[Frontiers in Bioscience E.1, 299-308, June 1, 2009] “Treatment strategies for pediatric idiopathic hypereatciuria Keith Kwong Lau ', Lavjay Butani® " Keith Kwong Lav, Deparment of Pediatrics, University of California, Davis, 2516 Stockion Bid. Sacramento, CA 95817, USA, *Lavjay Bulan, Deparment of Pediatrics, University of Calformia, Davis, 2516 Stockion Bh, Sacramento, CA 95817, usa TABLE OF CONTENTS. 1 Absiract 2 Introduction 3. Dietary modifations 31 Pld intake 3.2 Calcium 353 Sodium 3.4 Animal protein 33 Potasinm 4: Pharmacological reaiments “41. Thizide diuretics 42 Curate 43 Bisphosphonates 5. Management issues: Team approach ‘$1. Dietitian 152 Pedic nephrologist 5.3 Patients and families 6. Prognosis 2. Sunmary and perspectives 8 References ABSTRACT. Iiopathic bypereaciuia (IH) is a. common Itaboli disorder in children and is associated with the evelopment of renal eaeuli, nephrocaleinosis, hematuria and osteopenia. The effect of various dietary modifiatons and available pharmacologic theapies on reducing urinary calcium ‘exeretion andlor urinary” supersauration i fiscussed in his “article, The imponance of a ‘mulidiseptinary. approach involving. the patent, their Samiles, and health-care professionals is also addressed a9 2. INTRODUCTION 1H was initially thought to be either due to increased intestinal caleium ~ absorption (absorptive Ihypercalciurs) oF fom the impairment of renal tubular reabserption of calcium (renal_hyperealiuria) (1) However, i is now apparent thatthe previously described sub-ypes of TH are pars of a spectrum of a single disease @), ‘with an additional contribution of bone demineralization to excessive urinary calcium excretion, Therefore, the management of children with TH of either‘Treatment for pediatric idiopathic hyperealeiuria ‘Decrease bone resorption Awd comin 63) Carreupreemtsysenie CP ‘sins \\ phosphonate \\ Dacca rim: Diu malian + Rolie _ Soiuminahe + High trate conning () Nal alam al pritcia intake 27 paste rating + Urine volun! rine specie grvity + Gira exert (etary o parmacalag) Thies Figure 1, Potential sites of action of different treatment modalities in pediatric idiopathic byperaleuria sub-ype isthe same and we will ot separate the discussion fof treatment strategies into’ absorptive or renal hypercaleiura, The main goal of treatment in eile wit TH is to deerease their risk of future stone forstion by reducing urinary calcium oxalate supersaturation and to Iimprovelmainiain bone mineralization. As depicted in Figure I, a variety of approaches, often in combination, are necessary to achieve these aims (Figure 1) 3. DIETARY MODIFICATIONS Dietary medications are the mainstay of inital therapy for 1H in cldren. Dietary changes lone may not always be succesful but inadequate dietary control wll Almost alvays diminish the clinical elfcacy of other ‘adjunctive medical therapies 3.4. Fluid: Increasing Mui intake is probably the single ‘most important intervention 'As data from aut staies has demonstrated that increasing Muid intake roduces the risk of stone formation (G6), fhid intake has been viewed a5 the most ervial omponeat of management of Tit in both aduls and 300 children. Although it has been recommended thot Mid intake be adjusted to produce a daily urinary volume of at least 2 Titers in adults who are at ssk of calium stone recurence (7), no similar clinical guidelines have een developed or validated for children, In one pediatric study, the authors recommended that children with IHL consume fluid to about 1-1 i times their usual maintenance requirement (8). In adolescents, targeting a 24-hour urinary volume of more than 2 liters has also ben advocated (9), An allemaive approach has been to monitor and keep urinary specific gravity of children with TH below 1.010, a5. a surrogate marker of determining the adequacy of Mud intake (10). Although increasing the urine volume will not decrease urinary ‘calcium excretion, diluting the urine offers the benefit of decreasing urinary supersaturation and the chance of ‘stone Formation, Specific beverages that may reduce the risk of recurent nephroithisis, based on adult data, include ‘orange juice and lemonade (11-14). Whether there is a benefit to specifically timing and spacing uid intake ‘through the day or specifically at night stl controversial‘Treatment for pediatric idiopathic hyperealluria “Table L. Recommendations to reduce sodium (sat) intake include the following “Avoid ating out, especially in fast food restaurants Look at fo labels when buying groceries and avoid foods with high salt content ‘+ Cook using fresh ingredients whenever possible [nou arises to cook with items having high salt content such a canned foods, drain the water from can and rinse ‘before cooking Use itl o no salt during food preparation. Use les than recipe recommended amount of