Genetic and molecular characterisation of sodium reabsorption by thiazide-sensitive pathways in the kidney
Lead Research Organisation:
University of Nottingham
Department Name: Div of Therapeutics & Molecular Medicine
Abstract
High blood pressure (hypertension) affects one in three adults in the UK and causes heart attacks and strokes. Thiazide water tablets (diuretics) are one of the most widely used and cost-effective group of medicines to treat hypertension. They work by causing the kidneys to lose sodium salt into the urine but are usually only partly effective in lowering blood pressure and can cause debilitating side effects, such as confusion, falls and seizures due to low sodium levels in the blood (hyponatraemia).
We want to understand how thiazides cause sodium loss at a molecular level so that we may avoid their use in those at risk of hyponatraemia and also inform the design of new thiazide-like medicines which are more effective at lowering blood pressure and less likely to cause low sodium levels.
To do this we will conduct genetic studies and analyse blood and urine samples from two unique patient groups. The first group have a very rare, inherited and exquisitely thiazide-responsive syndrome of hypertension, known as Gordon syndrome but who do not carry mutations established for this condition. The second group of patients are those admitted to hospital with thiazide-induced hyponatraemia. Nine hospitals throughout the UK will help us recruit hyponatraemic patients and initial genetic results from Nottingham (candidate gene seqeuncing) are encouraging and require replication.
The role or function of identified genes from both patient groups will be studied in our laboratories. We will also investigate whether more subtle abnormalities in these genes may contribute to blood pressure and blood sodium regulation in the general population by collaboration with the UK Biobank.
We want to understand how thiazides cause sodium loss at a molecular level so that we may avoid their use in those at risk of hyponatraemia and also inform the design of new thiazide-like medicines which are more effective at lowering blood pressure and less likely to cause low sodium levels.
To do this we will conduct genetic studies and analyse blood and urine samples from two unique patient groups. The first group have a very rare, inherited and exquisitely thiazide-responsive syndrome of hypertension, known as Gordon syndrome but who do not carry mutations established for this condition. The second group of patients are those admitted to hospital with thiazide-induced hyponatraemia. Nine hospitals throughout the UK will help us recruit hyponatraemic patients and initial genetic results from Nottingham (candidate gene seqeuncing) are encouraging and require replication.
The role or function of identified genes from both patient groups will be studied in our laboratories. We will also investigate whether more subtle abnormalities in these genes may contribute to blood pressure and blood sodium regulation in the general population by collaboration with the UK Biobank.
Technical Summary
Aims:
To advance understanding of the thiazide-sensitive pathway(s) of sodium reabsorption by studying two clinical manifestations of dysregulation of this pathway: Gordon syndrome (GS) and Thiazide-Induced Hyponatraemia (TIH).
Objectives
1.To establish the genetic basis for Gordon syndrome (GS) in patients without mutation in WNK1/4, CUL3 or KLHL3 mutation and explore phenotype-genotype correlations within GS
2.To build on pilot work in Nottingham to establish the genetic basis for predisposition to severe TIH and detailed description of the TIH phenotype
3.To investigate whether the identified genes are associated with blood pressure and sodium concentration in the general population using the UK Biobank
4. in vitro characterisation of identified genes and their variants, including novel CUL3, KLHL3 and TIH candidates already identified.
Methods
1.Recruitment of GS patients with Professors Gordon and Jeunemaitre and TIH patients through an ongoing multi-site programme in the UK
2.A variety of genetic methods will be used to investigate GS and TIH including:
-Whole exome reseqencing (GS)
-Exon-directed beadchip analysis (TIH)
-Targeted resequencing of candidate genes (TIH)
3. Association study of BP and serum sodium in the UK Biobank population.
4. Functional studies using Xenopus oocytes & cell culture.
Scientific/Medical value of results
1.Further understanding of the molecular mechanisms regulating sodium trafficking will advance the understanding of:
a.the regulation of human blood pressure
b.additional mechanisms of action of thiazide diuretics
c.predisposition to TIH
2.This will inform:
a.The discovery of new anti-hypertensive drug targets
b.The design of new diuretics less prone to induce hyponatraemia
c.Functional and pharmacogenetic characterisation of hypertensive patients to avoid thiazides in those susceptible to hyponatraemia
To advance understanding of the thiazide-sensitive pathway(s) of sodium reabsorption by studying two clinical manifestations of dysregulation of this pathway: Gordon syndrome (GS) and Thiazide-Induced Hyponatraemia (TIH).
