BioWorld International Correspondent

LONDON - Genetic variations that affect the workings of the innate immune system are more common among people who suffer from repeated severe urinary infections than in healthy controls, a study in Sweden has found.

The study linked low levels of the chemokine receptor, CXCR1, to a higher risk of acute pyelonephritis.

Catharina Svanborg, professor of clinical immunology at the University of Lund in Sweden, told BioWorld International: "Until now, the treatment of urinary tract infections, which mainly affect women, children and the elderly, has been relatively neglected. This finding now gives a solid foundation for regarding urinary tract infections as a disease with a molecular cause, which is worthy of diagnostic work-up and future research."

A report on the study appears in the September issue of the journal PLoS ONE. Its title is: "A Genetic Basis of Susceptibility to Acute Pyelonephritis."

Urinary tract infections are very common, affecting about 1 percent of girls, about 2 percent of pregnant women and up to 20 percent of elderly people. Some of the infections, in which bacteria enter the urinary tract, cause no symptoms, but some people develop very severe kidney infections called acute pyelonephritis.

Among those with acute pyelonephritis is a subgroup of people who will go on to have repeated episodes of that condition and in whom the kidneys become scarred. Kidney damage may be severe, so that renal dialysis and transplantation become necessary.

Understanding the factors that determine why those in the latter subgroup develop such severe infections is therefore of great interest. Researchers have known for some time that the innate immune response is involved in clearing bacteria from the urinary tract.

Invading bacteria stick to the internal wall of the urinary tract, triggering an inflammatory response with release of chemokines into the tissues. The chemokines attract neutrophils, which leave the tissues, enter the urinary tract, engulf bacteria and exit in the urine, removing both the bacteria and the toxic content of the neutrophils themselves.

Svanborg and her colleagues have studied those processes for years, including bacterial markers of pathogenesis, with the aim of identifying those patients who are at greatest risk of kidney damage.

"We were very interested to see that in knockout mice that lacked a functional copy of the gene for the chemokine receptor CXCR1, the animals developed very severe urinary tract infections, with lots of bacteria, and kidney damage," she said.

That observation stimulated the team to study the sequence of the gene encoding CXCR1 in two groups of patients known to be susceptible to severe acute pyelonephritis, and compared those sequences to those from healthy controls.

"We found that the patients were heterozygous for this receptor," Svanborg said, "so that they have very low expression of this protein. In addition, when we excluded patients who also have urine reflux, which can also cause kidney scarring, we found that half of the remaining patients also had polymorphisms in this gene."

Investigations showed that one of the polymorphisms affected a transcription-factor binding site. "We have shown that this polymorphism leads to reduced transcription of the gene," Svanborg said.

"In another case, we believe that the polymorphism affects the stability of the messenger RNA. However, we need to do some more work on the link between the polymorphisms and the phenotype," she added.

The findings fit well with what is known about the pathogenesis of kidney scarring in acute pyelonephritis. In the knockout mice, neutrophils lacking CXCR1 are unable to leave the kidneys. As a result, the kidneys remain full of neutrophils, and eventually become fibrotic. Neutrophils that lack CXCR1 also are unable to phagocytose bacteria in the normal way.

"Our discovery could influence the clinical treatment of urinary tract infections," Svanborg predicted. "These infections are sometimes not taken seriously - often urine cultures are not even carried out. But now there is definitely room for the development of a diagnostic test that would identify those at highest risk of kidney damage."

Future work by the team will focus on determining whether there are any links between other genetic variants and the risk of developing less severe urinary tract infections such as cystitis or asymptomatic bacteriuria.