sl + Use sal allematives such as pepper, heths,non-sodium seasonings. Avoid adding extra salt by removing th slshaker fm the dining table ‘32, Calcivm: Restricting calcium intake in children is ot recommended ‘Avoiding an excessively hih-caleium diet has ‘been suggested in adult caleium stone formers in the past (05,16 such recommendations are no longer widely practiced and are, in fe, not advisable. Extensive urinary renal losses of aleium’ may have already occured in Patients with TH, even children, causing them to become ‘osteopenic (17), Moreover, evidence demonstrates that any ‘theoretical benefit of adopting a severely low ealeium diet. is countered bythe occurence of absorptive hyperoxaluria, (418), actualy. inereasing. the risk of stone. formation. Patonis with IM who have a dietary calcium intake less than the Daly Recommended Intake (DRI) may even need to be on. calcium supplementation to counteract the dowimental effects from their being in a state of negative alium balance (4,19). Interestingly, there is growing epidemiologic evidence that suggests that higher calcium, ke may actually also reduce the risk of tone formation (€-5,20) laa prospective Wal involving 45619 men ars of nephrolithisss, dietary calcium intake was inversely fsssociated with the risk of kidney stone formation (3), 1s nother study onthe association between intake of dietary and supplemental calcium and the sk of neprolithiasis in ‘women, high inlake of dietary calcium again appeared to have protective effect against stone Formation ()-A recent follow up study from the same group suggested that within the adult population, the ellis of dctary factors on the risk of stone formation vary with age: hence, whether the resulis (rom these adull studies can be exrapolated to shildren remsins co be detemnined (21). Alko, © recent randomized study in heathy men showed that a high calcium diet alone, without concomitant modifiation of caer dietary factors, offered litle benefit in educing stone formation (22), At our conter, we recommend keoping dietary ealeium intake for children with IH at or slghly above the _DRI (600-800 mg/day in prepuberal chiliren). For etldren with TH who have Tow bone mineral density, caleium Supplementation with calcium ciate i recommended, This combination has been suggested fo be the most elfetive in Timitig the new stone formation rate for hose who requir calcium supplements 23). 33. Sodium: Should be restricted in the diet Tiereased sodium intake has been observed to be associated with higher urinary calcium excretion in adults ‘with TH (2426). Conversely, reduction in datary sodium inake has ‘hoes shown to decrease rina” caleiam excretion (24,26). Renal tubular handliag of eleium has ‘been studied in setings of extceceluar Auld volume expansion using hypertonic saline (27). In that setting, caleium reabsorption is inhibited in the proximal tubule Teading wo hyperalciaria, The risk of nephvolithiasis on 8 high sodium dit was evaluated in 14 normal subjects (28). Increasing dietary sodium intake from $0 mmel/day to 300, smmolay significantly increased urinary calcium (fom 273 4 103 to 393 2 1.51 mmolday) and decreased ‘inary ciate (rom 3.14 = 1.19 0 282 4 0.83 mmoliy). In another study, daily urinary calcium excretion was shown (© increase on average from 110 meday to 167 mglday by daily supplementation of 240 mEq of sodium (9), Hence, excesive salt intake may increase the risk of epholithiass by increasing urinary caleium excretion and ecreasing urinary ciate. Although there are no definitive juldelines avilable on how restrictive to be with dietary sodium intake in children with TH, at our conter Wwe recommend that such children limit their daily intake of sodium wo less than 2 grams (30). Paints and thee faniios should be made aware that most spacks and fastfood items ‘contain a considerable amount of sodium. Similarly, many prepared foods, including canned soups and cold meats, so have large amounts of sodium. Table T depicts some dictry recommendations to keep sodium intake low. (Table 1) 34. Animal protein: Although restricting animal protein may be beneficial, it is rarely indicated in rowing children ‘Animal. peoteins ave high methionine and cystine content The sulphur in methionine and cystine [Benerate sulphates wher oxidized, The sulphates then Increase urinary calcium excretion by complexing with ina-uminal calcium and. preventing it Irom boing absorbed. Urinary calcium exeretion has been shovwn to corelat diecly with the level of dietary protein intake {G1 Ina metabolic sud, adult mien were given a diet that Provided either 12 grams or 36 grams of nitrogen per day. All subjects were maintained on approximately 1400 mg of Glictry calcium per day. Urinary caleivm excretion was signilcanly higher in subjects roesving the high nitrogen