Nephrocalcinosis and urolithiasis in children
2011; Elsevier BV; Volume: 80; Issue: 12 Linguagem: Inglês
10.1038/ki.2011.336
ISSN1523-1755
AutoresSandra Habbig, Bodo B. Beck, Bernd Höppe,
Tópico(s)Renal function and acid-base balance
ResumoThe incidence of adult urolithiasis has increased significantly in industrialized countries over the past decades. Sound incidence rates are not available for children, nor are they known for nephrocalcinosis, which can appear as a single entity or together with urolithiasis. In contrast to the adult kidney stone patient, where environmental factors are the main cause, genetic and/or metabolic disorders are the main reason for childhood nephrocalcinosis and urolithiasis. While hypercalciuria is considered to be the most frequent risk factor, several other metabolic disorders such as hypocitraturia or hyperoxaluria, as well as a variety of renal tubular diseases, e.g., Dent's disease or renal tubular acidosis, have to be ruled out by urine and/or blood analysis. Associated symptoms such as growth retardation, intestinal absorption, or bone demineralization should be evaluated for diagnostic and therapeutic purposes. Preterm infants are a special risk population with a high incidence of nephrocalcinosis arising from immature kidney, medication, and hypocitraturia. In children, concise evaluation will reveal an underlying pathomechanism in >75% of patients. Early treatment reducing urinary saturation of the soluble by increasing fluid intake and by providing crystallization inhibitors, as well as disease-specific medication, are mandatory to prevent recurrent kidney stones and/or progressive nephrocalcinosis, and consequently deterioration of renal function. The incidence of adult urolithiasis has increased significantly in industrialized countries over the past decades. Sound incidence rates are not available for children, nor are they known for nephrocalcinosis, which can appear as a single entity or together with urolithiasis. In contrast to the adult kidney stone patient, where environmental factors are the main cause, genetic and/or metabolic disorders are the main reason for childhood nephrocalcinosis and urolithiasis. While hypercalciuria is considered to be the most frequent risk factor, several other metabolic disorders such as hypocitraturia or hyperoxaluria, as well as a variety of renal tubular diseases, e.g., Dent's disease or renal tubular acidosis, have to be ruled out by urine and/or blood analysis. Associated symptoms such as growth retardation, intestinal absorption, or bone demineralization should be evaluated for diagnostic and therapeutic purposes. Preterm infants are a special risk population with a high incidence of nephrocalcinosis arising from immature kidney, medication, and hypocitraturia. In children, concise evaluation will reveal an underlying pathomechanism in >75% of patients. Early treatment reducing urinary saturation of the soluble by increasing fluid intake and by providing crystallization inhibitors, as well as disease-specific medication, are mandatory to prevent recurrent kidney stones and/or progressive nephrocalcinosis, and consequently deterioration of renal function. In the past decade, a significant increase in both incidence and prevalence of adult urolithiasis (UL) has been noted in industrialized countries. In addition, in pediatric patients, hospitalization for kidney stone disease has steadily increased.1.VanDervoort K. Wiesen J. Frank R. et al.Urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome.J Urol. 2007; 177: 2300-2305Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar,2.Sas D.J. Hulsey T.C. Shatat I.F. et al.Increasing incidence of kidney stones in children evaluated in the emergency department.J Pediatr. 