ABSTRACT
Although urolithiasis is still not as prevalent among children as it is among adults, over the past several years we have seen an increasing incidence of children with stones.(1, 2, 3, 4) Although not yet conclusive, epidemiological studies are suggesting this is due to a change in social conditions and eating habits.(5)
In 1951, Lattimer reported no cases of urolithiasis in 21,835 children at the Babies Hospital in New York.(6) More recently, the literature has become populated with many series of children who have urolithiasis. The actual incidence of pediatric urolithiasis and the predominant types of stones produced in children varies throughout the world. In the United States, the reported incidence of children admitted to the hospital for management of a stone has ranged from 1 per 1,000 to 1 per 7,6000 pediatric hospital admissions in 1989.(7, 8) However, since many children with stones are not admitted for their treatment, this is a poor estimation of the actual incidence of stones in this country. A 1973 study from the United Kingdom cited an annual incidence of pediatric urolithiasis of two per one million children.(9) A very inclusive 2005 Icelandic study reported a much higher incidence of heritable genetic mutations which contribute to stones in their children at a higher rate of 6 per 100,000. These children accounted for approximately 1 per 1,000 pediatric hospital admissions.(10) In most parts of the developed world, children are still believed to represent only 2% to 3% of the overall population of stone formers.(11, 12) In parts of the Middle East and Southeast Asia, pediatric urolithiasis is endemic.(13) These stones, however, are much more likely to develop in the bladder, as opposed to the upper urinary tract, and are believed to be due to malnutrition and a low-protein, high-starch diet.(7, 13, 14, 15)
Historically, adult males develop significantly more stones than females. However in children, the ratios of boys to girls with urolithiasis appear to be more equal at 1-1.5 boys to 1 girl. A 2005 review of urolithiasis in India demonstrated a male to female ratio of 1.5: 1.(16) A 2002 report from the Vanderbilt group identified a 1: 1 ratio. And a multi-institutional study from Michigan and Virginia cited a 1.1:1 male to female ratio.(17, 18) In 2007, the Pittsburgh group reported a female preponderance of 1.4 girls to each boy.(3) In Iceland, the incidence in girls is also higher than in boys at 1.4 girls to 1 boy.(10)
Familial Inheritance Although most children with stones do not have a family history of urolithiasis, many studies report at least a 20 to 40% incidence of a first-or second-degree relative with a history of stones.(19, 20, 21) In Iceland, where there is a higher than normal incidence of Adenine Phosphoribosyltransferase deficiency (APRT), 33% of the children had a first-or second-degree relative with a past history of stones.(10) In a 2002 report, 34% of children in Brazil had a firstdegree family member with a history of stones.(20)
The genetic causes of urolithiasis have been well studied but are still inconclusive. The only conclusive findings are that the etiology is usually polygenic and partially penetrative.(22, 23) Fewer than 2% of children who form stones can be identified with a monogenic abnormality.(24)
Just as there are various kinds of kidney stones, there are also various genetic causes for stone formation. Various chromosomal loci have been recognized as playing a part in the development of stones.(17, 25) For example, more frequent polymorphisms in the vitamin Dreceptor (VDR) gene have been identified in children with a history of stones when compared to normal control children without stones.(26) Dent’s disease is an X-linked spectrum of entities comprised of hypercalciuria, urolithiasis, nephrocalcinosis, proteinuria, and in some patients, renal failure. A mutation of the renal-specific chloride channel gene CLCN-5 on chromosome Xp11.22 has been identified as a contributor to this disease spectrum.(27) This mutation impairs
expression of the chloride transport channel in the proximal tubule, thick ascending limb of Henle, and proximal collecting ducts.(28)
Cystinuria is a recessively inherited aminoaciduria caused by a defect in the transport of cystine, arginine, lysine, and ornithine in the renal tubular and intestinal epithelium. At least two genes, SLC3A1 and SLC7A9, are known to be responsible for this defect. A Chinese study from 2006 identified heterogeneous mutations in these genes that lead to different cystine concentrations in the urine of patients.(29) Cystinuria’s prevalence varies throughout the world. Newborn screening programs have estimated it to be 1:15,000 in the United States, 1:2,000 in the United Kingdom, 1:4,000 in Australia, and 1:2,500 in Libyan Jews.(30)
