Educational review: role of the pediatric nephrologists in the work-up and management of kidney stones

Carmen Inés Rodríguez Cuellar1,2,3,4, Peter Zhan Tao Wang5, Michael Freundlich6, Guido Filler1,3,7,8
1Lilibeth Caberto Kidney Clinical Research Unit, London Health Sciences Centre
2Instituto Nacional de Pediatría, Ciudad de México, Mexico
3Department of Pediatrics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada
4Universidad Autónoma de México, Ciudad de México, Mexico
5Department of Surgery, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada
6Department of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, USA
7Children’s Health Research Institute, University of Western Ontario, London, Canada
8Children’s Hospital, London Health Science Centre, University of Western Ontario, London, Canada

Tóm tắt

Từ khóa


Tài liệu tham khảo

Kit LC, Filler G, Pike J, Leonard MP (2008) Pediatric urolithiasis: experience at a tertiary care pediatric hospital. Can Urol Assoc J 2:381–386

Scales CD Jr, Smith AC, Hanley JM, Saigal CS, Urologic Diseases in America P (2012) Prevalence of kidney stones in the United States. Eur Urol 62:160–165

Worcester EM, Coe FL (2010) Clinical practice. Calcium kidney stones. N Engl J Med 363:954–963

Kusumi K, Becknell B, Schwaderer A (2015) Trends in pediatric urolithiasis: patient characteristics, associated diagnoses, and financial burden. Pediatr Nephrol 30:805–810

Sharma AP, Filler G (2010) Epidemiology of pediatric urolithiasis. Indian J Urol 26:516–522

Sas DJ, Hulsey TC, Shatat IF, Orak JK (2010) Increasing incidence of kidney stones in children evaluated in the emergency department. J Pediatr 157:132–137

Fakheri RJ, Goldfarb DS (2011) Ambient temperature as a contributor to kidney stone formation: implications of global warming. Kidney Int 79:1178–1185

Brikowski TH, Lotan Y, Pearle MS (2008) Climate-related increase in the prevalence of urolithiasis in the United States. Proc Natl Acad Sci U S A 105:9841–9846

Safarinejad MR (2007) Adult urolithiasis in a population-based study in Iran: prevalence, incidence, and associated risk factors. Urol Res 35:73–82

Jazayeri SM, Mamaghani ME, Pourmoghaddam A, Azarfar A, Beni MH, Emam SJ (2011) Need for emergent studies on dietary factors among infancy nephrolithiasis. Arch Ital Urol Androl 83:133–135

Issler N, Dufek S, Kleta R, Bockenhauer D, Smeulders N, Van’t Hoff W (2017) Epidemiology of paediatric renal stone disease: a 22-year single centre experience in the UK. BMC Nephrol 18:136

Cochat P, Pichault V, Bacchetta J, Dubourg L, Sabot JF, Saban C, Daudon M, Liutkus A (2010) Nephrolithiasis related to inborn metabolic diseases. Pediatr Nephrol 25:415–424

Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT, Gucev ZS, Fisher B, Spaneas L, Porath JD, Braun DA, Wassner AJ, Nelson CP, Tasic V, Sayer JA, Hildebrandt F (2015) Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 26:543–551

Halbritter J, Seidel A, Muller L, Schonauer R, Hoppe B (2018) Update on hereditary kidney stone disease and introduction of a new clinical patient registry in Germany. Front Pediatr 6:47

Tasian GE, Ross ME, Song L, Sas DJ, Keren R, Denburg MR, Chu DI, Copelovitch L, Saigal CS, Furth SL (2016) Annual incidence of nephrolithiasis among children and adults in South Carolina from 1997 to 2012. Clin J Am Soc Nephrol 11:488–496

Edvardsson VO, Ingvarsdottir SE, Palsson R, Indridason OS (2018) Incidence of kidney stone disease in Icelandic children and adolescents from 1985 to 2013: results of a nationwide study. Pediatr Nephrol 33:1375–1384

