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Bush Beats 2015 › Bush Beats Issue 10, 2015

Urolithiasis in pediatric population: A growing concern

Introduction: Global trends in prevalence of urolithiasis in children

Although considered relatively rare in the past; the rising incidence and prevalence of urolithiasis makes it an increasingly important clinical problem in current pediatric urology practice.1-4Knoll T, Humke U. Urolithiasis in childhood. Urologe A. 2013 Aug;52(8):1084- 91.
Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.
Gnessin E, Chertin L, Chertin B. Current management of paediatric urolithiasis. Pediatr Surg Int. 2012 Jul;28(7):659-65.
Sharma AP, Filler G. Epidemiology of pediatric urolithiasis. Indian J Urol. 2010;26(4):516-522.   A 3-5 fold increase in this incidence has been observed in last few decades, substantiating the common theme, in that children are a high-risk population with regards to both stone formation and recurrence5-9Dwyer 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 Jul;188(1):247-52.
VanDervoort K, Wiesen J, Frank R, Vento S, Crosby V, Chandra M, Trachtman H. Urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome. J Urol. 2007 Jun;177(6):2300-5.
Sabnis RB, Chhabra JS, Ganpule AP, Abrol S, Desai MR. Current role of PCNL in pediatric urolithiasis. Curr Urol Rep. 2014 Jul;15(7):423.
Aydogdu O, Karakose A, Celik O, Atesci YZ. Recent management of urinary stone disease in a pediatric population. World J Clin Pediatr. 2014;3(1):1-5.
Straub M, Gschwend J, Zorn C. Pediatric urolithiasis: the current surgical management. Pediatr Nephrol (2010) 25:1239-1244.   Numerous factors, including obesity, intake of sweetened beverages, animal protein consumption, and climate change have been linked with this increased incidence of urinary stone disease in the pediatric population10Chen JN, Dieguez LM, Trachtman H. The Changing Epidemiology of Urolithiasis in Pediatric Patients. J Nephrol Therapeutic 2014;S11:S11-006.  ; whilst time trends have been tested in various regions across the globe. For instance, one such pediatric study, of

a population based design, was conducted in US to determine incidence of symptomatic kidney stones during a 25-year period (1984-2008). The study found an increase of 4% per calendar year in the incidence rate amongst patients < 18 years throughout the 25-year period (Figure 1).5Dwyer 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 Jul;188(1):247-52.   This increase was largely due to the 6% yearly increased incidence seen in adolescents (children 12-17 years).

Race and geography seems to play an important contributory role in the prevalence and cause of pediatric stone disease as in certain regions of the world, mainly in Far East11Bartosh SM. Medical management of pediatric stone disease. Urol Clin North Am. 2004 Aug;31(3):575-87, x-xi.  , Southeast Asia, Middle East, India, and Pakistan, calculi may be widely present.2 Urolithiasis has therefore been identified as a significant health problem in children in India.12Selvaraju R, Raja A, Thiruppathi G. FT-IR spectroscopic, thermal analysis of human urinary stones and their characterization. Spectrochim Acta A Mol Biomol Spectrosc. 2014 Sep 28;137C:1397-1402.   A gender difference has been reported in some studies, but this has not been a consistent finding, and might be of limited significance meanwhile. Incidentally, a male predominance was documented in a recent Indian study demonstrating experience from a tertiary referral center.13Abhishek, Kumar J, Mandhani A, Srivastava A, Kapoor R, Ansari MS. Pediatric urolithiasis: experience from a tertiary referral center. J Pediatr Ural. 2013 Dec;9(6 Pt A):825-30.  

Etio-pathophysiology of urolithiasis in children

The etiology of urolithiasis in children is really variable, as a number of risk factors – including those metabolic, genetic, anatomic, dietary and environmental – have been identified in children with urinary tract calculi. Broadly, the etiology can therefore be divided into three major categories: (i) metabolic abnormalities that lead to excessive urinary excretion of solutes those are susceptible to crystallization or reduced excretion of inhibitors of crystallization, (ii) anatomic defects that cause disturbances in voiding, or urinary stasis, and (iii) idiopathic.10Chen JN, Dieguez LM, Trachtman H. The Changing Epidemiology of Urolithiasis in Pediatric Patients. J Nephrol Therapeutic 2014;S11:S11-006.   Even

