Kidney stone disease has been on the rise over the last two decades among children and adolescents in developed countries.1–4 Bush et al.1 reported that children with nephrolithiasis accounted for 1 in 685 hospitalizations from 2002 to 2007, with more than one-half of patients younger than age 13 years. Furthermore, Sas et al.4 have shown that emergency department encounters in South Carolina for adolescents with kidney stones increased by 2.5% annually from 1996 to 2007. Data from 1999 to 2008 using the Pediatric Health Information System national database demonstrated a 10.6% annual increase in the incidence of nephrolithiasis in hospital encounters, including inpatient admissions, emergency department, and outpatient visits in the US.3 Recent trends in pediatrics have shown an increasing number of girls with renal stone disease1,3,5 and a rise among the adolescent age group.3,4 It is also notable that boys tend to present at an earlier age compared to girls; median age of onset is 4.4 years for boys and 7.3 years for girls.6 As for ethnicity/race distribution, the incidence of renal stones appears to be highest among non-Hispanic white children, followed by Hispanics and African Americans.1,3,4 Risk of recurrence in pediatric urolithiasis is high and estimated to be up to 50%,7 which is usually related to metabolic, genetic, and anatomic abnormalities.
The changing epidemiology of kidney stone disease in children has been suggested to be related to environmental factors as well as metabolic abnormalities and genetic components. Some of the commonly discussed speculative contributors to the rising incidence of kidney stone disease are obesity and dietary habits such as decreased fluid intake, increased sodium intake, and decreased calcium intake.
The current epidemic of childhood obesity has led to several studies examining the relation between obesity and kidney stone disease in the pediatric population. Although adult literature suggests a relationship between a higher body mass index and stone risk,8,9 pediatric data have had mixed results with no evidence linking obesity to pediatric nephrolithiasis.2,10
The role of dietary imbalance has also been well recognized in the pathogenesis of stone disease. Inadequate fluid intake with low urine volume leads to supersaturation of the urine with calcium, phosphate, and oxalate that promote aggregation and increased risk of stone formation.11 The well-recognized increase in salt intake among US children12 has also been linked to increased stone risk through increased excretion of urinary calcium. Decreased dietary calcium intake along with increased consumption of sugary drinks have both been suggested as factors contributing to stone formation in older children.13 Excessive animal protein intake or ketogenic diets cause an acid load that leads to hypercalcemia and hypocitraturia contributing to nephrolithiasis.11
Metabolic abnormalities contributing to the formation of stones in children can be identified in up to 80% of children with kidney stones with various estimates in the literature.14–16 Metabolic factors can increase the risk of recurrence. The most commonly identified metabolic abnormalities in stone-forming children are hypercalciuria (accounting for 34%–50%), followed by hypocitraturia, hyperuricosuria, cystinuria, and hyperoxaluria.13 Calcium oxalate stones are the most common type of stones found in children, accounting for 75% to 80% according to a literature review by Tasian and Copelovitch.17 Calcium phosphate stones account for 5% to 10%, 10% to 20% are struvite, and 5% are pure uric acid.17 It has also been noted that infection-related stone formation, such as struvite (ammonium-magnesium-phosphate or triple phosphate) has decreased over time in developed countries due to early treatment of conditions leading to urinary stasis and infections as well as effective treatment of infections.11
Genetic causes for nephrolithiasis should be considered in children with recurrence of stones, bilateral stone disease, presentation in early childhood, family history of stone disease, or consanguinity. Some of these conditions carry the risk of chronic kidney disease especially if early diagnosis is not made. Monogenic causes of stones account for 16% to 20% of cases of nephrolithiasis.18,19 Recessive monogenic diseases tend to manifest earlier (infantile presentation) compared to dominant monogenic genes.19 A study by Daga et al.20 employed whole exome sequencing (WES) in families where stone disease or nephrocalcinosis presented before age 25 years. This study detected a monogenic causative mutation in 15 of 51 families (29.4%), which is higher than the two previously quoted studies.18,19 In the study by Daga et al.,20 recessive mutations formed the majority of mutations identified (80%), and the majority of patients with a pathologic mutation presented before age 10 years. These recessive mutations included primary hyperoxalurias, cystinuria, renal tubular acidosis with deafness, familial hypomagnesemia, and infantile hypercalcemia with hypophosphatemia. The genetic diagnosis in these families resulted in implications to those individuals as well as their family members, which prompted the authors to present WES as a rapid and reliable tool for patients with kidney stone disease presenting at younger than age 25 years with at least one stone or nephrocalcinosis.
