Blood & Lymphoreticular

Tumor lysis syndrome: prevention and management

Clinical Overview and When to Suspect Tumor Lysis Syndrome

— Uric acid ≥8 mg/dL or 25% increase

— K⁺ ≥6 mEq/L or 25% increase

— Phosphate ≥4.5 mg/dL (adult) or 25% increase

— Calcium ≤7 mg/dL or 25% decrease

— Patient with high-grade lymphoma (Burkitt), ALL with WBC >100k, AML with WBC >50k, CLL on venetoclax ramp-up

— First 12–72 hours after induction chemo, rituximab, or even steroids alone

— Bulky disease, elevated LDH (>2× ULN), pre-existing CKD, dehydration, oliguria

Step 3 management: On the CCS, the moment you admit a high-risk heme malignancy patient, your initial orders should include IV fluids (normal saline 2–3 L/m²/day), allopurinol or rasburicase, baseline CMP, uric acid, LDH, phosphate, ionic calcium, and continuous telemetry — before chemotherapy starts.

Board pearl: The pathognomonic biochemical quartet is ↑K, ↑PO₄, ↑uric acid, ↓Ca²⁺. Hypocalcemia is secondary to calcium-phosphate precipitation — do NOT empirically replete calcium unless symptomatic (tetany, arrhythmia, seizure), because it accelerates CaPO₄ deposition in kidneys and worsens AKI.

Definition: Tumor lysis syndrome (TLS) is an oncologic emergency from massive release of intracellular contents (K⁺, PO₄³⁻, nucleic acids → uric acid) after rapid tumor cell death, causing hyperkalemia, hyperphosphatemia, hyperuricemia, secondary hypocalcemia, and AKI.

Cairo-Bishop criteria — Laboratory TLS = ≥2 of the following within 3 days before to 7 days after cytotoxic therapy:

Clinical TLS = laboratory TLS + AKI (Cr ≥1.5× ULN), seizure, arrhythmia, or sudden death.

When to suspect:

Spontaneous TLS: Can occur before therapy in Burkitt lymphoma and ALL — uric acid is high but phosphate often normal (purines reincorporated by viable cells).

Presentation Patterns and Key History

— Most TLS occurs 48–72 hours after initiation of cytotoxic therapy

— Venetoclax in CLL → during weekly dose ramp-up (20→400 mg)

— CAR-T therapy → may overlap with cytokine release syndrome

— Spontaneous TLS → before any treatment (Burkitt, T-ALL)

— Hyperkalemia: weakness, paresthesias, palpitations, syncope, cardiac arrest

— Hyperphosphatemia/hypocalcemia: muscle cramps, carpopedal spasm, Chvostek/Trousseau, tetany, seizures, prolonged QT

— Hyperuricemia/AKI: flank pain, oliguria, hematuria, nausea, lethargy, uremic encephalopathy

— Volume status: often oliguric from urate nephropathy and CaPO₄ deposition

— Recent diagnosis of hematologic malignancy; type and bulk

— LDH trend (surrogate for tumor burden and turnover)

— Pre-chemo hydration and prophylaxis (allopurinol vs rasburicase)

— Baseline renal function, G6PD status (rasburicase contraindication)

— Nephrotoxins: NSAIDs, contrast, aminoglycosides, ACEi

— Urate-raising drugs: thiazides, loop diuretics

— High risk: Burkitt, lymphoblastic lymphoma, ALL WBC >100k, AML WBC >100k, bulky DLBCL with LDH >2× ULN

— Intermediate: DLBCL with normal LDH, AML 25–100k, CLL on venetoclax

— Low risk: indolent lymphomas, most solid tumors, multiple myeloma

Key distinction: Spontaneous TLS vs treatment-induced TLS — spontaneous has normal or low phosphate (rapidly dividing tumor cells recycle phosphate into new nucleic acids), while post-chemo TLS has hyperphosphatemia because cells are dying en masse without reincorporation.

Board pearl: A patient with Burkitt lymphoma and acute renal failure before any chemo is the classic spontaneous TLS vignette — uric acid is the dominant driver; start rasburicase + IV fluids immediately, even pre-treatment.

Timing pattern:

Symptom clusters by electrolyte:

Critical history elements:

Risk tiering (Cairo-Bishop/Howard):

Physical Exam Findings and Hemodynamic Assessment

— Often oliguric or anuric with rising creatinine despite hydration attempts

— Paradoxically may appear volume overloaded (crackles, JVD, edema) if aggressive fluids given to failing kidneys

— Hypotension if sepsis or hyperkalemic arrhythmia supervenes

— Irregular rhythm, bradycardia, or wide-complex tachycardia from hyperkalemia

— Prolonged QT from hypocalcemia → risk of torsades

— Pericardial friction rub if uremic pericarditis

— Chvostek sign — facial twitch on tapping CN VII

— Trousseau sign — carpopedal spasm with BP cuff inflation

— Hyperreflexia, tetany, seizure

— Lethargy, asterixis from uremia

— Diffuse weakness, muscle cramps

— Flank tenderness from urate crystal nephropathy

— Bulky lymphadenopathy, mediastinal mass (SVC syndrome in T-ALL)

— Hepatosplenomegaly

— Testicular mass in pediatric ALL

— Skin infiltration (leukemia cutis)

— Continuous telemetry in any high-risk patient — peaked T waves are an early warning

— Strict I/O monitoring, target urine output ≥80–100 mL/m²/hr (≥2 mL/kg/hr)

— Daily weights; assess for pulmonary edema if anuric

CCS pearl: On the CCS interface, order "continuous cardiac monitoring," "strict ins and outs," "daily weight," and "vital signs q1h" for any TLS-risk admission. Failing to monitor closely is a frequent CCS scoring deduction even when pharmacotherapy is correct.

