HaematologyTier 1Disease (DEADMAN)

Haematological emergencies - tumour lysis syndrome

Description

Massive release of intracellular contents from dying tumour cells outpacing renal clearance
The tetrad: inc K+, inc phosphate, inc urate, dec Ca2+ (secondary, from calcium-phosphate precipitation)
- -> AKI, arrhythmia, seizures, death
Usually 12-72 h after starting cytotoxic therapy, but can be spontaneous in very high-turnover disease
- Spontaneous TLS: urate high, phosphate often normal - the cells reuse released phosphate for continued proliferation
Preventable. The only reliably effective management is anticipating it.

Commonest in Burkitt lymphoma, ALL, high-grade lymphoma, AML with high WCC
Clinical TLS in ~5-10% of high-risk haematological malignancy despite prophylaxis
Increasingly seen with targeted agents in previously low-risk disease - venetoclax in CLL, bispecifics, CAR-T
Rare but recognised in bulky chemo-sensitive solid tumours - small cell lung, germ cell, neuroblastoma

Urate

Nucleic acid -> purine -> hypoxanthine -> xanthine -> uric acid (xanthine oxidase)
Urate is poorly soluble, and least soluble in acid urine
Causes AKI by two mechanisms:
- Crystal-dependent - intratubular urate crystal precipitation, obstruction
- Crystal-independent - renal vasoconstriction, impaired autoregulation, dec renal blood flow, oxidative stress and inflammation
- This is why urate can cause AKI at levels below the crystallisation threshold
Humans lack uricase - hence the drug

Phosphate and calcium

Malignant lymphoblasts contain up to 4x the phosphate of normal lymphocytes
inc phosphate -> calcium-phosphate precipitation -> hypocalcaemia + nephrocalcinosis
Ca x PO4 product >4.6 mmol^2/L^2 -> tissue deposition

Potassium

Risk determinants

Cairo-Bishop definition

Laboratory TLS - >=2 of the following within 3 days before to 7 days after starting therapy:

Clinical TLS = laboratory TLS plus one of:

Risk stratification - this drives everything

Risk	Examples
High	Burkitt, ALL with WCC >100, AML with WCC >100, bulky high-grade lymphoma with LDH >2x ULN, venetoclax ramp-up with bulky nodes/high lymphocyte count, any of the above with renal impairment
Intermediate	AML WCC 25-100, DLBCL/other aggressive lymphoma with high LDH, CLL with high WCC starting targeted therapy
Low	Indolent lymphoma, most solid tumours, myeloma

Monitoring

UEC, calcium, phosphate, magnesium, urate, LDH 6-12 hourly during the at-risk window (high risk: 4-6 hourly)
Continuous cardiac monitoring if K+ high or high risk
Ionised or corrected calcium - albumin falls with hydration
Strict fluid balance and hourly urine output

A. Prophylaxis - risk-stratified

Risk	Approach
Low	Oral hydration, monitor
Intermediate	IV hydration + allopurinol 300 mg daily (from 24-48 h before therapy)
High	IV hydration + rasburicase, inpatient, frequent bloods, nephrology aware

IV hydration 2-3 L/m2/day - the single most effective measure. Aim urine output >100 mL/m2/h
*Do NOT alkalinise the urine - it improves urate solubility but promotes calcium-phosphate and xanthine precipitation*. Abandoned practice
*Do NOT add potassium to fluids*; stop K-sparing diuretics, ACEi/ARB, NSAIDs, nephrotoxins
Prephase/debulking (steroid, low-dose cyclophosphamide, or a venetoclax ramp-up) reduces the lysis burden

B. Urate-lowering

Agent	Action	Notes
Allopurinol	Xanthine oxidase inhibitor - prevents new urate formation, does nothing to urate already present	Renally dose-adjust. Accumulated xanthine can itself crystallise. Interacts with azathioprine/6-MP
Rasburicase	Recombinant uricase - degrades existing urate to allantoin (5-10x more soluble)	Onset within 4 h. First line for high risk and for established TLS
Febuxostat	Alternative xanthine oxidase inhibitor	No renal dose adjustment; used if allopurinol intolerant

*Rasburicase contraindications*
- G6PD deficiency - hydrogen peroxide is generated -> haemolysis and methaemoglobinaemia. Screen high-risk ethnic groups; do not delay treatment in an emergency if screening is unavailable - discuss
- Pregnancy, breastfeeding
*Samples for urate after rasburicase must go on ice and be processed immediately* - the enzyme keeps degrading urate in the tube -> falsely low result
Do not combine allopurinol with rasburicase routinely - allopurinol reduces the substrate rasburicase acts on

C. Treating established metabolic derangement

Hyperkalaemia - the immediate threat. Calcium gluconate (if ECG changes), insulin-dextrose, salbutamol, resonium/sodium zirconium; dialysis if refractory
Hyperphosphataemia - oral phosphate binders, hydration; dialysis if severe
Hypocalcaemia - *treat only if symptomatic*
- Giving calcium into a high phosphate load worsens calcium-phosphate deposition and nephrocalcinosis
Hyperuricaemia - rasburicase

D. Renal replacement therapy - low threshold

Indications: refractory hyperkalaemia, severe hyperphosphataemia, volume overload, oliguric AKI, symptomatic hypocalcaemia with high phosphate
Continuous modalities preferred where solute generation is ongoing - rebound after intermittent HD is common
Involve nephrology and ICU before the patient needs them, not when

Burkitt lymphoma, ALL, high-grade B-cell lymphoma, AML/CML blast phase
Venetoclax initiation in CLL (the reason for the 5-week ramp-up)
CAR-T cell therapy, bispecific antibodies, obinutuzumab, immune checkpoint inhibitors
Bulky chemosensitive solid tumours - small cell lung, germ cell, neuroblastoma, hepatoblastoma
Corticosteroids alone in lymphoid malignancy (a single dose of dexamethasone can precipitate it)
Pre-existing CKD, volume depletion, urate nephropathy, gout

Fully preventable in most cases with risk stratification, hydration and rasburicase
Established clinical TLS: mortality ~15%, higher with AKI needing dialysis
Most patients who require dialysis for TLS recover renal function - it is usually reversible
Risk window closes once cytoreduction is achieved (typically 3-7 days)

Complications

Sudden cardiac death from hyperkalaemia - the commonest immediate cause of death
AKI - urate nephropathy, nephrocalcinosis, obstruction
Seizures, tetany, QT prolongation from hypocalcaemia
Metabolic acidosis, fluid overload
Delay to definitive cancer treatment - itself a cause of worse outcome
Rasburicase: haemolysis, methaemoglobinaemia, anaphylaxis, antibody-mediated loss of efficacy on re-exposure

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