# 🚨 Tumor Lysis Syndrome (TLS)

## 🧬 Tumor Lysis Syndrome

A life-threatening oncologic emergency requiring immediate recognition and intervention

⚡ Medical Emergency 🕐 Peak Risk: 12-72 hours 🎯 Prevention Key **🏅 Updated to reflect KDIGO 2026 draft AKI/AKD Guideline recommendations** — includes revised uric acid management (PP 3.7.2) and volume expansion without urinary alkalinization (PP 3.7.1).

### 🚨 CRITICAL RECOGNITION ALERT

**TLS kills through hyperkalemia-induced cardiac arrest.** This is a time-sensitive emergency where delay in recognition and treatment can be fatal within hours.

#### 🚨 Immediate Action Required If:

- **Recent chemotherapy (0-7 days)** in high-risk patient
- **Potassium \>6.0 mEq/L** with cardiac changes
- **Rising creatinine** with electrolyte abnormalities
- **Oliguria or anuria** post-chemotherapy
- **Neurological changes** (confusion, seizures)

## 🧬 Definition & Pathophysiology

**Tumor Lysis Syndrome (TLS)** is a constellation of metabolic abnormalities that result from the rapid breakdown of tumor cells, leading to the release of intracellular contents into circulation.

#### 💥 Cellular Destruction

**Trigger:** Chemotherapy, radiation, or spontaneous tumor breakdown

- Massive cell lysis releases intracellular contents
- High-grade malignancies most susceptible
- Peak risk 12-72 hours post-treatment
- Can occur spontaneously in rapidly growing tumors

#### 🧪 Metabolic Consequences

**The "Big Four" Abnormalities:**

- **Hyperuricemia:** Purine metabolism → uric acid
- **Hyperkalemia:** Release of intracellular K+
- **Hyperphosphatemia:** DNA/RNA breakdown
- **Hypocalcemia:** Ca-PO4 precipitation

#### 🫘 Kidney Injury Mechanisms

**Multiple pathways leading to AKI:**

- **Uric acid crystalluria:** Tubular obstruction
- **Calcium-phosphate precipitation:** Nephrocalcinosis
- **Volume depletion:** Poor oral intake, vomiting
- **Direct cytotoxic effects:** Inflammatory cascades

#### ⚡ Life-Threatening Complications

**Immediate threats to life:**

- **Cardiac arrhythmias:** Hyperkalemia (most common cause of death)
- **Seizures:** Hypocalcemia, uremia
- **Acute kidney injury:** Requiring dialysis
- **Multi-organ dysfunction:** Electrolyte chaos

## 📊 Cairo-Bishop Classification Criteria

**Gold standard for TLS diagnosis** - distinguishes laboratory TLS from clinical TLS

### 🧪 Laboratory TLS Criteria

*Two or more of the following within 3 days before or 7 days after chemotherapy:*

| Parameter | Laboratory TLS Threshold | Clinical Significance | Normal Range |
|----|----|----|----|
| **Uric Acid** | ≥8 mg/dL OR 25% increase | Crystal formation, AKI risk | 2.4-6.0 mg/dL |
| **Potassium** | ≥6.0 mEq/L OR 25% increase | Cardiac arrhythmias, death | 3.5-5.0 mEq/L |
| **Phosphorus** | ≥4.5 mg/dL OR 25% increase | Ca-PO4 precipitation | 2.5-4.5 mg/dL |
| **Calcium** | ≤7 mg/dL OR 25% decrease | Neuromuscular irritability | 8.5-10.5 mg/dL |

### 🏥 Clinical TLS Criteria

*Laboratory TLS PLUS one or more of the following:*

#### 🫘 Acute Kidney Injury

- Creatinine ≥1.5× upper limit of normal
- Rising creatinine from baseline
- Oliguria or anuria