Board pearl: A new wide-complex tachycardia in a freshly chemo-treated leukemia patient is hyperkalemia until proven otherwise — give IV calcium gluconate for cardiac membrane stabilization (the one time you do give calcium in TLS despite hyperphosphatemia, because the arrhythmia will kill faster than CaPO₄ deposition).

Volume and perfusion:

Cardiovascular:

Neuromuscular (hypocalcemia/uremia):

Musculoskeletal:

Tumor-related findings (don't miss):

Hemodynamic assessment priorities:

Diagnostic Workup — Initial Labs, Imaging, and ECG

— CMP: K⁺, phosphate, Ca²⁺ (ionized preferred), creatinine, BUN, bicarbonate

— Uric acid (baseline and serial)

— LDH — tumor burden surrogate; trend reflects response

— Magnesium (often low, worsens arrhythmia risk)

— CBC with differential, peripheral smear

— Coags (DIC common in APL, high-grade lymphomas)

— Uric acid crystals (rhomboid, yellow-brown) suggest urate nephropathy

— Urine pH — historically alkalinized, no longer recommended routinely (precipitates CaPO₄, xanthine)

— Urine output measurement is more important than chemistry

— Peaked T waves → early hyperkalemia (K⁺ 5.5–6.5)

— Loss of P wave, widened QRS → severe (K⁺ >7)

— Sine wave → preterminal

— Prolonged QT from hypocalcemia

— Combined K⁺/Ca²⁺ disturbances can produce odd patterns — interpret with electrolytes in hand

— Renal ultrasound if AKI to rule out obstruction (and bulky retroperitoneal nodes)

— CT chest/abdomen/pelvis for tumor staging if not done

— Echocardiogram if arrhythmia or pericardial concern

Step 3 management: Order labs as a TLS panel q6h for the first 24–48 hours after chemo initiation in high-risk patients — K⁺, phosphate, calcium, uric acid, creatinine, LDH. On CCS, the test author rewards proactive serial monitoring.

Board pearl: A rising LDH with stable uric acid during treatment is often the first sign of impending TLS — anticipate the surge and ensure rasburicase is ready, fluids are running, and nephrology has been touched base with. Don't wait for K⁺ to peak.

Core labs (q6–8h in high-risk, q4h if active TLS):

Urinalysis:

ECG — must obtain at baseline and with electrolyte shifts:

Imaging:

G6PD screen: Required before rasburicase — hemolysis and methemoglobinemia in deficient patients

Diagnostic Workup — Advanced and Confirmatory Studies

— Urine uric acid : creatinine ratio >1.0 (mg/mg) suggests urate nephropathy

— Ratio <0.6–0.75 → consider other AKI etiologies (ATN, contrast, sepsis)

— Bland urine sediment with crystals favors TLS over glomerular disease

— Continuous telemetry with rhythm strips during electrolyte shifts

— Echocardiogram if pericardial rub or hemodynamic instability

— Troponin if ischemic ECG changes (demand ischemia from hyper-K, anemia)

— Flow cytometry, cytogenetics, FISH — guides chemo choice and TLS risk

— Bone marrow biopsy if leukemia suspected

— Excisional lymph node biopsy for lymphoma (FNA usually insufficient)

— Confirm vascular access feasibility (HD catheter placement) — type and screen, platelets ≥30–50k, INR <1.5–2

— Consider CRRT if hemodynamic instability

— Renal US — rule out obstruction by bulky nodes or ureteral compression

— CT abdomen if flank pain, hematuria, or concern for retroperitoneal mass

Key distinction: Urate nephropathy (low urine pH, uric acid crystals, urine UA:Cr >1) vs calcium phosphate nephropathy (alkaline urine, CaPO₄ product >70, often after over-alkalinization). The latter is iatrogenic and explains why routine urinary alkalinization has fallen out of favor in modern TLS protocols.

Board pearl: If a patient is hemolyzing after rasburicase, suspect undiagnosed G6PD deficiency — order G6PD assay (will be falsely normal during acute hemolysis; recheck in 2–3 months), measure methemoglobin level, and treat with supportive care (not methylene blue, which itself causes oxidative stress).