2010; 157: 132-137Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Definite incidence rates are, however, not available for UL, nor for nephrocalcinosis (NC) in children. The increase of stone disease in adults was most likely related to (changing) environmental factors such as dietary habits, fluid intake, and obesity, all subsumed in the metabolic syndrome. Although this will clearly also gain importance in the pediatric population, genetic and anatomical causes are still the main determinants. UL subsumes stones formed in the kidney but localized anywhere in the urinary tract, as well as primary bladder stones3.Hoppe B. Leumann A. Milliner D.S. Urolithiasis and nephrocalcinosis in childhood.in: Geary D.F. Schaefer F. Comprehensive Pediatric Nephrology. Elsevier, Philadelphia2008: 499-525Crossref Scopus (13) Google Scholar (Figure 1a). Nephrolithiasis describes stones residing in the kidney (Figure 1b–d). NC comprises deposits of calcium salts in the tubules, the tubular epithelium, and/or the interstitial tissue of the kidney3.Hoppe B. Leumann A. Milliner D.S. Urolithiasis and nephrocalcinosis in childhood.in: Geary D.F. Schaefer F. Comprehensive Pediatric Nephrology. Elsevier, Philadelphia2008: 499-525Crossref Scopus (13) Google Scholar (Figure 1e). Although the composition of the deposits mostly remains unclear and cannot be identified by ultrasound, pathologists distinguish between NC due to calcium phosphate and oxalosis due to calcium oxalate deposition. NC can also be classified according to the anatomic area involved. Medullary NC, subdivided into three subtypes according to the degree of echogenicity, is distinguished from cortical (e.g., in acute cortical necrosis) and diffuse NC.4.Hoppe B. Kemper M. Diagnostic examination of the child with urolithiasis or nephrocalcinosis.Pediatr Nephrol. 2010; 25: 403-413Crossref PubMed Scopus (47) Google Scholar,5.Dick P.T. Shuckett B.M. Tang B. et al.Observer reliability in grading nephroc ultrasound examinations in children.Pediatr Radiol. 1999; 29: 68-72Crossref PubMed Scopus (22) Google Scholar Adult data describe an incidence of UL of approximately 1.5% and a prevalence of 5.2%.6.Persaud A.C. Stevenson M.D. McMahon D.R. et al.Pediatric urolithiasis: clinical predictors in the emergency department.Pediatrics. 2009; 124: 888-894Crossref PubMed Scopus (12) Google Scholar,7.Johnson C.M. Wilson D.M. O′Fallon W.M. et al.Renal stone epidemiology: a 25-year study in Rochester, Minnesota.Kidney Int. 1979; 16: 624-631Abstract Full Text PDF PubMed Google Scholar About 12% of men and 5% of women in industrialized countries will therefore develop a kidney stone at least once in their life.8.Coe F.L. Evan A. Worcester E. Kidney stone disease.J Clin Invest. 2005; 115: 2598-2608Crossref PubMed Scopus (307) Google Scholar The incidence of UL in pediatric patients is considered to be approximately 10% of that in adults. As incidental discovery occurs in 15–40% of children due to the high proportion of unspecific symptoms, the real incidence in childhood is likely to be underestimated. During past decades, studies reported that 1 in 1000 to 1 in 7500 pediatric hospital admissions were related to UL.9.Walther P.C. Lamm D. Kaplan G.W. Pediatric urolithiases: a ten-year review.Pediatrics. 