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Childhood Kidney Stones: Their Surprising Connection to Future Disease

October 18, 2016
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Once thought to be an adult condition, urinary stone disease is increasingly found in children – and may be related to the development of cardiovascular disease, chronic kidney disease and low bone density.

By one well-regarded estimate, the risk of developing urinary stone disease in childhood doubled between 1997 and 2012.

That’s worrying enough on in its own. But in the last decade or so, another issue has started to become clear as well. Experts once thought stones were problematic only when causing pain. Now they say:

“(Urinary stone disease) is more than just a symptomatic stone…the body of evidence today suggests not only a chronic metabolic condition punctuated by severely symptomatic acute events, but also a condition that heralds substantial future chronic morbidity and demands preventive efforts,” in the words of a paper published this year from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH).

Or, as Andrew L. Schwaderer, MD, research director in the Division of Nephrology at Nationwide Children’s Hospital and co-author of the NIDDK paper puts it: “We are realizing how serious this is.”

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At the same time as the prevalence of stones is increasing, evidence is building of urinary stone disease’s connection to cardiovascular issues, low bone density and chronic kidney disease. Taken together, those two ideas signal major implications for public health, says Ziya Kirkali, MD, senior scientific officer at the Division of Kidney, Urologic, and Hematologic Diseases at the NIDDK.

“This is a large issue in the pediatric population,” according Dr. Kirkali, who was the lead author of the recent paper from NIDDK detailing the seriousness of the disease. “It’s going to affect a large number of people into the future.”

Dr. Kirkali makes clear that his concern is for everyone, adults and children. All ages may be at risk for stones, and the connection to other conditions was established in adults first. Approximately 1 in 11 people will have a stone in their lifetimes.

But it’s one thing for a 65-year-old to develop a stone, and another for a 13-year-old, who faces many decades of possible recurrences and sequelae.

Pediatric nephrology subspecialists and researchers know this relatively new information about urinary stone disease. Some primary care providers may not. While investigation into stone formation and prevention is accelerating, experts in the field say primary care physicians need to think right now about improving outcomes of their patients with stones.

THE INCREASING PREVALENCE

It’s hard to know when urinary stone disease took hold in the pediatric population. It’s possible, though, to put a date on the beginning of the national conversation about it, says Dr. Schwaderer, who is also a clinical professor of Pediatrics at The Ohio State University College of Medicine.

The New York Times carried a story on October 1, 2008 headlined “A Rise in Kidney Stones is Seen in U.S. Children.” It didn’t contain much in the way of hard data. It just quoted a number of specialists who all had the same experience: trained to believe that kidney stones were almost exclusively an adult problem, they were now regularly finding them in children.

This squared with what Dr. Schwaderer and many others were seeing. David Sas, DO, MPH, was a pediatric nephrologist practicing in South Carolina who had little knowledge about kidney stones initially. But he started seeing so many patients with them that he quickly became interested out of necessity.

 

“When I was talking to pediatricians, family practice doctors and emergency medicine physicians, I heard this over and over again; ‘I was shocked to see this kid had a kidney stone. I didn’t know kids could get kidney stones.’” – David Sas, DO, MPH

“When I was talking to pediatricians, family practice doctors and emergency medicine physicians, I heard this over and over again; ‘I was shocked to see this kid had a kidney stone. I didn’t know kids could get kidney stones,’” says Dr. Sas, now at the Mayo Clinic Children’s Center.

He became the lead author on one of the first population-based studies quantifying what The New York Times had identified. From 1996-2007, the incidence of pediatric kidney stones rose dramatically in South Carolina, the study found.

An expanded study that Dr. Sas co-authored this year revealed that the incidence of kidney stones increased 27 percent every five years in females ages 10-19. Risk of nephrolithiasis is increasing in this group faster than any other. Males 15-19 aren’t far behind, though, with a 23 percent increase every five years.

Plenty of epidemiological work remains, but pediatric nephrologists broadly accept an increase in urinary stone disease – which has led to obvious questions with few good answers:

“What causes the stones? What is causing the increase?” asks Dr. Schwaderer. “We don’t really understand the molecular basis for stone formation. We know stones have a genetic component, that approximately 70 percent of kids who have kidney stones have a first or second degree relative who also has kidney stones. That doesn’t explain the increase, though. Why are adolescent females developing more stones than males? What role do diet and environment play?”