Distinguishing TLS-AKI from other causes:

Cardiac evaluation if arrhythmia:

DIC panel: Fibrinogen, D-dimer, PT/PTT, smear for schistocytes — common in APL and high-grade lymphoma; coexists with TLS

Tumor characterization (if not yet done):

Nephrology preparedness studies:

Methemoglobin level / G6PD assay: if rasburicase given to a patient of African, Mediterranean, or Southeast Asian ancestry without prior G6PD testing

Imaging for complications:

Risk Stratification and First-Line Management Logic

— High risk: Burkitt, lymphoblastic lymphoma/ALL, AML with WBC >100k, ALL with WBC >100k, bulky DLBCL with LDH >2× ULN, CLL with venetoclax ramp-up and high tumor burden

— Intermediate risk: DLBCL normal LDH, AML 25–100k, ALL <100k, multiple myeloma with high tumor burden, CLL on venetoclax with moderate burden

— Low risk: Indolent lymphomas, CLL, most solid tumors, MM standard burden

— Low risk: Oral hydration, monitor labs daily; allopurinol not routinely required

— Intermediate risk: IV fluids + allopurinol (300 mg PO daily, adjust for renal function); monitor labs q12–24h

— High risk: IV fluids + rasburicase (0.15–0.2 mg/kg IV × 1, often single dose suffices); labs q6–8h; ICU-level monitoring

— 2–3 L/m²/day (or 3 L/day in adults) of isotonic fluid — normal saline or D5½NS

— Urine output goal ≥80–100 mL/m²/hr (≥2 mL/kg/hr in children)

— Avoid potassium-containing fluids (no LR initially)

— Avoid routine bicarbonate/alkalinization

Step 3 management: The first orders for any high-risk admission are: (1) NS 250–300 mL/hr IV, (2) rasburicase 0.2 mg/kg IV ×1, (3) check G6PD, (4) TLS panel q6h, (5) telemetry, (6) strict I/Os, (7) renal & ICU consults if labs deranged. Sequence matters on CCS.

Board pearl: Rasburicase + allopurinol together is generally avoided — allopurinol blocks xanthine oxidase, preventing xanthine→uric acid conversion, so rasburicase has less substrate to act on, and xanthine itself can precipitate (xanthine nephropathy). Use one or the other.

Howard/Cairo-Bishop risk stratification drives prophylaxis intensity:

Prophylaxis matrix:

Hydration target:

Loop diuretics: Only if euvolemic-to-hypervolemic with adequate intravascular volume; not for forcing diuresis in dehydrated patients

Phosphate binders: Sevelamer preferred (non-calcium binder) for hyperphosphatemia

Pharmacotherapy — First-Line Agents in Detail

— Dose: 300 mg PO daily (up to 600–800 mg/day); reduce 50% if CrCl <30

— Start 24–48 hours before chemo in intermediate-risk patients

— Blocks new uric acid formation but does not lower existing uric acid

— Onset of effect: 24–72 hours

— Toxicities: rash, SJS (HLA-B*5801 in Asians), hepatitis, marrow suppression

— Drug interactions: increases 6-MP and azathioprine levels (reduce dose 75%); warfarin potentiation

— Dose: 0.15–0.2 mg/kg IV over 30 min; a single dose often sufficient (cost-effective strategy)

— Converts uric acid → allantoin (highly water-soluble, renally excreted)

— Onset: drops uric acid within 4 hours

— Contraindications: G6PD deficiency (hemolysis), pregnancy, lactation, prior hypersensitivity

— Sample handling: place blood sample on ice for uric acid measurement (rasburicase continues degrading UA ex vivo → falsely low)

— IV calcium gluconate 1–2 g (membrane stabilization)

— Insulin 10 U + D50 (intracellular shift)

— Albuterol nebulizer (adjunct shift)

— Avoid sodium bicarbonate in TLS — promotes CaPO₄ precipitation

— Patiromer or sodium zirconium for ongoing GI elimination; avoid SPS (Kayexalate) if possible (colonic necrosis)

— Loop diuretic if volume permits

Board pearl: Rasburicase is the drug of choice when uric acid is already elevated or when AKI is established — it works in hours, allopurinol takes days. Always check G6PD first, but in true emergencies, treat empirically and check status afterward.

Allopurinol (xanthine oxidase inhibitor):

Rasburicase (recombinant urate oxidase):

Febuxostat: Alternative xanthine oxidase inhibitor; useful if allopurinol-allergic; cardiovascular mortality signal — avoid in established CV disease

Hyperkalemia treatment cascade:

Hyperphosphatemia: sevelamer; aluminum hydroxide short-term

Hypocalcemia: Replete only if symptomatic (tetany, seizure, QT prolongation, arrhythmia)

Renal Replacement Therapy and Procedural Management

— Acidosis refractory (pH <7.1)

— Electrolytes: K⁺ >6.5–7 not responsive to medical therapy

— Ingestion — not applicable

— Overload: volume overload with oliguria

— Uremia — symptomatic, pericarditis, encephalopathy

— TLS-specific: phosphate >10 mg/dL, symptomatic hypocalcemia with high CaPO₄ product, severe oliguric AKI

— Intermittent HD preferred — high clearance of uric acid, phosphate, potassium

— CRRT (CVVH/CVVHDF) if hemodynamically unstable; slower clearance, may need extended duration

— Peritoneal dialysis not adequate for TLS (clearance too low)

— Often need daily or twice-daily HD for 2–4 days

— Phosphate clearance is the rate-limiter; phosphate has slow intercompartmental shifts

— Recheck labs post-HD and 2–4 hours later to catch rebound

— Leukapheresis if hyperleukocytosis (WBC >100k with leukostasis) — reduces tumor burden before chemo

— Cytoreduction with low-dose hydroxyurea or steroids prior to full-intensity chemo in very high-risk cases

— Central venous access for fluids, electrolyte infusions

— Foley catheter for accurate I/O in critically ill patients

CCS pearl: In a CCS case where K⁺ is 7.5 with peaked T waves and the patient is anuric, the correct sequence is: calcium gluconate IV → insulin/D50 → albuterol → call nephrology → order emergent HD. Don't waste time on Kayexalate; advance the clock and order HD.