James WP, Ralph A, Sanchez-Castillo CP (1987) The dominance of salt in manufactured food in the sodium intake of affluent societies. Lancet 1:426–429

(2010) In: Henney JE, Taylor CL, Boon CS (eds) Strategies to Reduce Sodium Intake in the United States, Washington (DC)

Centers for Disease C, Prevention (2011) Usual sodium intakes compared with current dietary guidelines—United States, 2005–2008. MMWR Morb Mortal Wkly Rep 60:1413–1417

Centers for Disease C, Prevention (2012) Vital signs: food categories contributing the most to sodium consumption—United States, 2007–2008. MMWR Morb Mortal Wkly Rep 61:92–98

Picon RV, Fuchs FD, Moreira LB, Fuchs SC (2013) Prevalence of hypertension among elderly persons in urban Brazil: a systematic review with meta-analysis. Am J Hypertens 26:541–548

Nordin BE, Need AG, Morris HA, Horowitz M (1993) The nature and significance of the relationship between urinary sodium and urinary calcium in women. J Nutr 123:1615–1622

Matkovic V, Ilich JZ, Andon MB, Hsieh LC, Tzagournis MA, Lagger BJ, Goel PK (1995) Urinary calcium, sodium, and bone mass of young females. Am J Clin Nutr 62:417–425

Osorio AV, Alon US (1997) The relationship between urinary calcium, sodium, and potassium excretion and the role of potassium in treating idiopathic hypercalciuria. Pediatrics 100:675–681

Kovacevic L, Wolfe-Christensen C, Edwards L, Sadaps M, Lakshmanan Y (2012) From hypercalciuria to hypocitraturia—a shifting trend in pediatric urolithiasis? J Urol 188:1623–1627

Heilberg IP, Goldfarb DS (2013) Optimum nutrition for kidney stone disease. Adv Kidney Dis 20:165–174

Sellmeyer DE, Schloetter M, Sebastian A (2002) Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab 87:2008–2012

Asplin JR (2009) Obesity and urolithiasis. Adv Chronic Kidney Dis 16:11–20

Shavit L, Ferraro PM, Johri N, Robertson W, Walsh SB, Moochhala S, Unwin R (2015) Effect of being overweight on urinary metabolic risk factors for kidney stone formation. Nephrol Dial Transplant 30:607–613

Caltik Yilmaz A, Buyukkaragoz B, Oguz U, Celik B (2015) Influence of body mass index on pediatric urolithiasis. J Pediatr Urol 11(350):e351–e356

Kuroczycka-Saniutycz E, Porowski T, Protas PT, Pszczolkowska M, Porowska H, Kirejczyk JK, Wasilewska A (2015) Does obesity or hyperuricemia influence lithogenic risk profile in children with urolithiasis? Pediatr Nephrol 30:797–803

Prochaska ML, Taylor EN, Curhan GC (2016) Insights into nephrolithiasis from the Nurses’ health studies. Am J Public Health 106:1638–1643

Peerapen P, Thongboonkerd V (2018) Caffeine in kidney stone disease: risk or benefit? Adv Nutr 9:419–424

Copelovitch L (2012) Urolithiasis in children: medical approach. Pediatr Clin N Am 59:881–896

Chu DI, Tasian GE, Copelovitch L (2016) Pediatric kidney stones—avoidance and treatment. Curr Treat Options Pediatr 2:104–111

Srivastava T, Schwaderer A (2009) Diagnosis and management of hypercalciuria in children. Curr Opin Pediatr 21:214–219

Van Batavia JP, Tasian GE (2016) Clinical effectiveness in the diagnosis and acute management of pediatric nephrolithiasis. Int J Surg 36:698–704

Passerotti C, Chow JS, Silva A, Schoettler CL, Rosoklija I, Perez-Rossello J, Cendron M, Cilento BG, Lee RS, Nelson CP, Estrada CR, Bauer SB, Borer JG, Diamond DA, Retik AB, Nguyen HT (2009) Ultrasound versus computerized tomography for evaluating urolithiasis. J Urol 182:1829–1834