1980; 65: 1068-1072PubMed Google Scholar,10.Milliner D.S. Murphy M.E. Urolithiasis in pediatric patients.Mayo Clin Proc. 1993; 68: 241-248Abstract Full Text Full Text PDF PubMed Google Scholar A recent single-center study reported a nearly fivefold increase in hospital admissions for pediatric UL during the past decade.1.VanDervoort K. Wiesen J. Frank R. et al.Urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome.J Urol. 2007; 177: 2300-2305Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Another study from the southeast United States, known as the US ‘stone-belt’, identified an increase of children with UL in an Emergency Room setting from 7.9 to 18.5 per 100,000 from 1996 to 2007. Interestingly, the number of African-American children remained relatively low, 3.2 to 4.5, whereas the number of Caucasian children in that setting rose from 10.9 to 26.2 per 100,000 in 2007. Caucasian children are thus 5.6 times more likely to have kidney stones compared with African-American children.2.Sas D.J. Hulsey T.C. Shatat I.F. et al.Increasing incidence of kidney stones in children evaluated in the emergency department.J Pediatr. 2010; 157: 132-137Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar UL and/or NC affect children of all ages.11.Alon U.S. Nephrocalcinosis.Curr Opin Pediatr. 1997; 9: 160-165Crossref PubMed Scopus (37) Google Scholar NC seems to primarily appear in the first years of life, which might be due to the fact that it is frequently based on tubulopathies or inborn errors of metabolism (Table 1). Sound data on sex and age distribution are, however, only known for UL. Younger children are described to present with a higher proportion of renal calculi,12.Pietrow P.K. Pope J.C. Adams M.C. et al.Clinical outcome of pediatric stone disease.J Urol. 2002; 167: 670-673Abstract Full Text Full Text PDF PubMed Google Scholar,13.Kalorin C.M. Zabinski A. Okpareke I. et al.Pediatric urinary stone disease--does age matter?.J Urol. 2009; 181: 2267-2271Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,14.Cameron M.A. Sakhaee K. Moe O.W. Nephrolithiasis in children.Pediatr Nephrol. 2005; 20: 1587-1592Crossref PubMed Scopus (66) Google Scholar whereas older children rather present with ureteral stones. Contradictory data exist on a higher or equal probability of spontaneous passage in children older or younger than 10 years of age.13.Kalorin C.M. Zabinski A. Okpareke I. et al.Pediatric urinary stone disease--does age matter?.J Urol. 2009; 181: 2267-2271Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,14.Cameron M.A. Sakhaee K. Moe O.W. Nephrolithiasis in children.Pediatr Nephrol. 2005; 20: 1587-1592Crossref PubMed Scopus (66) Google Scholar Data on sex distribution have changed over the past years. In adults, a male predominance is no longer found. Interestingly, the risk of stone disease due to increased body mass index and waist circumference is more pronounced in women.15.Taylor E.N. Stampfer M.J. Curhan G.C. Obesity, weight gain, and the risk of kidney stones.JAMA. 2005; 293: 455-462Crossref PubMed Scopus (434) Google Scholar,16.Ogden C.L. Carroll M.D. Curtin L.R. et al.Prevalence of overweight and obesity in the United States, 1999-2004.JAMA. 2006; 295: 1549-1555Crossref PubMed Scopus (6161) Google Scholar,17.West B. Luke A. Durazo-Arvizu R.A. Cao G. et al.Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988-1994.Am J Kidney Dis. 2008; 51: 741-747Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar,18.Duffey B.G. Pedro R.N. Kriedberg C. et al.Lithogenic risk factors in the morbidly obese population.J Urol. 2008; 179: 1401-1406Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar A recent study analyzed the Kids’ Inpatient large-scale pediatric database for sex distribution in more than 2 million children hospitalized because of UL and reported a changing sex distribution according to age.19.Novak T.E. Lakshmanan Y. Trock B.J. et al.Sex prevalence of pediatric kidney stone disease in the United States: an epidemiologic investigation.Urology. 