Tumour lysis syndrome

Tumour lysis syndrome is for whatever reason a greatly beloved metabolic syndrome, which the college examiners seem to dredge it up at a rate greatly out of proportion to its actual hospital incidence. Hsu et al (2004) reported its incidence as 1% among cancer patients with renal failure. However, one might make the argument that this 1% will end up in the ICU. The medical oncology services essentially act as a filter to identify and concentrate exotic metabolic disturbances for CICM fellows to marvel at. Moreover, we may be seeing more and more of this in the near future, as various novel mibs and mabs come on to the market (Howard et al in 2015 noted that the more effective the treatments become at killing tumours, the more tumour lysis syndrome we will end up with).

This topic has come up several times in the SAQs:

• Question 19.2 from the second paper of 2019
• Question 25 from the second paper of 2017
• Question 13.3 from the first paper of 2015
• Question 8 from the second paper of 2014
• Question 27 from the first paper of 2013
• Question 2 from the second paper of 2009

Generally, the college seems to ask for a definition of the syndrome, a list of differentials, risk factors, preventative strategies, management approaches and a pathophysiologic rationale for these therapies.

Of the published literature, the best short introduction is probably the 2007 review by Tiu et al, from the Seminars in Thrombosis and Hemostasis. It is free on ResearchGate.  A good NEJM review article is also available for the time-rich exam candidate.

Definition of tumour lysis syndrome

Tumour lysis syndrome is a metabolic disorder characterized by the following tetrad of abnormalities:

• Hyperuricemia
• Hyperphosphatemia
• Hyperkalemia
• Hypocalcemia

These abnormalities are brought about by rapid tumor cell turnover.  The current classification system demands at least two of the abovementioned electrolyte abnormalities 2-7 days after the commencement of cancer therapy. Many patients develop these laboratory features, but these days few of them go on to develop the clinical syndrome which involves renal failure with urate crystals in the tubules. 

The pathophysiology of this syndrome can be summarised as follows:

• Rapid "turnover" of tumour cells basically means that they live and die at an accelerated rate. In the context of antineoplastic therapy, the cellular death rate is particularly increased.
• The dead cells release their contents into the bloodstream.
• The lab-detectable components of this contents classically consist of potassium, phosphate and LDH. Also, urate is detected, as it comes from purine metabolism.
• The clinical effects are mainly due to renal failure caused by urate crystals and due to the cardiovascular consequences of metabolic acidosis and hyperkalemia.

On hyperkalemia of tumour lysis syndrome:

The intracellular concentration of potassium is in the range of 70-100mmol/L, as it is the dominant intracellular cation. The breakdown of cell membranes allows the release of this highly potassium-rich soup into the systemic circulation. This gives rise to the earliest clinical manifestations of the syndrome (cardiac arrhythmias, ECG changes, cardiac arrest etc).

One needs to mention pseudohyperkalemia of malignancy here. The presence of haematological malignancy generally means a high white cell count; these extra cells are immature blasts which are structurally unsound, being exempt from normal cellular quality control mechanisms. The very act of aspirating these fragile cells into a syringe or vacutainer may give rise to wholesale cellular destruction by shear stress. The result is a falsely elevated potassium level. Kintzel and Scott presented a case report of this (2012) where the potassium level was 9.8mmol/L in the badly lysed sample and 4.1 mmol/L in the heparinised tube.

On the hyperuricaemia of tumour lysis syndrome:

In brief:

• Nucleic acids from tumour DNA which end up in the systemic circulation are usually metabolised by the liver in a process catalysed by xanthine oxidase, which (in case you care) is one of the few places in your body where a molybdenum atom might find gainful employment.  
• The final product of the purine metabolism pathway is urate.
• Urate is usually cleared renally, in a process which is some balance of reabsorption and secretion. There is usually no major excretion problem in tumour lysis syndrome - the main issue is overproduction. 
• An overabundance of urate gives rise to renal failure when tubular contents is concentrated as a part of the normal countercurrent mechanism; tubular urate concentration exceeds a certain saturation point and urate crystals precipitate in the tubule.
• Volume depletion makes this situation worse by increasing the tubular resorption of water, thereby concentrating the urate even more. 

Humans seem to be uniquely lacking in the next normal step of the urate metabolic pathway, which is to oxidise the urate into allantoin (a much more soluble molecule). Urate oxidase or uricase is available to all mammals other than primates ever since the gene which encodes it was wiped out by a nonsense mutation in the common primate ancestor (Oda et al, 2002; this thing probably looked a bit like a gibbon).  Ever since then, primates have lived with a urate level about 50 times higher than most other mammals, enjoying the delights of gout and tumour lysis syndrome.

On the dangers of raised phosphate in tumour lysis syndrome

As is discussed elsewhere, it is incredibly hard to be killed by a raised phosphate. For fatal complications, you are literally looking at levels which exceed normal laboratory values by 10-20 times. However, as the phosphate rises moderately there would still be some unpleasant features:

• Tetany (due to hypocalcemia)
• Confusion
• Decreased level of consciousness
• Hypotension
• Atrial arrhythmias
• Acute phosphate nephropathy

In tumour lysis syndrome, the rise in phosphate is defined as a 25% increase from baseline, which is a fairly low bar. At that level, there would be few clinical features. The main problems would really be due to the associated hypocalcemia, which has implications for the myocardium,  smooth muscle tone and the clotting cascade.