Objectives
1.To establish the genetic basis for Gordon syndrome (GS) in patients without mutation in WNK1/4, CUL3 or KLHL3 mutation and explore phenotype-genotype correlations within GS
2.To build on pilot work in Nottingham to establish the genetic basis for predisposition to severe TIH and detailed description of the TIH phenotype
3.To investigate whether the identified genes are associated with blood pressure and sodium concentration in the general population using the UK Biobank
4. in vitro characterisation of identified genes and their variants, including novel CUL3, KLHL3 and TIH candidates already identified.
Methods
1.Recruitment of GS patients with Professors Gordon and Jeunemaitre and TIH patients through an ongoing multi-site programme in the UK
2.A variety of genetic methods will be used to investigate GS and TIH including:
-Whole exome reseqencing (GS)
-Exon-directed beadchip analysis (TIH)
-Targeted resequencing of candidate genes (TIH)
3. Association study of BP and serum sodium in the UK Biobank population.
4. Functional studies using Xenopus oocytes & cell culture.
Scientific/Medical value of results
1.Further understanding of the molecular mechanisms regulating sodium trafficking will advance the understanding of:
a.the regulation of human blood pressure
b.additional mechanisms of action of thiazide diuretics
c.predisposition to TIH
2.This will inform:
a.The discovery of new anti-hypertensive drug targets
b.The design of new diuretics less prone to induce hyponatraemia
c.Functional and pharmacogenetic characterisation of hypertensive patients to avoid thiazides in those susceptible to hyponatraemia
Planned Impact
There are many potential beneficiaries of my research other than the academic community:
1) Patients and patient groups
The 30% of the adult population in the UK who are hypertensive would benefit from the design of more efficacious anti-hypertensive drugs by improved blood pressure control and so lower incidence of cardiovascular disease and events such as heart attacks and strokes. Patients would also benefit from drugs with fewer side effects or from avoiding drugs to which they were predisposed to develop side effects from. It is notable that the vast majority of patients with severe TIH (and mental capacity) we have approached have agreed to contribute to the TIH research project. Patients often comment us how debillitating being admitted to hospital with TIH is and as a patient group they are overwhelmingly in support of research into this severe side effect.
Patients will also benefit by understanding they have hypertension, and by better understanding how their medicines work and how and why they can cause side effects. The patients' 'Blood Pressure Association' is particularly well suited to convey developments in hypertension from researchers to patients.
2) Clinicians
Both doctors and nurses, specialist and non-specialist, would benefit from advances in understanding of the pathophysiology of hypertension as well as clinical and genetic associations with the development of hyponatraemia after prescription of thiazide diuretics. This would arise not only through changes to hypertension guidelines but more directly through continued professional development and engagement with developments in Medicine.
3) The Pharmaceutical industry
Identification of new anti-hypertensive drug targets and the design of thiazide-like agents with fewer side-effects would benefit the pharmaceutical industry. It would also contribute to the reputation of the UK as a centre of excellence and innovation in biomedical research. This in turn is valuable in determining where multi-national companies such as those in the pharmaceutical industry choose to locate their resources.
4) Policy makers and Government agencies
Bodies such as NICE and the British Society of Hypertension, who formulate clinical guides on the treatment of hypertension in the UK, may incorporate any beneficial new anti-hypertensive agents or pharmacogenomic prescribing algorithms informed by this research into treatment guidelines. This not only ensures that newly emerging medical evidence is used to benefit patients nationally but also maximises health gains with limited public resources, for example avoiding the costs of hospitalisation with thiazide-induced hyponatraemia or a cardiovascular event. These benefits would also apply to international counterparts.
Timescale of benefits:
Understanding of the mechanisms of hypertension and adverse effects of thiazide-diuretics will occur during the tenure of the Fellowship
It will however take many years for this to result in new anti-hypertensive agents. This does not diminish the final benefits of any such agents but reflects the complex and demanding process of developing new drugs. As the UK population ages and hypertension becomes more prevalent, the need for superior and innovative anti-hypertensive agents will be even greater in the future than at present.
Personalised prescribing based on pharmacogenomic risk prediction models may be realised sooner than the development of new drugs but would still be measured in years.
1) Patients and patient groups
The 30% of the adult population in the UK who are hypertensive would benefit from the design of more efficacious anti-hypertensive drugs by improved blood pressure control and so lower incidence of cardiovascular disease and events such as heart attacks and strokes. Patients would also benefit from drugs with fewer side effects or from avoiding drugs to which they were predisposed to develop side effects from. It is notable that the vast majority of patients with severe TIH (and mental capacity) we have approached have agreed to contribute to the TIH research project. Patients often comment us how debillitating being admitted to hospital with TIH is and as a patient group they are overwhelmingly in support of research into this severe side effect.
Patients will also benefit by understanding they have hypertension, and by better understanding how their medicines work and how and why they can cause side effects. The patients' 'Blood Pressure Association' is particularly well suited to convey developments in hypertension from researchers to patients.
