Quantifying the risk of precipitating drug induced crystalluria (XTALURIA)

The growth of crystals in the body often results in pain, damage, and gross harm. Conditions that arise from various kinds of crystal growth are well described qualitatively in the medical and scientific literature (e.g., gout, cystinosis, crystalluria) but there is poor understanding of the discrete chemical mechanisms that give rise to crystal growth in these conditions due to a lack of biorelevant in vitro methods and techniques. The central vision of my research is to develop this fundamental understanding for drug induced crystalluria (the precipitation of drug crystals in the kidney) which causes acute kidney injury.

Precipitating Drug induced Acute Kidney Injury (P-DAKI) is a poorly understood phenomenon that is identified following the appearance of crystals in the urine alongside reduced kidney function and pain. These precipitates can cause direct damage to the kidneys – a sensitive apparatus – which can be irreversible, as such there is a critical need to understand the underlying chemistry of precipitation in the urinary tract to prevent P-DAKI. Fundamentally, precipitates will only nucleate when their solubility limit has been exceeded, but the challenge is finding out where that limit lies, particularly in complex solvents such as urine.

P-DAKI is often presented in the literature as case reports, the lowest level in the hierarchy of evidence. The volume of these reports has warranted comprehensive description in several narrative reviews with little mechanistic explanation. Such that physicians rely on their clinical experience to reduce the risks of and effectively respond to P-DAKI, but this is clearly not enough as recent estimates suggest that P-DAKI occurs in 5% of patients treated with high-dose IV amoxicillin, this lengthens hospital stay and, in some cases, can lead to death. P-DAKI has also been thought to occur in up to 40% of patients treated with oral antiretrovirals such as indinavir. Although atazanavir and darunavir superseded indinavir to reduce this risk, crystalluria still occurs. Only after a public health disaster did P-DAKI receive significant attention. Where in China approximately 300,000 babies fell ill because of melamine spiked baby milk. The causative agent remains a subject of debate.

You will work with Dr Kavanagh in his EPSRC funded lab to understand the underlying pathophysiological mechanism for P-DAKI by combining pharmacokinetic behaviour along with drug physicochemistry in urine.