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22nd February 2024
A study shows that gout not only increases the risk of a broad range of cardiovascular diseases but also leads to a higher prevalence of other health conditions, including chronic kidney disease, high blood pressure and an increased body mass index (BMI).
Researchers from the Universities of Oxford, Glasgow, and KU Leuven in Belgium found that having gout is linked with a 58% higher risk of cardiovascular disease. This risk increased further for females and people under the age of 45.
Gout has previously been linked with an increased risk of cardiovascular disease, but this study, published in The Lancet Rheumatology, is the first to link gout with a broader range of health issues.
The condition can be extremely painful and is caused by a build-up of uric acid in the body, which crystallises around joints, causing pain, swelling and redness. Gout is one of the most common types of inflammatory arthritis in the world and is particularly common in older men.
Using the Clinical Practice Datalink, the researchers were able to analyse the electronic health records of over 860,000 people from the UK and Europe. Over 152,000 individuals who had gout were identified, alongside more than 700,000 matched population controls.
People with gout were found to be at a higher risk of cardiovascular disease than those without the condition. In particular, women with gout had an 88% higher relative risk of heart disease. For men, the risk was 49% higher for those with gout when compared to the control group.
The increased risk was seen across all of the twelve heart conditions analysed in the study, including heart failure, ischaemic heart disease, arrhythmias, valve diseases, and venous thromboembolism and was amplified in younger patients.
People under 45 years of age who had gout were found to have more than twice the risk of cardiovascular disease than a similar-aged person without gout.
BMIs were also found to be higher in patients with gout, and higher rates of other health conditions, such as chronic kidney disease and high blood pressure, were also observed.
Dr Nathalie Conrad, a senior author on the paper from KU Leuven and an honorary research fellow at the University of Oxford and the University of Glasgow, said: ‘The present results complement a now large body of evidence of substantial cardiovascular risks associated with gout, as well as other immune-mediated inflammatory conditions.
‘To date, these conditions are less commonly considered in cardiovascular disease prevention guidelines and risk scores, nor are there specific prevention measures for these patients.
‘These data suggest this might need to change, and the clinical community may need to consider cardiovascular disease screening and prevention as an integral part of the management of gout.’
The researchers highlight the importance of screening for and managing a range of cardiovascular diseases in people with gout.
Dr Lyn Ferguson, from the University of Glasgow, added: ‘Gout could be considered a metabolic condition, and management should include addressing the heart and body weight alongside joints.’
A version of this article was originally published by our sister publication Nursing in Practice.
16th February 2024
Patients who successfully reversed a type 2 diabetes diagnosis though lifestyle changes substantially reduced their cardiovascular disease (CVD) and chronic kidney disease (CKD) risk in the long term, a study has found.
Published in the journal Diabetologia, the results came from a large trial of almost 4,500 participants in which doctors were comparing an intensive lifestyle programme with standard diabetes education and support.
Taking no diabetes medications and having a HbA1c of less than 48 mmol/mol (6.5%) at a single point in time was classed as remission.
Overall, those who achieved remission through the lifestyle changes – in whichever group – had a 33% lower rate of CKD and a 40% lower rate of CVD.
But those who had the most intensive support were more likely to be in remission from their diabetes, with 12% meeting the criteria at least one follow-up and falling to 7% over time compared with around 2% in the regular support group.
Being in remission overall was significantly linked to changes in weight and risk factors over the years, the study found.
Average weight loss associated with remission was 7.3kg after one year and 4.5kg after four years.
There were also significantly greater improvements in HDL-cholesterol and fitness after one and four years, and significantly greater systolic blood pressure improvements after one year among participants with remission compared with those without remission, the team said.
The analysis also showed systolic blood pressure decreased more and HDL-cholesterol increased more among participants who achieved a greater duration of diabetes remission.
There was a dose-response relationship with those who had remission for at least four visits seeing the most impact, the researchers said.
Those taking part in the study – which ran between 2001 and 2016 – had a mean age of 59 years and on average were in the range of severe obesity.
It was noted that while 18% of participants achieved remission at some point during follow-up, the percentage of participants with current remission had decreased to 3% by the eighth year of the study.
The figures underline, the challenges of keeping weight off using lifestyle interventions, the researchers said.