so, pediatric urolithiasis with a metabolic etiology is the most common form.14Ba;tug F, Du;iinsel R. Pediatric urolithiasis: causative factors, diagnosis and medical management. NatRev Ural. 2012 Feb 7;9(3):138-46.  ,15Cameron MA, Sakhaee K, Moe OW. Nephrolithiasis in children. PediatrNephrol. 2005 Nov;20(11):1587-92.   An identifiable metabolic abnormality can be seen in ∼ 40% to 50% of children with urolithiasis, while genitourinary anomalies (such as hydronephrosis, duplex ureter, posterior uretheral valves, and bladder exstrophy) can be found in up to 30% of such patients.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.  ,16Pietrow PK, Pope JC 4th, Adams MC, ShyrY, BrockJW 3rd. Clinical outcome of pediatric stone disease.JUrol. 2002 Feb;167(2 Pt 1):670-3.  ,17Coward RJ, Peters CJ, Duffy PG, Corry D, Kellett MJ, Choong S, van’t Hoff WG. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child. 2003 Nov;88(11):962-5.   The major metabolic abnormalities seen in children with urolithiasis include hypercalciuria, hypocitraturia, hyperoxaluria, cystinuria, and hyperuricosuria (Figure 2);18Elmaci AM, Ece A, Akin F. Pediatric urolithiasis: metabolic risk factors and follow-up results in aTurkish region with endemic stone disease. Urolithiasis. 2014 Oct;42(5):421-6.   with the former two – hypercalciuria and hypocitraturia – being the most frequently reported abnormalities in stone-forming children.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.   Concerning stones composition, calcium stones are the most common types (Table 1) just like adults; most commonly associated with idiopathic hypercalciuria (i.e., normocalcemic hypercalciuria without an obvious etiology).20Gillespie RS, Stapleton FB. Nephrolithiasis in children. Pediatrics in Review 2004;25(4): 131-139.  ,21Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008;35(2):369-91, vii.  

Table 1. Urinary stone types and frequencies in children
Stone type Frequency
Calcium oxalate 75% to 80%
Calcium phosphate 5% to 10%
Uric acid 5%
Cystine 5%
Struvite 10% to 20%
Adapted from: 1. Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008 Jun;35(2):369-91, vii. 2. Tasian GE, Copelovitch L. Evaluation and Medical Management of Kidney Stones in Children. J Urol. 2014 Nov;192(5):1329-1336.

Pathophysiology – balance of stone promoting and inhibiting factors

Crystals in the urine generally form on surface of a nidus that allows nucleation, growth, and aggregation of stone particle at much lower concentrations than would be required otherwise.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.   Any source of uroepithelial damage (such as, infection, or Randall plaques) can serve as a nidus, and urinary crystals coalesce and precipitate when physical and biochemical conditions disturb the delicate balance of stone-promoting and -inhibiting factors.20Gillespie RS, Stapleton FB. Nephrolithiasis in children. Pediatrics in Review 2004;25(4): 131-139.   The initiation of calculi requires supersaturation of certain ions in the urine that – for stone salts – is often expressed as the ratio of concentration in urine to the known solubility; a level more than one indicates that urine is supersaturated with a given substance.21Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008;35(2):369-91, vii.   Thus, total urine volume, the concentration of stone-forming ions, the concentration of inhibitors of crystallization, the concentration of promoters of crystallization, and the urine pH are most important determinants of urine solubility and the likelihood of ion supersaturation (crystallization). While citrate, pyrophosphate, magnesium, certain glycosaminoglycans, nephrocalcin, and phytates all act to inhibit crystallization of calcium oxalate and calcium phosphate; the presence of uric acid promotes calcium oxalate crystallization, which exemplifies the process of epitaxy, wherein crystal base of one material allows growth of a second mineral that it is in the same crystalline orientation.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.   Urine pH is important in that certain crystals like calcium phosphate (pH > 6.0) are more likely to precipitate in alkaline urine, whereas others like cystine (pH < 7.5) and uric acid (pH < 6.0) are more likely to aggregate in acidic urine. Solubility of certain crystals like calcium oxalate is however not appreciably affected by changes in urinary pH within the physiological range.