2009; 74: 104-107Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Boys were more frequently affected during the first decade (1.2:1 for 0–5 years, 1.3:1 for 6–10 years), whereas girls were more frequently affected during the second decade of life (0.96:1 for 11–15 years, 0.3:1 for 16–20 years).19.Novak T.E. Lakshmanan Y. Trock B.J. et al.Sex prevalence of pediatric kidney stone disease in the United States: an epidemiologic investigation.Urology. 2009; 74: 104-107Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Data from the southeast United States show even more pronounced changes in sex distribution. Whereas in 1996 the reported incidence in boys (8.0/100,000) did not differ from that in girls (7.7/100,000), the incidence in girls showed a faster and stronger increase to 21.9/100,000 in 2007 (boys 15.3/100,000).2.Sas D.J. Hulsey T.C. Shatat I.F. et al.Increasing incidence of kidney stones in children evaluated in the emergency department.J Pediatr. 2010; 157: 132-137Abstract Full Text Full Text PDF PubMed Scopus (52) Google ScholarTable 1Genetic diseases with urolithiasis and/or nephrocalcinosis according to underlying metabolic derangementEntity/disorderGene/gene product/locusInheritanceHints and hallmarksHypercalciuria Autosomal dominant hypocalcemic hypercalciuria48.Gambaro G. Vezzoli G. Casari G. et al.Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms.Am J Kidney Dis. 2004; 44: 963-986Abstract Full Text Full Text PDF PubMed Scopus (38) Google ScholarCASR/CaSR, 3q21.1 Gain-of-function mutations usually private mutations leading to leftward shift of extracellular calcium dose–response curveadMild, usually asymptomatic hypocalcemia, hypercalciuria, with elevated serum phosphate and low serum magnesium levels, PTH in the low-normal range nota bene: vitamin D substitution will result in excess hypercalciuria, leading to NC, UL and eventually CRF note: inactivating mutations of CaSR increase the threshold for negative feedback and cause hypocalciuric hypercalcemia Hypercalcemia with hypercalciuria169.Stechman M.J. Loh N.Y. Thakker R.V. Genetic causes of hypercalciuric nephrolithiasis.Pediatr Nephrol. 2009; 24: 2321-2332Crossref PubMed Scopus (34) Google Scholar-familial isolated hyperparathyroidismMenin, 11q13 Parafibromin, 1q31.3 CaSR, 3q21.1adFamilial isolated parathyroid tumors, inactivating mutations in CaSR Idiopathic hypercalciuria170.Geng W. Wang Z. Zhang J. et al.Cloning and characterization of the human soluble adenylyl cyclase.Am J Physiol. 2005; 288: 1305-1316Crossref PubMed Scopus (72) Google Scholar,171.Wolf M.T.F. Zalewski I. Martin F.C. et al.Mapping a new suggestive gene locus for autosomal dominant nephrolithiasis to chromosome 9q33.2-q34.2 by total genome search for linkage.Nephrol Dial Transplant. 2005; 20: 909-914Crossref PubMed Scopus (11) Google Scholar,172.Scott P. Ouimet D. Valiquette L. et al.Suggestive evidence for a susceptibility gene near the vitamin D receptor locus in idiopathic calcium stone formation.J Am Soc Nephrol. 1999; 10: 1007-1013PubMed Google ScholarSAC/soluble adenyl cyclase, 1q23.3–q24; sequence variations but no causative mutationsadAssociated with absorptive type of hypercalciuria, normocalcemia, normal PTH levels, low bone mineral densityVDR/Vitamin D receptor, 12q12–q14, polymorphisms, but no causative mutationsadAssociated with resorptive type of hypercalciuriaGene remains to be found, 9q33.2–q34.2 locusadAutosomal dominant nephrolithiasisBS169.Stechman M.J. Loh N.Y. Thakker R.V. Genetic causes of hypercalciuric nephrolithiasis.Pediatr Nephrol. 