But for those with at least four years of remission the risk of CKD and CVD was reduced by 55% and 49% respectively.
The analysis also noted participants with a short duration of diabetes, low starting HbA1c and a large magnitude of weight loss were most likely to experience remission.
Study lead Professor Edward Gregg, head of the School of Population Health, RCSI University of Medicine and Health Sciences in Dublin, said: ‘As the first intervention study to associate remission with reduction of diabetes-related complications, this is encouraging news for those who can achieve remission from type 2 diabetes.
‘While our study is also a reminder that maintenance of weight loss and remission is difficult, our findings suggests any success with remission is associated with later health benefits.’
Another recent study has found that regular bouts of moderate to vigorous physical activity can protect patients with type 2 diabetes from developing kidney disease.
A version of this article was originally published by our sister publication Pulse.
12th February 2024
Regular bouts of moderate to vigorous physical activity can protect patients with type 2 diabetes from developing kidney disease, a new study has found.
Overweight and obese people with type 2 diabetes who undertook moderate to vigorous physical activity every week were significantly less likely to progress to chronic kidney disease than those who undertook minimal physical activity.
Increasing cumulative exercise by just over an hour a week is linked to a 33% reduction in risk of renal disease. The researchers showed that the increase in physical activity is just as effective whether the extra exercise is undertaken in short bursts of less than 10 minutes or for long periods of 10 minutes and over.
The findings, published in the British Journal of Sports Medicine, show that being physically active is one of the most effective ways to prevent kidney disease in people with type 2 diabetes and can even help patients unable or unwilling to engage in physical activity for over 10 minutes.
Diabetes accounts for 30-50% of chronic kidney disease cases globally, making it the leading cause of renal disease. Patients who have diabetes and chronic kidney disease have a 10-fold higher risk of death from any cause compared with those who have diabetes alone.
To determine whether there was an association between physical activity and chronic kidney disease risk in patients with type 2 diabetes, the researchers undertook a secondary analysis of an activity tracker study, which was part of the US Look AHEAD trial.
The study involved 1,746 participants, with an average age of 58.
The participants were monitored for moderate to vigorous levels of physical activity and the extent of chronic kidney disease at the start of the study and again at one, four and eight years later.
Chronic kidney disease was defined as a deterioration of at least 30% in the estimated glomerular filtration rate, the rate at which kidneys remove waste and extra water from the blood to make urine (less than 60 ml/min).
On average, participants undertook 329 minutes of moderate to vigorous physical activity every week. Over 80% of this was accumulated in periods of less than 10 minutes, with the remaining 12.5% in periods of more than 10 minutes.
Over the duration of the study, around one in three of the participants developed chronic kidney disease.
The participants who undertook the most moderate to vigorous physical activity, between 329 to 469 mins per week, were significantly less likely to progress to chronic kidney disease than those who did the least physical activity (under 220 mins).
The researchers found that for every 100 minutes of moderate to vigorous activity, there was a 9% lower risk of developing chronic kidney disease. This increased to 19% if the exercise sessions lasted for at least 10 minutes.
Participants who increased their weekly exercise tally by 63 minutes over the first four years of the study had a 33% lower risk of kidney disease than those with the most significant decrease of minutes per week. The improvement was seen whether the physical activity sessions were greater than or less than 10 minutes.
The researchers stated: ‘These findings are consistent with evidence that regular [physical activity] has direct anti-inflammatory effects, and can promote glycaemic control, improve insulin sensitivity, blood pressure, lipid profiles and other metabolic and cardiovascular risk factors, all of which are associated with renal function.’
The researchers suggest that all patients with diabetes should be encouraged to engage in as much exercise intensity as they can tolerate to maximise the benefits.
Just over an hour a day of walking, cycling, jogging or swimming could help overweight and obese adults with type 2 diabetes reduce their risk of progression to chronic kidney disease.
A previous study from 2022 showed that increased coffee consumption lowered rate of kidney function decline in people with type 2 diabetes.
A version of this article was originally published by our sister publication Nursing in Practice.
17th January 2024
The National Institute for Health and Care Excellence (NICE) has recommended that empagliflozin can be used as an option for treating chronic kidney disease (CKD) in adults under some circumstances.