Clinical presentation of urolithiasis in children

The clinical presentation of urolithiasis in children can be similar to adults (renal colic with acute, severe flank pain radiating to the groin); but more often it is relatively subtle and may be without the classic symptoms of renal colic,22Palmer JS, Donaher ER, O’Riordan MA, Dell KM. Diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. J Ural. 2005 Oct;174(4 Pt 1):1413-6.   consisting only of hematuria (macroscopic or microscopic), generalized abdominal pain or urinary tract infection.21Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008;35(2):369-91, vii.   Yet, abdominal or flank pain is a predominant manifestation seen in 56-76% of patients. Gross hematuria is less common, present in about 18%,23Kit LC, FillerG, Pike J, Leonard MP. Pediatric urolithiasis: experienceat a tertiary care pediatric hospital. CUAJ 2008;2(4): 381-386.   while microscopic hematuria can be

Table 2 Normal urinary values in children

present in up to 90%.24Tanaka ST, Pope IV JC. Pediatric stone disease. Current Urology Reports 2009;10(2):138-143.   Generally, adolescents present similarly to adult patients, and younger children, particularly those < 5 years, have varied presentations, including non-specific pain localized to the abdomen, flank or pelvis, nausea, vomiting, or even fever without overt pain.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.  ,25Giraudon A, Richard E, Godron A, Bouty A, Dobremez E, Barat P, Blouin JM, Llanas B, Harambat J. Clinical and biochemical characterization of childhood urolithiasis. Arch Pediatr. 2014 Oct 3. pii: 50929-693X(14)00372-8.   The typical presentation of renal colic mostly relates to ureteral stones as those are much more likely to cause obstruction which leads to pain. Also, lower urinary tract symptoms (LUTS), such as dysuria, urgency and frequency, can be present with calculi localized to the lower urinary tract. Conversely, renal stones may be an incidental finding, remaining present for years without causing symptoms.

Diagnosis of urolithiasis in children

Since symptoms in children may not be as obvious as in adults, the index of suspicion must be high.10Chen JN, Dieguez LM, Trachtman H. The Changing Epidemiology of Urolithiasis in Pediatric Patients. J Nephrol Therapeutic 2014;S11:S11-006.   Generally, the evaluation, including history and examination, is similar to that performed in an adult, and should be directed towards identifying any physicochemical, anatomic, and genetic factors predisposing to urolithiasis.11Bartosh SM. Medical management of pediatric stone disease. Urol Clin North Am. 2004 Aug;31(3):575-87, x-xi.  ,26Hoppe B, Kemper MJ. Diagnostic examination of the child with urolithiasis or nephrocalcinosisPediatrNephrol 2010;25:403-413   The history should encompass information pertaining to family history of calculi (as about 40% of children with urolithiasis have a positive family history)26Hoppe B, Kemper MJ. Diagnostic examination of the child with urolithiasis or nephrocalcinosisPediatrNephrol 2010;25:403-413  , hematuria, and renal failure; dietary history, with emphasis on fluid and salt intake, vitamin and mineral supplementation, and special diets (such as ketogenic diet); a detailed medication history, with emphasis on corticosteroids, diuretics, protease inhibitors, and anticonvulsants; history of prematurity, urinary tract abnormalities, urinary tract infections, intestinal malabsorption, and prolonged immobility.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.   Likewise, a detailed physical examination may point towards the possible underlying abnormality.

Laboratory investigations

Laboratory evaluation in cases of pediatric urolithiasis includes selective blood tests, but has primarily focused on 24-hour urine collections to measure excretion of calcium, oxalate, citrate, cystine, uric acid, magnesium, and creatinine.10Chen JN, Dieguez LM, Trachtman H. The Changing Epidemiology of Urolithiasis in Pediatric Patients. J Nephrol Therapeutic 2014;S11:S11-006.   ,19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.    It is however prudent to consider that a 24-hour urine collection may not be practical in many children those not yet trained to use toilet. In such cases, evaluation may be performed by measuring the ratio of calcium, uric acid, citrate, and oxalate levels to creatinine level in a random urine sample (Table 2).20Gillespie RS, Stapleton FB. Nephrolithiasis in children. Pediatrics in Review 2004;25(4): 131-139.   A repeat urine testing may be done for metabolic evaluation after several weeks to months after a change in diet or initiation of a medication. Microscopic urinalysis for crystalluria is generally not diagnostic, unless hexagonal crystals (cystine) or coffin lid-shaped triple phosphate crystals (struvite) are observed.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.  