Specialists have some educated guesses. The large majority of stones are calcium based. An increase in dietary sodium, which leads the kidneys to excrete more calcium into the urine, may play a role, says Dr. Sas. So may a decrease in dietary calcium; calcium in food, as opposed to excreted calcium, can actually help prevent the formation of stones. (Obesity, while associated with stones in adults, doesn’t seem to be implicated in children.)

A number of studies have noted that warmer temperatures have a correlation with increased incidence of urinary stone disease: dehydration can lead to concentrated levels of calcium oxalate and uric acid in the urine, which are factors in kidney stone formation. At least two recent studies have speculated that climate change might have some involvement in the rising incidence.

The growing incidence is worrying – and magnified by newly discovered relationships to other lifelong diseases.

Andrew Schwaderer, MD, research director, Division of Nephrology, Nationwide Children's Hospital
Ziya Kirkali, MD, senior scientific officer, Division of Kidney, Urologic and Hematologic Diseases, NIDDK
Davis Sas, DO, MPH, pediatric nephrologist, Mayo Clinic Children's Center
Seth Alpert, MD, attending urologist, Nationwide Children's Hospital

A MULTI-SYSTEM CONDITION?

When a patient comes to Nationwide Children’s with a kidney stone, Dr. Schwaderer tests for rare underlying issues that may have contributed to the stone, such as metabolic acidosis and hypercalcemia. He asks about hydration and diet. Those are the basics.

But in a move that may seem strange to children and their families at first, he also takes a fracture history. He wants to know about family experience with osteoporosis and bone complications. Depending on what the history reveals, he may recommend a bone density scan.

“Even though there are no standard recommendations about screening kidney stone patients for low bone density, we know there is a clear association between the two,” Dr. Schwaderer says. “Osteoporosis may not be diagnosed in a patient until she is 70. If we can see it beginning in an adolescent because a kidney stone prompts us to look, we may be able to take some very early steps to help.”

It’s one thing to talk about the increase in kidney stones by themselves – how painful they are, or how they affect healthcare spending. It’s another to talk of them as signals of conditions that the public takes more seriously such as low bone density, atherosclerosis or chronic kidney disease.

The connection of low bone density and kidney stones first emerged in adults in the 1970s, says Dr. Schwaderer. The association in adults between stones, cardiovascular conditions and chronic kidney disease has come more sharply into focus in the last decade. A 2010 study, for example, showed that adults with kidney stones have higher risks of carotid atherosclerosis and myocardial infarction.

And just in the last few years, evidence for associations in children has started to emerge as well. Dr. Schwaderer was the senior author of a 2015 study that found preliminary evidence of atherosclerosis in children with kidney stones. None of the study participants had been diagnosed with conditions known to cause atherosclerosis, so the authors suggested that damage to the arteries was related to the stones.

Evidence of association is not, of course, evidence of causality. It remains unclear if kidney stones cause these other conditions, if these other conditions cause kidney stones or if some underlying issue contributes to all of them. Some researchers have suggested that calcium leaches from bones, leading to higher urine calcium and kidney stones. If that’s true, it still doesn’t tell the whole story, says Dr. Schwaderer.

The 2015 atherosclerosis study authors hypothesized that vascular and urinary calcifications have overlapping formation mechanisms, and that inflammation plays a role. Chronic kidney disease may be related to stone obstruction and other damage caused by stones.

A lot is left to learn. But the growing knowledge of future morbidities means early diagnosis, proper treatment and ongoing management of urinary stone disease have become crucial to overall childhood health.

DIAGNOSIS AND TREATMENT

According to pediatric nephrologists, this still happens all the time:

A child presents to a primary care doctor or a community Emergency Department with non-specific symptoms – vague back or abdominal pain. The child is diagnosed with a urinary tract infection or constipation, receives treatment but continues to hurt.

The pattern of pain, diagnosis, treatment and more pain continues, even after the child tries another provider. Maybe it goes on for months. Then the child ends up at Nationwide Children’s or another large pediatric institution, where the correct diagnosis of kidney stones is finally made.

 

“There is still this idea, especially when children are initially treated at adult facilities, that kidney stones don’t happen in pediatric patients. Urinary stone disease is often not initially in the differential diagnosis, and so we see delays.” – Andrew Schwaderer, MD

“There is still this idea, especially when children are initially treated at adult facilities, that kidney stones don’t happen in pediatric patients,” says Dr. Schwaderer. “Urinary stone disease is often not initially in the differential diagnosis, and so we see delays.”