Another genetically linked illness that often leads to the development of stones during childhood is the autosomal recessively inherited primary hyperoxaluria (PH). Type 1 PH is caused by a mutational error on chromosome 2, which leads to a deficiency of hepatic alanine-glyoxalate aminotransferase. Type 2 PH involves a deficiency of glyoxalate reductase/ hydroxypyruvate reductase. Through a series of hepatic enzymatic deficiencies, this leads to an overproduction of oxalate. Hyperoxaluria then can lead to renal failure, which in turn leads to increased serum oxalate levels and deposition of calcium oxalate throughout solid organs and bone. Although most affected individuals develop renal failure during adolescence, some do so during infancy.(31)
A 2006 study of the genetic inheritability of urinary stone risk in identical twins revealed interesting findings. The authors found a high heritability coefficient (H2 of 90% or greater) indicating a significant genetic component for urinary levels of calcium (94%), oxalate (94%), citrate (95%), and uric acid (96%). In contrast urinary pH and sodium levels had low degrees of heritability. The authors concluded that since urinary calcium, oxalate, and citrate had a high heritability coefficient, they might be associated with specific genes that impact stone risk. They also felt that since urinary pH and sodium may be weakly linked genetically, improvement in these lithogenic risk factors might be more amenable to dietary or pharmacologic intervention.(19)
Stone Recurrence Rates Stone recurrence rates in the pediatric literature have covered quite a range (16%–48%).(21, 32, 33) Some reports also show a close association between recurrence rates and metabolic abnormalities or recurrent urinary tract infections (UTIs).(33) In 1989, Diamond published a 27-year review of 270 children with stones from Massachusetts and Liverpool with an overall recurrence rate of 16%. He found the children with a lithogenic metabolic abnormality had a higher 30% chance of recurrence, while the children with an anatomic abnormality had a 27% chance. The children with infection as well as the idiopathic stone formers each had only a 14% recurrence rate.(32) Since some of their patients did not develop their recurrent stones for 7-13 years, they recommended prolonged follow up for children with stones.(32) The Vanderbilt group reported a recurrence rate of 19% for all children evaluated. This rate approached 50% when reviewing only those children younger than 10 years of age with an identifiable metabolic abnormality. The recurrence rate was less than 10% if no metabolic abnormality was identified.(18)
Presenting Symptoms While typically the adult with urolithiasis presents with unilateral colicky flank pain, the signs and symptoms of urolithiasis in children are more varied and likely to be different for different age groups.(4) Most of the literature concerning pediatric urolithiasis suggests that the clinical presentation is often more subtle and not as likely to be pain-related when compared to their adult counterparts. Younger children are more likely to have their calculi diagnosed after undergoing an evaluation for hematuria, urinary tract infections, or vague abdominal pain, whereas it is the older children who are more likely to present with classic renal colic.(4, 34, 35) However, in Milliner’s 1993 landmark study the chief presenting complaint was most often pain in 47%, gross or microscopic hematuria in 33%, UTI in 15%. Asymptomatic stones were found incidentally 15% of the time.(21) Similarly in a 2002 report, 92% of the children presented with flank pain, 40% had hematuria, 20% had UTI, 44% had nausea and/or vomiting, and 12% were azotemic.(17) Even in the retrospective review of Icelandic children, 80% presented with abdominal pain and /or irritability. Thirty one percent each had gross hematuria and/or dysuria.(10)
Imaging Techniques Because of a low clinical suspicion for urolithiasis in the younger child with vague abdominal pain, primary care physicians are more likely to initially diagnose the presence of a renal stone by ultrasonographic imaging (US). Stones seen by US are usually hyperechoic and may have a shadowing effect. Newer ultrasound technology may cause the stone to produce more of a twinkling effect. Ureteral stones may not be seen by US, but if hydronephrosis is present, it should be visible. Palmer found that US failed to detect a stone in 41% of patients that presented with colicky pain. US’s ability to detect a stone was dependent on the stone’s location (kidney 90%, kidney and ureter 75%, and ureter alone 37%). Noncontrast computerized tomography (CT) was much more sensitive in detecting a stone in children with colicky pain regardless of the stone’s location (96-100%). He therefore concluded that although US was a reasonable screening tool, it should be followed by a noncontrast CT if the child’s symptoms persist.(36) Further, now that more community emergency departments have CT scanners available for the evaluation of abdominal pain, more children may have their initial stone diagnosed by CT. CT can identify renal and ureteral stones in children as well as in adults. However, most are hesitant to obtain many scans due to possible harmful long-term effects from exposing children to the ionizing radiation.