2009; 24: 2321-2332Crossref PubMed Scopus (34) Google Scholar Type 1SLC12A1/NKCC2 (bumetanide-sodium-potassium-chloride cotransporter); 15q15–q21.1arClassical BS: hypokalemic alkalosis, renal salt wasting, hyperreninemic hyperaldosteronism, hyperprostaglandinemia, hypercalciuria and NC, potential CRF antenatal BS (polyhydramnios, salt wasting, prematurity, volume depletion) Type 2KCNJ/ROMK (renal outer-medullary potassium channel); 11q24arClassical/antenatal BS, hypercalciuria and NC transient neonatal hyperkalemia later evolving into (modest) hypokalemia, potential CRF Type 3CLCNKB/CLC-Kb (voltage-gated chloride channel); 1q36arMostly classical BS, wide phenotype variation (diagnosis neonatal period to adulthood), less hypercalciuria and NC, potential CRF Type 4BSND/Barttin; 1q31arUsually severe antenatal BS with sensorineuronal deafness, but less hypercalciuria and NC, CRF Type 5CASR/CaSR, (severe gain-of-function mutations); 3q21.1adEarly (symptomatic) hypocalcemia and hypercalciuria with NC (see above) followed later by classical BS featuresDent's disease Dent 1 (ref. 53.Lloyd S.E. Pearce S.H. Fisher S.E. et al.A common molecular basis for three inherited kidney stone diseases.Nature. 1996; 379: 445-449Crossref PubMed Scopus (498) Google Scholar)CLCN5 chloride/proton antiporter CLC5; Xp11.22 (Dent 1), mutations in 60% of casesXrMale gender, FS (aminoaciduria, phosphaturia, glycosuria, kaliuresis, impaired acidification), LMW proteinuria, hypercalciuria (less severe with age), NC/UL, CRF regular Dent 2 (ref. 173.Hoopes R.R. Shrimpton A.E. Knohl S.J. et al.Dent disease with mutations in OCRL1.Am J Hum Genet. 2005; 76: 260-267Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar)OCRL1 (Dent 2), mutations in 15% of casesXrPatients with OCRL1 mutation and Dent's disease lack cataracts (BS-like phenotype termed BS type 6 was reported in a single Turkish patient with CLCN5 mutation) Lowe's (oculorenocerebral) syndrome174.Leahey A.M. Charnas L.R. Nussbaum R.L. Nonsense mutations in the OCRL-1 gene in patients with the oculocerebrorenal syndrome of Lowe.Hum Mol Genet. 1993; 2: 461-463Crossref PubMed Google ScholarOCRL1/phosphatidylinositol-4,5-biphosphate-5-phosphatase ocrl1; Xq25XrMale gender, congenital cataracts, mental retardation, hypotonia, rickets, proximal tubular defect (bicarbonate, phosphate, aminoaciduria), nephrotic range proteinuria, metabolic acidosis, hypercalciuria and NC/UL, CRF regular Urolithiasis, osteopetrosis and persistent hypophosphatemia175.Prié D. Huart V. Bakouh N. et al.Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter.N Engl J Med. 2002; 347: 983-991Crossref PubMed Scopus (168) Google ScholarNPT2a/sodium-phosphate-cotransporter type 2a (SLC34A1); 5q35adExcess urinary phosphate excretion, hypophosphatemia, elevated 1,25OH vitamin D, elevated AP, suppressed PTH, hypercalcemia and hypercalciuria Hereditary hypophosphatemic rickets with hypercalciuria176.Bergwitz C. Roslin N.M. Tieder M. et al.SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.Am J Hum Genet. 