Laboratory TLS: two or more of (within − 3 to + 7 days relative to treatment)
Clinical symptoms
(any of)
Clinical I
Clinical II
Clinical III
Clinical IV
Uric acid
>8 mg/dL (476 µmol/L) in adults,
>age- normal in children
Potassium
>6 mmol/L
Creatinine [9]
or
estimated kidney function [10]a
<1.5 × ULN,
30–45 ml/min
1.5–3xULN,
10–30 ml/min
3–6xULN,
10–20 ml/min
>6 x ULN,
<10 ml/min or kidney replacement therapy
Phosphorous
>4.5 mg/dL (1.5 mmol/L) (adults) or
>6.5 mg/dl (2.1 mmol/L) (children)
Cardiac
Arrhythmia, no intervention
Nonurgent medical treatment
Symptomatic; incompletely controlled medically, or needing device (e.g., defibrillator)
Life-threatening with shock, syncope, hypotension, or CHF
Calcium:
<7 mg/dL, 1.75 mmol/L (corrected for albumin), or ionized
<1.12 mmol/L; omitted by most recent schema [38]
Neuromuscular
Single brief generalized seizure, rare focal motor seizures, or seizures well-controlled medically
Seizure with altered consciousness; generalized seizures despite medication
Repetitive seizures despite medication (e.g., status epilepticus)
Any of the above with
>25 % increase from recent baseline (or decrease for calcium) [9, 10, 38] ; others specifically exclude this
Criterion [3]
Clinical Presentation
TLS is most commonly seen after directed therapy has caused rapid tumor cell death, but can also occur spontaneously . High-grade, aggressive tumors like Burkitt lymphoma or T-cell acute lymphoblastic leukemia (ALL) represent the majority of cases, but TLS may complicate other tumor types associated with large tumor burdens, rapid proliferation rates, or high sensitivity to chemotherapy. The first signs and symptoms may appear within 24–72 h of initiation of chemotherapy or embolization, but a more indolent course has been observed over weeks to months with spontaneous development of TLS .
Case #1
A 42-year-old man presented with 3 months of lethargy, malaise, intermittent low-grade fevers, and a 10-kg weight loss. He was actively treated with hydrochlorothiazide for hypertension diagnosed 4 years earlier. One week prior to presentation, he noted painful swelling in his neck, axillae, and groin, and 2 days earlier developed palpitations, restless legs, and paresthesias in his fingertips. On examination, his temperature was 38.7 °, heart rate 92 bpm, and blood pressure 96/62 mmHg. His conjunctivae were pale and mucous membranes dry. He had tender lymphadenopathy in both axillae, in the groin, and on neck exam in the posterior cervical chain. His heart rate was regular with frequent premature ventricular contractions. His lungs were clear. On abdominal examination, his liver span was slightly increased and tender, and a spleen tip was palpable at the level of the umbilicus. Extremities revealed 2+ dependent edema, scattered petechiae, and 2+ distal pulses. Cranial nerves were intact, but a Chvostek sign was noted upon tapping the left facial nerve. Laboratory testing identified potassium 6.6 mEq/L, bicarbonate 16 mEq/L, anion gap 22, creatinine 5.8 mg/dL, albumin 3.1 mg/dL, calcium 5.9 mg/dL, phosphate 18.7 mg/dL, and uric acid 21.3 mg/dL. Blood counts showed a white blood count (WBC) of 125 K with abundant blasts, hemoglobin 7.2 mg/dL, and platelets 17 K. Urinalysis demonstrated a specific gravity of 1.012, pH 5.5, 1+ protein and 2+ blood, and sediment with degenerating tubular cells and amorphous phosphate crystals. Because of progressive kidney failure, hyperkalemia, and dropping urine output in the setting of TLS, urgent dialysis was initiated. Computed tomography of the chest, abdomen, and pelvis identified diffuse lymphadenopathy, and bone marrow biopsy confirmed the diagnosis of T-cell ALL.
Which of the following tumor types is least commonly associated with TLS?
a.
Burkitt’s lymphoma
b.
T cell ALL
c.
Non-Hodgkin lymphoma (NHL)
d.
Breast cancer with high tumor load
e.
Chronic myelogenous leukemia (CML)
Epidemiology and Risk Factors
As mentioned earlier, the majority of the reported cases have been observed in hematologic malignancies [11], although the incidence varies widely by tumor type . A series of 102 patients with NHL showed an overall incidence of nearly 50 % by laboratory values, although only 6 % met clinical criteria [8]. In an observational study of patients with acute myeloid leukemia (AML), 17 % had TLS (12 % by laboratory values alone and 5 % by clinical criteria as well) [12]. An incidence of 46 % has been reported in chronic lymphocytic leukemia (CLL) [13].