Imaging

Accurate detection and localization of calculus is invariably an essential initial step in evaluation of all patients with urolithiasis that should follow history and examination. Various imaging modalities, including plain abdominal radiography, ultrasound, intravenous pyelogram, computed tomography (CT), and magnetic resonance imaging, are available for this need and to determine the renal structure and function; but the choice is generally dependent on the clinical scenario, indication for imaging, patient age, and advantages and disadvantages of each method.27Mandeville JAGnessinELingemanJE.Imagingevaluationinthepatientwith, renal stone disease.Semin Nephrol. 2011 May;31(3):254-8.   Although many stones are radiopaque (except for calculi comprising uric acid, xanthine, cystine, or indinavir, which are generally radiolucent), radiography alone is usually insufficient in evaluation of a patient with suspected urolithiasis. Herein, the non-radiating nature of ultrasound makes it the first study of choice in assessment of calculi in children, which may yield other clinically important findings as well. Ultrasound however appears better suited for proximal stones, with detection of up to 90% of renal calculi; and has a poor sensitivity for detecting the ureteral calculi.22Palmer JS, Donaher ER, O’Riordan MA, Dell KM. Diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. J Ural. 2005 Oct;174(4 Pt 1):1413-6.   In such cases of non-diagnostic ultrasound, an unenhanced CT scan is advised to be performed in all children with persistent urolithiasis symptoms. Non-contrast CT scanning is the most sensitive imaging modality to detect urinary stone disease, with ability to image very small stones, and a greater potential to identify alternative diagnoses.24Tanaka ST, Pope IV JC. Pediatric stone disease. Current Urology Reports 2009;10(2):138-143.   It also serves as a valuable tool to guide management in that it can evaluate total stone burden efficiently and can localize ureteral stones with great precision as well as detect obstruction.20Gillespie RS, Stapleton FB. Nephrolithiasis in children. Pediatrics in Review 2004;25(4): 131-139.  

Management of urolithiasis in children

The objectives of stone management in children are broadly similar to adults and encompass complete stone clearance, prevention of stone recurrence, preservation of renal function, control of urinary tract infections, correction of anatomical abnormalities, and correction of the underlying metabolic disorders.1Knoll T, Humke U. Urolithiasis in childhood. Urologe A. 2013 Aug;52(8):1084- 91.   There are a wide variety of treatment modalities available for this therapeutic need, with options ranging from non-invasive medical therapy to major surgical interventions depending on the indication.28Hwang K, Mason MD, Peters CA. Clinical practice. Surgical approaches to urolithiasis in children. EurJPediatr. Jun 2011; 170(6): 681-688.   Generally, the choice of therapy is made considering stone size, location, and composition, and patient factors, such as age and urinary tract anatomy. Commonly, a trial of expectant management for attempted spontaneous passage seems appropriate in those without signs of infection or intractable pain, or having ureteral calculi less than 4−5 mm. This is because stones with such smaller diameter are likely to pass spontaneously in majority of cases, while those > 5 mm rarely pass spontaneously.11Bartosh SM. Medical management of pediatric stone disease. Urol Clin North Am. 2004 Aug;31(3):575-87, x-xi.  ,24Tanaka ST, Pope IV JC. Pediatric stone disease. Current Urology Reports 2009;10(2):138-143.  

Acute management: the need for safe and effective analgesia

Acute management in cases of urolithiasis is mostly directed towards control of acute complications. In individuals presenting with the typical renal colic, pain management is of major significance. Besides, it is important to maintain a high urine flow rate, possibly through parenteral hydration, in case the patient is vomiting or is unable to drink.

As the pain associated with stone passage is often severe, prompt resolution of pain can be achieved using opiates (such as morphine sulfate) and/or non-steroidal anti-inflammatory drugs. However, it is often seen that a majority of physicians are not comfortable with using opiates due to their side effects, which include nausea, vomiting, constipation, sedation, dizziness, lightheadedness, disorientation, respiratory depression and hypotension. Besides, there is conflicting data on the effect of opiates on ureter muscle tone.29Golzari SEJ, Soleimanpour H, Rahmani F, Mehr NZ, Safari S, Heshmat Y, Bakhtavar HE. Therapeutic approaches for renal colic in the emergency department: a review article. Anesth Pain Med. 2014; 3(3): el 6222.   The effect of NSAIDs on relieving pain in acute renal colic is similar to opiates, but alike to the latter, side effects of NSAIDs, such as nausea, vomiting, feeling of heat or pressure in the chest, fatigue and lethargy, warrants cautious approach to their use mainly in the long-term. For this analgesic application, an alternative like drotaverine may therefore be used, together considering its advantage of ureteral muscle relaxation. Drotaverine is an inhibitor of Phosphodiesterase 4 (PDE4) in smooth muscles and exerts anti-spasmodic effect without anti-muscarinic adverse effects.29Golzari SEJ, Soleimanpour H, Rahmani F, Mehr NZ, Safari S, Heshmat Y, Bakhtavar HE. Therapeutic approaches for renal colic in the emergency department: a review article. Anesth Pain Med. 2014; 3(3): el 6222.   In a placebo-controlled, multicentre, multinational, randomized, double-blind study, the spasmolytic effect of drotaverine hydrochloride was