Board pearl: Modern oncology centers often start a slow-rise venetoclax ramp with admission for the first dose to allow inpatient monitoring — a Step 3-flavored systems-based answer when asked how to mitigate TLS risk in CLL.

Indications for emergent hemodialysis in TLS (AEIOU + TLS-specific):

Modality choice:

Access: Tunneled or non-tunneled HD catheter; coordinate with nephrology and interventional radiology

Dialysis intensity in TLS:

Other procedural considerations:

Post-dialysis monitoring: Continue TLS panel q6h, telemetry, urine output tracking

Special Populations — Elderly and Renal/Hepatic Impairment

— Baseline reduced GFR (sarcopenia masks true CKD; use measured CrCl or cystatin C)

— Higher baseline cardiovascular risk → tighter telemetry needs

— Polypharmacy increases nephrotoxin exposure (NSAIDs, ACEi, diuretics)

— Reduced thirst response → start IV hydration earlier rather than oral

— Reconcile home meds: hold ACEi/ARB, NSAIDs, K-sparing diuretics, K supplements

— Major TLS risk factor independent of tumor type

— Lower thresholds for rasburicase and HD initiation

— Be cautious with hydration volume — may precipitate pulmonary edema; consider concurrent loop diuretic and CVP monitoring

— Nephrology consult on admission, not after AKI develops

— CrCl 60–90: 200 mg/day

— CrCl 30–60: 150 mg/day

— CrCl 10–30: 100 mg/day

— CrCl <10: 100 mg every other day

— Higher SJS risk with under-adjusted doses in renal impairment

— Allopurinol cleared partially hepatically — monitor LFTs

— Coagulopathy increases hemorrhage risk with line placement for HD

— Reduced albumin → altered ionized calcium interpretation (use ionized Ca measurement)

— Schedule chemo and HD in coordination — HD typically the day after chemo

— May not need rasburicase if anuric — uric acid cleared by HD

Step 3 management: For an elderly CLL patient starting venetoclax with baseline CrCl 35, the right answer is inpatient ramp-up with IV hydration, rasburicase if uric acid elevated, q6h labs during dose escalation, and nephrology on standby — not outpatient initiation.

Board pearl: Always recalculate creatinine clearance after the first dose of chemo — TLS-induced AKI can develop within hours, and renally-cleared antineoplastics (methotrexate, cisplatin) need re-dosing.

Elderly considerations:

Pre-existing CKD:

Allopurinol dosing:

Rasburicase in CKD: Dose unchanged; arguably more important given limited renal reserve to excrete uric acid

Hepatic impairment:

Dialysis-dependent ESRD patients with cancer:

Special Populations — Pediatrics and Pregnancy

— Most common TLS scenarios: T-cell ALL, Burkitt lymphoma, AML with hyperleukocytosis

— Pediatric-specific risk: mediastinal mass with SVC syndrome (T-ALL)

— Hydration: 2–3 L/m²/day (or 200 mL/kg/day in infants <10 kg); urine output goal ≥4 mL/kg/hr

— Avoid potassium-containing fluids

— Rasburicase dose: 0.15–0.2 mg/kg IV; very effective in children

— Use weight-based dosing for all agents; double-check at the pharmacy

— Burkitt patients with elevated LDH should receive prephase cytoreduction (low-dose cyclophosphamide, vincristine, prednisone) before full COPADM-style chemo

— Hematologic malignancy in pregnancy is rare but high-stakes

— Rasburicase is contraindicated in pregnancy (Category C; risk of fetal hemolysis, especially with G6PD)

— Allopurinol is generally avoided in first trimester; can be used in later trimesters with caution

— Manage with aggressive IV hydration, dialysis if needed, and multidisciplinary maternal-fetal medicine + heme-onc coordination

— Delivery timing balances maternal disease urgency vs fetal maturity

— Avoid rasburicase and methylene blue

— Use allopurinol with hydration; lower threshold for early HD

— Document G6PD status prominently in the chart

Key distinction: In pediatric Burkitt, spontaneous TLS is so common that rasburicase + IV fluids are started at diagnosis, often before histopathology returns. In adult Burkitt, the same approach applies — don't wait for confirmation if clinical picture (rapid LDH rise, abdominal mass, B-symptoms) is consistent.

Board pearl: A neonate with rasburicase-induced hemolysis suggests G6PD deficiency (X-linked, screened at birth in many states but not all) — always check status before rasburicase regardless of age.