It has also become apparent that tumor lysis can occur in many situations other than hematologic malignancies being treated with standard chemotherapy. Tumor lysis has been reported in the treatment of solid cancers such as breast [14], melanoma [15], gallbladder [16], lung [17], liver [18], gastric or gastrointestinal [19, 20], pancreatic [21], yolk sac [22], prostate [23], colorectal [24], testicular [25], medulloblastoma [26], and sarcoma [27]; although the incidence with these tumors remains unknown due to the limits of case reporting. In addition, it has become apparent that the trigger need not be standard cytotoxic therapy, with TLS reported after treatment with steroids, biological agents such as rituximab or interferon [14, 28−31], embolization [18, 32], surgery/anesthesia [33, 34], and even vaccination [35]. A tumor lysis-like condition has been reported during the use of granulocyte colony-stimulating factor in the correction of leucopenia [36]. Clearly, it is important to be cognizant of this syndrome outside of the more traditional framework of hematologic malignancy .
Case #1 Follow-up and Discussion
The patient presented above has TLS. As discussed, all hematologic malignancies have been associated with TLS. Most of the cases of solid tumor-associated lysis occur in the setting of high tumor burden, and have been isolated case reports. Indolent cancers like CML rarely cause TLS.
Patient Risk Factors
Certain patient characteristics have been associated with an increased likelihood of developing TLS . Intuitively, the risk would be expected to be highest when tumor burden is large and in those diseases highly responsive to treatment. In a series of 328 children with ALL, TLS was noted in 74 (23 %). Factors predictive of TLS on a multiple regression analysis included age ≥ 10 years (OR 4.5), the presence of splenomegaly (OR 3.3) or a mediastinal mass (OR 12.2), and WBC ≥ 20 × 109/L (OR 4.7) [37]. Other authors studying AML have reported an association with high LDH, WBC count over 25 × 109/L, as well as an elevated creatinine and uric acid [12]. The usefulness of these predictors has generally not been studied in validation cohorts or in patients with malignancies other than those from which the predictors were derived. Nevertheless, there have been several risk stratification algorithms proposed [38−40] which involve the general consideration of laboratory values, tumor type, and preexisting chronic kidney disease .
As previously mentioned, the presentation of TLS may occur with either abnormal laboratory parameters or the clinical manifestations of these disturbances. The laboratory presentation results from the release of intracellular molecules into the plasma, or the secondary effect of these chemicals on serum calcium levels. The abnormalities of the laboratory presentation according to the Cairo–Bishop criteria are listed in Table 8.1, and include the presence of two or more of hyperuricemia , hyperkalemia , hyperphosphatemia , and hypocalcemia . Nucleic acids, potassium, and phosphates are in high concentration in the intracellular environment, and released into the plasma under circumstances of rapid and extensive cell death. Hypocalcemia is a secondary effect of released phosphates complexing with plasma calcium and depositing in soft tissues and interstitial spaces. This typically occurs when the calcium phosphate product reaches levels greater than 60 mg2/dl2.
The clinical presentation occurs when symptoms and signs develop as a result of these changes. Generalized symptoms of anorexia, nausea, vomiting, diarrhea, and lethargy are common. Cardiac complications, including cardiac dysrhythmias, heart failure, syncope, and possible sudden death, may reflect hyperkalemia , hypocalcemia, and deposition of calcium phosphate in the myocardium disrupting contractility and electrical conduction. Neuromuscular effects include muscle spasms, tetany, and seizures .
The manifestations of TLS in the kidney include AKI , hematuria, oliguria, flank pain, and nephrolithiasis. The development of AKI is related to a variety of factors, including renal vasoconstriction, disrupted autoregulation, reduced renal blood flow, inflammation, tubular epithelial cell injury, and intra tubular deposition and obstruction by crystals. Uric acid and calcium phosphate deposition within the renal pelvis or as ureteral stones may be responsible for many of these clinical manifestations. The urinalysis often demonstrates uric acid crystals or amorphous urate in acidic urine. The kidney pathology includes calcium phosphate crystals in the interstitium (Fig. 8.1a) and uric acid crystals resulting in tubular obstruction (Fig. 8.1b). Xanthine is another poorly soluble metabolite of purine metabolism that can deposit in tissues.