Tasian GE, Copelovitch L (2014) Evaluation and medical management of kidney stones in children. J Urol 192:1329–1336

Tefekli A, Esen T, Ziylan O, Erol B, Armagan A, Ander H, Akinci M (2003) Metabolic risk factors in pediatric and adult calcium oxalate urinary stone formers: is there any difference? Urol Int 70:273–277

Edvardsson VO, Goldfarb DS, Lieske JC, Beara-Lasic L, Anglani F, Milliner DS, Palsson R (2013) Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol 28:1923–1942

Coe FL, Worcester EM, Evan AP (2016) Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol 12:519–533

Worcester EM, Coe FL, Evan AP, Bergsland KJ, Parks JH, Willis LR, Clark DL, Gillen DL (2008) Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients. Am J Physiol Renal Physiol 295:F1286–F1294

Marra G, Taroni F, Berrettini A, Montanari E, Manzoni G, Montini G (2018) Pediatric nephrolithiasis: a systematic approach from diagnosis to treatment. J Nephrol. https://doi.org/10.1007/s40620-018-0487-1

Arrabal-Polo MA, Arias-Santiago S, Giron-Prieto MS, Abad-Menor F, Lopez-Carmona Pintado F, Zuluaga-Gomez A, Arrabal-Martin M (2012) Hypercalciuria, hyperoxaluria, and hypocitraturia screening from random urine samples in patients with calcium lithiasis. Urol Res 40:511–515

Butani L, Kalia A (2004) Idiopathic hypercalciuria in children—how valid are the existing diagnostic criteria? Pediatr Nephrol 19:577–582

Penniston KL, Nakada SY (2018) Updates in the metabolic management of calcium stones. Curr Urol Rep 19:41

Sakhaee K, Nicar M, Hill K, Pak CY (1983) Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int 24:348–352

Paterson R, Fernandez A, Razvi H, Sutton R (2010) Evaluation and medical management of the kidney stone patient. Can Urol Assoc J 4:375–379

Hwang KS, Kim GH (2010) Thiazide-induced hyponatremia. Electrolyte Blood Press 8:51–57

Zuckerman JM, Assimos DG (2009) Hypocitraturia: pathophysiology and medical management. Rev Urol 11:134–144

Domrongkitchaiporn S, Stitchantrakul W, Kochakarn W (2006) Causes of hypocitraturia in recurrent calcium stone formers: focusing on urinary potassium excretion. Am J Kidney Dis 48:546–554

Nishijima S, Sugaya K, Naito A, Morozumi M, Hatano T, Ogawa Y (2002) Association of vitamin D receptor gene polymorphism with urolithiasis. J Urol 167:2188–2191

Mossetti G, Vuotto P, Rendina D, Numis FG, Viceconti R, Giordano F, Cioffi M, Scopacasa F, Nunziata V (2003) Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 253:194–200

Corbin Bush N, Twombley K, Ahn J, Oliveira C, Arnold S, Maalouf NM, Sakhaee K (2013) Prevalence and spot urine risk factors for renal stones in children taking topiramate. J Pediatr Urol 9:884–889

Srivastava T, Winston MJ, Auron A, Alon US (2009) Urine calcium/citrate ratio in children with hypercalciuric stones. Pediatr Res 66:85–90

DeFoor W, Jackson E, Schulte M, Alam Z, Asplin J (2017) Calcium-to-citrate ratio distinguishes solitary and recurrent urinary stone forming children. J Urol 198:416–421

Bastug F, Dusunsel R (2012) Pediatric urolithiasis: causative factors, diagnosis and medical management. Nat Rev Urol 9:138–146

Kang DE, Sur RL, Haleblian GE, Fitzsimons NJ, Borawski KM, Preminger GM (2007) Long-term lemonade based dietary manipulation in patients with hypocitraturic nephrolithiasis. J Urol 177:1358–1362 discussion 1362; quiz 1591