The urinary stone disease community should and will do more to educate physicians outside of the field, says Dr. Kirkali of the NIDDK. Dr. Sas, of Mayo, says that in conversations with primary care and emergency medicine physicians, he talks about the rising incidence of stones in children. But he also emphasizes the systemic nature of the disease, in part so other physicians will take the stones seriously.

“With adult kidney stones, a urologist may take care of the stone itself, and that’s kind of it,” Dr. Sas says. “That shouldn’t be it for children. Every child who has a kidney stone warrants a comprehensive evaluation by experts.”

And those should be pediatric experts, says Seth Alpert, MD, attending urologist at Nationwide Children’s and a clinical associate professor of Urology at the OSU College of Medicine. Some children will have acute, symptomatic stones, and they need surgical intervention.

Those interventions require small scopes and stents, along with special training and expertise, which adult urologists do not always have.

“Along with the rise in stones overall, we seem to be seeing more kids, younger kids, who need surgery,” says Dr. Alpert. “A small child’s anatomy can be challenging for an adult urologist.”

Whether surgery is necessary or not, a pediatric multidisciplinary team can be useful in urinary stone disease management. Nephrologists, urologists, radiologists and dieticians all have roles. Medications to prevent stone formation may be necessary. So may a change in eating and drinking patterns.

Subspecialists are also keeping their eyes on new research about those connections to other conditions.

Dr. Schwaderer has decided that best practice is to take a fracture history; so has Dr. Sas. Neither yet regularly screens for cardiovascular problems in patients with stones, though are open to it if future studies show them they should.

And with children’s overall health so much at stake, that research into pediatric urinary stone disease is gaining momentum.

“With adult kidney stones, a urologist may take care of the stone itself, and that’s kind of it. That shouldn’t be it for children. Every child who has a kidney stone warrants a comprehensive evaluation by experts.” – David Sas, DO, MPH

ACCELERATING RESEARCH

Last year, Dr. Kirkali and the NIDDK convened a national meeting called “Urinary Stone Disease: Research Challenges and Opportunities.” Approximately 100 experts came together and laid out goals.

“With the epidemiological data we have, and our awareness that urinary stone disease poses a growing public health problem, we thought we really needed to do some focused research,” says Dr. Kirkali. “We have held meetings before on the subject, but this was the first one that resulted in solid research priorities and funding opportunities. It’s an exciting time in this field, and we’re excited for what’s coming.”

Perhaps most importantly, the NIH has announced $20 million in funding over five years to establish the multicenter, multidisciplinary Urinary Stone Disease Research Network. The network will allow large-scale clinical studies of the kind that haven’t been possible before, especially to determine the best strategies to prevent stones across the population, Dr. Kirkali says.

On the pediatric side, Dr. Sas has led the creation of a multicenter registry called Collaborative Research on Children With Kidney Stones. Dr. Sas’ Mayo Clinic Children’s Center was the first site for the registry, and Nationwide Children’s and Children’s Hospital of Philadelphia have joined the collaborative.

“I noticed in talking to other researchers in the field that we each had interesting findings, but none had enough numbers of patients to come to meaningful conclusions about what we had been seeing,” he says. “If we’re going to make headway, we need to go beyond single institution data sets.”

This infrastructure allows for randomized controlled trials in children, says Dr. Schwaderer. Some studies to evaluate the effectiveness of drugs and diet have been published for adults, but almost none exist for the pediatric population. Until those are completed, many prevention and treatment strategies in pediatrics involve at least some degree of guesswork, he says.

Dr. Sas and Dr. Schwaderer are both investigating how the urinary system microbiome affects stone formation, and Dr. Sas is studying genes that may contribute to stones. Dr. Schwaderer recently collaborated with Daniel Cohen, MD, associate director of Emergency Medicine at Nationwide Children’s, in research on the use of ultrasound versus computed tomography to detect stones in pediatric emergency centers. (International guidelines recommend ultrasound to limit radiation exposure.)

The adult disease has become one of childhood. The stones, once believed largely benign, now appear to be markers of other major conditions. And the healthcare field that used to worry about stones only when they became painful is working to keep pace with the new knowledge.

“Ten years ago, there was a paucity of pediatric research,” Dr. Schwaderer says. “We were managing stones based on adult data. Now, we have more of an impetus to focus on children.”

HOW SHOULD PRIMARY CARE AND EMERGENCY MEDICINE PHYSICIANS HANDLE KIDNEY STONES?