Fig. 8.1
Panel a shows cortical tubules with injury and calcium phosphate deposition in lumen, epithelium, and interstitium. Von Kossa stain demonstrates-phosphate (but not oxalate) deposition (original magnification 40 ×). Panel b shows urate deposits in renal medulla (Masson Trichrome, original magnification 40 ×)
Outcomes
The development of TLS is associated with a series of clinical complications, including prolonged hospitalization, increased morbidity, and reduced survival . In a retrospective series of 772 patients with AML, clinical TLS (but not laboratory TLS) was associated with a 79 % risk of death (30 of 38 patients) versus 23 % in those who failed to meet criteria. This mortality included kidney failure, arrhythmias, and coma felt to be directly attributable to TLS [12].
Though not specifically addressing tumor lysis as a cause, the development of AKI complicating treatment of hematologic malignancies (excluding Hodgkin’s disease) has been identified as a major factor in prolonged hospitalization and higher inpatient medical costs. Analysis of data on over 400,000 patients from the Health Care Utilization Project revealed patients who developed AKI requiring dialysis, developed AKI without dialysis, and had no kidney complications has mean hospital stays of 17.6, 12.2, and 7.4 days, with hospitalization costs (in 2006 dollars) of $ 44,619, 25,638, and 13,947, respectively [41].
In another European analysis of 755 patients with ALL, AML, or NHL, 27.8 % met criteria of TLS. Patients requiring dialysis for TLS had hospitalization costs 26-fold greater than patients who developed hyperuricemia without fulfilling criteria for TLS or requiring dialysis. Death was attributable to TLS in 15 (2 %) patients [42].
Pathophysiology and Pathology
As noted, the laboratory and clinical manifestations of TLS result from the release of intracellular contents such as nucleic acids, potassium, phosphates, and other chemicals after extensive tumor lysis which results in a cascade of pathologic and pathophysiologic processes . The intracellular concentration of potassium is approximately 150 mEq/L, and cellular damage results in the spillage of this potassium into the extracellular space and plasma. This hyperkalemia may disrupt the Nernst potential governing cellular depolarization, opening voltage-gated sodium channels before inactivating the same channels. This action impairs neuromuscular, cardiac, and gastrointestinal function, thereby affecting cardiac conduction and inciting ventricular arrhythmias and asystole.
Phosphate is the most abundant intracellular anion, found primarily as adenosine phosphates (AMP, ADP, and ATP) and in DNA and RNA. Furthermore, tumor cells may have a phosphate content greater than four times that of normal cells [43]. The clinical manifestations of an extracellular phosphate load induced by extensive cell death are typically kept in check by the high capacity of the kidney to excrete phosphate. However, in the setting of reduced kidney function or simultaneous kidney injury as occurs in TLS, phosphate accumulation results in hyperphosphatemia . The direct clinical manifestations of hyperphosphatemia are limited, but extracellular phosphate complexes with ionized plasma calcium and deposits as calcium phosphate crystals in the kidneys, vasculature, and soft tissues . This results in a fall in plasma concentrations of free calcium and clinical hypocalcemia . Since calcium inhibits sodium channels and depolarization of nerves and muscles, acute hypocalcemia lowers the threshold for depolarization and clinically manifests as tetany, seizures, hyperreflexia, cardiac arrhythmias, and possibly death. Tetany is neuromuscular irritability and hyperexcitability with symptoms ranging from perioral numbness and paresthesias to carpopedal spasm and laryngospasm. Trousseau sign (carpopedal spasm induced by inflation of a sphygmomanometer above systolic blood pressure for 3 min) and Chvostek sign (contraction of the ipsilateral facial muscles elicited by tapping the facial nerve just anterior to the ear) are two of the more common features of tetany in hypocalcemia. The cardiac complications of hypocalcemia include impaired inotropy leading to reversible heart failure, and electrophysiologic derangements from prolonged QT interval to heart block and ventricular arrhythmias. Other manifestations of hypocalcemia in TLS include psychiatric lability, mood instability, and papilledema .
The effects of calcium and phosphate deposition in the kidney induce a variety of insults. Calcium phosphate crystals that deposit in tubular lumina can result in urinary obstruction. In addition, these crystals appear within tubular epithelial cells where they exert direct tubular toxicity and in the interstitium where they incite an inflammatory response. This is evident on kidney biopsy that demonstrates localization of phosphate using von Kossa stain in the lumen of the distal tubule, with lesser deposits in the tubular interstitium and in the epithelial cells (Fig. 8.1a) . Tubular atrophy, tubular necrosis, and nephrocalcinosis are consequences of calcium phosphate deposition. In the current era of uric acid-lowering therapy, calcium phosphate deposition presumably represents an increasingly important contributor to kidney damage.
