Fructose and uric acid: Survey Results

by Prof. Richard Johnson

We had over 600 nephrologists complete the survey on current opinions on the role of fructose and uric acid in kidney disease and metabolic syndrome. 

Most of the nephrologists were from Europe,

were specialists in clinical nephrology or dialysis,

and had hospital or academic- based positions. 

The topic is quite controversial, so it is interesting to see what current opinions are.

This was somewhat of a tricky question.  Honey is one of the most concentrated forms of fructose, and can have 42% fructose by weight.  Soft drinks contain either table sugar (50% glucose and 50% fructose) or high fructose corn syrup (55% fructose and 45% glucose).  However, the sugar content is diluted by the presence of water, and hence, on a percent weight basis, honey has the highest amount of fructose per gram.  So this was not an easy question.  While honey has the highest percent fructose, since we do not eat that much at a serving, the soft drink is the best (or worst, depending on your opinion) way to get a high dose of fructose  in your body fast.  Furthermore, since it is the concentration of fructose that the cells are exposed to, drinks that can be ingested rapidly are relatively more dangerous than solid foods containing the same amount of sugar.

Animal studies document that fructose can induce all features of the metabolic syndrome, and similar studies have now been shown in humans.  Thus, fructose raises postprandial triglycerides, lowers HDL, and can induce insulin resistance in humans.  Classically fructose does not raise LDL—cholesterol, however, some studies do show mild but statistically significant effects on LDL-cholesterol as well. Thus, there may be no truly correct answer here, but LDL--cholesterol would be the one most of us who study fructose would pick.

Both fructose and glucose can be metabolized to generate triglycerides and glycogen, although fructose may be more efficient at this.  In addition, while fructose is preferentially metabolised  by fructokinase, it can also be metabolized by hexokinase as can glucose.  However, fructose is distinct from glucose in its ability to transiently induce ATP depletion, which occurs as a consequence of the rapid phosphorylation of fructose to fructose 1 phosphate by fructokinase.  There is much evidence that the adverse metabolic effects of fructose are due to this specific effect of fructose.

Uric acid excretion is reduced in volume depletion and can result in mild hyperuricemia; in contrast, volume expansion can reduce serum urate levels. Urinary urate excretion is modulated by tubular flow rates and renal blood flow.  In addition, lead can increase serum uric acid, likely via effects on uric acid transport in the proximal tubule.  It is clear that gouty nephropathy, mediated by urate crystals, is not likely a true disease, or at least is not a major cause of ESRD.  However, there is emerging evidence that allopurinol may provide benefit in CKD in subjects with hyperuricemia, possibly by preventing the non-crystal effects of uric acid on the kidney.  However, data remains preliminary and pilot in nature and use of allopurinol is currently not recommended.

This is an opinion question on the potential significance of serum uric acid in subjects with CKD.  Ten years ago my belief is that the majority would have not considered uric acid important other than as a risk for gout or stones.  However, the last 5 years have seen a plethora of experimental and epidemiological data, as well as some small clinical trials, that suggest that uric acid may have a role in CKD progression and in cardiovascular events and metabolic syndrome.  It appears that this message has now reached the clinician. 

This is another opinion question related to whether treatment should be offered.  A serum uric acid over 600 uM is very high and the epidemiological evidence linking it with renal progression is also very solid.  However, while experimental data truly support reducing uric acid levels of this degree, clinical proof is still in need of more studies.   While I would not recommend this as a general treatment, I would consider giving allopurinol to my patient, as did the majority of nephrologists, provided the patient is aware and accepting of the risks of allopurinol for inducing hypersensitivity syndrome and provided the patient is aware that the recommendation is based on emerging clinical and experimental data, and that definitive evidence is still lacking.  Close monitoring of the patient is recommended and the patient should be instructed to stop allopurinol immediately at the signs of a rash.

This last question is also very interesting, and has mixed opinions.  Clearly fructose can induce obesity and metabolic syndrome in animals.  While excessive intake of fructose is clearly not a good idea in a normal individual, what about in the malnourished dialysis patient?  Would an attempt to increase fat in the liver be a good thing for these patients, or not?  Certainly we would not want to induce diabetes or hyperlipidemia, so my general feeling is that we would not want to encourage fructose intake in this population.  However, for the starving malnourished dialysis patient, perhaps fructose might be a good thing.  Clearly more studies are needed to sort this out, and this is why research is so important.