It has to be prescribed as an add-on to standard care including the highest tolerated dose of angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker unless contraindicated, a Technology Appraisal has stated.
Under the recommendations, patients with CKD must also have an estimated glomerular filtration rate of:
Clinicians in both primary and secondary care should make prescribing decisions based on cost of suitable treatments including dapagliflozin after discussing the pros and cons with the patient, NICE said.
The committee noted that some patients already take dapagliflozin as an add-on to standard care and empagliflozin would be used in a similar way but with a potentially broader population.
Evidence from the EMPA-KIDNEY trial suggests that empagliflozin plus standard care is more effective than standard care alone for CKD but there were limits on who was included in the studies, NICE said.
There are also no trials directly comparing empagliflozin plus dapagliflozin but it is likely that effectiveness and safety is similar, the committee said.
It was acknowledged that CKD can progress more quickly in some ethnic minority groups in people under 55 with type 2 diabetes but this could not be considered in the decision making, the committee noted.
The SGLT2 inhibitor is already recommended by NICE for the treatment of adult patients with type 2 diabetes and adult patients with heart failure with reduced ejection fraction.
NICE’s decision to include empagliflozin as an option in some patients with CKD means it must be made available within three months.
In papers published by the NICE committee, it notes that the use of SGLT2 inhibitors is not yet well established in clinical practice and there is ‘scope to expand the use of this drug class in this indication to slow CKD disease progression’.
Empagliflozin was approved by the European Medicines Agency for the treatment of adult patients with CKD in July 2023.
A version of this article was originally published by our sister publication Pulse.
28th July 2023
The recent development of a human kidney cell atlas will help researchers better understand the factors contributing to disease states and provide a critical foundation to help discover new treatments for acute kidney injury and chronic kidney disease.
In the study, published in the journal Nature, a team of US researchers developed a kidney tissue atlas consisting of 51 main cell types including rare and novel cell populations and 28 cellular states indicative of injury or disease.
The atlas also serves as a repository of raw gene data and interactive 3D models of cells and microenvironment relationships. It was created from 45 healthy donor organs and 48 kidney disease biopsies and allows for the comparison of healthy and injured cells.
Researchers applied multiple single-cell and single-nucleus assays and spatial imaging technologies to both healthy and diseased kidneys. This provided a high-resolution cellular atlas of 51 main cell types, which included rare and previously undescribed cell populations. The multiomic approach detailed transcriptomic profiles, regulatory factors and spatial localisations spanning the entire organ.
With the data, the researched were able to define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states.
The identification of molecular signatures also allowed researchers to determine the location of these states within the injury neighbourhoods using spatial transcriptomics. Furthermore, large-scale 3D imaging analysis of around 1.2 million neighbourhoods provided corresponding linkages to active immune responses.
Taken together, the analyses enabled researchers to define the biological pathways that are relevant to injury time-course and niches, including the signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function.
The atlas is part of the Kidney Precision Medicine Project (KPMP) and, according to Dr Eric Brunskill, KPMP program director, ‘represents open, public science at its best‘.
He added: ‘With the atlas, we’ve created an interactive, hypothesis-generating resource for kidney disease investigators and clinicians around the world.‘
This follows the recent development of a comprehensive heart cell atlas, which offers new and unique insight into heart cells and function.
27th July 2023
Empagliflozin has become the first SGLT2 inhibitor to be approved by the European Medicines Agency (EMA) for the treatment of adult patients with chronic kidney disease (CKD), Boehringer Ingelheim and Eli Lilly and Company have announced.
This EMA approval represents a major advance in the standard of care for the estimated 47 million patients living with the disease in Europe. CKD, characterised by a reduction in the glomerular filtration rate, is often progressive, and the presence of albuminuria is a key risk factor for the subsequent development of kidney failure. Hence, any treatment that slows disease progression offers a clinical benefit to patients.
In June 2023, the Committee for Medicinal Products for Human Use adopted a positive opinion to recommend a change to the terms of the marketing authorisation for the medicinal product Jardiance (empagliflozin). This was based on the findings of the EMPA-KIDNEY trial, which were published in the New England Journal of Medicine earlier in the year.