However, based on the cost of these genetic tests and the need for payment support in many countries, the role of genetic testing to establish the diagnosis or guide the treatment remains to be determined.21 A more personalized approach to the use of genetic testing based on the patient's phenotype and medical history would increase the likelihood of a genetic diagnosis being made. Some features to consider would be failure to thrive, tubular dysfunction, and dysmorphic features.
Medical Disorders and Anatomic Abnormalities
Several disease conditions and structural abnormalities can contribute to nephrolithiasis, and structural abnormalities that lead to urinary stasis can predispose to stone formation. Table 1 summarizes some known risk factors for stone formation.
Anatomic and Medical Risk Factors for Nephrolithiasis
Signs and symptoms of kidney stones are variable and depend on the age of the patient as well as stone size and location. Common presenting symptoms include abdominal/flank pain, dysuria, hematuria, nausea, and vomiting. Younger children tend to have vague and poorly defined symptoms. Stones can also be discovered during evaluation for urinary tract infections, and nephrocalcinosis can be an incidental finding on abdominal or renal ultrasound.
History and Physical Examination
The focus should be on identifying risk factors for stone disease, such as diet, medications and supplements, family history, and disorders that predispose to stone formation.
Diet history should assess the amount of fluid, sodium, and calcium intake. Excess animal protein can lead to increased excretion of calcium and uric acid and decreased citrate leading to calcium oxalate and uric acid stones. A ketogenic diet can also increase risk of uric acid stone formation.
Medications, supplements, and herbal remedies taken by the patient should be identified as some can be associated with nephrolithiasis (Table 1).
A family history of positive cases of stone disease can be present in up to 30% of children with nephrolithiasis.6 Other elements of family history such as consanguinity, chronic kidney disease or renal failure, and recurrent stone disease can be indicative of an inherited disorder. The patient's own past medical history can also offer information regarding predisposition to stone formation (Table 1).
Physical examination can be nonspecific during an acute episode of stone passage; generally, the patient appears in pain. However, abdominal examination focus should be on ruling out other causes of abdominal pain and an acute infection. Vital signs including blood pressure and growth parameters should be checked in children. Developmental delay, dysmorphic features, rickets, bony deformities, deafness, or ocular disease can all be indicative of an associated disorder.
Laboratory evaluation starts with analysis and microscopic evaluation of a urine sample to check for hematuria, proteinuria, leukocytes, crystals, specific gravity, and pH level. Urine culture should also be obtained to rule out an infection. Many crystals can be normally found in the urine depending on the pH level. However, cystine crystals are always pathological.
A 24-hour urine collection for measurement of urine volume, pH level, sodium, calcium, creatinine, citrate, cystine, oxalate, magnesium, and phosphate is needed to identify underlying metabolic abnormalities, because the presence of certain metabolic abnormalities can increase the risk of recurrence. The collection should be conducted when the child is at home and on a typical diet. The supersaturation of urine as an indicator of stone risk can now be calculated through several commercial laboratories. In children who are not toilet trained and unable to provide a 24-hour urine collection, a spot urine sample can be collected. The normative values for these parameters in a 24-hour and random samples can be found in the literature13 and is beyond the scope of this review.
Any child with kidney stones should have kidney function checked as well as a basic panel of serum electrolytes including calcium, magnesium, phosphorus, and uric acid. Further testing would be indicated based on data from collection mentioned above or clinical suspicion of a medical disorder. Genetic testing as mentioned earlier can be considered in children suspected of having an inherited condition based on available clinical and laboratory data. Stone analysis to determine all components of the stone should be conducted when stones are retrieved. It is also advisable to repeat analysis in children with recurrent stones as stone composition may change over time.22
Ultrasound is currently considered an appropriate first-line diagnostic imaging tool in children with nephrolithiasis.23 Although it is less sensitive than computed tomography (CT) scan, the lack of ionizing radiation and relatively low cost makes it the ideal screening tool. In a retrospective review by Johnson et al.,24 it was found that nearly 90% of pediatric patients treated for urolithiasis did not need CT scan for completion of evaluation and treatment. Alternatively, low-dose CT scan has been shown to reduce the radiation exposure in children without affecting the ability to diagnose stones in comparison to standard CT.25 Therefore, it is used as a complementary modality when ultrasound is nondiagnostic in the setting of high clinical suspicion or detection of complications.23 Plain abdominal radiograph may be used as a supplemental study for localization of ureteric radio-dense stones; however, it is of limited use (Figure 1).