The pathophysiological causes of this rise in phosphate are a combination of increased release and impaired excretion.  Release from destroyed tumour cells is an important component because phosphate is an important intracellular buffer and intracellular phosphate concentrations may be quite high in some cells, in the range of 20mmol/L.  On top of that, it is complexed with many proteins and lipids (hello, phospholidpid). As these undergo catabolism, phosphate ions are liberated. Everything is then exacerbated by the urate nephropathy, as it is very hard to maintain a disastrously high phosphate level with normal working kidneys.

Risk factors for tumour lysis syndrome

The NEJM article contains within it Table 2, which lists the following risk factors:

• Large amount of tumour mass
• Organ infiltration by tumour
• Bone marrow involvement
• Pre-existing renal disease
• High mitotic tumour activity
• The tumour's high sensivity to the cancer therapy
• High intensity of cancer therapy
• Highly effective targeted therapy (Howard et al, 2015 - rates of TLS are as high as 53% with alvocidib for acute leukaemia).
• Dehydration
• Acidic urine
• Nephrotoxin exposure
• Wanton and unchecked potassium and phosphate replacement
• Barriers to the clearance of uric acid
• Pre-existing gout

One might also add that some drugs (eg. pyrazinamide and nicotinic acid or Vitamin B3) inhibit the tubular URAT1 reabsorption transporter and therefore promote higher tubular urate levels. 

Preventative measures to protect patients against tumour lysis syndrome

You'd want to take the following preventative steps:

• Anticipate tumour lysis syndrome. You can predict the risk of developing TLS with various scoring systems, eg the Penn Predictive Score (Mato et al, 2006). Pre-chemotherapy creatinine elevation and serum urate levels (as well as male gender for some reason) were strongly predictive of TLS, and this can be used to target preventative therapy
• Adequate hydration mainly to prevent hypovolemia is usually described, but few authors give an actual fluid prescription. Tiu et al recommend at least 48 hours but does not offer an hourly rate or total volume; instead they suggested to aim for a urine output of 150-300ml/hr (i.e. 2-4ml/kg/hr). The fluid prescription is usually a bit weird (remember, these papers are not usually written by ICU specialists) - the literature lists such monstrous concoctions as 5% dextrose with 100mmol of sodium bicarbonate per litre, or half-saline (0.45% NaCl).
• Alkalinisation of urine is usually also performed, to prevent crystallisation of urate. This is done by using oral or IV bicarbonate. Generally, getting the serum bicarbonate to over 27-28 mmol/L should promote a vigorous renal clearance of any additional bicarbonate, as this is the usual homeostatic threshold for proximal tubular reabsorption of bicarbonate.
• Cessation of nephrotoxins:  intelligently stopping the ACE inhibitor and potassium-sparing diuretic, that sort of thing.
• Electrolyte monitoring and intelligent electrolyte replacement will be required for a week or two.
• Xanthine oxidase inhibitors  to inhibit the production of urate works as a premedication, but is largely ineffective once the urate is already high (which makes sense). Options include allopurinol and febuxostat (the latter may be approved for human use in the near future, if it isn't already).

Management strategies for established tumour lysis syndrome:

• Recombinant urate oxidase to enhance clearance of urate. Urate will also oxidise spontaneously, but the reaction is very slow at body temperature, taking hours. When catalysed by the enzyme, it takes seconds. Rasburicase is the usual drug. It is a recombinant enzyme drived from a genetically modified strain of Saccharomyces cerevisiae. It is a 34-Kd tetramer protein; usually you will need 0.15-0.20mg/kg of it, for 5-7 days. The main problem with this drug (apart from the substantial cost) is the tendency to form antibodies. It is after all a xenobiotic compound: you are essentially injecting the patient with purified fungal protein totally alien to the human organism. Almost 15% of patients will develop antibodies, and then will have some sort of hypersensitivity reaction the next time you give them rasburicase. Overall, it is kept in reserve until it is absolutely necessary. Attempts to PEGylate the enzyme (i.e. complex it with polyethylene glycol in an effort to reduce its antigenicity) are under way, and porcine "puricase" may soon become available. 
• Forced alkaline diuresis as distinct from the abovementioned "adequate hydration"  is a strategy which adds diuretics to the mix, increasing urine output. This has generally fallen out of favour, as frusemide has a tendency to decrease renal secretion of urate by interfering with the URAT1 transporter (Yamamoto et al, 2001)
• Haemodialysis  is ultimately the most immediately effective solution for the whole host of metabolic abnormalities. Urate potassium and phosphate are washed out easily with a CVVHDF circuit. One may need to rescue the situation with CRRT acutely, while waiting for the rasburicase and allopurinol to work. Rasburicase will not be cleared (the molecule is too large).