Kidney Stone Disease in Children
From The Child's Doctor, Fall 2012
- Gal Finer, MD, PhD
- Attending Physician, Kidney Diseases (Nephrology), Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Finer has no industry relationships to disclose and does not refer
to products that are still investigational or not labeled for the use
Other Disclosure Information
At the conclusion of this activity, participants will be able to:
- Recognize the risk factors for kidney stones in children
- Discuss the diagnostic approach
- Identify dietary and medical interventions to prevent stone recurrence
Kidney stone disease (nephrolithiasis) was once thought to be primarily an adult disease. We now recognize that kidney stones are occurring with increasing incidence across the entire pediatric age spectrum. To help pediatricians manage kidney stones in children, this article will discuss the pathogenesis, etiology, risk factors, and approaches to evaluation and prevention of stone recurrence.
Recent data suggest that the incidence of pediatric kidney stone disease in the United States is on the rise, increasing more than threefold in the past decade. A similar trend has been reported in adults, although to a much smaller extent. Although kidney stones occur throughout childhood the likelihood of a stone is 10 times more common during teenage years. Kidney stones do differ a bit between adults and children however, including the absence of male predilection to kidney stones during childhood and the occurrence of female predominance as children enter adolescence. In concordance with adults, stones are more prevalent in children of Caucasian decent as compared with African American individuals, whereas the risk in Hispanic children is higher than in African American children, but not as high as in Caucasian children.
What accounts for this observed increase in kidney stone disease in children over the past decade? Although there is no strong evidence to support a single factor as responsible, it has been postulated that today’s children have been subjected to life style changes that promote kidney stone formation. Dietary habits such as increased salt intake, inadequate calcium intake, and reduced fluid intake have been implicated. Recently, speculation regarding a possible link between higher rates of overweight and obesity in children to the increased incidence of pediatric nephrolithiasis has been suggested and will be discussed further here.
Types of kidney stones
Based on stone analysis, the vast majority of nephrolithiasis in children is comprised of calcium, either in the form of calcium oxalate (65%), calcium phosphate (45%) or in combination (up to 90% according to some series). Uric acid, struvite (ammonium magnesium phosphate) and cystine stones comprise about 10% of cases in pediatric patients. Very rarely the stone composition is that of calcium oxalate monohydrate or xanthine, heralding the diagnoses of primary hyperoxaluria and xanthinuria respectively, both important inborn errors of metabolism associated with variable stone burden in childhood. The focus of this article will be calcium-based stones, which pose the greatest impact on children’s health.
Presenting symptoms and signs
The clinical presentation of nephrolithiasis in the pediatric population is fairly heterogeneous. The classic renal colic of the adult is uncommon in younger children, who may present with isolated microscopic hematuria, irritability, abdominal pain, or urinary tract infection. Older children and adolescents can better localize pain to the flank or groin area and have increased chance for spontaneous stone passage. Recurrent stone disease frequently occurs in children and adolescents with nephrolithiasis.
Pathogenesis, etiology and risk factors
Stone formation is a multifactorial process that involves both the patient’s underlying metabolic background and environmental conditions that promote nephrolithiasis. The pathogenesis is a multi-step process that includes supersaturation of lithogenics (eg, calcium, oxalate, and phosphate), nucleation, crystal growth, crystal aggregation, and crystal retention. Calcium phosphate supersaturation increases rapidly as urine pH rises from 6 to 7 and accounts for the propensity to form calcium stones under conditions of alkaline urine. Conversely, prolonged metabolic acidosis, as occurs in renal tubular acidosis and using a ketogenic diet, has been shown to facilitate hypercalciuria. Normal urine contains molecules that can retard mineral crystallization. Among the known stone inhibitors are magnesium, glycosaminoglycans and osteopontin, but, in practice, only citrate, which slows the growth of calcium crystals by chelating calcium in the urine, can be modified.
Over the past decade and as a result of improvement in the diagnosis and treatment of urinary tract infections, the etiology of nephrolithiasis in children has shifted from predominantly infectious to metabolic causes. More than 50% of affected children have an identifiable metabolic risk factor – an innate characteristic of one’s physiology that is stable over time and results in urinary conditions that are more conducive to stone formation. Hypercalciuria is the most commonly found metabolic aberration and accounts for 50%-97% of all metabolic cases. Other metabolic risk factors include hypocitraturia (26%), hyperuricosuria (8%) and hyperoxaluria (5%).
