Uric acid: Biomarker or risk factor for diabetic nephropathy?

People who suffer from diabetes mellitus and have elevated uric acid levels, often also have diabetic nephropathy. The question was clearly answered: uric acid is a biomarker and not a risk factor.

Different therapies are studied

People who suffer from diabetes mellitus and have elevated uric acid levels often also have diabetic nephropathy. At a symposium during the virtual Annual Conference 2020 of the European Association for the Study of Diabetes, the question of the role of uric acid was clearly answered: Uric acid is a biomarker and not a risk factor for nephropathy.

According to Daniel I. Feig (University of Alabama, Birmingham, USA), uric acid is a product of purine metabolism and is produced with the help of xanthine oxidase (XO). Most uric acid is excreted through the kidneys. If serum levels are elevated, uric acid crystals can cause gout due to deposits in the joints or kidney stones due to deposits in the kidneys.

Hyperuricemia can be promoted by the intake of purine-rich foods. It is more frequent in obese people. Kidney dysfunction with reduced uric acid excretion can also cause uric acid levels to rise. Genetic polymorphisms also play a role.

Hyperuricemia, hypertension, and chronic kidney disease

Several studies have shown that elevated uric acid levels are associated with increased cardiovascular mortality. In the rat model, hyperuricemia can promote hypertension. When uric acid levels are lowered in rats, blood pressure returns to normal.

Feig presented a two-step model for the development of uric acid-mediated hypertension: In the first phase, uric acid induces acute vasoconstriction by activating the renin-angiotensin system (RAS). In this phase, hypertension is uric acid-dependent and sodium ion-independent. The changes are reversible.

In the second phase, uric acid is increasingly absorbed into the smooth vascular muscle cells (VSMCs) and increases cell proliferation. The wall thickness of the vessels increases. Hypertension becomes independent of the uric acid level and is sensitive to sodium ions. If the uric acid levels are lowered, high blood pressure remains.

The two-step model is supported by smaller clinical trials in adolescents and adults. In children and adolescents with newly diagnosed hypertension, the administration of allopurinol to lower uric acid levels has been shown to lower blood pressure. This was no longer successful in older hypertensive patients.

In older patients with chronic kidney disease, the uric acid-lowering treatment also had hardly any effect. In younger candidates and those with only mild kidney dysfunction, uric acid lowering showed improvements in the glomerular filtration rate (GFR), which also supports the 2-phase model.

Uric acid is only a marker

Niina Sandholm (University of Helsinki, Finland) has declared uric acid only as a biomarker for diabetic nephropathy, not as a risk factor.

Several studies have shown that elevated uric acid levels are a predictor of diabetic nephropathy. The Finnish Diabetic Nephropathy Study (FinnDiane) has also shown that uric acid levels are associated with the status of diabetic kidney disease and can be used to draw conclusions about progression.

The question of whether uric acid is a marker or a causal risk factor could be investigated in randomized controlled trials with uric acid-lowering drugs. However, such trials are long, time-consuming, and costly.

Mendelian randomized (MR) trials came closer to finding the answer, though. The trials showed that uric acid is not a causal risk factor for diabetic nephropathy. Mendel's randomization trials in the general population also showed, using data from the UK Biobank, that uric acid is not a causal risk factor for chronic kidney disease.

For control purposes, the association between elevated uric acid levels and gout was analyzed. The Mendelian randomization studies clearly showed that uric acid is a causal risk factor.

PERL study: Allopurinol in type 1 diabetics

In June, the PERL study (Preventing Early Renal Loss) was published in the New England Journal of Medicine. The research group of Michael Maurer (University of Minnesota, Minneapolis, USA) investigated whether lowering serum uric acid levels with allopurinol can delay the progression of kidney disease in type 1 diabetics with mild to moderate diabetic nephropathy. In the double-blind trial, 267 patients were randomly assigned to allopurinol and 263 to placebo. They were 51.1 years old on average and had had diabetes for 34.6 years.

Over the observation period of three years, the uric acid concentration under placebo remained constant at 6.1 mg/dl. Under allopurinol, the uric acid level dropped to 3.9 mg/dl and rose again to 5.9 mg/dl after a two-month washout period. Using two methods of GFR measurement, there was no difference between the placebo and allopurinol groups. After the washout period, albumin excretion in urine was 40% higher in the allopurinol group than in the placebo group.

The results thus showed no benefit of uric acid reduction with allopurinol in type 1 diabetics with mild to moderate diabetic nephropathy. However, this study again mainly included older patients who were in the irreversible second stage according to the two-stage hypothesis proposed by Daniel I. Feig.

Symposium "Uric acid: a biomarker or risk factor for disease - the answer is here! Virtual EASD Annual Meeting 2020. p36.