NIHR DC Discover

NIHR Signal Gout medication may slow progression of chronic kidney disease

Published on 20 February 2018

doi: 10.3310/signal-000561

In people with existing kidney disease, one in four will have worse disease within six to 12 months. Uric acid-lowering drugs such as allopurinol halve the risk of disease progression over this period. They also reduce heart attack or stroke by 60%.

Uric acid, the cause of gout, is produced when proteins are broken down by the body. It is excreted by the kidneys and often builds up in people with chronic kidney disease. It is not certain whether increased uric acid causes progression of kidney disease or is simply a marker of its severity.

This review included 16 small trials of 1,211 people with moderate chronic kidney disease from a variety of causes which were allocated to take a uric acid lowering medication or usual care. Although these results are promising, they are based on low-quality trials. The low rate of side effects should be taken into account when considering these drugs as an option to slow the progression of kidney failure and prevent heart disease.

Share your views on the research.

Why was this study needed?

Moderate to severe kidney disease affects 2.6 million people in England.  It has a variety of causes including diabetes and inflammation. Management aims to slow progression through a variety of measures including lowering blood pressure, blood thinners, stopping smoking and dietary advice.

Uric acid is a breakdown product of blood cells and foods rich in purines. Blood levels are often high in people with impaired kidneys. It is not known whether this is a cause or consequence of chronic kidney disease.

There has been renewed interest in the relationship between uric acid levels and kidney disease with recent research showing a possible link between uric acid and the worsening of kidney disease in patients with and without diabetes.  There has been conflicting evidence about whether reducing the levels of uric acid can limit the decline in kidney function or cardiovascular disease. The researchers aimed to address this through pooling the available research.

What did this study do?

This systematic review and meta-analysis included 16 randomised controlled trials of 1,211 adults with chronic kidney disease. Most had moderate disease with a glomerular filtration rate 30 to 60ml/min/1.73m2. People were allocated to uric acid-lowering therapy (allopurinol, febuxostat or pegloticase) or a control group who had usual treatment or a placebo.  

Trials followed people for about six or 12 months; one trial carried on for 84 months.

There are several limitations which reduce our confidence in the precision of the results. The cause, severity and definition of chronic kidney disease differed between studies. The trials were small, ranging from 36 to 140 participants. Only one trial was from the UK; many were from China. Most were of low quality and had a short follow-up. It is nevertheless likely that the direction of effect, at least, is reasonably certain.

What did it find?

  • Uric acid lowering therapy reduced the risk of a kidney failure event (defined as a reduction in kidney function of 25 to 50% or progression to end-stage renal disease) from 29% in the control group to 12% in the therapy group (relative risk [RR] 0.45, 95% confidence interval [CI] 0.31 to 0.64; 10 trials, 706 participants).
  • End-stage renal disease was reduced from 12% in the control group to 7% in the therapy group (RR 59%, 95% CI 0.37 to 0.96; 10 trials, 706 participants).
  • Cardiovascular events such as heart attack and stroke affected 27% in the control group compared to 15% in the therapy group (RR 040, 95% CI 0.17 to 0.62; 3 trials, 331 participants).
  • There was no difference between the groups regarding death from any cause; 4% died in the therapy group compared to 5% in the control group (RR 0.86, 95% CI 0.50 to 1.46; 12 trials, 841 participants).
  • There were low rates of side effects in the uric-acid lowering therapy group. Skin rash, muscle aches, and increased liver enzymes affected 2% of participants. There were no serious adverse effects.

What does current guidance say on this issue?

The NICE 2014 guideline on chronic kidney disease management updated in 2015 does not provide any recommendations on the use of uric acid-lowering therapy. This was due to a lack of high-quality evidence. 

What are the implications?

Chronic kidney disease is a lifelong condition which is often progressive. Treatment of kidney disease is limited to prevention of deterioration by control of blood pressure and other risk factors. For end-stage disease dialysis or kidney transplant may be required. As the incidence of chronic kidney disease is increasing, finding new ways to slow progression is important.

Some uric acid-lowering medications are cheap and relatively safe. These results should help inform shared decision making for people with high uric acid levels.

The results due next year from a larger Australian RCT of 369 adults are eagerly anticipated.

Citation and Funding

Su X, Xu B, Yan B, et al. Effects of uric acid-lowering therapy in patients with chronic kidney disease: A meta-analysis. PLOS One. 2017;12(11):e0187550.

This project was funded by the Science and Technology Project of Shanxi Province (Grant number 20140313013-5), the Natural Science FOUndation of Shanxi Province (Grant number 201701D221173) and the Shanxi Province Health and Family Planning Commission all in China.

Bibliography

NICE. Chronic kidney disease in adults: assessment and management. CG182. London: National Institute for Health and Care Excellence; 2014 (updated 2015).

PHE. Chronic kidney disease prevalence model. London: Public Health England; 2014.

Why was this study needed?

Moderate to severe kidney disease affects 2.6 million people in England.  It has a variety of causes including diabetes and inflammation. Management aims to slow progression through a variety of measures including lowering blood pressure, blood thinners, stopping smoking and dietary advice.

Uric acid is a breakdown product of blood cells and foods rich in purines. Blood levels are often high in people with impaired kidneys. It is not known whether this is a cause or consequence of chronic kidney disease.

There has been renewed interest in the relationship between uric acid levels and kidney disease with recent research showing a possible link between uric acid and the worsening of kidney disease in patients with and without diabetes.  There has been conflicting evidence about whether reducing the levels of uric acid can limit the decline in kidney function or cardiovascular disease. The researchers aimed to address this through pooling the available research.

What did this study do?

