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Fiona Karet

Renal tubular homeostasis in health and disease

My group's work lies in the area of renal tubular function and its associated diseases, many of which are inherited and most of which are rare but confer a major health burden on both patients and providers.

Our laboratory research has recently been focused on three areas: the molecular physiology and genetics of the human distal nephron, particularly as it relates to acid-base homeostasis and renal stone formation; molecular mechanisms associated with uromodulin (UMOD) nephropathy; and characterization of the human urinary exosome as a potential functional player (the first being maintenance of urinary sterility) and source of biomarkers.

Acid-base homeostasis is fine-tuned by highly polarized intercalated cells in the collecting duct of the nephron (the functional unit of the kidney), where multi-subunit proton pumps on the luminal surface function in tandem with the basolateral anion exchanger AE1. Genes encoding these proteins are mutated in inherited distal renal tubular acidosis (RTA). Our studies have identified various determinants of AE1's basolateral residency that are seated in the protein's C-terminal tail, and involve interactions with GAPDH and the sodium pump. Disruption of these interactions leads to dRTA. We have also shown in human and murine studies that some subunits of the specialised proton pump have extra-renal sites of action including the inner ear and the nasal mucosa, where they contribute to normal hearing and sense of smell.

In contrast, UMOD nephropathy (now called ADTKD) is caused by toxic build-up of mutated uromodulin within loop of Henle cells, a dominant-negative mechanism leading to renal fibrosis. We have built a molecular toolkit to test mutant gene silencing as a potential therapeutic approach.

Having previously demonstrated a role for urinary exosomes in maintenance of urinary sterility, our current characterization of human urinary exosomes focuses on their quantification, biomarker development in tubular disorders and function in recurrent urinary tract infections (UTIs).

Our laboratory work is complemented by clinic-based studies emanating from the Cambridge Renal Genetic and Tubular Disorders service that I lead, where patients with a variety of such disorders are investigated and managed. Current clinical studies focus upon patient cohorts with Polycystic Kidney Disease, Gitelman Syndrome and recurrent renal stone disease. We are also developing the technology suitable for a hand-held potassium sensing device.

 

Karet lab

Key papers

Day C, Søpstad S, Ma H, Jiang C, Nathan A, Elliott SR, Karet Frankl FE & Hutter TF. Impedance-based sensor for potassium ions. Analytica Chimica Acta (in press) (2018).

El-Damanawi R, Lee M, Harris T, Mader L, Bond S, Pavey H, Sandford RN, Wilkinson IB, Woznowski P, Ben-Shlomo Y, Karet Frankl FE & Hiemstra TF.A Randomised Controlled Trial of High versus Ad Libitum Water Intake in Patients with Autosomal Dominant Polycystic Kidney Disease: Rationale and Design of the DRINK Feasibility Trial. BMJ Open (in press) (2018).

Gracia TR, Wang X, Su Y, Norgett EE, Williams TL, Moreno P, Micklem G & Karet Frankl FE. Urinary exosomes contain microRNAs capable of paracrine modulation of tubular transporters. Sci. Rep. 7:40601 (2017).

Su Y, Hiemstra TF, Yan Y, Li J, Karet HI, Rosen L, Moreno P and Karet Frankl FE. PDLIM5 links kidney anion exchanger 1 (AE1) to ILK and is required for membrane targeting of kAE1. Sci. Rep. 7:39701 (2017).

Blanchard A, Bockenhauer D, Bolignano D,Calò LA, Cosyns E, Devuyst O, Ellison DH, Karet Frankl FE, Knoers NVAM, Konrad M, Lin S-H, R. Vargas-Poussou R (all joint, listed alphabetically). Gitelman syndrome: Consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int. 91:24-33 (2017).

Robinson C & Karet Frankl FE. Magnesium Lactate in the Treatment of Gitelman Syndrome – Patient Reported Outcomes. Nephrol. Dialysis Transplant 32:508-512 (2017).

Karet Frankl FE, Coward RJ, Gallagher H, Hilton R, Loud F, Ormandy K & Woolf AS. U.K. National Renal Research Strategy, UKKRC. ISBN 978-1-5262-0191-1 (2016).

Karet Frankl FE. The importance of being rare. Lancet 388:632 (2016).

Stewart AP, Sandford RN, Karet Frankl FE & Edwardson JM. Pathogenic uromodulin mutations result in premature intracellular polymerization. FEBS Lett. 89, 89-93 (2015).

Su Y, Al-Lamki RS, Blake-Palmer KG, Best A, Zhou A & Karet Frankl FE. Physical and functional links between kidney anion exchanger 1 and the sodium pump J. Am. Soc. Nephrol. 6, 400-9 (2015).

Hiemstra TF, Charles PD, Gracia T, Hester SS, Gatto L, Al-Lamki R, Floto RA, Su Y, Skepper JN, Lilley KS & Karet Frankl FE. Human urinary exosomes as innate immune effectors. J. Am. Soc. Nephrol. 25, 2017-27 (2014).

Berry MR, Robinson C & Karet Frankl FE. Unexpected clinical sequelae of Gitelman Syndrome: Hypertension in adulthood is common and females have higher potassium requirement. Nephrol Dial Transplant 28, 1533-1542 (2013).

Fiona Karet

Professor Fiona Karet

Professor of Nephrology; Honorary Consultant in Renal Medicine

Department: Medical Genetics

Contact: fek1000@cam.ac.uk

01223 762 812 (PA)

 

Plain English

Our kidneys are responsible for keeping many substances in the body in balance (such as salt, potassium, calcium and acid) and, when any of these goes wrong, disorders including Gitelman syndrome, hypertension or recurrent kidney stones can result. Our research aim is to characterize the genes that are mutated in these diseases, and to understand their underlying function in the kidney. A second aim focuses on small packages termed 'exosomes' that are released by kidney cells into urine that we have discovered kill bacteria, and may also have potential for diagnosis of kidney malfunction. We also study common inherited kidney disorders such as polycystic kidney disease.

Group members

Susana Borja Boluda · Liz Norgett · Caroline Robinson · Andrew Stewart · Ya Su · Tim Williams

Funding

Kidney Research UK

NIHR Cambridge Biomedical Research Centre

NIHR Rare Diseases Translational Research Collaboration (TRC)