid. As mentioned previously, TLS can be either spontaneous when cancer cells die without the preceding chemotherapy, embolization, or radiation therapy, or secondary to cancer targeted treatment.
In either case, the release of the above mentioned intracellular substances mediates the pathobiology of TLS and its complications. Hyperkalemia is one of the key laboratory manifestations of TLS. Increased serum concentrations of potassium can adversely affect the skeletal muscle and cardiac myocardium[ 67 ].
Indeed, hyperkalemia can mediate severe skeletal muscle dysfunction and weakness and induce various electrocardiogram ECG rumor including peaked narrow T waves, prolongation of the PR interval, prolongation lysia the QRS interval, as well as sine wave morphology[ 8 ]. Ultimately, the cardiac effects of excess potassium can lead lysix ventricular tachyarrhythmias and death.
Uric acid is ljsis byproduct of the purine nucleotides adenine and guanine, which constitute the backbone of nucleic acids[ 9 ]. Put simply, purines are metabolized initially to hypoxanthine and xanthine via enzyme xanthine oxidase to uric acid, which is a final byproduct in humans. However, some mammals have an additional enzyme called urate oxidase that converts uric acid to the much more water soluble allantoin, which is easily removed by renal system.
Given a high cellular turnover in cancer for syndtome reason, huge amounts of nucleic acids, purines, and eventually uric acid are released and formed. Uric acid can crystalize and obstruct the flow in the renal tubules, leading to acute kidney injury[ 2 – 410 ].
However, there are other mechanisms for uric acid mediated kidney impairment such as endothelial lysiis and local ischemia, proinflammatory and proxidative states, and impairment of local renal repair mechanisms[ 1011 ].
It tumof important to note ndjm calcium phosphate crystals facilitate the deposition of uric acid in renal tissue[ 2 ]. It is relevant to mention that in the contemporary era most individuals at risk of Nej at least in developed countries or with a full-blown TLS are treated with hypouricemic agents, which minimize the impact of uric acid on the occurrence of acute kidney injury.
An increase in serum phosphorus from cellular death can mediate acute kidney injury via similar mechanisms. When in excess, phosphorus tends to bind to calcium, lhsis the so-called calcium phosphorus product or calcium phosphate[ 2 – 4 ].
This product can be deposited in kidneys, mediating acute kidney injury, as well as in cardiac tissue, leading to arrhythmia. Furthermore, a secondary decrease in free calcium concentration due to phosphorus binding is manifested by indications of central nervous toxicity such as seizures and psychiatric complaints, prolongation of the QT interval tymor ECG, and muscle tetany[ 12 ].
It is interesting to observe that patients with spontaneous TLS may have lower rates of hyperphosphatemia due to phosphate uptake into rapidly dividing tumor cells[ 34 ]. An increase in lactate dehydrogenase LDH is typically seen in patients with TLS, probably because of anaerobic glucose metabolism. In conclusion, it is important to note that preexistent renal disease and the characteristics of certain patients increase the risk of full-blown clinical TLS.
These factors will be discussed in more detail in the next section. When assessing the risk of TLS in a particular patient, it is essential to bear in mind tujor the general and tumor-related predictors syndroms risk. An older age is associated with a reduction in the glomerular filtration rate[ 13 nsjm.
It is likely that advanced age predisposes to TLS via a decrease in the renal reserve, and may complicate volume replacement therapy due to higher rates of cardiac dysfunction. However, it is important to keep in mind that the impact of age on the occurrence of TLS has not been specifically studied. Other general patient characteristics sydrome as volume depletion should be syndrlme and corrected if present. Patients afflicted with cancer often have decreased oral intake due to the decrease in appetite and nausea.
Furthermore, cancer patients often suffer from vomiting and diarrhea, which can significantly diminish their volume status. Another important aspect which we routinely assess in our patients is the use of medications capable of detrimentally affecting renal function such as non-steroidal anti-inflammatory drugs, inhibitors of the angiotensin converting enzyme, and angiotensin receptor blockers, especially in patients with decreased volume status[ 4 ].
The medication list of every patient should be reviewed and medications with a nephrotoxic renal profile should be discontinued wherever possible. It is important to consider that baseline kidney disease is a well-established risk factor for TLS[ 414 ]. In addition, a baseline increase in serum uric acid, phosphorus, potassium, and LDH also portends a greater risk of TLS[ 4 ]. Other general comorbid conditions such as cardiac disease, diabetes mellitus, and renal disease should be considered prior to hydration since patients with these medical problems might easily develop symptomatic volume overload.
