Cairo-Bishop Criteria (2004) — Laboratory & Clinical TLS [1]

Laboratory TLS: Requires ≥2 of the following abnormalities within 3 days before or 7 days after chemotherapy initiation:

Clinical TLS: Laboratory TLS + ≥1 clinical manifestation: - Acute kidney injury: Cr ≥1.5 × upper limit normal - Cardiac arrhythmia or sudden death - Seizure - Other clinical complications of organ dysfunction

Key Limitation of Cairo-Bishop: Criteria were developed for chemotherapy-initiated TLS; spontaneous TLS (from tumor necrosis before chemo) is not captured but clinically important (see below).

Tumor-Specific Risk [1]

High-Risk Tumors (30–50% incidence): - Burkitt lymphoma — most common, highest risk - Acute lymphoblastic leukemia (ALL) — children especially high-risk - Acute myeloid leukemia (AML) with high WBC (>100,000) - Lymphoblastic lymphoma - Primary CNS lymphoma

Intermediate-Risk Tumors (5–30%): - Diffuse large B-cell lymphoma (DLBCL) — varies by bulk and stage - Chronic lymphocytic leukemia (CLL) — especially with targeted therapy (venetoclax) - Hodgkin lymphoma — less common than NHL - Small lymphocytic lymphoma (SLL) - Acute leukemia with lower tumor burden

Low-Risk Tumors (<5%): - Solid tumors (lung, colorectal, breast, etc.) - Low-grade lymphomas (follicular, marginal zone) - Chronic myeloid leukemia (CML) — except blast phase

Patient-Specific Risk Factors

The Metabolic Cascade [1]

Tumor cell death (rapid, massive)
    ↓
Release of intracellular contents:
├─ Potassium (K) — from cytoplasm (ICF K++ ~140 mEq/L)
├─ Phosphate (PO4) — from nuclei, mitochondria
├─ Uric acid — from DNA/RNA nucleotides
└─ Other: myoglobin, LDH, urea, creatinine
    ↓
Acute metabolic derangements:

1. HYPERKALEMIA (K >6.0 mmol/L)
   └─ Mechanism: K+ influx from dying cells exceeds renal excretion capacity
   └─ Effect: Cardiac arrhythmias (peaked T-waves, AV block, VF), muscle weakness
   └─ Timeline: Hours to days

2. HYPERPHOSPHATEMIA (PO4 >4.5 mg/dL)
   └─ Mechanism: PO4 release + reduced renal excretion (if AKI)
   └─ Secondary: Ca × PO4 product ↑ → precipitation in soft tissues
   └─ Effect: Hypocalcemia (symptomatic if severe: tetany, seizure)

3. HYPOCALCEMIA (Ca <7.0 mg/dL)
   └─ Mechanism: Secondary to Ca × PO4 deposition; also PO4 chelation
   └─ Effect: QT prolongation, tetany, seizures (IF symptomatic)
   └─ **KEY POINT:** Avoid treating asymptomia hypocalcemia (worsens CaPO4 precipitation)

4. HYPERURICEMIA (uric acid >8.0 mg/dL)
   └─ Mechanism: Massive nucleic acid catabolism → xanthine → uric acid
   └─ Renal toxicity: Uric acid crystals precipitate in distal tubules/collecting duct
   └─ Cascade: Crystal nephropathy → tubular obstruction → ↑ back-pressure → AKI
   └─ **Timing:** Uric acid rise lags K, PO4 (peaks day 2–3)

Uric Acid Cascade (Detailed)

Why uric acid causes AKI:

1. Solubility problem: Uric acid poorly soluble in tubular fluid (pKa 5.75)
2. Low urine pH → more undissociated uric acid → precipitates
3. High urine uric acid concentration (from massive release) + dehydration → crystal formation
4. Xanthine & alloxuric crystals also precipitate (if on allopurinol)
5. Tubular obstruction → back-pressure on glomerulus → prerenal AKI
6. Oxidant stress from uric acid metabolism → tubular cell injury

Risk Stratification & Prevention Strategy

Newly diagnosed high-risk hematologic malignancy
    ↓
RISK ASSESSMENT (see table above):
├─ HIGH-RISK patient + HIGH-RISK tumor → Aggressive prevention
├─ HIGH-RISK patient + INTERMEDIATE tumor → Standard prevention
└─ LOW-RISK patient + LOW-RISK tumor → Minimal prevention
    ↓
INITIATE PREVENTION BEFORE FIRST CHEMO DOSE:

Component 1: Aggressive IV Hydration [1]

Goal: Maximize urine output & dilute intratubular toxic substances.