diet (191 mplday versus 277 mg/day). Ina. recent ‘randomized tril that was designed to determine the relative clficacy of 2 diffrent dicts in preventing recurrence of stone formation in adult men with IK, restricted intake of animal protein and salt, combined with « normal caleium intake, provided greater protection than a taditional low ‘alelumn diet 20}, There is also evidence showing that ‘moderate protein restriction in_hypercaliurie. patents reduces urinary excretion of ealeium and bone resorption via. a decrease in exogenous acid load (32). In spite to these benefits to animal protsin rexriction, excessive restriction‘Treatment for pediatrie idiopathic hyperealeiuria ‘of animal protein in growing children cannot be encouraged Aue tothe potential for growth retardation, 35. Potassium: May reduce renal calcium excretion but ‘requires further data before it can be recommended ‘The role of potassium in the management of 1 has been studied both in adults and in children, Hypercalcuric. children have been Known 10. have eeteased factional excretion of potasium in the urine (G3), Cwillo etal found a high rine sodium to potassium ratio in adult stone formers compared o healthy now-stone fommers ($4). Furthermore, administration of potassium supplementation to healthy adults was shown to reduce trinary calcium excretion (38), suguesting that potassium ‘may promote renal calsivm retention and redaoe Fhypercaluria, Observational sties in auls also support 4 possible protective eect of dietary potasium ilake on sone risk (7) Similar observations were ooted in. 11 hileen wiih TH who were tested with potassium ‘supplementation {potassium at | mEgq/day), in tha the Urine calium to creatinine ratio decreased from 0.31 = 0.10, 100.14 007 (36. These data suggest that dats containing ‘more potassium may rectly a negative calcium balance and thus be beneficial to children with IH, However, randomized controled tals are still Tocking. and the ‘optimal dese for potasium supplementation is nat known 4. PHARMACOLOGICAL TREATMENTS 41. Thinzide diuretics: Useful but not without risks and side effects Thiavides are curently the most widely used medical therapy for ptints with TH Although the presse mechanism forthe hypoealeiuri eet oftiazides is still debatable, recent evidence shows that thiarides induce pshive paracellular calcium reabsorption inthe proximal tubule via volume contraction (37. Ina randomized study of 17S adult ptiens in Japan, ichloromethiazide teeatment sigifianlly reduced hyperealiuria and the ras of stone-ormation (38). Thiazides, in addition to their hypocaleiuric’ effet, also reduce intestinal calcium absorption; the nat result, however, remains induction of postive ealeium balance(39). Longterm use of thiszides, irefore, as might be expected, Is associated with favorable effects on bone mass in. Hypercaleiurc osteoporotic men and reduces the risk of hip fractures (G0.). This hypocalciure effect is reduced if sodium is not limited. Since thiazide diuretics can cause side effects such as weakness, nausea, dislipidemia and electrolyte abnormalities, especially hypokalemia and hhyponatermia, they should be used judiciously. Ta the authors practic, thiavide use is restricted to children with TH who have a history of nephroithiasis, especialy if recurrent, or inthe seing of recurrent painful bemaur 42. Citrate: Provides protection by reducing urinary supersaturation Ciuate is useful altemative therapy in children ‘wih IH decreases the rsk of stone recurrence by binding {o urinary calcium and forming soluble ealciimectate complexes, Various preparations containing citrate are available such "as Potassium cite "or potssiom- 302 magnesium ciate; the sodium salt of citrate should be voided die to sat load that is astocated with AIS, poussium rich citras fivts and juices, such as oranges, Brupefrut, and cranberries, are recommended. Orange Juice, for example, has high content of natural potassium Citra, Lemon juice also has very high erate conten, $0 Temonade made ffom real lemon juice is recommended, Long-term use of potassium citrate also increases bone mineral density (42), and may prevent age-related bone loss in adult patients (43). Those effets may be due to its alkaline eect, preventing aeidrelated bone resorption, Doe to its safety and. Tack of side effects, citrate supplementation may become the first Tine therapy in ulen with TH who. are deemed candidates for ‘Pharmacological intervention. However, some children ‘ont to have rourrence of renal stones after comection Of hypercaleiuria with potassium citrate. Tt has been Iaypotesized that citrate therapy, by elevating the urine pt, fly predispose pallets 10. develop caletum-posphats ‘ones, which precipitate ia. an alkaline envionment Researchers have just finished recruiting hypercaliuric children to