#### ⚡ Cardiac Arrhythmia

- New arrhythmias
- ECG changes (peaked T waves)
- Sudden cardiac death

#### 🧠 Seizures

- Hypocalcemia-induced
- Uremia-related
- Electrolyte imbalance

## 🎯 TLS Risk Stratification

Risk assessment guides prevention strategies and monitoring intensity

### 🔴 HIGH RISK (15-20% incidence)

#### 🩸 Hematologic Malignancies

- **Burkitt lymphoma** (highest risk)
- **Acute lymphoblastic leukemia** with WBC \>100,000
- **High-grade NHL** with bulky disease
- **Acute myeloid leukemia** with WBC \>100,000

#### 📊 High-Risk Features

- **WBC count \>100,000/μL**
- **LDH \>2× upper normal**
- **Bulky disease** (\>10 cm lymph nodes)
- **Elevated baseline uric acid** (\>7.5 mg/dL)

**Management:** Prophylactic rasburicase, aggressive hydration, intensive monitoring, nephrology consultation before chemotherapy

### 🟡 INTERMEDIATE RISK (1-5% incidence)

#### 🎗️ Hematologic

- **NHL** with LDH \<2× normal
- **ALL** with WBC \<100,000
- **AML** with WBC 25,000-100,000
- **CLL** with bulky disease

#### 🦴 Solid Tumors

- **Germ cell tumors** (testicular, ovarian)
- **Small cell lung cancer**
- **Breast cancer** with high proliferation
- **Neuroblastoma** in children

**Management:** Allopurinol prophylaxis, adequate hydration, close monitoring, rasburicase if develops laboratory TLS

### 🟢 LOW RISK (\<1% incidence)

#### 🎗️ Hematologic

- **Multiple myeloma**
- **CLL** without bulky disease
- **Low-grade lymphomas**
- **Hodgkin lymphoma**

#### 🦴 Most Solid Tumors

- **Colon cancer**
- **Lung adenocarcinoma**
- **Renal cell carcinoma**
- **Most carcinomas**

**Management:** Standard hydration, routine monitoring, consider allopurinol in high tumor burden

## 🧪 Laboratory Interpretation & Clinical Correlations

### 📈 Typical Laboratory Timeline

| Parameter | Peak Time | Critical Values | Clinical Significance | Emergency Action |
|----|----|----|----|----|
| **Uric Acid** | 6-12 hours | \>12 mg/dL | AKI, crystal formation | Rasburicase immediately |
| **Potassium** | 12-24 hours | \>6.5 mEq/L | Fatal arrhythmias | Cardiac monitoring, stabilization |
| **Phosphorus** | 24-48 hours | \>6.5 mg/dL | Ca-PO4 precipitation | Phosphate binders, avoid calcium |
| **Calcium** | 24-72 hours | \<7.0 mg/dL | Neuromuscular irritability | Careful calcium replacement |
| **Creatinine** | 24-72 hours | 2× baseline | Oliguric AKI | Nephrology consultation, consider RRT |

#### 🚨 Critical Laboratory Alert Values

**K+ \>6.5 mEq/L:** Immediate cardioprotection **Uric acid \>12 mg/dL:** Emergency rasburicase **PO4 \>8 mg/dL:** Ca-PO4 \>70 high risk **Ca \<7 mg/dL:** Monitor for seizures **Creatinine rising:** Early RRT consideration **Severe or refractory acidemia:** Urgent KRT assessment according to response, perfusion, ventilation, and accompanying complications

## ⚡ Hyperkalemia Emergency Management Protocol

**Hyperkalemia is the most immediately life-threatening complication of TLS**

1

#### IMMEDIATE ASSESSMENT (0-5 minutes)

- **12-lead ECG immediately** - Look for peaked T waves, widened QRS
- **Confirm K+ level** - Repeat if \>6.5 mEq/L
- **Continuous cardiac monitoring**
- **IV access** - Large bore for emergency medications

2

#### MEMBRANE STABILIZATION (5-10 minutes)

- **Calcium gluconate 1-2 grams IV** (10-20 mL of 10% solution)
- **Onset: 1-3 minutes, Duration: 30-60 minutes**
- **May repeat every 5-10 minutes** if persistent ECG changes
- **Does NOT lower K+ but prevents arrhythmias**

