Abstract
Congenital obstructive nephropathy (CON) is the leading cause of chronic kidney disease (CKD) in children. Anomalies of the urinary tract are often associated with abnormal nephrogenesis, which is compounded by obstructive injury and by maternal risk factors associated with low birth weight. Currently available fetal and postnatal imaging and analytes of amniotic fluid, urine, or blood lack predictive value. For ureteropelvic junction obstruction, biomarkers are needed for optimal timing of pyeloplasty; for posterior urethral valves, biomarkers of long-term prognosis and CKD are needed. The initial nephron number may be a major determinant of progression of CKD, and most patients with CON who progress to renal failure reach this point in adulthood, presumably compounded by episodes of acute kidney injury. Biomarkers of tubular injury may be of particular value in predicting the need for surgical intervention or in tracking progression of CKD, and must be adjusted for patient age. Discovery of new biomarkers may depend on “unbiased” proteomics, whereby patterns of urinary peptide fragments from patients with CON are analyzed in comparison to controls. Most promising are the analysis of urinary exosomes (restricting biomarkers to relevant tubular cells) and quantitative magnetic resonance imaging techniques allowing precise determination of nephron number and tubular mass. The greatest need is for large prospective multicenter studies with centralized biomarker sample repositories to follow patients with CON from fetal life through adulthood.
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References
Warady BA, Chadha V (2007) Chronic kidney disease in children: the global perspective. Pediatr Nephrol 22:1999–2009
Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, Degli Innocenti ML, Somenzi D, Trivelli A, Caridi G, Izzi C, Scolari F, Mattioli G, Allegri L, Ghiggeri GM (2009) Congenital anomalies of the kidney and urinary tract (CAKUT): longitudinal cohort study on renal outcome. Kidney Int 76:528–533
Wuhl E, van Stralen KJ, Verrina E, Bjerre A, Wanner C, Heaf JG, Zurriaga O, Hoitsma A, Niaudet P, Palsson R, Ravani P, Jager KJ, Schaefer F (2013) Timing and outcome of renal replacement therapy in patients with congenital malformations of the kidney and urinary tract. Clin J Am Soc Nephrol 8:67–74
Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95
Sala P, Prefumo F, Pastorino D, Bufi D, Gaggero CR, Foppiano M, De Baiasio P (2014) Fetal surgery: an overview. Obstet Gynecol Surv 69:218–226
Waikar SS, Betensky RA, Bonventre JV (2009) Creatinine as the gold standard for kidney injury biomarker studies? Nephrol Dial Transplant 24:3263–3265
Woolf AS (2000) A molecular and genetic view of human renal and urinary tract malformations. Kidney Int 58:500–512
Karami H, Kazemi B, Jabbari M, Rahjoo T, Golshan A (2009) Mutations in intron 8 and intron 9 of Wilms’ tumor genes in members of family with ureteropelvic junction obstruction. Urology 74:116–118
Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM (1981) Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 241:F85–F93
Trnka P, Hiatt MJ, Tarantal AF, Matsell DG (2012) Congenital urinary tract obstruction: defining markers of developmental kidney injury. Pediatr Res 72:446–454
Thornhill BA, Chevalier RL (2012) Variable partial unilateral ureteral obstruction and its release in the neonatal and adult mouse. Methods Mol Biol 886:381–392
Forbes MS, Thornhill BA, Chevalier RL (2011) Proximal tubular injury and rapid formation of atubular glomeruli in mice with unilateral ureteral obstruction: a new look at an old model. Am J Physiol Ren Physiol 301:F110–F117
Forbes MS, Thornhill BA, Minor JJ, Gordon KA, Galarreta CI, Chevalier RL (2012) Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis. Am J Physiol Ren Physiol 303:F120–F129
Chevalier RL, Charlton JR (2014) The human kidney at birth: structure and function in transition. In: Faa G, Fanos V (eds) Kidney development in renal pathology. Springer, New York, pp 49–58
Hartman HA, Lai HL, Patterson P (2007) Cessation of renal morphogenesis in mice. Dev Biol 310:379–387
Forbes MS, Thornhill BA, Galarreta CI, Minor JJ, Gordon KA, Chevalier RL (2013) Chronic unilateral ureteral obstruction in the neonatal mouse delays maturation of both kidneys and leads to late formation of atubular glomeruli. Am J Physiol Ren Physiol 305:F1736–F1746
Thornhill BA, Forbes MS, Marcinko ES, Chevalier RL (2007) Glomerulotubular disconnection in neonatal mice after relief of partial ureteral obstruction. Kidney Int 72:1103–1112
Chevalier RL (1984) Chronic partial ureteral obstruction in the neonatal guinea pig II: pressure gradients affecting glomerular filtration rate. Pediatr Res 18:1271–1277
Thornhill BA, Burt LA, Chen C, Forbes MS, Chevalier RL (2005) Variable chronic partial ureteral obstruction in the neonatal rat: a new model of ureteropelvic junction obstruction. Kidney Int 67:42–52
Sergio M, Galarreta CI, Thornhill BA, Forbes MS, Chevalier RL (2015) The fate of nephrons in congenital obstructive nephropathy: adult recovery is limited by nephron number. J Urol 194:1463–1472