2006; 78: 179-192Abstract Full Text Full Text PDF PubMed Scopus (198) Google ScholarNPT2c/sodium-phosphate-cotransporter type 2c (SLC34A3); 9q34arExcess loss of urinary phosphate, hypophosphatemia, severe rickets, hypercalciuria but no hypercalcemia, UL Williams–Beuren syndrome177.Schubert C. The genomic basis of the Williams-Beuren syndrome.Cell Mol Life Sci. 2009; 66: 1178-1197Crossref PubMed Scopus (80) Google ScholarContinuous gene deletion syndrome (1.55Mb, including ELN, LIMK1, RFC2); 7q11.23Mostly sporadicMultisystemic developmental disorder with mental retardation, distinctive neuropsychological profile ‘happy party manner’, variable cardiovascular findings (aortic stenosis), abnormalities of renal tract and connective tissue, temporary hypercalcemia and hypercalciuria, NC/UL Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)178.Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google ScholarCLDN16/claudin 16/paracellin 1; 3q27arSymptomatic hypomagnesemia and hypocalcemia, hypercalciuria and NC/UL, distal RTA, regular CRF FHHNC with ocular involvement179.Konrad M. Schaller A. Seelow D. et al.Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement.Am J Hum Genet. 2006; 79: 949-957Abstract Full Text Full Text PDF PubMed Scopus (201) Google ScholarCLDN19/claudin 19; 1p34.2arHallmarks of FHHNC with multiple ocular abnormalities Wilson's disease14.Cameron M.A. Sakhaee K. Moe O.W. Nephrolithiasis in children.Pediatr Nephrol. 2005; 20: 1587-1592Crossref PubMed Scopus (66) Google ScholarATP7B/copper transporting ATPase 2; 13q14.3arFanconi syndrome, liver dysfunction, neurological symptoms, Kayser–Fleischer cornea ring, elevated urinary copper excretion-reduced ceruloplasmin, hypercalciuria, UL, NC, CRF Tyrosinemia type 1 (ref. 14.Cameron M.A. Sakhaee K. Moe O.W. Nephrolithiasis in children.Pediatr Nephrol. 2005; 20: 1587-1592Crossref PubMed Scopus (66) Google Scholar)FAH/fumarylacetone-acetate hydrolase; 15q.23–q25arFanconi syndrome, rickets, liver failure, coagulopathy, hypercalciuria, UL, NC, CRF Liddle's syndrome (pseudohyperaldosteronism type 1)14.Cameron M.A. Sakhaee K. Moe O.W. Nephrolithiasis in children.Pediatr Nephrol. 2005; 20: 1587-1592Crossref PubMed Scopus (66) Google ScholarSCNN1B and SCNN1G/β- and γ-subunits of epithelial sodium channel (ENaC); 16p12adRare, triad of hypokalemia, alkalosis and sodium-sensitive hypertension, suppressed aldosterone levels, hypercalciuria and NC, risk of CRF, treatment with amiloride (ENaC blocker) Gordon's syndrome (pseudohypoaldosteronism type 2)14.Cameron M.A. Sakhaee K. Moe O.W. Nephrolithiasis in children.Pediatr Nephrol. 2005; 20: 1587-1592Crossref PubMed Scopus (66) Google ScholarWNK1 12p13.3, WNK4 17q21.31/serine-threonine kinaseadHyperkalemia, metabolic acidosis (reduced ammonium excretion), hypertension and hypercalciuria (RTA type 4)Hyperoxaluria Primary hyperoxaluria type I (PH I)76.Purdue P.E. Lumb M.J. Fox M. et al.Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase.Genomics. 1991; 10: 34-42Crossref PubMed Scopus (104) Google ScholarAGXT/alanin-glyoxylate-aminotransferase; 2q37.3 80–90% of PH casesarRecurrent UL and/or progressive NC, UTI, severe hyperoxaluria (>1mmol/1.73m2 per day), hyperglycolic aciduria, ESRF regular outcome (neonatal period to late adulthood), systemic oxalate deposition with advanced renal failure leads to a multisystemic disease character Primary hyperoxaluria type II (PH II)85.Blostosky R. Seboun E. Idelson G.H. et al.Mutations in DHDPSL are responsible for primary hyperoxaluria type III.Am J Hum Genet. 2010; 87: 392-399Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarGRHPR/glyoxylate reductase/hydroxylpyruvate reductase (GRHPR); 9q11, 10% of PH casesarHallmarks recurrent UL, NC less frequent, hyperoxaluria plus marked L-glyceric aciduria in most cases, lower (∼20%) risk of ESRF Primary hyperoxaluria type III (PH III)85.Blostosky R. Seboun E. Idelson G.H. et al.Mutations in DHDPSL are responsible for primary hyperoxaluria type III.Am J Hum Genet. 