With existing indications in type 2 diabetes and heart failure, empagliflozin could help manage the risks of cardio-renal-metabolic conditions.
Leonard Glass, senior vice president, diabetes and obesity global medical affairs at Lilly, said: ’CKD is closely linked to other cardio-renal-metabolic conditions such as type 2 diabetes and heart failure – thus an integrated approach is vital for optimised treatment of these interconnected conditions. We look forward to continuing conversations with other regulatory bodies worldwide so that empagliflozin can be made available for as many people living with these conditions as quickly as possible.’
Commenting on the approval, Daniel Gallego, president of European Kidney Patients’ Federation, added: ’We celebrate this significant milestone in the field of chronic kidney disease. CKD is a silent killer and prevention and early detection are crucial in the general population.
’This new treatment option has the potential to further improve the management of cardiorenal metabolic syndrome and renal disease, offering renewed hope and improved quality of life for countless individuals living with CKD worldwide.’
The EMPA-KIDNEY trial enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area. Alternatively, enrolled participants could have an eGFR of at least 45 but less than 90 with a urinary albumin-to-creatinine ratio of at least 200.
EMPA-KIDNEY showed that during a median of 2.0 years of follow-up, the use of empagliflozin was associated with a 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to the placebo (Hazard ratio, HR = 0.72, 95% CI 0.64 – 0.82, p < 0.001).
These findings were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. In addition, the rate of hospitalisation from any cause was lower in the empagliflozin group (HR = 0.86, 95% CI 0.78 – 0.95, p = 0.003).
2nd June 2023
Elevated levels of the protein Indian Hedgehog, which is released by a subset of aged and injured renal cells, have been identified in patients with chronic kidney disease (CKD) and is therefore a potential therapeutic target for the condition, according to a new study.
Published in the journal Science Translational Medicine, an international research team sought to understand the link between injury and inflammation in patients with CKD. The team hypothesised that signalling from renal epithelial cells activated glioma-associated oncogene 1 expressing cells (Gli1+) to induce fibrosis. But exactly how this process occurred was uncertain.
The ageing process is associated with chronic inflammation and a defective immune response. Conditions such as CKD are accompanied by immunosenescence, with such patients at a higher risk of cardiovascular disease. Previous work revealed a link between increased production of tumour necrosis factor (TNF), CKD and renal failure, but the underlying mechanism remains unclear, which led to the current study.
The researchers identified that leukocyte-derived tumour necrosis factor (TNF) promoted Gli1+ cell proliferation and cardio-renal fibrosis through induction and release of the Indian Hedgehog (IHH) protein from renal epithelial cells. Moreover, inhibition of TNF release led to a reduction in tissue fibrosis and also lowered Gli1+ cell proliferation.
In further work, it also became clear that increased circulating levels of IHH correlated with cardiovascular disease and loss of renal function in patients with CKD. Taken together, the authors suggested their findings indicated that IHH release from TNF-activated renal cells drove the activation and proliferation of Gli1+ expressing cells and was the missing link between inflammation and organ fibrosis.
While these represent preliminary findings, the authors suggested that therapies targeting TNF and/or IHH signalling warrant further investigation to assess their potential in patients with CKD and fibrosis.
12th August 2022
Higher serum aldosterone levels in those with chronic kidney disease (CKD) is associated with an increased risk of disease progression and of developing end-stage kidney disease, according to an analysis of data from the Chronic Renal Insufficiency Cohort (CRIC) by US researchers.
Aldosterone is produced by the adrenal glands and is known to play a role in the development of hypertension and kidney disease. Elevated levels of aldosterone (primary aldosteronism) are a factor in the development of hypertension, but while high among hypertensive patients, the condition is often unrecognised.
However, the extent to which aldosterone levels impact on the subsequent risk of progression in patients with CKD is uncertain and was the subject of the current retrospective analysis by the US team.
The researchers turned to data collected as part of the Chronic Renal insufficiency Cohort (CRIC) study and which was designed to investigate risk factors for mortality and worsening of disease in patients with CKD. They included individuals with an estimated glomerular filtration rate (eGFR) of between 20 and 70 ml/min/1.73 m2 and for whom aldosterone levels had been recorded and these levels were divided into quartiles
The researchers also collected demographic and co-morbidity data which was adjusted for in regression analysis. The primary outcome of interest was CKD progression and defined as the composite of a 50% decline in eGFR or incident end-stage kidney disease (ESKD), whichever came first.