Location of stones. (a) Upper tract stones on film and (b) ultrasound. (c) Ureteric stones in computed tomography and (d) ultrasound. (e) Bladder stones in an augmented bladder. (f) Stone in urethra in urethroscopy. Reprinted with permission from Harvey and Farhat.22
Acute Stone Management
During the initial evaluation of patients presenting with stones, identifying patients with obstruction or the combination of obstruction and infection is the first step to identify the need for surgical decompression. In most patients, renal and ureteral stones can be managed expectantly without surgical intervention using adequate analgesia and hydration, with or without medical expulsive therapy.
The 2016 American Urological Association (AUA)/Endourological Association guidelines recommends observation with or without medical expulsive therapy in pediatric patients with ureteral stones <10 mm.26 Medical expulsive therapy includes the use of alpha-blockers (tamsulosin) to relax ureteral smooth muscle and ease stone passage. In a 2014 cohort study by Tasian et al.27, it was concluded that the odds of spontaneous passage of ureteral stones were greater in children prescribed tamsulosin versus analgesics alone. Tian et al.28 carried out a systemic review and meta-analysis to evaluate the efficacy and safety of adrenergic alpha blockers for ureteral stones in pediatric patients and concluded that it was safe and effective for distal ureteral stones <10 mm. The use of medical expulsive therapy is only for ureteral stones, and confirmation of stone passage (actual stone or repeat imaging) should be sought.
Up to 22% of stone episodes in children require surgical intervention.29 The choice of surgical procedure is multifactorial including the location and size of the stone, stone characteristics, availability of equipment, and surgeon preference. Available surgical options for pediatric nephrolithiasis include shock wave lithotripsy (SWL), ureteroscopy, percutaneous nephrolithotomy, and open and minimally invasive pyelolithotomy. According to the 2016 AUA/Endourological Association guidelines,26 SWL and ureteroscopy are generally accepted modalities for small stones within the kidney and ureter with comparable rates of stone clearance. If the stone burden is >20 mm, both percutaneous lithotomy and SWL are acceptable treatment options. Open and laparoscopic pyelolithotomy is reserved for large stones in patients with anatomic abnormalities.
Another important consideration in pediatrics is radiation exposure, and the importance of reducing retreatment as each episode carries an additional diagnostic radiation that would increase the overall radiation exposure over a 5-year period. The use of intraoperative ultrasound with SWL, ureteroscopy, and percutaneous nephrolithotomy to reduce radiation exposure has been described.30
Prevention of Recurrence
Prevention of recurrence in kidney stone formation should focus on modifying risk factors. Empiric management with increasing fluid intake and dietary modifications can be carried out as first line of management.
Fluid intake of 1.5 to 2 L/m2 per day is recommended to increase urine volume in children, decrease urinary supersaturation of stone promoters, and increase flow rate. Urine volumes of greater than 750 mL/day in infants, 1,000 mL/day in children younger than age 5 years, 1,500 mL/day in children between ages 5 and 10 years, and more than 2 L/day in children older than age 10 years are targeted.13,17
Decreasing sodium intake is advised to decrease hypercalciuria. Recommended daily allowance of calcium and vitamin D should be consumed to maintain bone health. Calcium intake should not be restricted in children as this may also increase intestinal oxalate absorption and its risk of stones. Excessive protein intake can result in urinary acidification leading to hypercalciuria and hypocitraturia, whereas restriction can affect growth; therefore, normal protein requirements should be incorporated in the diet without excess or restriction. Fruits and vegetables should be well integrated into the diet, which provide potassium and citrate acting as stone inhibitors.13
Some medications should also be considered in children with recurrent nephrolithiasis. Potassium citrate is used in the treatment of hypercalciuria, hypocitraturia, and increased urine pH level to prevent uric acid crystallization in hyperuricosuria. Thiazide diuretics, which reduce calcium excretion, are used in patients with persistent hypercalciuria and recurrent stones. Potassium-sparing diuretics, such as amiloride, can also enhance calcium reabsorption. Other medical therapies are tailored according to the patient's medical condition—tiopronine and penicillamine in cystinuria, allopurinol in hyperuricosuria, and pyridoxine in primary hyperoxalurias. Table 2 summarizes some aspects of the stone preventive therapies.
Management Recommendations in Metabolic Abnormalities
The treatment and prevention of kidney stone disease in children usually requires long-term compliance; continuous education in children and families is important. Monitoring with renal ultrasound and repeat 24-hour urine testing is needed after instituting dietary and pharmacologic therapy. The timing of follow-up should be individualized to the patient's clinical status and compliance. Multidisciplinary kidney stone clinics have been established in many institutions to facilitate a comprehensive care for these patients. Whether these clinics improve the outcomes in this patient population is not yet determined.