Pediatric considerations:

Adolescents: Counsel on fertility preservation before chemo (sperm banking, oocyte cryopreservation if time permits)

Pregnancy:

G6PD-deficient patients (any age):

Complications and Adverse Outcomes

— Acute kidney injury — urate nephropathy (intratubular UA crystals), CaPO₄ deposition, xanthine nephropathy (if allopurinol over-blocks)

— Up to 30% of clinical TLS requires dialysis

— Chronic kidney disease can persist after recovery

— Hyperkalemia-induced arrhythmias: bradycardia, AV block, VT/VF, asystole

— Hypocalcemia-induced QT prolongation → torsades

— Hypomagnesemia compounds arrhythmia risk

— Demand ischemia from rate/rhythm instability

— Seizures (hypocalcemia, uremia, hypomagnesemia)

— Encephalopathy

— Tetany

— DIC — particularly in APL (M3 AML), high-grade lymphomas

— Hemolysis after rasburicase in G6PD deficiency

— Methemoglobinemia (rasburicase)

— Volume overload from over-resuscitation in anuric patient

— CaPO₄ precipitation from sodium bicarbonate or empirical calcium replacement

— Xanthine nephropathy from allopurinol + rasburicase together

— SPS-induced colonic necrosis

— Clinical TLS mortality 15–20%; higher with cardiac arrest or refractory AKI

— Predictors of bad outcome: pre-existing CKD, oliguria at presentation, K⁺ >7, phosphate >8, age >60, ICU-level hemodynamics

CCS pearl: When the CCS clock advances and a TLS patient develops oliguria + K⁺ 6.8 + phosphate 9.5, do not just escalate medical therapy — call nephrology and order emergent HD. Failing to recognize when medical management has failed is a common scoring miss.

Board pearl: A patient who develops chest pain, hypotension, and bleeding soon after starting all-trans retinoic acid (ATRA) for APL has differentiation syndrome plus TLS plus DIC — manage with dexamethasone, supportive care, and continued ATRA unless severe; this is a Step 3 multi-system favorite.

Renal:

Cardiac:

Neurologic:

Hematologic:

Iatrogenic complications to avoid:

Mortality:

When to Escalate Care — ICU, Consults, and Transitions

— K⁺ >6.5 with ECG changes or refractory to medical therapy

— Hemodynamic instability or arrhythmia

— Anuric AKI requiring emergent HD

— Seizure, altered mental status

— Respiratory failure (volume overload, pulmonary leukostasis)

— Symptomatic hypocalcemia with QT prolongation

— Nephrology: any rising creatinine, oliguria, K⁺ >6, phosphate >6, or anticipation of HD; ideally engaged at admission in high-risk patients

— Heme-onc: primary team, but escalate for chemo modifications, prephase decisions

— Cardiology: arrhythmia, suspected ACS, prolonged QT

— Critical care: for ICU placement and CRRT

— Pharmacy: dose adjustments, G6PD verification, rasburicase handling

— Almost all high-risk patients should receive their first cycle inpatient

— Intermediate-risk patients with poor reliability for monitoring, distance from hospital, or social factors should be admitted

— Venetoclax ramp-up in CLL: admit for first dose at each level if high tumor burden

— Handoff from emergency department to inpatient: ensure TLS panel ordered, hydration started, rasburicase given if indicated

— Transfer between floor and ICU: communicate K⁺ trend, urine output, last labs

— Discharge: clear instructions on hydration, allopurinol continuation, follow-up labs in 1–2 days

Step 3 management: A patient in the ER with bulky lymphadenopathy, LDH 3000, creatinine 1.8, and K⁺ 5.4 should be admitted to a monitored bed (step-down or ICU), started on IV NS, given rasburicase after G6PD check, and have heme-onc + nephrology consulted — before any chemotherapy is initiated.

Board pearl: Never start chemotherapy on a TLS-high-risk patient in an outpatient infusion center — this is a patient-safety red flag question. Admit, prophylax, monitor.

ICU transfer criteria:

Consult triggers:

Inpatient admission criteria (vs outpatient management):

Transitions of care risks:

Key Differentials — Same-Category Causes

— Rhabdomyolysis — elevated CK, myoglobinuria, often after immobility or seizure; uric acid mildly elevated but not to TLS extent; phosphate elevated but LDH from muscle not tumor

— Hemolysis (intravascular) — low haptoglobin, high LDH, indirect bilirubinemia, schistocytes; potassium release from RBCs

— Pseudohyperkalemia — hemolyzed specimen, marked leukocytosis (>100k) or thrombocytosis releasing K⁺ in vitro; redraw in heparinized tube

— Adrenal insufficiency — hyponatremia, hyperkalemia, hypotension; cortisol and ACTH testing

— Type 4 RTA — chronic, mild, often diabetics on RAAS blockade

— Gout flare — joint-focused, less systemic, normal phosphate/K⁺

— Lesch-Nyhan — pediatric, neurologic phenotype

— Lead nephropathy — chronic, saturnine gout

— Diuretic-induced — thiazides, loops; gradual, not acute crisis

— Acute kidney injury of any cause — but without massive K⁺/UA surge

— Rhabdomyolysis — overlapping electrolyte profile; distinguish by CK, history

— Phosphate enema toxicity — iatrogenic, especially in children/elderly

— Hypoparathyroidism — chronic, low PTH

Key distinction: Rhabdomyolysis vs TLS — both cause AKI, hyperkalemia, hyperphosphatemia, hypocalcemia, and elevated LDH. Rhabdomyolysis has markedly elevated CK (>5,000–10,000) and myoglobinuria; TLS has markedly elevated uric acid (>15) and LDH with hematologic malignancy context. Both treated with aggressive IV hydration; rhabdo additionally with consideration of bicarbonate (controversial); TLS specifically avoids bicarbonate.