2) Clinicians
Both doctors and nurses, specialist and non-specialist, would benefit from advances in understanding of the pathophysiology of hypertension as well as clinical and genetic associations with the development of hyponatraemia after prescription of thiazide diuretics. This would arise not only through changes to hypertension guidelines but more directly through continued professional development and engagement with developments in Medicine.
3) The Pharmaceutical industry
Identification of new anti-hypertensive drug targets and the design of thiazide-like agents with fewer side-effects would benefit the pharmaceutical industry. It would also contribute to the reputation of the UK as a centre of excellence and innovation in biomedical research. This in turn is valuable in determining where multi-national companies such as those in the pharmaceutical industry choose to locate their resources.
4) Policy makers and Government agencies
Bodies such as NICE and the British Society of Hypertension, who formulate clinical guides on the treatment of hypertension in the UK, may incorporate any beneficial new anti-hypertensive agents or pharmacogenomic prescribing algorithms informed by this research into treatment guidelines. This not only ensures that newly emerging medical evidence is used to benefit patients nationally but also maximises health gains with limited public resources, for example avoiding the costs of hospitalisation with thiazide-induced hyponatraemia or a cardiovascular event. These benefits would also apply to international counterparts.
Timescale of benefits:
Understanding of the mechanisms of hypertension and adverse effects of thiazide-diuretics will occur during the tenure of the Fellowship
It will however take many years for this to result in new anti-hypertensive agents. This does not diminish the final benefits of any such agents but reflects the complex and demanding process of developing new drugs. As the UK population ages and hypertension becomes more prevalent, the need for superior and innovative anti-hypertensive agents will be even greater in the future than at present.
Personalised prescribing based on pharmacogenomic risk prediction models may be realised sooner than the development of new drugs but would still be measured in years.
Organisations
- University of Nottingham (Fellow, Lead Research Organisation)
- Royal Free Hospital (Collaboration)
- University College London (Collaboration)
- Radboud University Nijmegen Medical Center (Collaboration)
- UNIVERSITY OF LEICESTER (Collaboration)
- National Institute of Health and Medical Research (INSERM) (Collaboration)
- Great Ormond Street Hospital (GOSH) (Collaboration)
- University of Queensland (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Notts University Hospitals NHS Trust (Project Partner)
People |
ORCID iD |
Mark Glover (Principal Investigator / Fellow) |
Publications
Barber J
(2014)
Thiazide-Induced Hyponatraemia:a systematic review and meta-analysis
in British Society of Hypertension. Published in the Journal of Human Hypertension
Barber J
(2015)
A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation?
in British Journal of Clinical Pharmacology
Billington CK
(2018)
Impact of hydration status on haemodynamics, effects of acute blood pressure-lowering treatment, and prognosis after stroke.
in British journal of clinical pharmacology
Boffa RJ
(2019)
Hypertension in adults: summary of updated NICE guidance.
in BMJ (Clinical research ed.)
Channavajjhala
(2015)
Urinary Exosome Profiling in Thiazide Induced Hyponatremia. FR-PO140
Channavajjhala S
(2016)
OS 08-05 NOVEL MOLECULAR INSIGHTS IN URINARY EXOSOME PROTEIN PROFILING IN THIAZIDE INDUCED HYPONATREMIA
in Journal of Hypertension
Channavajjhala SK
(2015)
Stratified novel molecular insights in thiazide induced hyponatremia
Description | Appointed hypertension specialist member of NICE Hypertension and Lipids (update) guideline Guideline committee (2021-2023) |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Impact | Enables cost effective treatment of hypertension and hypercholesterolaemia to prevent heart attacks, strokes and length of life |
Description | Appointment as a Clinical Pharmacologist and General Physician to NICE technology appriasal committee B |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Impact | Technology appraisals (mostly novel therapeutic medicines) carry a requirement for the National Health Service to fund these new treatments which result in additional QALYS of life in a way which ensures equitable access to new medicines on a national basis. It also provides cost efficiency for the health service. NICE technology appraisal guidance often has impact beyond the U.K. |
URL | https://www.nice.org.uk/get-involved/meetings-in-public/technology-appraisal-committee |
Description | BHS guidelines committee |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Contribution to formulation of national guidance on the management of hypertension; British Hypertension Society guideline V to be published in 2015. Specifically most input to management of acute hypertension. |
Description | Co-authorship of the revised (2019) treatment of hypertension in adults NICE guideline (to replace CG127). I was appointed to be one of two UK hypertension specialists on the guideline committee |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Impact | This national guideline to be published in 2019 provides an update on the optimal and most cost-efficient way to treat hypertension to prevent cardiovascular disease and its related mortality |