Penniston KL, Nakada SY, Holmes RP, Assimos DG (2008) Quantitative assessment of citric acid in lemon juice, lime juice, and commercially-available fruit juice products. J Endourol 22:567–570

Rahman MM, Abdullah RB, Wan Khadijah WE (2013) A review of oxalate poisoning in domestic animals: tolerance and performance aspects. J Anim Physiol Anim Nutr (Berl) 97:605–614

Caspary WF (1977) Enteric hyperoxaluria. N Engl J Med 296:1357

Assimos DG (2004) Vitamin C supplementation and urinary oxalate excretion. Rev Urol 6:167

Danpure CJ, Rumsby G (2004) Molecular aetiology of primary hyperoxaluria and its implications for clinical management. Expert Rev Mol Med 6:1–16

Lorenzo V, Torres A, Salido E (2014) Primary hyperoxaluria. Nefrologia 34:398–412

Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE, Frishberg Y, Milliner DS (2011) Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol 6:2289–2295

Bhasin B, Urekli HM, Atta MG (2015) Primary and secondary hyperoxaluria: understanding the enigma. World J Nephrol 4:235–244

Milliner DS, Eickholt JT, Bergstralh EJ, Wilson DM, Smith LH (1994) Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med 331:1553–1558

Zimmermann DJ, Voss S, von Unruh GE, Hesse A (2005) Importance of magnesium in absorption and excretion of oxalate. Urol Int 74:262–267

Milliner D (2006) Treatment of the primary hyperoxalurias: a new chapter. Kidney Int 70:1198–1200

Hoppe B, Kemper MJ, Bokenkamp A, Portale AA, Cohn RA, Langman CB (1999) Plasma calcium oxalate supersaturation in children with primary hyperoxaluria and end-stage renal failure. Kidney Int 56:268–274

Compagnon P, Metzler P, Samuel D, Camus C, Niaudet P, Durrbach A, Lang P, Azoulay D, Duvoux C, Bayle F, Rivalan J, Merville P, Pascal G, Thervet E, Bensman A, Rostaing L, Deschenes G, Morcet J, Feray C, Boudjema K (2014) Long-term results of combined liver-kidney transplantation for primary hyperoxaluria type 1: the French experience. Liver Transpl 20:1475–1485

Millan MT, Berquist WE, So SK, Sarwal MM, Wayman KI, Cox KL, Filler G, Salvatierra O Jr, Esquivel CO (2003) One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation 76:1458–1463

Mehta TH, Goldfarb DS (2012) Uric acid stones and hyperuricosuria. Adv Chronic Kidney Dis 19:413–418

Vasudevan V, Samson P, Smith AD, Okeke Z (2017) The genetic framework for development of nephrolithiasis. Asian J Urol 4:18–26

Eggermann T, Venghaus A, Zerres K (2012) Cystinuria: an inborn cause of urolithiasis. Orphanet J Rare Dis 7:19

Chillaron J, Font-Llitjos M, Fort J, Zorzano A, Goldfarb DS, Nunes V, Palacin M (2010) Pathophysiology and treatment of cystinuria. Nat Rev Pediatr Nephrol 6:424–434

Wong KA, Mein R, Wass M, Flinter F, Pardy C, Bultitude M, Thomas K (2015) The genetic diversity of cystinuria in a UK population of patients. BJU Int 116:109–116

Afsar B, Kiremit MC, Sag AA, Tarim K, Acar O, Esen T, Solak Y, Covic A, Kanbay M (2016) The role of sodium intake in nephrolithiasis: epidemiology, pathogenesis, and future directions. Eur J Intern Med 35:16–19

Printza N, Koukourgianni F, Papathanasiou A, Augoustides-Savvopoulou P, Papachristou F (2007) Efficacy of captopril therapy in cystinuria lithiasis. A case report. Hippokratia 11:83–85

