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The Pediatric Nephrology  Region makes its inaugural entry into NephMadness ’16. Without a doubt this region represents an all-star cast of “diaper dandies”, literally.  Think Kentucky, Duke, North Carolina, and Kansas all in the same region of the bracket (in fact, the post was co-written by Duke and North Carolina nephrons- see, we can get along). The top half of the bracket features a UTI battle royal. The recent report of the RIVUR trial represented a major advance in what we know about the medical treatment of vesiculoureteral reflux. Imaging after UTI (when and where) is always controversial topic in peds nephrology and is sure to “light up” the competition. The bottom half of the bracket is another nail biter. During medical school, Teams typical and atypical HUS often lead to much confusion. With the recent signing of Eculizumab (a NephMadness veteran) to team Atypical HUS is sure to stop the offensive complement cascade of team Typical. We welcome Peds Nephrology to the Fray and hope to see more Peds regions in the future.

Selection Committee member for the Pediatric Nephrology Region:

John D. Mahan, MD

Dr. Mahan is Professor of Medicine and General Pediatric Residency and Pediatric Nephrology Fellowship Program Director at Nationwide Children’s Hospital/The Ohio State University College of Medicine.  He serves as Associate Director of Medical Education in the OSU Center for Faculty Advancement, Mentoring and Encouragement.  He also serves as Co-Chair of the American Society of Pediatric Nephrology (ASPN) Training Program Directors (TPD) Committee and as a member of the American Society of Nephrology (ASN) TPD Executive Committee. Dr. Mahan completed his pediatric nephrology fellowship at the University of Minnesota and his research interests include pediatric CKD, growth issues in pediatric renal disorders and evidence-based medical education.  He is actively involved in educational efforts in the ASN, ASPN, and American Academy of Pediatrics.

Meet the Competitors for the Pediatric Nephrology Region

Imaging after UTI
Prophylactic Antibiotics after UTI

Typical HUS
Atypical HUS

Imaging after UTI vs Prophylactic Antibiotics after UTI

This matchup pits 2 teams fighting to prevent recurrent urinary tract infection (UTI) in children—a topic that has left some players scarred for life. UTIs are a common problem in both the outpatient and inpatient pediatric setting. Symptoms can range from a fussy baby to pyelonephritis to bacteremia (even leading to sepsis and death). A huge risk factor for frequent UTIs is vesicoureteral reflux (VUR) or the retrograde passage of urine from the bladder to upper urinary tract. In fact, VUR is the most common urologic anomaly occurring in 1 in every 100 newborns.

But what does this have to do with Nephrology? Is this an “only airing on ESPN 3” kind of game? Absolutely not! This matchup is on primetime ESPN! Why is this? Well, for one, frequent UTIs can result in renal scarring, which can lead to hypertension, proteinuria, and even ESRD! In fact, a 2014 meta-analysis in JAMA Pediatrics found that even after the first UTI, ~15% of patients had evidence of renal scarring. The combination of VUR + UTI puts patients at an even higher risk of renal scarring. The loss of renal parenchyma (aka scarring) associated with VUR is known as “reflux nephropathy” is more likely to occur with worse VUR. Let’s move on to the matchups and see what can be done to prevent renal scarring. The first round matchup pits prophylactic antibiotics versus urinary tract imaging which are two common maneuvers frequently employed to either reduce scarring or better understand the anatomical anomaly leading to VUR. Let’s take a look at how these two teams matchup.

Imaging After UTI

This next team prides itself on precision and you can almost feel their energy on the court in the form of electromagnetic waves. Imaging children after a UTI has been an extremely controversial and frequently discussed topic. On one hand, imaging can help detect important genitourinary (GU) tract abnormalities that can potentially be modified. However, this can be costly, painful to the child, and may expose kids to unnecessary radiation. Okay, let’s meet this team’s line up: first up is ULTRASOUND, who is known for playing it safe. Renal and bladder ultrasound is a noninvasive test that can reveal anatomical abnormalities of the GU system and the presence of renal or perirenal abscess. Next, we have voiding cystourethrogram (VCUG), who has made a name for itself by identifying the reflux of urine from the bladder to the upper urinary system. That’s right, VUR (vesicoureteral reflux), which is a HUGE risk factor for renal scarring, is in trouble when this player is guarding it. Can we get a play-by-play? First, the patient is catheterized and bladder is filled with radiocontrast. Next, under fluoroscopy, the patient voids and the Radiologist watches for reflux of the contrast. Given the exposure to radiation and invasive nature, this can be a little risky and doesn’t always score (many patients at risk of renal scarring are missed!). Last but not least, we have renal scintigraphy with (dimercaptosuccinic acid) DMSA! This radioactive tracer is intravenously injected and uptake in the kidney is identified a few hours later. Decreased uptake may represent pyelonephritis or renal scarring. As previously mentioned, this is the MVP of detecting renal scarring! There have been a number of analysts trying to figure out this complicated and controversial team. The UK based NICE (National Institute for Health and Care Excellence) guidelines recommend ultrasound in all children <6mo and in older children with recurrent or “atypical” UTIs (i.e., very sick kid, elevated creatinine, weird infection, etc), VCUG in kids <6mo with “atypical UTI”, and DMSA in children <3yr presenting with recurrent or “atypical” UTI. The AAP (American Academy of Pediatrics) has other thoughts about this team.