Another aspect of the risk stratification which we use is bejm type and burden of malignancy. We agree with the clinical risk stratification proposed by Cairo et al[ 15 ] who stratified cancers into three risk groups: Furthermore, njm have recently reported that TLS in patients with solid malignancies may be higher than previously thought, and certain cancers with a sensitivity to therapy may be at higher risk for TLS, such as small cell lung cancer[ 4 ]. In summary, it is recommended that both general and cancer-related factors are included in the risk assessment of every patient.
Certain patient factors such advanced age and the presence of preexistent renal and cardiac diseases warrant a closer follow up during preventive hydration. The clinical presentation and symptomatology is directly linked to the biochemical derangements observed in this disorder. As discussed earlier, the biochemical evidence of TLS includes hypocalcemia, hyperkalemia, hyperphosphatemia, and hyperuricemia[ 2 ].
Therefore, the presentation of these biochemical disorders is typically represented by a clinical constellation of symptoms. For example, patients with Ssyndrome who have hypocalcemia may present with such symptoms as nausea, vomiting, muscular hyperactivation such as spasms and tetany, seizures, prolongation of QT interval on syncrome ECG, cardiac dysrhythmias, and alterations of mental status[ 12 ].
Hyperphosphatemia may actually be a key mediator of acute kidney impairment as well as cardiac rhythm disturbances. Patients with hyperkalemia, if symptomatic, present with generalized fatigue, ECG abnormalities[ 8 ], and serious cardiac arrhythmias including cardiac arrest. Elevations of uric acid can lead to acute renal insult manifested as an increase in serum creatinine and decrease in urine output.
Therefore, it is essential to be highly suspicious if any of the above symptoms arise in patients with cancer, especially those with tumors in a high risk group In rare instances at least in syndfome countriesTLS may present prior to the diagnosis of cancer.
The tumor lysis syndrome.
Nevertheless, a clinician should differentiate TLS from other causes of acute kidney injury such as sepsis, obstructive renal disease, medication toxicities including those of chemotherapeutic agentsuse of contrast dye for imaging studies, and rhabdomyolysis, as well as other rarer conditions such as vasculitis and primary glomerulopathies in appropriate clinical scenarios[ 16 ]. Thus, a thorough clinical history is of paramount importance when dealing with a cancer patient who has presented with an acute decline in kidney function.
The minimum amount of testing should include urinalysis and urine microscopy, comprehensive metabolic panel, uric acid, LDH, complete blood count, and renal ultrasound. In conclusion, the clinical presentation of TLS is based on the constellation of individual metabolic derangements in a particular patient. It is essential to remember that the prevention of disease is always more cost-effective than the treatment of an established disease.
Therefore, it is important to address and target any underlying kidney disease and possible hypovolemia before the start of cancer targeted therapies.
Acute Kidney Injury in Patients with Cancer
Subjects at intermediate and high risk of TLS should be monitored in a hospital setting and possibly in an intensive care unit especially individuals at high risk of TLS. Potassium and phosphorus should be eliminated from the diet and intravenous IV fluids. Several features are the mainstay of treatment for the prevention of TLS in patients undergoing active therapy.
First, all patients at intermediate and high risk should be actively hydrated with IV fluids. The choice of the fluid varies and some recommend the use of dextrose in one quarter normal saline as the initial fluid of choice[ 17 ].
Also, it is prudent to limit the calcium and potassium content of the IV fluids in such patients. Nevertheless, it is essential to note that some patients with cancer have underlying cardiorenal disease, which puts them at high risk of fluid overload and pulmonary edema. Such patients should be followed in closely monitored settings and there should be a low threshold for initiating loop diuretics if signs of fluid overload appear shortness of breath, crackles on physical examination, desaturation, etc.
Loop diuretics are preferably used in clinical practice because of their potent diuretic properties as well as their hypokalemic effect, which can be of benefit in patients at risk of TLS. However, to the best of our knowledge there are no published scientific studies assessing the role of diuretics in the treatment of TLS.
Tumor lysis syndrome: A clinical review
Second, individuals at intermediate risk of TLS should be started on allopurinol at least 24 to 48 h prior to chemotherapy or radiation therapy to reduce the risk of uric acid nephropathy[ 17 ]. Patients who do not tolerate oral medication such as those with severe nausea, vomiting, or altered function of the gastrointestinal tract can be given allopurinol IV.
The recommended dose of allopurinol is up to mg a day orally or mg per square meter, and up to mg a day for IV formulation[ 17 ].