Pediatric nephrolithiasis is a disease of increasing prevalence and burden. Further understanding of risk factors and targeted therapies is needed. The use of genetic testing in this population is evolving and might become the future diagnostic approach.
- Bush NC, Xu L, Brown BJ, et al. Hospitalizations for pediatric stone disease in United States, 2002–2007. J Urol. 2010;183(3):1151–1156. doi:10.1016/j.juro.2009.11.057 [CrossRef] PMID:20096871
- Dwyer ME, Krambeck AE, Bergstralh EJ, Milliner DS, Lieske JC, Rule AD. Temporal trends in incidence of kidney stones among children: a 25-year population based study. J Urol. 2012;188(1):247–252. doi:10.1016/j.juro.2012.03.021 [CrossRef] PMID:22595060
- Routh JC, Graham DA, Nelson CP. Epidemiological trends in pediatric urolithiasis at United States freestanding pediatric hospitals. J Urol. 2010;184(3):1100–1104. doi:10.1016/j.juro.2010.05.018 [CrossRef] PMID:20650479
- Sas DJ, Hulsey TC, Shatat IF, Orak JK. Increasing incidence of kidney stones in children evaluated in the emergency department. J Pediatr. 2010;157(1):132–137. doi:10.1016/j.jpeds.2010.02.004 [CrossRef] PMID:20362300
- Novak TE, Lakshmanan Y, Trock BJ, Gearhart JP, Matlaga BR. Sex prevalence of pediatric kidney stone disease in the United States: an epidemiologic investigation. Urology. 2009;74(1):104–107. doi:10.1016/j.urology.2008.12.079 [CrossRef] PMID:19428065
- Issler N, Dufek S, Kleta R, Bockenhauer D, Smeulders N, Van't Hoff W. Epidemiology of paediatric renal stone disease: a 22-year single centre experience in the UK. BMC Nephrol. 2017;18(1):136. doi:10.1186/s12882-017-0505-x [CrossRef] PMID:28420322
- Tasian GE, Kabarriti AE, Kalmus A, Furth SL. Kidney stone recurrence among children and adolescents. J Urol. 2017;197(1):246–252. doi:10.1016/j.juro.2016.07.090 [CrossRef] PMID:27521691
- Maalouf NM, Sakhaee K, Parks JH, Coe FL, Adams-Huet B, Pak CY. Association of urinary pH with body weight in nephrolithiasis. Kidney Int. 2004;65(4):1422–1425. doi:10.1111/j.1523-1755.2004.00522.x [CrossRef] PMID:15086484
- Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293(4):455–462. doi:10.1001/jama.293.4.455 [CrossRef] PMID:15671430
- Sas DJ. An update on the changing epidemiology and metabolic risk factors in pediatric kidney stone disease. Clin J Am Soc Nephrol. 2011;6(8):2062–2068. doi:10.2215/CJN.11191210 [CrossRef] PMID:21737846
- Scoffone CM, Cracco CM. Pediatric calculi: cause, prevention and medical management. Curr Opin Urol. 2018;28(5):428–432. doi:10.1097/MOU.0000000000000520 [CrossRef] PMID:29901459
- Cogswell ME, Yuan K, Gunn JP, et al. Vital signs: sodium intake among U.S. school-aged children - 2009-2010. MMWR Morb Mortal Wkly Rep. 2014;63(36):789–797. PMID:25211544
- Hernandez JD, Ellison JS, Lendvay TS. Current trends, evaluation, and management of pediatric nephrolithiasis. JAMA Pediatr. 2015;169(10):964–970. doi:10.1001/jamapediatrics.2015.1419 [CrossRef] PMID:26302045
- Bevill M, Kattula A, Cooper CS, Storm DW. The modern metabolic stone evaluation in children. Urology. 2017;101:15–20. doi:10.1016/j.urology.2016.09.058 [CrossRef] PMID:27838366
- Kovacevic L, Wolfe-Christensen C, Edwards L, Sadaps M, Lakshmanan Y. From hypercalciuria to hypocitraturia—a shifting trend in pediatric urolithiasis?J Urol. 2012;188(4)(suppl):1623–1627. doi:10.1016/j.juro.2012.02.2562 [CrossRef] PMID:22910255
- Penido MG, Srivastava T, Alon US. Pediatric primary urolithiasis: 12-year experience at a Midwestern Children's Hospital. J Urol. 2013;189(4):1493–1497. doi:10.1016/j.juro.2012.11.107 [CrossRef] PMID:23201378
- Tasian GE, Copelovitch L. Evaluation and medical management of kidney stones in children. J Urol. 2014;192(5):1329–1336. doi:10.1016/j.juro.2014.04.108 [CrossRef] PMID:24960469
- Halbritter J, Baum M, Hynes AM, et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol. 2015;26(3):543–551. doi:10.1681/ASN.2014040388 [CrossRef] PMID:25296721
- Braun DA, Lawson JA, Gee HY, et al. Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin J Am Soc Nephrol. 2016;11(4):664–672. doi:10.2215/CJN.07540715 [CrossRef] PMID:26787776
- Daga A, Majmundar AJ, Braun DA, et al. Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int. 2018;93(1):204–213. doi:10.1016/j.kint.2017.06.025 [CrossRef] PMID:28893421
- Langman CB. A rational approach to the use of sophisticated genetic analyses of pediatric stone disease. Kidney Int. 2018;93(1):15–18. doi:10.1016/j.kint.2017.08.023 [CrossRef] PMID:29291816
- Harvey E, Farhat WA. Renal calculi. In: Denis F., Geary FS, eds. Pediatric Kidney Disease. 2nd ed. Springer; 2016:1135–1191.