Dosage of drotaverine in children
  Drotaverine HCl 10 mg/5ml Drotaverine HCl 20 mg/5ml
1-6 years 1ml/kg body weight TID
(upto 120 mg/day)		 0.5 ml/kg body weight
TID (upto 120 mg/day)
6-12 years 1ml/kg body weight TID
(upto 200 mg/day)		 0.5 ml/kg body weight
TID (upto 200 mg/day)
Figure 3 Stone free rate with tamsulosin

assessed in adults with colicky pain caused by renal and ureteric stones; and it was found to provide effective pain relief in more than 2/3rd (79%) of patients with renal colic, with no serious side-effects.30Romics I, Molnar DL,Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G.The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 J u 1;92(1):92-6.   The evidence though demonstrated in adults may be suitably extrapolated to children.

MET for stone expulsion: a valuable addition to expectant management

Medical expulsive therapy (MET), which includes use of medications to facilitate spontaneous stone passage and reduce symptoms, has been effectively used in adults with distal ureteral calculi. Of the various options available for MET, alpha-blockers are a particularly promising class of stone-expulsive agents.31Lipkin M,Shah O.The use ofalpha-blockers for the treatment of nephrolithiasis. Rev Ural. 2006;8 S u pp 14:535-42.   These drugs block alpha-adrenergic receptors present in the ureter, thereby causing smooth muscle relaxation, inhibition of peristalsis, and relieving spasm.32Arrabal-Martin M,Valle-Diaz de la Guardia F,Arrabal-Polo MA,Palao-Yago F, Mijan-Ortiz JL, Zuluaga-Gomez A. Treatment of ureteral lithiasis with tamsulosin: literature review and meta-analysis. Urollnt.2010;84(3):254-9.   Accordingly, they not only accelerate the passage of ureteral calculi, reducing expulsion time, but considerably decrease LUTS as well – reducing obstruction and improving the urine flow.33Porpiglia F, Ghignone G, Fiori C, Fontana D, Scarpa RM. Nifedipine versus tamsulosin for the management of lower ureteral stones. J Ural. 2004 Aug;172(2(:568-71.  ,34Cervenakov I, Fillo J, Mardiak J, Kopecny M, Smirala J, Lepies P. Speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1-blocker-Tamsulosin. Int UrolNephrol. 2002;34(1):25-9.   Tamsulosin – an alphablocker – alone as MET for distal ureteral calculi has been found to provide excellent expulsive effectiveness in adults.35Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidneyint. 2011 Feb;79(4):385-92.  ,36Dellabella M, Milanese G, Muzzonigro G. Medical-expulsive therapy for distal ureterolithiasis: randomized prospective study on role of corticosteroids used in combination with tamsulosin-simplified treatment regimen and health-related quality of life. Urology 2005 Oct;66(4):712-5.   This efficacy of MET does not seem to be limited to adults. A recent study demonstrated that MET with tamsulosin is a successful procedure for lower ureteric stones in children as well, likely increasing the spontaneous passage of ureteral stones. The

Figure 4 Mean stone expulsion time with tamsulosin

prospective randomized controlled study included 61 children (aged 8.1±6.8 years; 25 females, 36 males) with distal ureteric calculi (< 12 mm).37Mokhless I, Zahran AR, Youssif M, Fahmy A. Tamsulosin for the management of distal ureteral stones in children: a prospective randomized study.JPediatr Urol. 2012 Oct;8(5):544-8.   In the study, tamsulosin demonstrated no clinically significant adverse effect, while proving to be a safe and effective treatment option. Children were randomly divided into two groups: Group I (study group, n = 33) received tamsulosin and standard analgesia, and Group II (placebo group, n = 28) received standard analgesia and placebo. The stone-free rate was 87.8%

Dose of tamsulosin in children37Mokhless I, Zahran AR, Youssif M, Fahmy A. Tamsulosin for the management of distal ureteral stones in children: a prospective randomized study.JPediatr Urol. 2012 Oct;8(5):544-8.  