• Ultrasound in all kids under 2 with a first febrile UTI (unless 30-32 weeks gestation prenatal ultrasound was normal)
  
• Ultrasound in all kids regardless of age with recurrent UTI
• VCUG only if ultrasound is concerning
• DMSA is not recommended

Imaging is a team fraught with controversy but with great vision and depth. The role of imaging in UTIs continues to evolve especially with newer data emerging from the RIVUR and CUTIE studies. However, the matchup between prophy and imaging appears to be a tossup with both playing important roles in the management of UTIs but neither truly providing the definitive edge. Should be a good one!

Prophylactic Antibiotics After UTI

If reflux of urine leads to renal scarring, why not treat all kiddos with known VUR with antibiotics? This question remained elusive for years. Rock solid clinical trial evidence just did not exist. In fact, only a handful of trials exploring VUR treatment options had even been reported prior to 2014. Each of these trials had one fatal flaw, they did not include a placebo group but instead only compared antibiotics to surgical treatment of VUR. The data did not point to a difference between antibiotic prophylaxis versus surgical repair in terms of rates of UTIs or renal scarring. What about prophylactic antibiotics versus nothing? In the interim a few randomized, mostly non-blinded, studies have been attempted and yielded conflicting results with both decreases in UTIs and no difference in UTIs. However, none of these really addressed the all important kidney scarring question.

Figure adapted from The RIVUR Investigators, NEJM, 2014; 370:2367-2376

This was one of the questions recently asked by the RIVUR trial (Randomized Intervention for Children with Vesicoureteral Reflux). This study is by far the MVS (most valuable study) of prospective, randomized trials in children with VUR and one of the first papers discussed on NephJC. RIVUR enrolled over 600 children diagnosed with VUR after a first or second febrile UTI and sought to evaluate the role of antimicrobial prophylaxis in preventing recurrent UTIs and importantly reducing eventual renal scarring in this population. The main findings of the RIVUR trial were reported in the NEJM in 2014. So, did antibiotic prophylaxis decrease recurrent UTIs? Yep! The risk of UTIs decreased by 50% in the patients receiving prophylactic trimethoprim-sulfamethoxazole (see figure above). This dramatic reduction in UTIs is truly a diaper dandy (literally), but was this enough to reduce renal scarring and head to the NBA? To answer this question the participants underwent three dimercaptosuccinic acid (DMSA) renal scans during the study period. Once at 2 weeks, another at 1 year, and lastly one at 2 years. Before we go any further, let’s take an official time-out. What the heck is a DMSA scan?! It’s a radionuclide study where a radioisotope tracer is used to visualize renal morphology, structure, and excretory function. The DMSA renal scan is currently the gold standard in the diagnosis of renal scarring. Okay, back to the game: did prophylactic antibiotics decrease renal scarring compared to prophylaxis? NOPE. There was no significant difference in renal scarring between the two groups. However, we should keep in mind that renal scarring was a secondary outcome and the RIVUR study may not have been powered to detect a difference. They also reported, as expected, an increased rate of E. coli UTIs resistant to trimethoprim-sulfamethoxazole (63% versus 19%) in the prophylaxis group. So, this decrease in UTIs with antibiotic prophylaxis came at a price (resistance) and didn’t lead to improvements in scarring. But, was 2 years long enough to assess scarring? Maybe not. However, the RIVUR trial is a well-conducted blinded randomized controlled trial that provided key data on an important topic. Prophylactic antibiotics in VUR seem to have a one dimensional game plan. How will team Abx Prophy fare against Imaging? This could get ugly.

Team prophy isn’t done yet. They still have a few more tricks up their sleeves. What is the natural history in terms of scarring and infection in UTIs in patients without VUR? and how do they compare to patients with VUR in placebo group of RIVUR. This leads us to the CUTIE study. The Careful Urinary Tract Infection Evaluation (CUTIE) study evaluated patients initially screened for RIVUR, but found to NOT have VUR and were NOT treated with prophylactic antibiotics. The CUTIE cohort was compared to the placebo branch of RIVUR. The study found that in addition to VUR, risk factors for recurrent UTIs include bladder and bowel dysfunction and the presence of renal scarring at baseline. Are antibiotics after the first UTI the clear winner? Maybe. Broad antimicrobial prophylaxis may lead to bacterial resistance, so identifying risk factors for recurrent UTIs may be needed to help tilt the risk/benefit ratio.