2010; 87: 392-399Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarDHDPSL/4-hydroxy-2-oxoglutarate aldolase; 10q24.2arLikely the second most frequent PH type disease seems to remit with age. No case of ESRF reported (nota bene: very limited data) Atypical PHUnknown, negative AGXT, GRHPR, and DHDPSL mutational analysisHyperoxaluria and clinical features overlapping with PH type I–III Risk of ESRF not definedCystinuria Cystinuria type I (heterozygotes are silent)180.Font-Llitjós M. Jiménez-Vidal M. Bisceglia L. et al.New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype.J Med Genet. 2005; 42: 58-68Crossref PubMed Scopus (72) Google ScholarSLC3A1/rBAT; 2p16.3, causative mutations result mostly in type IarImpaired renal transport of cystine and dibasic amino acids, high urinary cystine levels Cystinuria type II (heterozygotes show a variable degree of hypercystinuria)180.Font-Llitjós M. Jiménez-Vidal M. Bisceglia L. et al.New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype.J Med Genet. 2005; 42: 58-68Crossref PubMed Scopus (72) Google ScholarSLC7A9/b0,+ AT; 19q13.1, causative mutations may result in type I phenotypeadip Mixed type I/II cystinuria phenotype180.Font-Llitjós M. Jiménez-Vidal M. Bisceglia L. et al.New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype.J Med Genet. 2005; 42: 58-68Crossref PubMed Scopus (72) Google ScholarAll genotypes possible but mostly SLC7A9 mutationsHyperuricosuria Lesch–Nyhan syndrome181.Wilson J.M. Young A.B. Kelley W.N. Hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular basis of the clinical syndromes.N Engl J Med. 2010; 309: 900-910Google ScholarHPRT/hypoxanthine-guanine-phosphoribosyltransferase; Xq26XrSymptomatic in males, normal at birth followed by progressive psychomotor delay, gout, hyperuricosuria, recurrent UL, automutilation Partial HPRT deficiency181.Wilson J.M. Young A.B. Kelley W.N. Hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular basis of the clinical syndromes.N Engl J Med. 2010; 309: 900-910Google ScholarHyperuricosuria, wide spectrum of symptoms with asymptomatic course in less severe forms Glycogenosis type 1a182.Cochat P. Pichault V. Bacchetta J. et al.Nephrolithiasis related to inborn metabolic diseases.Pediatr Nephrol. 2010; 25: 415-424Crossref PubMed Scopus (28) Google ScholarG6PC/glucose-6-phosphatase; 17q21arEpisodic severe hypoglycemic, lactic acedemia, hyperuricosuria, hypercalciuria, hypocitraturia, recurrent UL, NC, Fanconi syndrome, FSGS, renal amyloidosis, CRFHypouricosuria APRT deficiency183.Takeuchi H. Kaneko Y. Fujita J. et al.A case of a compound heterozygote for adenine phosphoribosyltransferase deficiency (APRT*J/APRT*Q0) leading to 2,8-dihydroxyadenine urolithiasis: review of the reported cases with 2,8-dihydroxyadenine stones in Japan.J Urol. 1993; 149: 824-826PubMed Google ScholarAPRT/adenine-phosphoribosyltransferase; 16q24.3arUrinary accumulation of the insoluble purine 2,8 dihydroxyadenine (round + brown crystals), UL, CRF Xanthinuria110.Arikyants N. Sarkissia A. Hesse A. et al.Xanthinuria type I: a rare cause of urolithiasis.Pediatr Nephrol. 2007; 22: 310-314Crossref PubMed Scopus (24) Google ScholarXDH/xanthine dihydrogenase oxidase; 2p22 (type 1) Type 2 dual deficiency of XDH plus aldehyde oxidasearNoticeable low levels of uric acid in serum and urine, xanthinuria, UL (radiotransparent) Urate transporter 1 (ref. 184.Wakida N. Tuyen D.G. Adachi M. et al.Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia.J Clin Endocrinol Metab. 