  • yy 0.2 mg daily in children ≤ 4 years
  • yy 0.4 mg daily in children > 4 years.
Tamsulosin in MET

in the tamsulosin group (29/33), compared to 64.2% (18/28) in the placebo group (Figure 3). In addition, a statistically significant difference was also recorded in the mean stone expulsion time, and those receiving tamsulosin had decreased time to stone expulsion; mean stone expulsion time of 8.2 and 14.5 days for Group I and II respectively (Figure 4). Thus, a trial of MET is reasonable in children in correct clinical setting.38Wood KID, Gorbachinsky 1, Gutierrez J. Medical expulsive therapy. IndianJ Ural. 2014;30(1):60-4.  

Medical management of stones

The goal of medical treatment in urolithiasis is to protect the patient from formation of new stones and expansion of existing ones. Therefore, treatment is based on elimination of risk factors, and lowering supersaturation of salts, using both nonpharmacological (fluids and dietary changes) and pharmacological (drug) therapy.39Taylor EN, Curhan GC. Diet and fluid prescription in stone disease. Kidney Int. 2006 Sep;70(5):835-9.   ,40Aaslid A,Tkaczyk M.The clinical course of urolithiasis in children under 3 years of age. Prog Health Sci 2014;4(1):68-74.  

Fluids

Given that all types of calculi are less likely to form in dilute urine with reduced concentration of lithogenic factors, adequate intake of fluids is advocated to prevent stone recurrence regardless of the etiology. Increased urine volume decreases solute concentration and consequently supersaturation, thus reducing the risk of all kinds of renal stones.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.   Fluid intake mainly should include water. However, this recommendation for high fluid intake has only limited success in children; hence, other preventive means also needs to be utilized.

Diet

Diet plays an important role in the development of urolithiasis, particularly in the pediatric population.4Sharma AP, Filler G. Epidemiology of pediatric urolithiasis. Indian J Urol. 2010;26(4):516-522.  ,10Chen JN, Dieguez LM, Trachtman H. The Changing Epidemiology of Urolithiasis in Pediatric Patients. J Nephrol Therapeutic 2014;S11:S11-006.   Hence, besides increasing the fluids intake, dietary modification should constitute another main non-pharmacological intervention in the medical management of urolithiasis.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.   As endemicity of calculi observed in developing nations often seems to correlate with a decreased availability of dietary phosphates, this dietary need can be of major significance.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.   Yet, recommendations should be tailored based on the stone type and urinary profile. In this context, since majority of kidney stones (∼80%) contain calcium, most studies have focused on the prevention of calcium stones. As high dietary sodium intake is linked with hypercalciuria, for majority of patients with calcium stones and most other types

Table 3 Adequate intakes of sodium

of stones, dietary sodium adjustment indicates a significant reduction in its intake (Table 3). Conversely, high potassium intake has the opposite effect on urine calcium, namely it decreases it.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.   Potassium in nature (fruits and vegetables) comes in alkali form, such as potassium citrate, which has a more potent effect in decreasing the urine calcium excretion. Another important aspect of decreasing urine calcium is by reducing the intake of animal-protein (meat, fish, and poultry); which per se will change the diet to be less acidic.

Pharmacotherapy

Pharmacotherapy is generally recommended for children in whom fluid and dietary therapy is ineffective in controlling the stones formation; or for those with primary hyperoxaluria, cystinuria, or a known genetic condition associated with normocalcemic hypercalciuria.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.   Various agents, including diuretics, alkalinizing agents (like potassium citrate), thiolcontaining agents, allopurinol, and pyridoxine are available for pharmacotherapy, with choice of agent depending on the type of urinary stone (Table 4). Thus, pharmacotherapy is specific to the type of the stone, and can usually be said to be preventive.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.   ,41Akin Y, U4ar M, Yucel S. Current medical treatment in pediatric urolithiasis. Turkish Journal of Urology 2014; 39(4): 253-63.  

Alkalinizing agents for stones dissolution

In most cases, patients who do not require urgent surgical intervention for reasons of pain, obstruction, or infection can have their stones dissolved with alkalinization of the urine; struvite stones which form only in the setting of infection are however an exception to urinary alkalinization.

