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Biography

I am a Wellcome Trust Clinical Career Development Fellow and Honorary Consultant Urological Surgeon working at the Churchill Hospital, Oxford. My clinical and research interest is kidney stone disease. 

I studied medicine at Cambridge and Oxford Universities between 1999 and 2005, and since qualification have worked in the Oxford region, entering the Urology training scheme in 2010. In 2011 I was appointed Wellcome Trust Clinical Training Fellow, joining Professor Thakker’s group as a DPhil student. I defended my thesis in 2015 and continued as a clinical academic between 2015 and 2020 as an NIHR Academic Clinical Lecturer in Urology. I took up my current post with the Nuffield Department of Surgical Sciences in 2021. 

Sarah Howles

DPhil, MRCS (Eng), MA (Cantab)


Clinical Research Fellow

Kidney stones are a major clinical and economic health burden. Up to 50% of individuals who have formed a kidney stone will experience a second stone episode within 10 years of presentation and renal stone formers are at increased risk of chronic kidney disease. Unfortunately, current prevention strategies are relatively ineffective and the systemic and renal tubular mechanisms underlying this disease are poorly understood, thereby limiting opportunities to develop novel treatments. My research aim is to increase understanding of the pathophysiology of renal stone disease and to identify new therapeutic targets for the prevention of kidney stone recurrence.

Kidney stone formation may be due to rare monogenic disorders or, more commonly, be the result of a multifactorial process involving both genetic and environmental influences. I study both monogenic and polygenic factors that increase risk of nephrolithiasis. As a DPhil student and post-doctoral scientist, I focused on disorders of the calcium sensing receptor (CaSR) signalling pathway. Loss-of-function mutations of the CaSR cause familial hypocalciuric hypercalcaemia type 1 (FHH1), whilst gain-of-function mutations are associated with autosomal dominant hypocalcaemia (ADH), which is associated with hypercalciuria, and therefore an increased risk of renal stone formation, in ~10% of individuals. However, 35% of cases of FHH and 60% of cases of ADH are not due to CaSR mutations. I demonstrated that FHH type 2 (FHH2) and the new clinical disorder, ADH type 2 (ADH2), are due to loss- and gain-of-function mutations in the G-protein subunit, Gα11, respectively; a protein through which the CaSR signals. I have also demonstrated that FHH3 is due to loss-of-function mutations in the adaptor protein 2 sigma subunit, AP2σ2, due to impaired CaSR endocytosis. Furthermore, I have demonstrated that these signalling defects can be rectified using the CaSR allosteric modulator cinacalcet. These studies have facilitated improved molecular diagnosis of FHH and ADH and enabled better treatment of FHH3.

More recently, to elucidate the common genetic causes of kidney stones, I undertook a collaborative genome-wide association study (GWAS) in a British population and transethnic meta-analysis with a Japanese cohort to include 12,123 stone formers and 417,378 controls. Twenty genetic loci associated with kidney stone disease were identified, seven of which are novel. I predicted that five of the identified loci are linked to genes that influence calcium-sensing receptor (CaSR) signalling and was able to demonstrate that knockdown of one of these genes, DGKD, resulted in biased CaSR signalling. These findings implicate biased CaSR signalling as a common cause of kidney stone disease suggest that the CaSR-signalling pathway may be a novel target for prophylactic kidney stone treatments. 

My current research aims to increase understanding of the role of CaSR-signalling in the pathophysiology of renal stone disease and to elucidate the mechanisms by which common genetic variants identified at GWAS perturb renal tubular function and urinary solute composition. My long-term goal is to establish a precision medicine framework for the management of individuals with kidney stone disease. 

Recent publications

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