2005; 90: 2169-2174Crossref PubMed Scopus (35) Google Scholar)SLC22A12/renal urate anion exchanger URAT1; 11q13arSporadic/familial renal hypouricemia, UL, and risk of exercise-induced ARFRTA hypocitraturia + hypercalciuriaRTA54.Buckalew V.M. Nephrolithiasis in renal tubular acidosis.J Urol. 1989; 141: 731-737PubMed Google Scholar,185.Fry A.C. Karet F.E. Inherited renal acidoses.Physiology (Bethesda). 2007; 22: 202-211Crossref PubMed Scopus (0) Google Scholar,186.Chadha V. Alon U.S. Hereditary renal tubular disorders.Semin Nephrol. 2009; 29: 399-411Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar RTA type 1ATP6V1/B1 subunit of H+ ATPase; 2cen–q13arDistal RTA, metabolic acidosis (impaired H+ excretion) of early onset with early NC and hearing loss, hypocitraturia, hypercalciuria, UL, NC, hypokalemia, rickets, failure to thriveATPV0A4/ A4 subunit of H+ ATPase; 7q33–34arLater onset of sensorineural deafness (sometimes normal hearing)SLC4A1/basolateral Cl/HCO3 exchanger AE1; 17q21–22adDistal RTA of later onset, milder metabolic acidosis, urine pH>6.1, hypokalemia, hypocitraturia, hypercalciuria, UL, NC, sometimes ricketsSLC4A1/basolateral Cl/HCO3 exchanger AE1; 17q21–22arDistal RTA of childhood onset, metabolic acidosis plus hemolytic anemia in southeast Asians RTA type 2SLC4A4/NBC1 sodium bicarbonate cotransporter; 4q21arProximal RTA, (milder) metabolic acidosis by bicarbonate wasting, hypokalemia, growth retardation, ocular abnormalities, enamel defects, intellectual impairment, less severe hypercalciuria and hypocitraturia RTA type 3 (mixed type)CA2/carboanhydrase 2arBicarbonate wasting + inability to acidify the urine: RTA plus osteopetrosis (Guibaud–Vainsel syndrome), intracerebral calcification, growth failure, intellectual impairment, conductive deafnessAbbreviations: AD, autosomal dominant; ADIP, autosomal dominant with incomplete penetrance; AP, alkaline phosphatase; AR, autosomal recessive; ARF, acute renal failure; BS, Bartter syndrome; CaSR, calcium-sensing receptor; CRF, chronic renal failure; ESRF, end-stage renal failure; FS, Fanconi syndrome; FSGS, focal segmental glomerulosclerosis; LMW, low-molecular weight; PTH, parathyroid hormone; RTA, renal tubular acidosis; NC, nephrocalcinosis; UL, urolithiasis; Xr, x-linked recessive.References are imbedded in table. Open table in a new tab Abbreviations: AD, autosomal dominant; ADIP, autosomal dominant with incomplete penetrance; AP, alkaline phosphatase; AR, autosomal recessive; ARF, acute renal failure; BS, Bartter syndrome; CaSR, calcium-sensing receptor; CRF, chronic renal failure; ESRF, end-stage renal failure; FS, Fanconi syndrome; FSGS, focal segmental glomerulosclerosis; LMW, low-molecular weight; PTH, parathyroid hormone; RTA, renal tubular acidosis; NC, nephrocalcinosis; UL, urolithiasis; Xr, x-linked recessive. References are imbedded in table. Compared with adults, children are more likely to have an underlying metabolic disorder, and subsequently a higher risk of stone recurrence16.Ogden C.L. Carroll M.D. Curtin L.R. et al.Prevalence of overweight and obesity in the United States, 1999-2004.JAMA. 2006; 295: 1549-1555Crossref PubMed Scopus (6161) Google Scholar,17.West B. Luke A. Durazo-Arvizu R.A. Cao G. et al.Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988-1994.Am J Kidney Dis. 2008; 51: 741-747Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar or progression of NC3.Hoppe B. Leumann A. Milliner D.S. Urolithiasis and nephrocalcinosis in childhood.in: Geary D.F. Schaefer F. Comprehensive Pediatric Nephrology. Elsevier, Philadelphia2008: 499-525Crossref S
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