Aldosterone levels and disease progression
A total of 3680 individuals with a mean age of 58.1 years (44.7% female) were included in the analysis, of whom 48.1% were diabetics with the overall mean serum aldosterone being 10 ng/dL, although this was significantly higher in men than women (10.5 vs 9.4, p < 0.001).
After a median follow-up of 9.6 years, 1412 individuals developed CKD disease progression and 1129 developed ESKD. In fully adjusted models, those with the highest quartile serum aldosterone level had a 45% higher risk of CKD progression compared to those in the lowest quartile (hazard ratio, HR = 1.45, 95% CI 1.22 – 1.73).
Using aldosterone levels as a continuous variable in the models, indicated that there was an 11% higher risk of CKD progression (HR = 1.11, 95% CI 1.04 – 1.18). Furthermore, those with the highest aldosterone serum levels also had a 46% increased risk of developing ESKD (HR = 1.46).
While there was also a 22% increased risk of all-cause mortality for individuals in the highest versus the lowest aldosterone levels, this became non-significant when levels were considered as a continuous variable (HR = 1.05, 95% CI 0.99 – 1.12). There was also no relationship between the adverse outcomes from higher levels of aldosterone and diabetes status.
The authors concluded by suggesting that aldosteronism may play a role in CKD progression.
Citation
Verma A et al. Aldosterone in chronic kidney disease and renal outcomes. Eur Heart J 2022
10th August 2021
In patients with chronic kidney disease, a mortality benefit from dapagliflozin has led to a license extension for use in this condition.
According to the UK Kidney Association, chronic kidney disease (CKD) is defined by abnormalities of kidney function or structure and which are present for more than three months.
This definition will include those with an estimated glomerular filtration rate (eGFR) of less than 60ml/min/1.73m2 on at least two occasions, 90 days part.
The condition is common and thought to affect and left untreated, chronic kidney disease is a major cause of kidney failure, leading to around one million deaths per year.
Moreover, figures compiled by Kidney Care UK, suggest that around three million people in the UK have CKD and that are currently receiving treatment for kidney failure and that 40,000 to 45,000 premature deaths occur every year in the UK due to CKD.
Globally, it is thought that there are around 840 million people with CKD, acute kidney injury and renal replacement therapy.
While there are several recognised causes of kidney disease, the top two causes are hypertension and diabetes, followed by glomerulonephritis, in which damage occurs to the glomeruli, although the condition is usually asymptomatic and only revealed upon testing.
The only known treatments capable of slowing a reduction in kidney function are angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs). Now, a UK license extension has been granted to manufacturer, AstraZeneca, for the use of its drug, dapagliflozin (brand name Forxiga), in the treatment of patients with chronic kidney disease, with or without diabetes.
Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor and which is indicated for the management of type 2 diabetes as an adjunct to diet and exercise for the management of type 2 diabetes as an adjunct to diet and exercise, either alone or in combination with other diabetic treatments. It is also licensed in patients with symptomatic chronic heart failure with a reduced ejection fraction.
The license extension was granted based on the findings of the DAPA-CKD Phase 3 trial. This was an international, multi-centre, randomised, double-blind, placebo-controlled study in adults with and without type 2 diabetes and who had stage 2 to 4 (i.e. eGFR 25 to 75 ml/min/1.73m2) CKD.
A total of 4,304 patients were randomised to either dapagliflozin 10mg or placebo and the primary outcome was a composite of a sustained decline in eGFR of at least 50%, end-stage kidney disease (i.e. stage 5) or death from either renal or cardiovascular causes.
The study was terminated early after only 2.4 years when the primary outcome had occurred in 9.2% of those taking dapagliflozin and 14.5% in the placebo arm, giving a hazard ratio, HR, of 0.61 (95% CI 0.51–0.72, p < 0.001).
There was also a significant mortality difference between both groups (HR = 0.69, 95% CI 0.53–0.88, p = 0.004) and the effect of taking dapagliflozin was similar in patients with and without type 2 diabetes.
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