Board pearl: A leukemia patient with WBC 200k whose stat chem panel shows K⁺ 7 but no ECG changes — suspect pseudohyperkalemia from in vitro leukocyte lysis; verify with plasma (heparinized) potassium before treating.

Other causes of acute hyperkalemia in cancer patients:

Other causes of acute hyperuricemia:

Other causes of hyperphosphatemia + hypocalcemia:

DIC mimickers: TTP/HUS, HIT, sepsis-induced coagulopathy

Key Differentials — Other-Category Causes

— Can mimic TLS with AKI, electrolyte derangements, hemodynamic instability

— Distinguish: fever, hypotension, lactate, procalcitonin, infectious source

— Coexists frequently — neutropenic fever post-chemo is high-risk

— Manage with antibiotics within 1 hour, fluids, source control

— Recent contrast (staging CT) → AKI 24–72h later

— Bland sediment, no urate crystals, normal uric acid

— Cancer patients often have multiple insults stacked

— Epigastric pain, elevated lipase

— Hypocalcemia from saponification, not CaPO₄ precipitation

— Normal uric acid and phosphate

— Opposite calcium picture — but a cancer patient can have both at different timepoints

— Treat with IV fluids, bisphosphonate, denosumab, calcitonin

— In a cancer patient, also consider PE, anthracycline cardiotoxicity, pericardial tamponade

— Methotrexate (high-dose, especially with low urine pH) — manage with leucovorin rescue, urinary alkalinization (different from TLS!), glucarpidase

— Cisplatin nephrotoxicity

— Amphotericin

— Post-CAR-T or post-blinatumomab patients can present with hypotension, AKI, electrolyte shifts overlapping with TLS

— Tocilizumab for CRS; manage TLS in parallel

Key distinction: Methotrexate nephrotoxicity vs TLS — both occur after chemo, both cause AKI. Methotrexate AKI is treated with urinary alkalinization (target urine pH >7), leucovorin, and glucarpidase; TLS is treated with avoidance of alkalinization. Wrong choice can worsen TLS.

Board pearl: A leukemia patient post-chemo with fever, hypotension, AKI, and electrolyte derangements has TLS + neutropenic sepsis until proven otherwise — culture, start broad-spectrum antibiotics (cefepime ± vancomycin) within 1 hour, and continue TLS management concurrently.

Sepsis with multiorgan failure:

Contrast-induced nephropathy:

Acute pancreatitis with hypocalcemia:

Hypercalcemia of malignancy (PTHrP, lytic lesions):

Cardiac arrest from other etiologies:

Drug-induced AKI:

Capillary leak / cytokine release syndrome:

Secondary Prevention and Long-Term Plan

— TLS risk is highest with cycle 1; subsequent cycles usually lower-risk if tumor burden reduced

— Continue prophylaxis (allopurinol + hydration) for cycles 2–3 in originally high-risk patients

— Re-stratify before each cycle based on disease response and renal function

— Each dose escalation step requires renewed TLS risk assessment

— Tumor burden often shrinks during ramp, allowing outpatient continuation at higher doses

— Maintain hydration and allopurinol throughout ramp

— Allopurinol 300 mg PO daily until total tumor burden adequately reduced (often 5–7 days post-chemo)

— Continue if intermediate-to-high risk for subsequent cycles

— Avoid nephrotoxins: NSAIDs, IV contrast unless essential

— Resume ACEi/ARB only when creatinine has stabilized to baseline

— Address comorbidities: hypertension, diabetes, gout

— Some patients have persistent CKD post-TLS — annual GFR monitoring

— Avoid future nephrotoxic exposures

— Refer to nephrology if eGFR <60 persists at 3 months

— Recognize symptoms of recurrent TLS (oliguria, weakness, palpitations)

— Maintain oral hydration goals (≥2 L/day)

— Adherence to allopurinol, lab follow-up

— Bring medication list to every visit

Step 3 management: At discharge after TLS resolution, the orders should include: (1) Allopurinol 300 mg PO daily, (2) Outpatient BMP and uric acid in 48–72 hours, (3) Heme-onc follow-up within 1 week, (4) Nephrology follow-up at 4 weeks if AKI occurred, (5) Avoidance of NSAIDs, (6) Hydration counseling.

Board pearl: Patients on venetoclax for CLL must continue allopurinol and lab monitoring at each weekly dose escalation — outpatient labs the day before and day after each ramp dose are standard of care.