Dietary habits are important determinants of stone occurrence and are thought to be implicated in the increasing incidence of the disease. Low urine volume, representing inadequate fluid intake, is a common lithogenic factor in the majority of children with kidney stones. The role of volume contraction in the pathogenesis of nephrolithiasis is further supported by the finding of higher prevalence of kidney stones in adults living in the southeastern United States, area known as the “kidney stone belt.” The American Urological Association has projected that increasing global temperatures will lead to an increased incidence of kidney stones in the United States by expanding the “kidney stone belt.” Although data regarding the geographical distribution of nephrolithiasis in the pediatric population are lacking, ample evidence suggests that children in general are drinking less water than in the past and are therefore more prone to forming stones.
Increased salt intake has been linked epidemiologically and mechanistically to nephrolithiasis. Calcium is reabsorbed passively in the kidney tubules along with reabsorption of sodium. Similarly, there is a linear positive correlation between urinary sodium and calcium excretion. As many American children consume excess of salt, the increased incidence of pediatric nephrolithiasis is almost expected.
Other dietary factors that promote stone formation in children include oxalate overload, and increased intake of uric acid from of purine-rich food; both have shown to reduce the solubility of calcium oxalate in the urine.
Although the available data linking obesity and higher stone rates in children are not compelling, the lithogenic effect of higher body mass index (BMI) has been supported by a few studies in pediatrics. One suggested mechanism linking obesity to stones is increased urinary uric acid excretion, which may serve as a nidus for nucleation and crystallization of calcium.
Anatomic abnormalities, in particular those that result in urinary stasis such as ureteropelvic junction obstruction, horseshoe kidney or polycystic kidney, may precipitate or worsen stone formation. Patients with a single functioning kidney are at particular risk, since stone passage with ureteral obstruction can result in acute kidney injury.
Certain exposures have been associated with increased propensity for calcium stones, including high dose vitamin C, topiramate administration (through inhibition of renal carbonic anhydrase), vitamin D intoxication, excessive calcium and alkali consumption (eg, milk alkali syndrome), and consumption of melamine-contaminated powdered formula (the 2008 epidemic of nephrolithiasis in infants in China). Table 1 provides some of the more common predisposing risk factors for nephrolithiasis in children.
Table 2 designates clinical entities with known predisposition for nephrolithiasis of non-calcium composition.
Idiopathic hypercalciuria is the most common cause of calcium-containing stones with prevalence of 2%-6% in the pediatric population. The pathophysiology remains elusive but involves complex interplay between enhanced gastrointestinal calcium absorption, increased urinary calcium excretion, and accelerated bone resorption. Up to 50% of patients have a positive family history of nephrolithiasis, although the condition has not proven to be monogenic. The diagnosis can be established only with the exclusion of other conditions leading to hypercalciuria, such as Bartter syndrome, Dent disease and familial hypomagnesemia with hypercalciuria. It is noteworthy that in addition to the detrimental long-term effects on kidney function, over a third of children with idiopathic hypercalciuria develop low bone mineral density.
Diagnostic approach to the child with kidney stone disease
The evaluation of a child with nephrolithiasis begins with a thorough history and physical examination, which may assist in detecting predisposing conditions. During the acute presentation, radiologic assessment, urine analysis, and urine culture are recommended, because these tests will reveal the need for urologic intervention or antimicrobial therapy. Figure 1 demonstrates the microscopic appearance of common urine crystals.
Generally, ultrasonography should be used first in children with suspected nephrolithiasis. Although many radio-opaque stones can be identified with simple abdominal flat-plate examination, the presence of bowel gas in children and infants makes this imaging modality less reliable for the diagnosis of nephrolithiasis. Helical computed tomography (CT) without the use of contrast material is more sensitive than ultrasound in providing information regarding the presence, size, and location of stones, but given its expense and radiation exposure, it should be used judiciously. If the stone is available it should be analyzed to classify its type by x-ray diffraction crystallography. Metabolic testing, including a 24-hour urine collection, should be done after the resolution of the acute episode of renal colic or stone passage, when the child resumes his/her usual diet and activity. Analysis of a 24-hour urine collection should preferably be performed twice, because mineral excretion may vary from day to day. Evaluation also includes blood tests to screen for hypercalcemia, chronic kidney disease, and renal tubular acidosis among others. Table 3 depicts the normal metabolic profile of urine in children.
Although detailed discussion of the therapeutic approach to pediatric nephrolithiasis is beyond the scope of this article, a few aspects of prevention and treatment of calcium stones in children should be mentioned.