3

#### POTASSIUM SHIFTING (10-30 minutes)

- **Insulin 10 units IV + D50 25 grams IV** (if glucose \<250 mg/dL)
- **Albuterol 10-20 mg via nebulizer** (or 0.5 mg IV if available)
- **Sodium bicarbonate 50 mEq IV** (if acidotic, pH \<7.20)
- **Effect: 0.5-1.0 mEq/L K+ reduction, Duration: 4-6 hours**

4

#### POTASSIUM ELIMINATION (30+ minutes)

- **Sodium zirconium cyclosilicate (Lokelma) 10 g PO** (preferred)
- **Patiromer (Veltassa) 25.2 g PO** (alternative)
- **Sodium polystyrene sulfonate** (older agent, GI concerns)
- **Urgent dialysis assessment** for severe or refractory hyperkalemia; stabilize and shift potassium promptly while arranging definitive removal

#### ⚠️ Special Considerations in TLS

- **Avoid calcium if PO4 \>6.5 mg/dL** - Risk of calcium-phosphate precipitation
- **Monitor glucose closely** - Insulin can cause severe hypoglycemia
- **Serial K+ monitoring** - Every 1-2 hours until \<6.0 mEq/L
- **Early dialysis consideration** - Don't wait for refractory hyperkalemia

## 💊 Rasburicase (Urate Oxidase) Therapy

**Revolutionary treatment for hyperuricemia** - Rapidly converts uric acid to allantoin

#### 🧬 Mechanism of Action

- **Recombinant urate oxidase** enzyme
- **Converts uric acid → allantoin**
- **Allantoin 5-10× more soluble** than uric acid
- **Bypasses purine catabolism pathway**
- **Produces H2O2 as byproduct**

#### 🎯 Indications

- **High-risk TLS prevention**
- **Treatment of established TLS**
- **Uric acid \>8 mg/dL** with clinical TLS
- **Failed allopurinol therapy**
- **Contraindication to allopurinol**

#### 💉 Dosing & Administration

- **FDA-label dose: 0.2 mg/kg IV daily for up to 5 days** (Elitek package insert)
- **Single-dose / weight-based abbreviated regimens** (e.g., flat 3 mg, 6 mg, or 7.5 mg) are *off-label* dose-finding strategies — not an FDA maximum
- **Dilute in 50 mL normal saline**
- **Infuse over 30 minutes**
- **Repeat daily as needed; reassess uric acid before each dose**

#### ⚡ Clinical Effects

- **Onset: 4 hours**
- **Peak effect: 4-24 hours**
- **Uric acid reduction: 85-95%**
- **Duration: 12-24 hours**
- **Superior to allopurinol**

### 🚨 Critical Contraindications

#### ❌ Absolute Contraindications

- **G6PD deficiency** (risk of severe hemolysis)
- **Pregnancy** (safety not established)
- **Previous severe hypersensitivity**

#### ⚠️ Relative Contraindications

- **History of asthma** (bronchospasm risk)
- **History of atopy** (hypersensitivity risk)
- **Previous allergic reactions**

#### 🧪 G6PD Deficiency - Critical Safety Alert

- **Mechanism:** H2O2 byproduct causes oxidative stress in G6PD-deficient RBCs
- **Result:** Severe hemolysis, methemoglobinemia, can be fatal
- **Testing:** G6PD level MUST be checked before first dose
- **Prevalence:** 10-15% African males, Mediterranean populations
- **Alternative:** Allopurinol + aggressive hydration if G6PD deficient

#### 📊 Monitoring Parameters

**Pre-Administration:**

- G6PD level (mandatory)
- Baseline uric acid
- CBC with hemolysis markers
- Methemoglobin level

**Post-Administration:**

- Uric acid at 4 hours
- CBC for hemolysis
- LDH, haptoglobin
- Methemoglobin if indicated

#### ⚠️ Lower-Risk TLS Management (KDIGO 2026 draft PP 3.7.2)

When rasburicase is **contraindicated** (G6PD deficiency) or **inaccessible**, xanthine oxidase inhibitors (**allopurinol** or **febuxostat**) may be used as alternative urate-lowering therapy for TLS prevention and treatment.

