BackgroundFor unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.Methods and FindingsWe have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.ConclusionsThe results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring.

This study describes the pattern of urinary tract infections (UTI) in 87 females prospectively followed for a median of 23 years from their first recognized symptomatic infection in childhood. At 16 years of age they were selected for follow-up into adulthood because of renal scarring (reflux nephropathy) in 45 and recurrent UTI in 42. The attack rate (number of urinary tract infections per individual per observation year) was highest during the 1st year of life (1.9), with a gradual decrease to the lowest rate (0.2) at age 11-15 years. A moderately increased attack rate (0.4), was seen in the late teens, extending through to the mid twenties. The proportion of infections having a pyelonephritic character decreased with age and number of infection episodes, but not in females with severe renal scarring. Pyelonephritic infections were correlated with vesicoureteric reflux, and renal scarring to low age at the index infection, total number of pyelonephritic episodes and reflux. Females with renal scarring continued to have a high proportion of pyelonephritic recurrences after 10 years of age, implying that they risk progressive renal disease and should be closely followed into adulthood.

The mucosal and systemic interleukin-6 (IL-6) response to urinary tract infection was analyzed in women with acute pyelonephritis or asymptomatic bacteriuria. Urine and serum samples were obtained at diagnosis and after treatment. IL-6 activity was elevated in urine samples from most bacteriuric women, regardless of the severity of infection. Urinary levels greater than 20 units/mL occurred in 25 of 29 women with acute pyelonephritis and in 36 of 42 women with asymptomatic bacteriuria. Elevated serum IL-6 levels were found mainly in patients with acute pyelonephritis: Levels greater than 20 units/mL occurred in 14 of 28 women with acute pyelonephritis compared with 0 of 28 women with asymptomatic bacteriuria. These results suggest that bacteriuria is accompanied by elevated urinary IL-6 levels and that this IL-6 is locally produced. The spread of IL-6 to the circulation in patients with acute pyelonephritis may contribute to the elevation of fever and C-reactive protein characteristic of the disease.

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This study describes blood pressure and renal function, as well as indices of renal disease, in females with and without renal scarring followed from their first urinary tract infection (UTI) in childhood. Of the 111 patients with a median follow-up time of 15 years, 54 had renal scarring (reflux nephropathy) on urography, which was severe in 19 and moderate in 35. The glomerular filtration rate was lower in patients with severe renal scarring and correlated with renal area on urography. However, the filtration rate was decreased below the lower reference limit in only 7 patients, with a lowest value of 70 ml/min per 1.73 m2. The diastolic blood pressure was higher in women with severe scarring. Hypertension of at least 140/90 mmHg was diagnosed in 3 of 54 (5.5%) females with renal scarring, 2 before and 1 at the follow-up examination. The excretion of albumin in urine was low and not correlated to filtration rate. Tubular enzymes in urine were similar in all groups. Thus the renal function was well preserved and the incidence of hypertension low. Within this range of renal function, the level of albumin in urine did not predict the degree of renal scarring.