- Riccabona M, Avni FE, Blickman JG, et al. Imaging recommendations in paediatric uroradiology. Minutes of the ESPR uroradiology task force session on childhood obstructive uropathy, high-grade fetal hydronephrosis, childhood haematuria, and urolithiasis in childhood. ESPR Annual Congress, Edinburgh, UK, June 2008. Pediatr Radiol. 2009;39(8):891–898. doi:10.1007/s00247-009-1233-6 [CrossRef] PMID:19565235
- Johnson EK, Faerber GJ, Roberts WW, et al. Are stone protocol computed tomography scans mandatory for children with suspected urinary calculi?Urology. 2011;78(3):662–666. doi:10.1016/j.urology.2011.02.062 [CrossRef] PMID:21722946
- Karmazyn B, Frush DP, Applegate KE, Maxfield C, Cohen MD, Jones RP. CT with a computer-simulated dose reduction technique for detection of pediatric nephroureterolithiasis: comparison of standard and reduced radiation doses. AJR Am J Roentgenol. 2009;192(1):143–149. doi:10.2214/AJR.08.1391 [CrossRef] PMID:19098193
- Assimos D, Krambeck A, Miller NL, et al. Surgical management of stones: American Urological Association/Endourological Society Guideline, PART I. J Urol. 2016;196(4):1153–1160. doi:10.1016/j.juro.2016.05.090 [CrossRef] PMID:27238616
- Tasian GE, Cost NG, Granberg CF, et al. Tamsulosin and spontaneous passage of ureteral stones in children: a multi-institutional cohort study. J Urol. 2014;192(2):506–511. doi:10.1016/j.juro.2014.01.091 [CrossRef] PMID:24518765
- Tian D, Li N, Huang W, Zong H, Zhang Y. The efficacy and safety of adrenergic alpha-antagonists in treatment of distal ureteral stones in pediatric patients: a systematic review and meta-analysis. J Pediatr Surg. 2017;52(2):360–365. doi:10.1016/j.jpedsurg.2016.10.003 [CrossRef] PMID:27837990
- Routh JC, Graham DA, Nelson CP. Trends in imaging and surgical management of pediatric urolithiasis at American pediatric hospitals. J Urol. 2010;184(4)(suppl):1816–1822. doi:10.1016/j.juro.2010.03.117 [CrossRef] PMID:20728146
- Morrison JC, Kawal T, Van Batavia JP, Srinivasan AK. Use of ultrasound in pediatric renal stone diagnosis and surgery. Curr Urol Rep. 2017;18(3):22. doi:10.1007/s11934-017-0669-8 [CrossRef] PMID:28233230
Anatomic and Medical Risk Factors for Nephrolithiasis
|Anatomic or structural abnormalities
Ureteropelvic junction obstruction
Posterior urethral valves
Inflammatory bowel disease
Short gut syndrome
Antiepileptic medications: topiramate, felbamate, zonisamide
Carbonic anhydrase inhibitors: acetazolamide
Antiretrovirals: indinavir sulfate
Excess vitamin C or D
Management Recommendations in Metabolic Abnormalities
||Increase fluids, limit sodium diet, thiazide diuretics
||Increase fruits and vegetables in diet, potassium citrate
||Increase fluid intake, avoid excess protein intake, potassium citrate(urinary alkalinization), allopurinol
||Increase fluid intake, limit oxalate in diet, appropriate calcium in diet, avoid excess vitamin C and D, potassium citrate, thiazide diuretics, pyridoxine