- **Allopurinol 300-600 mg/day:** Blocks new uric acid production (does NOT break down existing uric acid)
- **Febuxostat:** Alternative xanthine oxidase inhibitor, may be used when allopurinol is not tolerated
- **Key limitation:** These agents only prevent NEW uric acid formation — they cannot reduce already-elevated uric acid levels like rasburicase

**Important:** Rasburicase remains the preferred agent for **high-risk TLS** (Rec 3.7.1, 1B). Xanthine oxidase inhibitors are a lower-risk alternative — not a replacement for rasburicase in high-risk patients when it is available and not contraindicated.

## 🩺 Renal Replacement Therapy (RRT) in TLS

**Early consideration of RRT can be life-saving** - Don't wait for traditional dialysis indications

#### 🚨 Absolute Indications

- **Refractory hyperkalemia** (K+ \>6.5 mEq/L despite treatment)
- **Life-threatening arrhythmias**
- **Severe acidosis** (pH \<7.20)
- **Volume overload** with pulmonary edema
- **Uremic complications** (encephalopathy, pericarditis)

#### ⚠️ Relative Indications

- **Creatinine \>4 mg/dL** with oliguria
- **Phosphorus \>8 mg/dL**
- **Symptomatic hypocalcemia** with high PO4
- **Persistent severe TLS with worsening AKI or uncontrolled complications** despite appropriate treatment; an isolated urate concentration is not an automatic dialysis indication
- **Multiple electrolyte abnormalities**

#### 🎯 Modality Selection

- **CRRT preferred** if hemodynamically unstable
- **Intermittent HD** if stable and urgent correction needed
- **Higher efficiency** for rapid electrolyte correction
- **Avoid rapid fluid/osmolality changes**

#### 📊 Monitoring During RRT

- **Electrolytes every 2-4 hours**
- **Continuous cardiac monitoring**
- **Phosphorus removal rate**
- **Volume status assessment**
- **Calcium-phosphate product**

### 💡 RRT Clinical Pearls for TLS

- **Early intervention is better than late:** Consider RRT when 2+ absolute indications present
- **Phosphorus is poorly dialyzed:** Use phosphate-free dialysate, consider extended treatments
- **Calcium supplementation during dialysis:** Monitor Ca×PO4 product carefully
- **Rebound phenomenon:** Electrolytes may worsen after stopping RRT
- **Duration:** Usually 2-7 days until kidney recovery and tumor response

## 🛡️ TLS Prevention Strategies

**Prevention is superior to treatment** - Risk stratification guides intervention intensity

#### 🔴 High-Risk Prevention

- **Rasburicase 0.2 mg/kg IV** - Start before chemotherapy
- **Aggressive IV crystalloid hydration:** 3-4 L/day (if tolerated)
- **No urinary alkalinization** (KDIGO 2026 draft PP 3.7.1)
- **Intensive monitoring:** Q6-8h electrolytes
- **Nephrology consultation** before treatment
- **Admit to monitored setting** (ICU/step-down)

#### 🟡 Intermediate-Risk Prevention

- **Allopurinol 300-600 mg daily**
- **Adequate hydration:** 2-3 L/day
- **Monitor electrolytes** Q12h × 48h
- **Rasburicase if lab TLS develops**
- **Avoid nephrotoxic agents**
- **Consider inpatient monitoring**

#### 🟢 Low-Risk Prevention

- **Maintain hydration:** 1.5-2 L/day
- **Monitor electrolytes** at 24-48h
- **Consider allopurinol** if bulky disease
- **Patient education** on warning signs
- **Outpatient monitoring** acceptable

### 💧 Volume Expansion Protocol (KDIGO 2026 draft PP 3.7.1)

**KDIGO 2026 draft Update:** Volume expansion should be done **WITHOUT urinary alkalinization** using intravenous crystalloids. Urinary alkalinization is **no longer recommended** as part of TLS prevention — it may worsen calcium-phosphate precipitation and has not shown benefit over crystalloid hydration alone. **🚰 Fluid Selection:**

