What is the issue?
There is some evidence to suggest that patients with higher uric acid levels in the blood may be more at risk for either developing kidney damage or for kidney damage that they already have getting worse. This study is designed to answer the question "if we reduce uric acid levels in the blood with specific treatments, will that protect the patient from worsening kidney damage or from developing kidney damage in the first place?"
Long-term damage to the kidney (chronic kidney disease) is an increasing problem across the world. With worse damage to the kidney, there are increasing risks of heart disease and death, as well as the increased need for dialysis treatment when kidneys finally fail. There is a great deal of research being performed aimed at reducing both the occurrence of kidney damage and the gradual worsening of damage that is present. This is aimed at reducing death, heart disease, and the need for dialysis treatment.
Uric acid, or urate, is an end product of the breakdown of DNA and is present in everyone. Increasing levels of urate are thought to be potentially damaging to the heart and blood vessels and possibly also the kidney. In kidney patients, it is well known that as kidney damage worsens, the level of urate in the blood tends to rise. There is increasing suspicion that this rise in urate levels in kidney patients is not just the result of kidney damage but may be actually making the situation worse.
What did we do?
We collected all the data from studies that consider patients treated with urate lowering medications for more than 3 months and that report data on death, blood pressure and kidney function in their outcomes.
Twelve studies comprising 1187 participants were included in the review. Duration of the studies was between four months and two years. The types of patients included varied across the studies including diabetes, heart failure, and chronic kidney disease.
What did we find?
The quality of the included studies was difficult to grade due to a lack of information. These are not, therefore, high quality studies.
We found a small amount of evidence that reducing uric acid levels may slow down damage to kidneys but no evidence that it improves blood pressure or any of the other cardiovascular markers that were investigated. The number of patients requiring dialysis treatment for complete kidney failure appears unchanged. Two measures of kidney failure (serum creatinine and glomerular filtration rate) were improved at six and 12 months but not at two years. The amount of protein in the urine was also reduced by treatment. We found no clear effect on death, blood pressure, rates of hospitalisation, or side effects of treatment.
Conclusions
There is limited data which suggests urate lowering therapy may slow down damage to the kidneys but the conclusion is very uncertain. Benefits were not observed at all time points and study quality was generally low. Larger studies are required to study the effect of uric acid lowering therapy on CKD progression.
There is limited data which suggests uric acid lowering therapy may prevent progression of chronic kidney disease but the conclusion is very uncertain. Benefits were not observed at all time points and study quality was generally low. Larger studies are required to study the effect of uric acid lowering therapy on CKD progression. Three ongoing studies will hopefully provide much needed high quality data.
Non-randomised data have shown a link between hyperuricaemia and the progression or development of chronic kidney disease (CKD). If this is correct, urate lowering therapy might form an important part of chronic kidney disease care, reducing risks for cardiovascular outcomes and end-stage kidney disease.
This review aims to study the benefits and harms of uric acid lowering therapy on the progression of CKD and other cardiovascular endpoints.
We searched the Cochrane Kidney and Transplant Specialised Register to 20 July 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
All randomised controlled trials testing primary urate lowering therapy in patients with or without CKD.
Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes or mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) if different scales were used.
Twelve studies (1187 participants) were included in the review. Risk of bias was unclear for the majority of domains in each study.
Uric acid lowering therapy may make little or no difference in death at six months (2 studies, 498 participants: RR 1.66, 95% CI 0.61 to 4.48) or two years (2 studies, 220 participants): RR 0.13, 95% CI 0.02 to 1.06) (low certainty evidence). Uric acid lowering therapy may make little of no difference (low certainty evidence) in the incidence of ESKD at one or two years. Kidney function may be improved by uric acid lowering therapy at one year with a reduction in serum creatinine (2 studies, 83 participants: MD -73.35 µmol/L, 95% CI -107.28 to -39.41) and a rise in eGFR (1 study, 113 participants: MD 5.50 mL/min/1.73 m2, 95% CI 0.59 to 10.41). However it probably makes little or no difference to eGFR at two years (2 studies, 164 participants: MD 4.00 mL/min, 95% CI -3.28 to 11.28). Uric acid lowering therapy reduced uric acid levels at all time points (3, 4, 6, 12 and 24 months) (high certainty evidence).
There is insufficient evidence to support an effect on blood pressure, proteinuria or other cardiovascular markers by uric acid lowering therapy. It should be noted that the apparent benefits of treatment were not apparent at all time points, introducing the potential for bias.