Subsequent cycles of chemotherapy:

Venetoclax ramp-up (CLL):

Discharge medications:

Long-term renal sequelae:

Patient education at discharge:

Follow-Up, Monitoring Parameters, and Counseling

— TLS panel (K⁺, phosphate, calcium, uric acid, creatinine, LDH) q6h × 24–48 hours, then q12h × 24 hours, then daily as labs normalize

— Continuous telemetry until K⁺ <5.5 and stable for 24 hours

— Strict I/O, daily weights

— Magnesium daily; replete to >2.0

— 48–72 hours post-discharge: BMP, uric acid, phosphate by primary or oncology

— 1 week: Heme-onc visit for chemo response assessment and next cycle planning

— 2–4 weeks: Nephrology if AKI occurred or eGFR <60

— 3 months: Repeat eGFR, urinalysis; consider G6PD assay if rasburicase given without prior testing

— Each cycle: reassess tumor burden, LDH, creatinine, urine output history

— De-escalate from rasburicase to allopurinol when burden decreases

— Document TLS prophylaxis plan in pre-chemo orders

— Hydration: ≥2 L/day oral fluids unless restricted

— Recognize warning symptoms — muscle weakness, palpitations, decreased urination

— Medication adherence; pill counts at visits

— Lifestyle: avoid alcohol excess, purine-rich diet during prophylaxis

— Vaccinations updated (influenza, pneumococcal, COVID-19, shingles when eligible)

— Long-term renal function tracking; document any persistent CKD

— Manage downstream complications (hypertension, anemia of CKD)

— Psychosocial support — TLS is frightening for patients and families

CCS pearl: On CCS, after TLS resolution always advance the clock and order outpatient follow-up labs and clinic visits explicitly — "schedule BMP in 72 hours" and "heme-onc clinic in 1 week" are scoring items that students miss when ending cases.

Board pearl: Persistent hyperuricemia 72 hours after rasburicase suggests either ongoing tumor lysis (need re-dose) or sample handling error (specimen wasn't kept on ice — ex vivo degradation falsely lowers reading but here would falsely raise — clarify with lab).

Inpatient monitoring during active TLS:

Post-resolution follow-up:

Cycle-by-cycle prophylaxis review:

Patient counseling:

Survivorship:

Ethical, Legal, and Patient Safety Considerations

— Patients must be informed of TLS risk, the rationale for hospitalization, monitoring intensity, possible need for dialysis

— In Burkitt and ALL, where TLS can be life-threatening or even fatal, this discussion is non-negotiable

— Document discussion specifically — generic chemo consent is insufficient

— Patient safety standard: check G6PD before rasburicase whenever feasible; if emergent and unknown, document risk-benefit reasoning

— Failure to check in a high-risk ancestry patient is a medication safety event

— Many institutions require pharmacy verification before dispensing

— A capacitated patient can refuse HD even when life-saving; explore reasons, offer palliative alternatives

— Document capacity assessment

— Engage palliative care early in refractory or end-of-life scenarios

— ED → floor handoff: TLS prophylaxis often missed

— Floor → ICU: drug doses and electrolyte trends must be communicated explicitly

— Hospital → home: ensure allopurinol prescription filled and follow-up arranged

— Read-back of critical labs (K⁺ >6, Ca²⁺ <7) is institutional policy at most centers

— Adolescents (~14+) should have age-appropriate assent discussions

— Fertility preservation discussion before gonadotoxic chemo is a quality metric

— Maternal-fetal medicine involvement, shared decision-making about chemo timing vs delivery

— Rasburicase contraindicated; document alternative plan

— Rasburicase is expensive — institutions should have stewardship protocols (single-dose strategies have parity outcomes at fraction of cost)

Step 3 management: When a leukemia patient develops AKI requiring HD but refuses dialysis, the correct steps are: (1) assess decision-making capacity, (2) involve palliative care and ethics consult, (3) explore reversible reasons for refusal, (4) respect the decision if capacitated, (5) document conversation thoroughly.

Board pearl: Giving rasburicase to an unscreened patient who then hemolyzes is a preventable adverse event — root cause analysis territory. Pharmacy verification of G6PD status is a safety best practice.

Informed consent for chemotherapy:

G6PD testing and rasburicase:

Refusal of dialysis:

Transitions of care risks:

Pediatric assent and parental consent:

Pregnancy and fetal considerations:

Disparities and access:

High-Yield Associations and Rapid-Fire Clinical Facts

Step 3 management: When the vignette gives you a patient with a hematologic malignancy, the first three orders should always be IV isotonic fluids, urate-lowering therapy (allopurinol or rasburicase per risk), and continuous cardiac monitoring with serial labs.

Board pearl: The single most common Step 3 TLS trap is routinely repleting low calcium in an asymptomatic patient with hyperphosphatemia — the right answer is do not replete unless symptomatic (tetany, QT-related arrhythmia, seizure).

Burkitt lymphoma + abdominal mass + AKI before chemo → spontaneous TLS; rasburicase + IV fluids immediately

Venetoclax in CLL → highest TLS risk during weekly dose ramp-up (especially 50 → 100 → 200 → 400 mg steps)

APL (AML M3) + ATRA → differentiation syndrome + DIC + TLS triad

Peripheral smear with starry sky → Burkitt → expect TLS

LDH >2× ULN → strong predictor of TLS regardless of histology

Rasburicase + G6PD deficiency → hemolysis, methemoglobinemia

Sample on ice rule: Rasburicase degrades uric acid ex vivo at room temperature → must transport on ice

Avoid sodium bicarbonate in TLS → CaPO₄ deposition worsens AKI

Avoid empirical calcium in asymptomatic hypocalcemia → CaPO₄ deposition

Allopurinol + 6-MP or azathioprine → reduce thiopurine dose 75%

Allopurinol HLA-B*5801 → SJS risk in Han Chinese, Thai, Korean populations; consider testing