Rationale for NS: Normal saline is preferred over hypotonic fluids because: - Maintains osmolality → reduces cellular water shift → limits hyperkalemia - Maintains renal perfusion pressure - Avoids hyponatremia (which can occur with ½ NS + SIADH from malignancy)

Complications of aggressive hydration: - Volume overload → pulmonary edema, HTN (especially in AML with leukostasis risk) - Hyponatremia (if dilute fluids used) → seizure risk - Electrolyte wasting (from forced diuresis)

Assessment: Daily weights, JVD, lung auscultation; adjust if volume overload develops.

Component 2: Xanthine Oxidase Inhibitor — Allopurinol

Allopurinol (Zyloprim): Blocks conversion of hypoxanthine → xanthine → uric acid

Dosing: - Standard: 300 mg daily (in high-risk) or 600 mg daily (very high-risk) - Renal dose: Reduce dose if eGFR <30 (allopurinol itself nephrotoxic in renal failure) - Onset: 24–48 hours (slow; starts blocking NEW acid production) - Limitation: Does NOT clear existing uric acid; slow onset makes it NOT ideal as monotherapy

Mechanism of AKI with allopurinol: Xanthine crystals (intermediate product) also precipitate in tubules — “converting one crystal problem to another”

Current role: Allopurinol is secondary agent now; rasburicase (urate oxidase) is preferred.

Component 3: Urate Oxidase (Rasburicase) — FIRST-LINE [1]

Rasburicase (Elitek): Recombinant urate oxidase; catalyzes conversion of uric acid → allantoin (5–10× more soluble than uric acid)

Mechanism: Uric acid → [urate oxidase] → Allantoin + H2O2 (H2O2 rapidly degraded by catalase)

Dosing:

DOSE:
├─ Standard: 0.2 mg/kg IV over 30 minutes
├─ Range: 0.15–0.25 mg/kg (single or divided doses)
├─ Repeat: Usually single dose sufficient; repeat if uric acid remains >8 mg/dL at 4 hr
└─ Infusion time: ≥30 minutes (do NOT push)

TIMING:
├─ Initiate: BEFORE chemotherapy (12–24 hr before preferred)
├─ Can use: Up to 7 days post-chemo if uric acid rising
└─ Effect: Rapid (uric acid begins to fall within 4 hr; half-life of urate oxidase ~6 hr)

Efficacy: Rasburicase reduces serum uric acid by 80–90% within 4 hours [1]

Advantages over allopurinol: 1. Rapid onset (hours vs. days) 2. Clears existing uric acid (vs. allopurinol which only blocks new production) 3. Does NOT produce xanthine crystals (allantoin is soluble) 4. Preferred for immediate TLS risk

Critical Contraindications:

Cost: ~$500–$1000 per dose (significantly more expensive than allopurinol); often requires prior authorization

Laboratory monitoring after rasburicase: - Cannot measure uric acid for ~4–6 hours post-infusion (enzymatic assay reads as low even if acid present — assay is blocked) - Plan labs accordingly; draw uric acid BEFORE rasburicase or >4 hr after

Component 4: Phosphate Binders (Targeted Approach)

If hyperphosphatemia develops (PO4 >4.5 mg/dL):

Strategy: If initial PO4 <5 mg/dL, defer binders; recheck in 4 hours. If PO4 rising rapidly, consider CRRT early.

Component 5: Allopurinol as Adjunct (When to Use)

Current role of allopurinol (2026): - Intermediate-risk patients without absolute need for rasburicase - Cost considerations (if rasburicase unavailable or not covered) - Chronic prevention (after acute TLS phase controlled, allopurinol for maintenance)

Do NOT use allopurinol as monotherapy for high-risk patients expecting high tumor burden.

Clinical Scenario: Day 1–2 Post-Chemo, Labs Show Cairo-Bishop Positive

Patient with TLS-level labs (K 6.5, PO4 5.0, uric acid 9.0, Ca 6.8)
    ↓
IMMEDIATE ASSESSMENT:
├─ Continuous cardiac monitoring (peaked T-waves, AV block?)
├─ Airway/breathing/circulation assessment
├─ Urine output assessment (oliguria = bad sign)
└─ Check previous baseline labs (acute vs. chronic TLS pattern)
    ↓
HYPERKALEMIA FIRST — MOST URGENT:

CALCIUM GLUCONATE: 10 mL of 10% solution (10 grams) IV over 2–5 min
└─ Can repeat q5–10 min if ECG remains abnormal
└─ Target: Normalize ECG

INSULIN + DEXTROSE:
├─ Insulin: 10 units IV push
├─ Dextrose: 25 grams (50 mL of 50% solution) IV
└─ Recheck K+ in 20 min; repeat if K still >6.0

ALBUTEROL: 10–20 mg nebulized over 10 min OR 0.5 mg IV

Hypocalcemia (Ca <7.0 mg/dL) detected
    ↓
Symptomatic? (tetany, seizures, QT >500 ms)
    ├─ YES → Give calcium gluconate 10 mL of 10% IV slowly (1–2 min)
    │         Can repeat q5 min if symptoms persist
    └─ NO → OBSERVE; Do NOT treat
    ↓
Regardless of Ca level:
├─ Lower phosphate (see Component 4 above): Phosphate binders or CRRT
├─ Check Ca × PO4 product (goal <60–70)
└─ Recheck Ca in 4 hr; treat only if becomes symptomatic

Uric acid nephropathy suspected (high UA, AKI, low UOP, muddy urine)
    ↓
IMMEDIATE:
├─ Aggressive NS hydration (2–3 L/m²/day) if not already
├─ Rasburicase 0.2 mg/kg IV if not yet given
├─ Hold allopurinol (if on it) until post-rasburicase
└─ Alkalinize urine?
    └─ TRADITIONAL: Sodium bicarbonate to target urine pH >6.5
    └─ MODERN: NOT recommended due to PO4 precipitation risk
    └─ CURRENT: Rare indication; CRRT preferred
    ↓
Monitor:
├─ Uric acid level at 4 hr post-rasburicase (expect drop to <3 mg/dL)
├─ Cr trend: Expect improvement over 24–48 hr if urate oxidase working
└─ UOP: Target 100–200 mL/hr with hydration
    ↓
If improving:
└─ Continue hydration; repeat rasburicase PRN if UA rises >8 again
    ↓
If worsening (Cr still rising, UOP <50 mL/hr):
└─ CRRT indicated (see below)

When to Initiate Dialysis

Indications for dialysis in TLS:

CRRT vs. Hemodialysis in TLS [1]

Recommendation: CRRT is preferred in TLS due to superior hemodynamic tolerance and continuous solute clearance.

CRRT modality in TLS: - CVVHD (continuous veno-venous hemodialysis) — if blood flow adequate; dialysate rate 1–2 L/hr - CVVHDF (hemodiafiltration) — combines dialysis + convection; slightly superior clearance - Avoid SCUF alone — insufficient solute clearance; need dialysis component

Spontaneous TLS (Before Chemotherapy)

Definition: TLS occurring from natural tumor necrosis without chemotherapy initiation.

Incidence: 5–15% of high-risk tumors (Burkitt, ALL, high-grade NHL)

Clinical presentation: Patient presents with newly diagnosed malignancy already meeting Cairo-Bishop criteria; Cr elevated from outset

Management: Identical to chemotherapy-induced TLS; aggressive hydration, rasburicase, dialysis PRN. Begin chemo when metabolically stable.

Prognosis: Often worse than chemotherapy-induced TLS (massive tumor burden); higher dialysis requirement.

TLS from Targeted Therapy (e.g., Venetoclax in CLL)

Emerging issue: Targeted agents (especially venetoclax, a BCL-2 inhibitor) can trigger massive TLS comparable to chemotherapy.

Risk factors: CLL with high tumor burden, early in venetoclax treatment (first week)

Prevention & management: Same as chemotherapy-induced TLS; rasburicase, aggressive hydration, early dialysis if needed.

Recovery from TLS-Associated AKI

Prognosis: 70–80% of TLS patients who survive acute episode have complete renal recovery (Cr returns to baseline within weeks to months).

Predictors of persistent renal dysfunction: - Severity of initial AKI (Cr >3–4 with dialysis dependence) - Duration of oliguria (>5–7 days) - Baseline CKD - Concurrent nephrotoxic agents (especially cisplatin in ALL protocols)

Chronic CKD in TLS Survivors

Incidence of lasting CKD: 10–20% of TLS survivors

Mechanism: - Residual tubular damage (uric acid crystal deposition) - Contrast-induced nephropathy (if imaging done acutely) - Cisplatin co-exposure (in ALL/AML regimens)

Management: Annual Cr/eGFR assessment in TLS survivors; aggressive CKD prevention (BP control, ACE-I/ARB, avoid NSAIDs).