Table 4 Pharmacotherapeutic agents for potential

This goal of urinary alkalinization can be effectively achieved through use of alkalinizing agents, like oral potassium citrate, which increase the urinary pH and/or provide increased citrate in the urine.42Fathallah-Shaykh S, Neiberger R, Langman CB, et al. Pediatric Urolithiasis. Available at: http://emedicine.medscape.com/article/983884-medication#2 [Accessed on 25/11/14].  ,43Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidneylnt. 1983 Sep;24(3):348-52.   Nonetheless, dosage of the alkalinizing agent needs to be adjusted, such that the urinary pH is maintained between 6.5 and 7.0; and not exceeding 7.5. A urine sodium/potassium ratio may be used to check efficiency of the dietary modulation; and ratio should be less than 2.5.

Benefit of citrate in urine

The benefit of citrate in urolithiasis is well-documented. It has been shown that high availability of citrate in urine helps in reducing the stone formation owing to the powerful inhibitory effect of citrate on calcium salts crystallization.44del Valle EE, Spivacow FR, Negri AL. Citrate and renal stones. Medicina (BAires). 2013;73(4):363-8.   Citrate binds to urinary calcium, thereby forming a soluble complex, which decreases the availability of free ionic calcium necessary for calcium oxalate or calcium phosphate crystallization. Additionally, citrate also acts as a direct inhibitor of calcium crystal aggregation and growth.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.  

Dosage of potassium citrate in children:

  • 5 ml of supplement [containing potassium citrate monohydrate 1100 mg, which provides 10 mEq of potassium, and citric acid monohydrate 334 mg] to be taken after meals three times a day, after being diluted in one glass of water.

Why selecting potassium citrate for supplementation?

Oral potassium citrate is mainly used for supplementation because of its documented superior efficacy in urine alkalinization. It is preferred over sodium-containing salts, such as sodium bicarbonate or sodium citrate, as a first line urine alkalinizing agent since sodium loads are known to increase urinary calcium excretion and stone formation.45Xu H, Zisman AL, Coe FL, Worcester EM. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013;14(4):435-447.   Potassium citrate in fact targets multiple metabolic abnormalities in stone formers: normocalcemic hypercalciuria; hypocitraturia; hyperuricosuria; cysteinuria; thereby preventing stone recurrence in general.46Singh SK, Agarwal MM, Sharma S. Medical therapy for calculus disease. BJU Int. 2011 Feb;107(3(:356-68.   Treatment of patients with calcium stones due to idiopathic hypercalciuria with potassium citrate has the dual advantage of decreasing urine calcium and increasing urine citrate. Also, it is the first line of treatment in patients with uric acid stones47Tasian GE, Copelovitch L. Evaluation and Medical Management of Kidney Stones in ChildrenJ Ural2014 Nov;192(5):1329-1336.  , and may prevent complication of calcium sodium citrate may not.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.  ,43Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidneylnt. 1983 Sep;24(3):348-52.   An additional application of potassium citrate is in mitigating the effects of potassium depletion in case thiazide diuretic is being used in children with hypercalciuria not responding to sodium restriction.4Sharma AP, Filler G. Epidemiology of pediatric urolithiasis. Indian J Urol. 2010;26(4):516-522.   While the drug (potassium citrate) is considered as quite safe when used at therapeutic doses48Zmonarski SC, Klinger M, Puziewicz-Zmonarska A, Krajewska M, Mazanowska 0, Dembinska E. Therapeutic use of potassium citrate. Przegl Lek. 2001;58(2):82-6.  , there are other distinct clinical advantages as well which may increase the compliance; such as high palatability, pleasant taste, and tolerability even with long-term use.