Typical HUS vs Atypical HUS

Next up in the Pediatric Nephrology bracket is typical hemolytic uremic syndrome (HUS) versus atypical HUS—a storied rivalry with high emotions and low RBCs/platelets. Atypical HUS (aHUS) is a returning favorite in NephMadness and after Eculizumab’s stunning loss to Belatacept in 2014, aHUS is back with a vengeance. HUS is a major cause of acute kidney injury (AKI) in the pediatric population and is defined by the triad of

• microangiopathic hemolytic anemia
• thrombocytopenia
• AKI

The majority of HUS in children is linked to Shiga toxin producing E. coli (or typical HUS); however, this syndrome can also occur due to complement dysregulation without coexisting disease (or atypical HUS). This is expected to be a fierce match-up! Is atypical HUS ready to stop living in typical HUS’s shadow? Can typical HUS prove that it’s more than just the “diarrhea” HUS?

Typical HUS

First up, we have typical HUS aka diarrhea-positive HUS aka secondary HUS aka tHUS. There is nothing “typical” about this aggressive competitor who is a large cause of kidney injury in kids and the most common type of HUS in children. However, the history of this team Typical HUS is indeed a bit murky. It wasn’t until 1966 that we saw the first report of an outbreak. The concept of HUS occurring from an infectious etiology was debated up until this time. A quote from this paper in 1966.

“Since it is almost invariably preceded by a gastrointestinal or respiratory illness, it seems probable that it represents a response to an infection. Although Gianantonio et al. (1964) have identified one possible causative virus, it may be that various infective agents can initiate the syndrome.”

However, this debate continued to persist for the next 20 years, likely because the genetics of atypical (familial) HUS had yet to be worked out. Therefore, the grouping of both aHUS and tHUS resulted in continued confusion.

This team comes in many flavors, but 90% of HUS is caused by shigatoxin-producing enterohemorrhagic E. coli (STEC). This form of HUS double-teams the kidney with a prodrome of vomiting and bloody diarrhea (#prerenalAKI) and glomerular thrombotic microangiopathy, which can extend to the afferent arteriole. Additionally, cortical necrosis can affect the superficial cortex in severe cases of STEC HUS. Shigella dysenteriae can have a similar presentation due to STEC release and is typically seen in India, Bangladesh, and southern Africa. HUS can also present after a Streptococcus pneumoniae infection, HIV, and H1N1 Influenza A. Pneumococcal associated HUS can be seen in 5-15% of cases in the US and its pathogenesis is thought to be linked to release of N-acetyl neuraminidase that strips glycoproteins from the surfaces of endothelial cells, RBCs, and platelets. The main pathology of typical HUS is endothelial inflammation leading to activated coagulation, which causes the formation of fibrin thrombosis. Vascular thrombosis eventually results in the HUS triad.

This team is tough to beat because there is no specific therapy and the only recourse is supportive care. It is interesting to note that eculizumab first made headlines back in 2011 during an outbreak of E. coli O104:H4 secondary to contaminated sprouts that occurred in Germany. This resulted in reports of using eculizumab in several children with typical HUS in NEJM. In fact, this story was catapulted to number 8 on the 2011 top nephrology stories on RFN. However, in ensuing years eculizumab has made a real name for itself in the atypical and not the typical HUS world.

Atypical HUS (aHUS)

Atypical HUS or HUS without a coexisting toxin as cause of the disease, has been a hot topic in nephrology over that past decade. The genetic underpinnings of aHUS results from dysfunction of the alternative complement pathway. The first description of the potential genetic component was from a 1975 NEJM paper examining HUS in 3 siblings. Atypical HUS is a very versatile team with a few different ways of firing up the crowd and the complement cascade. Without further ado, let’s introduce the starting line-up in the pathogenesis of aHUS! #1 A mutation in genes that code complement proteins (50-60% of patients); #2 Antibodies to complement proteins (8-10%); and #3 Other genetic causes (DGKE mutation [encoding diacylglycerol kinase ɛ], plasminogen [PLG] mutations).

So what is this team’s winning play? It starts with a trigger, like infection or pregnancy, in patients with the gene mutation or complement antibodies listed above. Uninhibited activation of the alternative pathway causes unregulated generation of MAC (membrane attack complex), which leads to renal endothelium damage and activation of the coagulation cascade and thrombotic microangiopathy.

We have come a long way in treating this life-threatening disease. The international consensus on managing atypical HUS (2014) is first line therapy with eculizumab, a monoclonal anti-C5 antibody working on the terminal complement cascade. This should be initiated within the first 24-48hr of symptom onset because delaying treatment may affect recovery of renal function. If you don’t have a vial of eculizumab lying around, plasma exchange is recommended as second line. Also, it is NOT necessary to confirm a complement mutation before starting treatment. TIME IS NEPHRON. What sorts of studies have been performed examining eculizumab in aHUS? A 2013 study in NEJM examined 37 patients with aHUS and this showed dramatic improvements in eGFR, discontinuation of HD, and hematologic improvements.

Atypical HUS represent a new era in nephrology. Targeted therapy directed at the pathological derangement is just what nephrology needs.

– Post written and edited by Drs. Mona Shaban, Matt Sparks, and John Mahan.

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