During the acute phase when the stone is being passed, management is directed toward pain control and facilitating passage or removal of the stone(s). Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids can be cautiously used to control acute pain. Medical expulsive therapy for an acute stone episode includes tamsulosin and alpha blockers such as doxazosin. Indications and modes of operative management of stones in pediatrics (eg, extracorporeal shock-wave lithotripsy, percutaneous nephrolithotomy, ureteroscopic lithotripsy and open surgery) are based on stone size, location and composition in addition to other patient related factors and will not be discussed here. After the acute episode, management is directed toward prevention of stone recurrence by reducing risk factors associated with stone formation.
Dietary preventive measures
Increased fluid intake to target urine output of greater than 30 ml/kg/day has been shown to significantly reduce recurrence of nephrolithiasis of all types and could not be overly emphasized. Since salt is a strong promoter of kidney stone formation, a low-sodium diet (80-100 mEq/day or 2 gm/day) enhances sodium and calcium renal tubular reabsorption, thereby reducing urinary calcium excretion. Foods rich in potassium, particularly fruits and vegetables, may reduce the risk of calcium oxalate stone formation through increasing citrate excretion. Almost counterintuitively, a calcium restricted diet should be avoided in patients with hypercalciuria because this does not prevent stone formation, may perpetuate negative calcium balance, and may result in a reduction in bone mineral density. Moreover, in light of data indicating a decreased milk intake in children in recent years and increased consumption of sugary drinks, it is imperative to ensure adequate dietary intake of calcium in patients with hypercalciuria. Beyond the beneficial effect of counterbalancing urinary loss, intestinal calcium binds with oxalate in the gut and hinders its absorption.
Children with an intractable seizure disorder receiving a ketogenic diet benefit from the empiric use of oral potassium citrate for stone prevention. These patients have been shown to have increased risk for calcium stones (which occur in up to 6%) and potassium citrate can alkalinize the urine and solubilize urine calcium, without abolishing the ketotic acidosis. Universal supplementation is therefore warranted.
Aspects of medical treatment of hypercalciuria and calcium stones
Medications should be used once dietary modifications have failed to normalize urinary calcium excretion. In adults, outcome data demonstrate that medical intervention reduces the rate of recurrent stone disease, and although similar data are not available for children, we believe that these findings are directly applicable to the prevention of recurrent stones in children.
Thiazide diuretics: Evidence in adults supports the use of thiazide therapy to lower urinary calcium excretion. Although the precise mechanism is not known, thiazides induce mild volume depletion, leading to a compensatory rise in the proximal reabsorption of sodium, and therefore of passive calcium reabsorption. Chlorthalidone (longer half-life) or hydrochlorothiazide can be used. The full benefit may not be seen unless dietary sodium intake is also restricted. Hypokalemia should be avoided, because low potassium levels reduce urinary citrate excretion. Thiazide-induced positive calcium balance may have an additional beneficial effect on bone mineralization as shown by a decreased incidence of hip fracture in adults.
Potassium citrate: Increasing urinary citrate excretion is the goal of therapy in patients with hypocitraturia. However, pH should not exceed 7 to avoid calcium phosphate supersaturation. Additionally, empiric citrate therapy has been shown to decrease recurrence of new calcium stones in children.
Bisphosphonates: Bisphosphonates, osteoclast inhibitors, were previously shown to improve bone mineral density in adults with hypercalciuria. Similar results were recently reported in a small case series of children with osteopenia and hypercalciuria. However, the place for bisphosphonates in the treatment of children with idiopathic hypercalciuria and reduced bone mineral density requires further research.
Nephrolithiasis in children is a painful and costly disease that may also have detrimental long-term effects on kidney function. Stone disease has been associated with numerous complications in adult life including chronic kidney disease, bone disease, and hypertension, although it is yet to be determined whether effective stone prevention decreases all of these risks.
For Further Reading
[1.] Sas DJ. An update on the changing epidemiology and metabolic risk factors in pediatric kidney stone disease. Clin J Am Soc Nephrol 2011 Aug;6(8):2062-2068.
[2.] Routh JC, Graham DA, Nelson CP. Epidemiological trends in pediatric nephrolithiasis at United States freestanding pediatric hospitals. J Urol 2010 Sep;184(3):1100-1104.
[3.] Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and nephrolithiasis in children. Kidney Int 2011 Dec;80(12):1278-1291.
[4.] Srivastava T, Schwaderer A. Diagnosis and management of hypercalciuria in children. Curr Opin Pediatr 2009 Apr;21(2):214-219.
[5.] Worcester EM, Coe FL. Clinical practice. Calcium kidney stones. N Engl J Med 2010 Sep 2;363(10):954-963.
[6.] Cameron MA, Sakhaee K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol 2005 Nov;20(11):1587-1592.
[7.] McNally MA, Pyzik PL, Rubenstein JE, et al. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet. Pediatrics 2009 Aug;124(2):e300-304.