sudy the effect of chat on urine chemistries fand acid-base balance (48), 43. Bisphosphonates: Very 1 date ited data available to Bisphosphonates are analogues of pyrophosphate ‘with a high affinity for the hydroxyapatite matrix in bene, especially in areas of rapid turnover and bone resorption Data on the use of bisphosphonates, which reduce bone resorption via inhibition of osteoclast setivation, for the ‘reuiment of TH are sil very limited. Animal studies have show tht alendronate decreases urinary calium exerstion in genetic hypercaleiuri as, supporting the ol of bone as mayor contributor to wrinary calcium excretion in 1H (45). To our krowiedge, the only 2 published human studies of bisphosphonates in patients wid IH are in adults and both have shown a decrease in urinary calcium excretion and increase in bone mineral density (BMD) in the weated subjects (46,47) In 7 young adult men, mean lumbar spine BMD increased significantly by 2.6 4 1.0% in the first ‘year after treatment with etidronat (46). Using a model of bd rest immobilization in 16 male subjects, slendronae ignifcanly inhibited bone mineral loss and avered the Inyperaleuria inthe treatment group (47). However, due to lack of adequate experience with bisphosphonates in chiliren, and their possible side “eflecs such as ‘steanecosis of ja (48,49), the use of bisphosphonates in ‘ilren with IH seeds 10 be studied before their use Thecomes more widespread ‘5, MANAGEMENT ISSUES: TEAM APPROACH. 5. Dietitian Since dietary modificaion is a crucial and ‘mandatory port of a. succesful management strategy, children with IF should be refered a diedian to accurately assess dietary intake of calcium and sodium. Because ofthe concer regarding bone growth, no child should receive les than the DRI of calcium. Reduction of Sesium intake ad judicious animal protein restition also‘Treatment for pediatric idlopathiebypercaliuria ‘aciitates lowering of urinary calcium excretion and goes Jong ways in preventing recurrent stone formation, ‘Children with TH should be followed at epular intervals by a pediatric nephvoogist. Growth parameters should be followed in ll children and BMD should be ‘measured if there is any suspicion of demincalization Random urine calcium to creatinine ratio otimed 24-hour urinary collections for calcium excretion should be tonitored at 6smonth intervals. If dietary conto, by itself, is not able 10 induce symptomatic relief and reduce recurrent stone formation, pharmacotherapy should rongly be considered. As pharmacological reatments are rot without side effets, serum eletrolyies and lipid panels should be followed closely in children on therapy with Patient involvement is very important in the seeatment of IM, Children and their families should be ‘encouraged to bean itinsic pat ofthe team. The patient should be educated on the nature of the disorder ineluding the associnted symptoms, complications and prognosis. The rationale behind the dietary modifieaions andthe indications for pharmacologic inerventions should also be explained. Motivated patien's who understand the Significance of prolonged treatment are more Tkely to adhere in the lang rut the individvalized preventive program designed, 6, PROGNOSIS Children with IH are at increased risk of developing urinary stones. The vast majority of children diagnosed with IH do extremely well. They normally have preserved renal funtion and ean have symptom fee lives With appropriate management. However, in some eases, Tite-ong therapy is required 7. SUMMARY AND PERSPECTIVES Treatment goals in TH are to decrease urinary superseturation and to promote a postive caleium balance With the ulimate goa of decreasing the risk of stone formation and improving bore mineral deasty. This can best be accomplished by an increased Hud intake and low salt dit: pharmacotherapy consisting ofthiasdes diuetis andor potassium citrate may be nevessary in some eases. However, since none of the medications are without side ets, in view ofthe additonal benefits offered by high ‘vid and low sodium in the dict of children, it seems reasonable «0 emphasize dietary modification as the primary weatment 8. REFERENCES 1. Chars Pak: Physiological basis for absorptive and renal hyperealinrias. An J Physiol 237, FALSHA23 (1979) 2. 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Clin Ther 29, 183 1558 2007) Abbreviations: IH: idiopathic hypereaeiuia; DRE daily recommended intake; BMD: bone mineral density Key Words Idiopathic hypercaeiuria, Children, Dietary modifications, Pharmacological treatment, Bone demineralization Send correspondence to: Keith K, Lau, Department of Pediauics, University of Califia, Davis, 2816 Stockton vd, Sacramento, CA 95817, USA, Tel 916-734-8118, ax: 916-734-0629, Email: keith laud vedme uedaviseds utpywmw bioscience orgicurrentivoltE.him os