Description | Member of the Pharmacovigilance Expert Advisory Group (PEAG) |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | The Pharmacovigilance Expert Advisory Group (PEAG) at the MHRA advises the Commission on Human Medicines regarding monthly safety updates on Medicines used in the UK including new safety alerts, cautions or restrictions of the use of medicines, including withdrawal. |
Description | CLRN research nurse support |
Amount | £64,236 (GBP) |
Organisation | National Institute for Health Research |
Department | Comprehensive Clinical Research Network (Coordinating Centre) – NIHR |
Sector | Public |
Country | United Kingdom |
Start | 03/2012 |
End | 04/2018 |
Description | MRC PhD Studentship |
Amount | £84,257 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 03/2019 |
Description | PhD studentship consumables grant |
Amount | £24,397 (GBP) |
Organisation | Nottingham University Hospitals NHS Trust |
Department | Nottingham University Hospitals Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2014 |
End | 09/2018 |
Description | CPU cambridge |
Organisation | University of Cambridge |
Department | Clinical Pharmacology Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Resequencing and data analysis |
Collaborator Contribution | recruitment of hypertension patients, data analysis |
Impact | Publication PMID: 24266877 |
Start Year | 2010 |
Description | GOSH |
Organisation | Great Ormond Street Hospital (GOSH) |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Genetic sequencing and data analysis |
Collaborator Contribution | Recruitment of hypertension patients |
Impact | Publication PMID: 24266877 |
Start Year | 2011 |
Description | GWAS of thiazide-induced hyponatraemia patients |
Organisation | University of Leicester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Recruitment and phenotyping of TIH patients |
Collaborator Contribution | Association studies and analysis |
Impact | Pilot data to inform further research |
Start Year | 2011 |
Description | Genetic study of Gordon syndrome patients |
Organisation | National Institute of Health and Medical Research (INSERM) |
Country | France |
Sector | Academic/University |
PI Contribution | Genetic sequencing, data analysis and patient recruitment |
Collaborator Contribution | Genetic data analysis and patient recruitment |
Impact | Research ongoing |
Start Year | 2013 |
Description | Genotyping and phenotyping of Gordon syndrome patients |
Organisation | University of Queensland |
Department | Laboratory for Endocrinology and Metabolism |
Country | Australia |
Sector | Academic/University |
PI Contribution | Genetic analysis of patients with Gordon syndrome |
Collaborator Contribution | Recruitment and phenotyping of patients.DNA samples |
Impact | PMID: 24266877 |
Start Year | 2011 |
Description | Mendelian syndromes of hypertension Dr Stephen Walsh - UCL and Royal Free hospital |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration on phenotyping and genotyping of patients with Mendelian syndromes of hypertension including Gordon syndrome. It also involves the RADAR rare diseases network |
Collaborator Contribution | Collaboration on phenotyping and genotyping of patients with Mendelian syndromes of hypertension including Gordon syndrome. It also involves the RADAR rare diseases network |
Impact | . |
Start Year | 2018 |
Description | Molecular mechanisms underlying Gordon syndrome |
Organisation | Royal Free Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | The nephrology unit at the royal free has kindly agreed to collaborate in recruiting patients with Gordon syndrome using our portfolio adopted study |
Collaborator Contribution | Recruitment of Gordon syndrome patients |
Impact | The study site is now open and we are awaiting the recruitment of the first patients |
Start Year | 2018 |
Description | Thiazide-induced hyponatremia as clinical model to identify novel paracrine mechanisms in the renal tubule |
Organisation | Radboud University Nijmegen Medical Center |
Department | Department of Physiology |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | We jointly authored a research grant application to the Dutch Kidney Foundation to work on samples my group had collected from patients with Thiazide Induced Hyponatraemia. This grant is for a PhD student |
Collaborator Contribution | Coauthorship of grant application and providing human blood, urine and clinical details to the project |
Impact | The grant has been submitted and we are awaiting the outcome |
Start Year | 2018 |
Description | Australia Engagement day University of Nottingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | 50 scientists from my University and surrounding universities attended a day of talks to stimulate engagement with Australian Universities and specifically to promote scientific collaboration with Australian Universities. I was invited to give a talk regarding my experience of collaborating with University of Queensland in my MRC work. Subsequent contact with delegates for more information and plans for further Australian collaboration |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.nottingham.ac.uk/home/events/australian-engagement-event.aspx |
Description | Invited Lecture at the Americal Society of Nephrology annual meeting 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture at the American Society of Nephrology in San Diego, USA in 2018. Talk was entitled "Sodium Balance and Regulation: Still Learning After All These Years; Thiazide-Induced Hyponatremia" |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.asn-online.org/education/kidneyweek/2018/meeting-overview.aspx |