This systematic review and meta-analysis included 16 randomised controlled trials of 1,211 adults with chronic kidney disease. Most had moderate disease with a glomerular filtration rate 30 to 60ml/min/1.73m2. People were allocated to uric acid-lowering therapy (allopurinol, febuxostat or pegloticase) or a control group who had usual treatment or a placebo.  

Trials followed people for about six or 12 months; one trial carried on for 84 months.

There are several limitations which reduce our confidence in the precision of the results. The cause, severity and definition of chronic kidney disease differed between studies. The trials were small, ranging from 36 to 140 participants. Only one trial was from the UK; many were from China. Most were of low quality and had a short follow-up. It is nevertheless likely that the direction of effect, at least, is reasonably certain.

What did it find?

  • Uric acid lowering therapy reduced the risk of a kidney failure event (defined as a reduction in kidney function of 25 to 50% or progression to end-stage renal disease) from 29% in the control group to 12% in the therapy group (relative risk [RR] 0.45, 95% confidence interval [CI] 0.31 to 0.64; 10 trials, 706 participants).
  • End-stage renal disease was reduced from 12% in the control group to 7% in the therapy group (RR 59%, 95% CI 0.37 to 0.96; 10 trials, 706 participants).
  • Cardiovascular events such as heart attack and stroke affected 27% in the control group compared to 15% in the therapy group (RR 040, 95% CI 0.17 to 0.62; 3 trials, 331 participants).
  • There was no difference between the groups regarding death from any cause; 4% died in the therapy group compared to 5% in the control group (RR 0.86, 95% CI 0.50 to 1.46; 12 trials, 841 participants).
  • There were low rates of side effects in the uric-acid lowering therapy group. Skin rash, muscle aches, and increased liver enzymes affected 2% of participants. There were no serious adverse effects.

What does current guidance say on this issue?

The NICE 2014 guideline on chronic kidney disease management updated in 2015 does not provide any recommendations on the use of uric acid-lowering therapy. This was due to a lack of high-quality evidence. 

What are the implications?

Chronic kidney disease is a lifelong condition which is often progressive. Treatment of kidney disease is limited to prevention of deterioration by control of blood pressure and other risk factors. For end-stage disease dialysis or kidney transplant may be required. As the incidence of chronic kidney disease is increasing, finding new ways to slow progression is important.

Some uric acid-lowering medications are cheap and relatively safe. These results should help inform shared decision making for people with high uric acid levels.

The results due next year from a larger Australian RCT of 369 adults are eagerly anticipated.

Citation and Funding

Su X, Xu B, Yan B, et al. Effects of uric acid-lowering therapy in patients with chronic kidney disease: A meta-analysis. PLOS One. 2017;12(11):e0187550.

This project was funded by the Science and Technology Project of Shanxi Province (Grant number 20140313013-5), the Natural Science FOUndation of Shanxi Province (Grant number 201701D221173) and the Shanxi Province Health and Family Planning Commission all in China.

Bibliography

NICE. Chronic kidney disease in adults: assessment and management. CG182. London: National Institute for Health and Care Excellence; 2014 (updated 2015).

PHE. Chronic kidney disease prevalence model. London: Public Health England; 2014.

Effects of uric acid-lowering therapy in patients with chronic kidney disease: A meta-analysis

Published on 3 November 2017

Su, X.,Xu, B.,Yan, B.,Qiao, X.,Wang, L.

PLoS One Volume 12 , 2017

BACKGROUND AND OBJECTIVES: The effects of uric acid-lowering therapy in patients with chronic kidney disease (CKD) remain uncertain. Therefore, we undertook a systematic review and meta-analysis to investigate the effects of uric acid-lowering agents on major clinical outcomes of CKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: According to the pre-specified protocol that was registered with PROSPERO (No. CRD42016038030), we searched systematically in MEDLINE, EMBASE, and the Cochrane Library for trials up to February 2016. Prospective, randomized, controlled trials assessing the effects of uric acid-lowering agents on cardiovascular and kidney outcomes in patients with CKD were included. Random-effects analytical methods were used. RESULTS: Sixteen eligible trials were identified, providing data for 1,211 patients with CKD, including 146 kidney failure events and 69 cardiovascular events. Uric acid-lowering therapy produced a 55% relative risk (RR) reduction (95% confidence interval [95% CI], 31-64) for kidney failure events (P < 0.001), and a 60% RR reduction (95% CI, 17-62) for cardiovascular events (P < 0.001), but had no significant effect on the risk of all-cause death (RR, 0.86; 95% CI, 0.50-1.46). The mean differences in rate of decline in the estimated glomerular filtration rate (4.10 mL/min/1.73 m2 per year slower in uric acid-lowering therapy recipients, 95% CI, 1.86-6.35) and the standardized mean differences in the change in proteinuria or albuminuria (-0.23 units of standard deviation greater in uric acid-lowering therapy recipients; 95% CI, -0.43 to -0.04) were also statistically significant. CONCLUSIONS: Uric acid-lowering therapy seemed to improve kidney outcomes and reduce the risk of cardiovascular events in adults with CKD.

Expert commentary

Treating high uric acid levels, which causes severe joint pains (gout), now has more added benefits. Evidence is mounting on the strong association of uric acid-lowering treatment on both heart events and progression of kidney disease.

This means that people are less likely to suffer from debilitating physical and psychological heart events and kidney failure, both of which are life-changing. This means they are less likely to need kidney dialysis as uric acid-lowering treatment delays it potentially by at least one year for every year of treatment.

This is a win-win for patients (keeping them working) and use of resources (less use of transplantation and dialysis).

Professor Sunil Bhandari, Consultant Nephrologist/Physician, Hull and East Yorkshire Hospitals NHS Trust and Hull York Medical School