Alonso-Varela M, Gil-Pena H, Coto E, Gomez J, Rodriguez J, Rodriguez-Rubio E, Santos F, RenalTube G (2018) Distal renal tubular acidosis. Clinical manifestations in patients with different underlying gene mutations. Pediatr Nephrol 33:1523–1529

Grases F, Costa-Bauza A, Gomila I, Ramis M, Garcia-Raja A, Prieto RM (2012) Urinary pH and renal lithiasis. Urol Res 40:41–46

Lindberg J, Harvey J, Pak CY (1990) Effect of magnesium citrate and magnesium oxide on the crystallization of calcium salts in urine: changes produced by food-magnesium interaction. J Urol 143:248–251

Robertson WG (2017) Do “inhibitors of crystallisation” play any role in the prevention of kidney stones? A critique. Urolithiasis 45:43–56

Vaidyanathan S, von Unruh GE, Watson ID, Laube N, Willets S, Soni BL (2006) Hyperoxaluria, hypocitraturia, hypomagnesiuria, and lack of intestinal colonization by Oxalobacter formigenes in a cervical spinal cord injury patient with suprapubic cystostomy, short bowel, and nephrolithiasis. ScientificWorldJournal 6:2403–2410

Hedelin H (2002) Uropathogens and urinary tract concretion formation and catheter encrustations. Int J Antimicrob Agents 19:484–487

Borghi L, Nouvenne A, Meschi T (2012) Nephrolithiasis and urinary tract infections: ‘the chicken or the egg’ dilemma? Nephrol Dial Transplant 27:3982–3984

Abrahams HM, Stoller ML (2003) Infection and urinary stones. Curr Opin Urol 13:63–67

Schwaderer AL, Wolfe AJ (2017) The association between bacteria and urinary stones. Ann Transl Med 5:32

Siener R, Ebert D, Hesse A (2001) Urinary oxalate excretion in female calcium oxalate stone formers with and without a history of recurrent urinary tract infections. Urol Res 29:245–248

Sas DJ (2011) An update on the changing epidemiology and metabolic risk factors in pediatric kidney stone disease. Clin J Am Soc Nephrol 6:2062–2068

Siroky MB (2002) Pathogenesis of bacteriuria and infection in the spinal cord injured patient. Am J Med 113(Suppl 1A):67S–79S

Gambaro G, Fabris A, Puliatta D, Lupo A (2006) Lithiasis in cystic kidney disease and malformations of the urinary tract. Urol Res 34:102–107

Yang EM, Yoon BA, Kim SW, Kim CJ (2017) Clinical utility of spot urine protein-to-creatinine ratio modified by estimated daily creatinine excretion in children. Pediatr Nephrol 32:1045–1051

Goldfarb DS, Arowojolu O (2013) Metabolic evaluation of first-time and recurrent stone formers. Urol Clin North Am 40:13–20

Ben-Shalom E, Frishberg Y (2015) Primary hyperoxalurias: diagnosis and treatment. Pediatr Nephrol 30:1781–1791

Belostotsky R, Pitt JJ, Frishberg Y (2012) Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism. J Mol Med (Berl) 90:1497–1504

Srivastava T, Alon US (2005) Urolithiasis in adolescent children. Adolesc Med Clin 16:87–109

Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A (1996) Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 155:839–843

Miller LA, Stapleton FB (1989) Urinary volume in children with urolithiasis. J Urol 141:918–920

Lande MB, Varade W, Erkan E, Niederbracht Y, Schwartz GJ (2005) Role of urinary supersaturation in the evaluation of children with urolithiasis. Pediatr Nephrol 20:491–494

DeFoor W, Asplin J, Jackson E, Jackson C, Reddy P, Sheldon C, Erhard M, Minevich E (2006) Urinary metabolic evaluations in normal and stone forming children. J Urol 176:1793–1796

McGuire S (2011) US Department of Agriculture and US Department of Health and Human Services, Dietary Guidelines for Americans, 2010. Washington, DC: US Government Printing Office, January 2011. Oxford University Press