- Intravenous crystalloids (normal saline or balanced crystalloid)
- Avoid potassium-containing fluids
- **No sodium bicarbonate for alkalinization**

**🎯 Targets:**

- Urine output \>2 mL/kg/hr
- Specific gravity \<1.010
- Avoid volume overload

**⚖️ Monitoring:**

- Daily weights
- I/O balance
- Signs of CHF

## ⏰ TLS Monitoring Timeline

Structured monitoring approach based on risk stratification and clinical presentation

**Pre-Chemotherapy (Hours -24 to 0)**\
• Risk assessment and stratification • G6PD testing if rasburicase planned • Baseline labs: CBC, CMP, uric acid, LDH, phosphorus • Hydration initiation • Prophylactic therapy as indicated **0-6 Hours Post-Chemotherapy**\
• Continuous cardiac monitoring if high-risk • Electrolytes at 4-6 hours • Urine output monitoring • Early signs assessment • Rasburicase if indicated **6-24 Hours (Peak Risk Window)**\
• Electrolytes Q6-8h if high-risk • Q12h if intermediate risk • Nephrology consultation if abnormal • Aggressive intervention for lab TLS • Monitor for clinical TLS development **24-72 Hours (Critical Period)**\
• Peak risk for clinical complications • Q8-12h labs if stable • Daily weights and I/O • Assess for AKI development • RRT consideration if indicated **72+ Hours (Recovery Phase)**\
• Daily labs if improving • Q12-24h if stable • Monitor kidney recovery • Plan for discharge • Long-term nephrology follow-up

## 🧮 TLS Risk Assessment Calculator

Comprehensive risk stratification tool incorporating tumor factors, patient characteristics, and laboratory values

Tumor Type: WBC Count (/μL): 75000 LDH (U/L): 800 Baseline Uric Acid (mg/dL): 6.5 Patient Age: 55 Baseline eGFR: 75 Bulky Disease (\>10 cm): Elevated Baseline K+/PO4: Calculating TLS risk assessment...

### 🎯 Essential TLS Learning Points

#### 🚨 Emergency Recognition

- Hyperkalemia most immediately lethal
- Peak risk 12-72 hours post-chemo
- Cairo-Bishop criteria for diagnosis
- High-grade lymphomas highest risk

#### 💊 Rasburicase Revolution

- Converts uric acid to soluble allantoin
- 85-95% uric acid reduction
- Contraindicated in G6PD deficiency
- Superior to allopurinol in high-risk

#### ⚡ Emergency Management

- Calcium for membrane stabilization
- Insulin/D50 + albuterol for K+ shifting
- Avoid calcium if PO4 \>6.5 mg/dL
- Early RRT saves lives

#### 🛡️ Prevention Focus

- Risk stratification guides prevention
- Aggressive hydration essential
- Prophylactic rasburicase in high-risk
- Prevention superior to treatment

#### 🩺 RRT Indications

- Refractory hyperkalemia absolute
- CRRT preferred if unstable
- Early initiation better than late
- Phosphorus poorly dialyzed

#### 📊 Clinical Pearls

- Laboratory vs clinical TLS distinction
- Ca×PO4 product \>70 dangerous
- Tumor burden predicts risk
- Multidisciplinary approach essential

📚 For Educational Purposes Only - Emergency Management Guidelines

© 2025 Andrew Bland MD - All Rights Reserved

### Also on this topic

The same subject at other levels of depth.

- **Interactive case:** [Tumor Lysis Syndrome](https://urinenephrology.org/2025_UDPA_Lectures_Live/cases/case12_enhanced.html)
- **Clinical Mastery deep dive:** [Tumor Lysis Syndrome in Small Cell Lung Cancer](https://urinenephrology.org/mastery/onconephrology/tls-small-cell-lung-cancer.html)
- **Student handout:** [Student Handout: Tumor Lysis Syndrome](https://urinenephrology.org/student-resources/advanced/tumor-lysis-syndrome-student-handout.html)


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