Febuxostat → avoid in CV disease (mortality signal)

Xanthine nephropathy → don't combine allopurinol + rasburicase

Urine UA:Cr ratio >1.0 → suggests urate nephropathy

Pseudohyperkalemia in WBC >100k or platelets >1M → confirm with plasma K⁺

Hemodialysis clears uric acid effectively; phosphate clearance is rate-limiter

Single-dose rasburicase often suffices and is cost-effective vs daily × 5 dosing

Tumor types: Burkitt > T-ALL > B-ALL > AML > DLBCL > CLL on venetoclax for TLS risk

Solid tumors: TLS is rare but reported in small-cell lung, germ cell, neuroblastoma

Cairo-Bishop window: 3 days before to 7 days after chemo

First chemo cycle = highest TLS risk

Board Question Stem Patterns

— Answer: Aggressive IV NS hydration + rasburicase + admit to monitored unit + check G6PD; do NOT delay for biopsy

— Answer: Continue hydration, treat hyperphosphatemia (sevelamer) — do NOT give IV calcium

— Answer: G6PD deficiency–induced hemolysis; supportive care, transfusion; check methemoglobin level

— Answer: Hold venetoclax, admit, hydrate, rasburicase, resume ramp with closer monitoring — illustrates outpatient → inpatient transition

— Answer: Redraw in heparinized plasma tube before initiating hyperkalemia treatment

— Answer: Urinary alkalinization + leucovorin + glucarpidase — distinguished from TLS (where alkalinization is avoided)

— Answer: Emergent hemodialysis

— Answer: IV NS, rasburicase, telemetry, q6h TLS panel, G6PD, strict I/O, ICU consult if labs deranged

Step 3 management: Step 3 stems often layer systems issues — wrong site of care (outpatient when should be inpatient), missed prophylaxis at handoff, undocumented G6PD. The "best answer" is usually the safest, most monitored option.

Board pearl: When the question asks "what would have prevented this?" — the answer is almost always risk stratification + appropriate prophylaxis before chemo, not rescue therapy after the fact.

Stem 1 — "Burkitt before chemo": Young patient with rapidly enlarging abdominal mass, B-symptoms, LDH 4500, creatinine 2.1, uric acid 14, K⁺ 5.8 — biopsy pending. Best next step?

Stem 2 — "Don't give calcium": Post-induction ALL patient, K⁺ 5.9, phosphate 8, calcium 6.8, no symptoms, normal ECG. Next best step?

Stem 3 — "G6PD and rasburicase": Patient of Mediterranean descent receives rasburicase, develops jaundice, anemia, dark urine.

Stem 4 — "Venetoclax ramp": CLL patient on week 2 of venetoclax (50 mg) develops fatigue, K⁺ 6.2, uric acid 11.

Stem 5 — "Pseudohyperkalemia": AML with WBC 180k, K⁺ 7.2, no ECG changes.

Stem 6 — "Methotrexate confusion": Lymphoma patient on high-dose methotrexate with AKI.

Stem 7 — "Dialysis indication": TLS patient with phosphate 11, K⁺ 7, oliguric despite hydration.

Stem 8 — "CCS sequence": First orders for newly admitted high-risk DLBCL patient.

One-Line Recap

Tumor lysis syndrome is an oncologic emergency defined by hyperkalemia, hyperphosphatemia, hyperuricemia, and secondary hypocalcemia leading to AKI and arrhythmia after rapid tumor cell turnover — prevented by risk-stratified prophylaxis (IV isotonic fluids + allopurinol for intermediate risk, rasburicase for high risk) and managed by aggressive hydration, urate-lowering therapy, electrolyte correction without empirical calcium or bicarbonate, and early hemodialysis when medical therapy fails.

CCS pearl: A perfect CCS TLS case sequence reads: admit → monitored bed → NS 250–300 mL/hr → rasburicase 0.2 mg/kg IV ×1 → G6PD → TLS panel q6h → telemetry → strict I/O → heme-onc and nephrology consults → reassess labs → advance clock → discharge with allopurinol and 72-hour lab follow-up.

Board pearl: The patient who dies of TLS is almost always the one whose risk wasn't recognized before chemo started — prevention beats rescue, every time.

Risk stratification first: Burkitt, ALL/AML with high WBC, bulky DLBCL with elevated LDH, and venetoclax ramp-up are high-risk; match prophylaxis intensity to risk tier.

Pharmacology essentials: Rasburicase (single dose, check G6PD, sample on ice) for high-risk and established hyperuricemia; allopurinol for intermediate-risk prophylaxis; never combine allopurinol + rasburicase routinely (xanthine nephropathy risk).

The "do nots": Do not routinely alkalinize urine (CaPO₄ deposition); do not empirically replete asymptomatic hypocalcemia; do not start chemo on high-risk patients in outpatient settings; do not miss G6PD testing before rasburicase.

Escalation logic: Telemetry + q6h TLS labs + nephrology consult for any high-risk admission; emergent HD for refractory K⁺ >6.5, phosphate >10, oliguric AKI, symptomatic hypocalcemia, or uremia — and don't waste clock cycles on Kayexalate when dialysis is indicated.