Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.
In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter . The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.
This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.
VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011 .
The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.
With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators ( AAP News 2015;36:13 ). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.
A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [ doi:10.1542/peds.2015-0409 ]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”
The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”
But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “ perfect is the enemy of good.”
There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age . All medical treatments introduce a substantial risk of harm . As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.
Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. E-mail him at pdnews@frontlinemedcom.com .