Metabolic evaluation for prevention

Considering the high incidence of predisposing factors for urolithiasis in children and high stone recurrence rates, it is suggested that every child with urinary stone be given a complete metabolic evaluation to both effectively treat current stones and to prevent recurrence.3Gnessin E, Chertin L, Chertin B. Current management of paediatric urolithiasis. Pediatr Surg Int. 2012 Jul;28(7):659-65.  ,14Ba;tug F, Du;iinsel R. Pediatric urolithiasis: causative factors, diagnosis and medical management. NatRev Ural. 2012 Feb 7;9(3):138-46.   Ideally, such an evaluation is performed while the patient is at home and consuming the regular diet, and is important since choice of pharmacological agent is based on the chemical composition of the stone and the biochemical abnormalities causing its formation.19Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol 2009;24:2129-2135.   It has been seen that children with an identifiable metabolic abnormality have up to 5-fold increased risk of having a recurrence as compared to children with no identifiable metabolic disorder. A 24-hour urine collection is used for this purpose that should be analyzed for calcium, oxalate, citrate, uric acid, sodium, creatinine levels, volume, pH, and cystine, with results evaluated relating to weight, body surface area, and creatinine excretion.2Copelovitch L. Urolithiasis in Children. Medical Approach. Pediatr Clin North Am. Aug 2012; 59(4): 881-896.   However, controversy exists as to whether a single 24-hour urine collection is sufficient for proper metabolic evaluation of recurrent stone disease or not.49Castle SM, Cooperberg MR, Sadetsky N, Eisner BH, Stoller ML. Adequacy of a single 24-hour urine collection for metabolic evaluation of recurrent nephrolithiasis. J Ural. 2010 Aug;184(2(:579-83.  ,50Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inadequate for the medical evaluation of nephrolithiasis. J Ural. 2002 Apr;167(4):1607-12.   Therefore, for optimal outcomes, two 24-hours urine samples may be collected on free-choice diet not prior to three months after stone passage or urological intervention.51Hess B. Pathophysiology, diagnosis and conservative therapy in calcium kidney calculi. Ther Umsch. 2003;60(2):79-87.  

Surgical approach for stone removal

With advancing technology, surgical management of urolithiasis has dramatically evolved in the past few decades. Hence, for definite stone clearance, minimally invasive interventions have largely overtaken the open surgical approaches in pediatric urolithiasis. Progressing from least to most invasive, extracorporeal shock wave lithotripsy (ESWL), ureteroscopy, and percutaneous nephrolithotomy are now the surgical methods for renal and ureteral stones.52Granberg CF, Baker LA. Urolithiasis in children: surgical approach. Pediatr Clin North Am. 2012 Aug;59(4):897-908.   Majority of stones in children can be managed either with ESWL, which has a higher efficacy in children than in adults, percutaneous nephrolithotomy, ureterorenoscopy, or a combination of these modalities; and open or laparoscopic surgery is limited only to well-selected cases with underlying anatomical abnormalities.1Knoll T, Humke U. Urolithiasis in childhood. Urologe A. 2013 Aug;52(8):1084- 91.  ,53Dogan HS, Tekgul S. Minimally invasive surgical approaches to kidney stones in children. Curr Urol Rep. 2012 Aug;13 (4):298-306.   ESWL is the prime modality which has stone-free rates between 67% and 93% at short-term follow-up, and 57% to 92% at long-term follow-up in children.54Braun PM, Seif C, Jiinemann KP, Alken P. Urolithiasis in children. International BrazJ Ural. 2002;28(6):539-544.   Better tolerability is another advantage of ESWL over other modalities that makes it the procedure of choice for treating most upper urinary tract calculi in pediatric population.8Aydogdu O, Karakose A, Celik O, Atesci YZ. Recent management of urinary stone disease in a pediatric population. World J Clin Pediatr. 2014;3(1):1-5.  ,24Tanaka ST, Pope IV JC. Pediatric stone disease. Current Urology Reports 2009;10(2):138-143.   Endoscopic treatment is however also on rise with miniaturization of instruments and better optic and ancillary instruments.9Straub M, Gschwend J, Zorn C. Pediatric urolithiasis: the current surgical management. Pediatr Nephrol (2010) 25:1239-1244.   Overall, the choice of modality is individualized, considering the age of the child, stone size, number, location, and anatomic and clinical contributing factors.

Conclusion

Urolithiasis in a pediatric patient presents a unique challenge to the clinician particularly considering the morbidity and recurrence associated with it. Since children are part of the high-risk group for stone recurrence, management must be customized for each individual. The approach to management of ureteral stones in children is generally similar to adults, with conservative and medical therapy holding the first place. Unless otherwise indicated; drotaverine can be used for analgesia in acute cases to avoid the adverse effects of opioids and NSAIDs. While medical expulsion therapy – using tamsulosin – is a suitable option to facilitate spontaneous passage of most distal ureteral stones in them; addition of potassium citrate for urinary alkalinization will help in both managing the current episodes and to prevent recurrence as well. Potassium citrate is useful to correct both low urinary pH and hypocitraturia and reduce markedly the recurrence of kidney stones. Surgical treatment for stone removal should be promptly considered for stones not amenable to medical management, with choice of modality mostly depending on the stone size and location.

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