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SAN DIEGO -- Antibiotic prophylaxis may help to protect kidneys of kids with vesicoureteral reflux during febrile urinary tract infections (UTIs), according to another look at the trial.

Among 188 children with this common congenital anomaly, more than one febrile UTI during the 2-year study period had an average eGFR -16.7 mL/min/1.73 m² (95% CI -32.1 to -1.3) lower than kids with one or fewer UTIs in an adjusted model, reported David S. Hains, MD, MBA, of the Indiana University School of Medicine in Indianapolis at the American Society of Nephrology Kidney Week meeting.

"UTIs resulting in a negative eGFR change may have long-lasting consequences," Hains and colleagues underscored in a simultaneously published research letter.

But this eGFR decline was only seen in children who weren't receiving antibiotic prophylaxis during the study; kids who were on continuous antibiotic prophylaxis had a nonsignificant decline. Meanwhile, those on placebo had a substantial eGFR reduction associated with febrile UTIs:

• Prophylaxis: -8.0 mL/min/1.73 m² (95% CI -30.6 to 14.5)
• Placebo: -22.3 mL/min/1.73 m² (95% CI -43.5 to -1.0)

"We were pleasantly surprised by our findings," Hains told MedPage Today. "The trouble with children with vesicoureteral reflux is that what we see clinically doesn't always match up with what the clinical trials have shown. I think people were just looking at the wrong outcome historically."

trial didn't include eGFR decline as a main outcome. Instead, it looked at UTI recurrence prevention as the main outcome and kidney scarring on dimercaptosuccinic acid (DMSA) scan as one of the secondary outcomes. While trimethoprim-sulfamethoxazole prophylaxis reduced the risk of recurrences by 50% (HR 0.50, 95% CI 0.34 to 0.74) versus placebo, the occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively).

"Our study shows that UTIs do affect kidney function at the microscopic level, not necessarily the macroscopic level that we have historically monitored with DMSA scans," said Hains. "Perhaps we need to use GFR as a measure in kids with vesicoureteral reflux rather than DMSA scan results."

"It also raises the question of the utility of continuous antibiotic prophylaxis in protecting and or preserving kidney function," he added. "For the last 10 years or so, pediatricians have largely thought that continuous antibiotic prophylaxis may have limited value. I think it's a great lesson to not just accept a historic 'gold standard' and to constantly be questioning, 'Are we missing something?' when the clinical picture doesn't necessarily add up with the clinical trial results of yesteryear."

Monitoring children with vesicoureteral reflux with radiologic testing doesn't necessarily give insight into true kidney function, Hains said. "Pediatric nephrologists have largely not been involved in the longitudinal care of these kids unless they have significant kidney disease. But perhaps involving us in the care early on we can monitor and intervene when kidney function is changed."

"As a nephrologist, I see kids that have kidney disease with vesicoureteral reflux and the only differentiating component to their history from kids that don't is that they have lots of UTIs," he added. "Anecdotally, I've also seen a lot of children recently that have abnormal kidney function, and I believe that's because we have become a little bit more conservative in our management of this condition."

The current analysis looked at 89 RIVUR participants, ages 6 months and older, who were randomized to receive antibiotic prophylaxis. They were compared with 99 children on placebo, all of whom had data on entry and exit serum creatinine measurements available. All participants had grade I to IV vesicoureteral reflux diagnosed after a first or second febrile or symptomatic UTI.

The eGFR change was calculated as 2-year exit eGFR minus enrollment eGFR. The models were adjusted for eGFR at enrollment, bowel, and bladder dysfunction at baseline (absent or present, not toilet trained), and age in months.

Overall, the median eGFR change was a nonsignificant -2.6 (95% CI -11.4 to 6.3) for each additional lifetime UTI among study participants.

When looking at kids with more than one UTI during the study (not just febrile UTI), both study groups had nonsignificant decline in eGFR compared with those with one or fewer UTIs in adjusted models:

• Prophylaxis: -8.0 mL/min/1.73 m² (95% CI -30.6 to 14.5)
• Placebo: -11.3 mL/min/1.73 m² (95% CI -30.4 to 7.8)

Because the RIVUR trial wasn't designed or powered to properly evaluate eGFR change, Hains called for additional, larger studies of children with UTIs.

"Because we've gotten better at measuring creatinine more precisely and accurately as well as estimating GFR in children over the last 15 years, we need to look back at what we thought was canon and perhaps reanalyze things like this," he said.

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