Nucleic acids are also released following cellular destruction. Purines undergo a series of reactions resulting in their degradation, with guanosine metabolized by purine nucleoside phosphorylase to guanine, and then by guanine deaminase into xanthine (Fig. 8.2). Adenosine is metabolized by adenosine deaminase into inosine, and then purine nucleoside phosphorylase into hypoxanthine. Hypoxanthine is first converted to xanthine by xanthine oxidase, before xanthine is metabolized into uric acid. Uric acid is a weak acid with a pKa of 5.75. This means that at a physiologic pH of 7.4, 98 % of uric acid is in its ionized form of urate. In the acidic environment of the distal tubule where the pH falls below 5.0, equilibrium favors the less-soluble protonated form of uric acid that precipitates as crystals. The large load of filtered urate in TLS along with its rising concentration along the length of the tubule results in tubular precipitation in the increasingly acidic environment of the distal tubule. This leads to obstruction of tubules, collecting ducts, and even pelvises and ureters .
Fig. 8.2
Purine metabolism
The precipitation of uric acid in the tubules is enhanced by the presence of a calcium phosphate crystal nidus, and conversely, calcium phosphate precipitation is enhanced by the presence of uric acid crystals. Together, high concentrations of calcium phosphate and uric acid potentiate the risk of AKI .
Tubular obstruction from crystal deposition induces a cascade of processes that result in AKI. Increased tubular pressure raises intrarenal pressure and compresses venous channels within the kidney. The increase in vascular resistance reduces renal blood flow. Together, high tubular pressures and reduced renal blood flow lower glomerular filtration rate.
Case #2
A 14-year-old girl presented to her pediatrician with 1 week of abdominal bloating, nausea, vomiting, and malaise. She had previously been well, but the distension occurred rapidly and resulted in extreme discomfort. On examination, her temperature was 38.2 C, heart rate 110 bpm, and blood pressure 86/68 mmHg. Her oropharynx was clear and no cervical lymphadenopathy was present. Her heart was regular, and her lungs were clear. Her abdomen was distended and diffusely tender, with a palpable fluid wave. An epigastric mass was appreciated. Axillary and femoral lymphadenopathy was absent. Extremities revealed 2+ dependent edema. Laboratory testing showed potassium of 3.1 mEq/L, bicarbonate 22 mEq/L, creatinine 0.8 mg/dL, eGFR 111 ml/min/1.73 m2 by the CKD-EPI equation, albumin 4.2 mg/dL, calcium 8.6 mg/dL, phosphate 1.2 mg/dL, and LDH 850 U/L. Blood counts showed a WBC of 125 K, hemoglobin 13.8 mg/dL, and platelets 229 K. Computed tomography of the abdomen demonstrated ascites and a 14-cm mass compressing the antrum of the stomach. Biopsy of the abdominal mass showed monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm. Cell surface expression of CD19, CD20, CD22, CD79a, CD10, HLA-DR, and CD43 confirmed the diagnosis of Burkitt lymphoma. Treatment with EPOCH with rituximab was considered, but prophylaxis for TLS was first felt necessary.
What agent would you recommend for prevention of TLS?
a.
Volume expansion with bicarbonate based fluids
b.
N-acetyl-L-cysteine
c.
Recombinant urate oxidase
d.
Allopurinol
Prevention and Treatment
Although guidelines for the management of TLS exist, they are not grounded on large quantities of clinical trial data given the relatively rarity of the condition [39]. In general, the therapies for TLS are more effective when used for prevention, in part because kidney failure may not be readily reversed. Therefore, the mainstay is recognizing the possibility of tumor lysis and implementing an early and liberal administration of inexpensive preventative measures. There are additional therapies, either given preventatively to patients at particular risk or therapeutically as warranted by developments in the clinical course .
Related posts:
Acute Kidney Injury in Cancer Patients
Renal Cell Carcinoma and Chronic Kidney Disease
Biological Cancer Therapies and the Kidney
Glomerular Diseases Seen with Solid Tumors and Hematological Malignancies
Renal Disease Following Hematopoietic Stem Cell Transplantation
Dysproteinemias and Kidney Disease
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