Heilberg IP, Weisinger JR (2006) Bone disease in idiopathic hypercalciuria. Curr Opin Nephrol Hypertens 15:394–402

Ross A, Taylor C, Yaktine A, Del Valle H (2011) Committee to review dietary reference intakes for vitamin D and calcium, food and nutrition board, Institute of Medicine. DRI dietary reference intakes for calcium and vitamin D. National Academies Press, Washington, DC http://www.nap.edu/catalog.php. Accessed 15 Aug 2018

Hesse A, Schneeberger W, Engfeld S, Von Unruh GE, Sauerbruch T (1999) Intestinal hyperabsorption of oxalate in calcium oxalate stone formers: application of a new test with [13C2]oxalate. J Am Soc Nephrol 10(Suppl 14):S329–S333

Zerwekh JE (2010) Bone disease and hypercalciuria in children. Pediatr Nephrol 25:395–401

Freundlich M, Alonzo E, Bellorin-Font E, Weisinger JR (2002) Reduced bone mass in children with idiopathic hypercalciuria and in their asymptomatic mothers. Nephrol Dial Transplant 17:1396–1401

Sakhaee K, Maalouf NM, Kumar R, Pasch A, Moe OW (2011) Nephrolithiasis-associated bone disease: pathogenesis and treatment options. Kidney Int 79:393–403

Denburg MR, Leonard MB, Haynes K, Tuchman S, Tasian G, Shults J, Copelovitch L (2014) Risk of fracture in urolithiasis: a population-based cohort study using the health improvement network. Clin J Am Soc Nephrol 9:2133–2140

Ferraro PM, Taylor EN, Eisner BH, Gambaro G, Rimm EB, Mukamal KJ, Curhan GC (2013) History of kidney stones and the risk of coronary heart disease. JAMA 310:408–415

Rule AD, Roger VL, Melton LJ 3rd, Bergstralh EJ, Li X, Peyser PA, Krambeck AE, Lieske JC (2010) Kidney stones associate with increased risk for myocardial infarction. J Am Soc Nephrol 21:1641–1644

Alexander RT, Hemmelgarn BR, Wiebe N, Bello A, Samuel S, Klarenbach SW, Curhan GC, Tonelli M, Alberta Kidney Disease N (2014) Kidney stones and cardiovascular events: a cohort study. Clin J Am Soc Nephrol 9:506–512

Liu Y, Li S, Zeng Z, Wang J, Xie L, Li T, He Y, Qin X, Zhao J (2014) Kidney stones and cardiovascular risk: a meta-analysis of cohort studies. Am J Kidney Dis 64:402–410

Peng JP, Zheng H (2017) Kidney stones may increase the risk of coronary heart disease and stroke: a PRISMA-compliant meta-analysis. Medicine (Baltimore) 96:e7898

Fabris A, Ferraro PM, Comellato G, Caletti C, Fantin F, Zaza G, Zamboni M, Lupo A, Gambaro G (2015) The relationship between calcium kidney stones, arterial stiffness and bone density: unraveling the stone-bone-vessel liaison. J Nephrol 28:549–555

Reiner AP, Kahn A, Eisner BH, Pletcher MJ, Sadetsky N, Williams OD, Polak JF, Jacobs DR Jr, Stoller ML (2011) Kidney stones and subclinical atherosclerosis in young adults: the CARDIA study. J Urol 185:920–925

Kusumi K, Smith S, Barr-Beare E, Saxena V, Schober MS, Moore-Clingenpeel M, Schwaderer AL (2015) Pediatric origins of nephrolithiasis-associated atherosclerosis. J Pediatr 167:1074–1080 e1072

Rule AD, Bergstralh EJ, Melton LJ 3rd, Li X, Weaver AL, Lieske JC (2009) Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 4:804–811

Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, Howe NL, Ronckers CM, Rajaraman P, Sir Craft AW, Parker L, Berrington de Gonzalez A (2012) Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 380:499–505