The increase in urinary stone disease means that primary care and emergency department doctors either already see children with stones – or may start seeing them routinely in the near future. So increased knowledge of the disease among these physicians may be vital for improving outcomes.


ANDREW SCHWADERER, RESEARCH DIRECTOR IN THE DIVISION OF NEPHROLOGY AT NATIONWIDE CHILDREN’S HOSPITAL, OFFERS THESE SUGGESTIONS FOR PRACTITIONERS:

  • Know when to include urinary stone disease in the differential diagnosis.

A child with recurrent abdominal or flank pain, blood in the urine (hematuria) or voiding/obstructive symptoms may have stones. Those symptoms can overlap with urinary tract infections, and kidney stones are often initially misdiagnosed as a UTI. If urinalysis reveals white blood cells in the urine, but the culture is negative, stones are a possibility.

  • If ordering diagnostic imaging, use ultrasound instead of CT.

Many physicians already follow the “imaging gently” credo in order to limit the radiation exposure to their patients. Because many children who have stones will eventually have recurrences, the judicious use of CT in this population is particularly important.

  • Refer every suspected kidney stone case to a pediatric nephrologist.

Even if symptoms are mild or manageable in a primary care setting, pediatric nephrologists now believe that each case of urinary stone disease is serious enough to warrant evaluation by a subspecialist. A large pediatric institution has access to urologists, radiologists, dieticians and other experts who can contribute to treatment and ongoing management.


 

References:

  1. Tasian GE, Ross ME, Song L, Sas DJ, Keren R, Denburg MR, Chu DI, Copelovitch L, Saigal CS, Furth SL: Annual incidence of nephrolithiasis among children and adults in South Carolina from 1997 to 2012. Clinical Journal of the American Society of Nephrology. 2016 Mar 7;11(3):488-496.
  2. Scales CD Jr, Tasian GE, Schwaderer AL, Goldfarb DS, Star RA, Kirkali Z. Urinary stone disease: advancing knowledge, patient care, and population health. Clinical Journal of the American Society of Nephrology. 2016 Jul 7;11(7):1305-1312.
  3. Tarkan L. A rise in kidney stones is seen in U.S. Children. The New York Times. Oct 27, 2008. www.nytimes.com/2008/10/28/health/28kidn.html. Accessed Sept 8, 2016.
  4. Sas DJ, Hulsey TC, Shatat IF, Orak JK. Increasing incidence of kidney stones in children evaluated in the emergency department. Journal of Pediatrics. 2010 Jul;157(1):132-137.
  5. Kusumi K, Becknell B, Schwaderer A. Trends in pediatric urolithiasis: patient characteristics, associated diagnoses, and financial burden. Pediatric Nephrology. 2015 May; 30(5):805-810.
  6. Johnson RJ, Stenvinkel P, Jensen T, Lanaspa MA, Roncal C, Song Z, Bankir L, Sánchez-Lozada LG. Metabolic and kidney diseases in the setting of climate change, water shortage, and survival factors. Journal of the American Society of Nephrology. 2016 Aug;27(8):2247-2256.
  7. Glaser J, Lemery J, Rajagopalan B, Diaz HF, Garcia-Trabanino R, Taduri G, Madero M, Amarasinghe MD, Abraham G, Anutrakulchai S, Jha V, Stenvinkel P, Roncal-Jimenez C, Lanaspa M, Correa-Rotter R, Sheik-Hamad D, Burdmann EA, Andres-Hernando A, Milagres T, Weiss I, Kanbay M, Wesseling C, Sánchez-Lozada LG, Johnson RJ. Climate change and the emergent epidemic of chronic kidney disease from heat stress in rural communities. The case for heat stress nephrology. Clinical Journal of the American Society of Nephrology. 2016 Aug 8;11(8):1472-1483.
  8. Schwaderer AL, Kusumi K, Ayoob RM. Pediatric nephrolithiasis and the link to bone metabolism. Current Opinion in Pediatrics. 2014 Apr;26(2):207-214.
  9. Kusumi K, Smith S, Barr-Beare E, Saxena V, Schober MS, Moore-Clingenpeel M, Schwaderer AL. Pediatric origins of nephrolithiasis-associated atherosclerosis. Journal of Pediatrics. 2015 Nov;167(5):1074-1080.

 

Photo credits: Nationwide Children’s (Schwaderer, Alpert); Mayo (Sas); NIDDK (Kirkali)