Rosen S, Peters CA, Chevalier RL, Huang W-Y (2008) The kidney in congenital ureteropelvic junction obstruction: a spectrum from normal to nephrectomy. J Urol 179:1257–1263
Carmody JB, Charlton JR (2013) Short-term gestation, long-term risk: prematurity and chronic kidney disease. Pediatrics 131:1168–1179
Hsu CW, Yamamoto KT, Henry RK, De Roos AJ, Flynn JT (2014) Prenatal risk factors for childhood CKD. J Am Soc Nephrol 25:2105–2111
Luyckx VA, Bertram JF, Brenner BM, Fall C, Hoy WE, Ozanne SE, Vikse BE (2013) Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet 382:273–283
Chevalier RL, Thornhill BA, Forbes MS, Kiley SC (2010) Mechanisms of renal injury and progression of renal disease in congenital obstructive nephropathy. Pediatr Nephrol 25:687–697
Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244
Cost NG, Noh PH, Devarajan P, Ivancic V, Reddy PP, Minevich E, Bennett M, Haffner C, Schulte M, DeFoor WR (2013) Urinary NGAL levels correlate with differential renal function in patients with ureteropelvic junction obstrution undergoing pyeloplasty. J Urol 190:1462–1467
Caubet C, Lacroix C, Decramer S, Drube J, Ehrich JHH, Mischak H, Bascands JL, Schanstra JP (2010) Advances in urinary proteome analysis and biomarker discovery in pediatric renal disease. Pediatr Nephrol 25:27–35
Bates CM, Charlton JR, Ferris ME, Hildebrandt F, Hoshizaki DK, Warady BA, Moxey-Mims MM (2014) Pediatric kidney disease: tracking onset and improving clinical outcomes. Clin J Am Soc Nephrol 9:1141–1143
Little MH, Brown D, Humphreys BD, McMahon AP, Miner JH, Sands JM, Weisz OA, Mullins C, Hoshizaki D (2014) Defining biology to understand disease. Clin J Am Soc Nephrol 9:809–811
Zhang Z, Quinlan J, Hoy W, Hughson MD, Lemire M, Hudson T, Hueber PA, Benjamin A, Roy A, Pascuet E, Goodyer M, Raju C, Houghton F, Bertram J, Goodyer P (2008) A common RET variant is associated with reduced newborn kidney size and function. J Am Soc Nephrol 19:2027–2034
Chevalier RL (2011) Response to nephron loss in early development. In: Polin RA, Fox WW, Abman SH (eds) Fetal and neonatal physiology, 4th edn. Elsevier, Philadelphia, pp 1423–1428
Madsen MG, Norregaard R, Palmfeldt J, Olsen LH, Frokiaer J, Jorgensen TM (2012) Urinary NGAL, cystatin C, 2-microglobulin, and osteopontin significance in hydronephrotic children. Pediatr Nephrol 27:2099–2106
Saceidi B, Koralkar R, Griffin RL, Halloran B, Ambalavanan N, Askenazi DJ (2015) Impact of gestational age, sex, and postnatal age on urine biomarkers in premature neonates. Pediatr Nephrol 30:2037–2044
Alge JL, Arthur JM (2015) Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications. Clin J Am Soc Nephrol 10:147–155
Smeets B, Boor P, Dijkman H, Sharma SV, Jirak P, Mooren F, Berger K, Bornemann J, Gelman IH, Floege J, van der Vlag J, Wetzels JF, Moeller MJ (2013) Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration. J Pathol 229:645–659
Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK (2015) Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol 26:1765–1776
Schanstra JP, Zurbig P, Alkhalaf A, Argiles A, Bakker SJL, Beige J, Bilo HJG, Chatzikyrkou C, Dakna M, Dawson J, Delles C, Haller H, Haubitz M, Husi H, Jankowski J, Jerums G, Kleefstra N, Kuznetsova T, Maahs DM, Menne J, Mullen W, Ortiz A, Persson F, Rossing P, Ruggenenti P, Rychlik I, Serra AL, Siwy J, Snell-Bergeon J, Spasovski G, Staessen JA, Vlahou A, Mischak H, Vanholder R (2015) Diagnosis and prediction of CKD progression by assessment of urinary peptides. J Am Soc Nephrol 26(8):1999–2010
Mallik M, Watson AR (2008) Antenatally detected urinary tract abnromalities; more detection but less action. Pediatr Nephrol 23:897–904
Dos Santos J, Parekh RS, Piscione TD, Hassouna T, Figueroa V, Gonima P, Vargas I, Farhat W, Rosenblum ND (2015) A new grading system for the management of antenatal hydronephrosis. Clin J Am Soc Nephrol 10:1783–1790
Liu DB, Armstrong WR, Maizels M (2014) Hydronephrosis. Prenatal and postnatal management. Clin Perinatol 41:661–678
Conway JJ (1992) The “well tempered” diuretic renogram: a standard method to examine the asymptomatic neonate with hydronephrosis or hydroureteronephrosis. J Nucl Med 33:2047–2051
Peters CA (1995) Urinary tract obstruction in children. J Urol 154:1874–1883
Sarma D, Barua SK, Rajeev TP, Baruah SJ (2012) Correlation between differential renal function estimation using CT-based functional renal parenchymal volume and (99m)Tc-DTPA renal scan. Indian J Urol 28:414–417
Chevalier RL, Thornhill BA, Chang AY (2000) Unilateral ureteral obstruction in neonatal rats leads to renal insufficiency in adulthood. Kidney Int 58:1987–1995
Cassart M, Massez A, Metens T, Rypens F, Lambot MA, Hall M, Avni FE (2004) Complementary role of MRI after sonography in assessing bilateral urinary tract anomalies in the fetus. AJR Am J Roentgenol 182:689–695
Clermont MJ, Brion LP, Schwartz GJ (1986) Reliability of plasma creatinine measurement in infants and children. Clin Pediatr (Phila) 25:569–572
Guignard J-P, Drukker A (1999) Why do newborn infants have a high plasma creatinine? Pediatrics 103:e49
Mandell J, Peters CA, Estroff JA, Allred EN, Benacerraf BR (1993) Human fetal compensatory renal growth. J Urol 150:790–792
Simoes e Silva AC, Valerio FC, Vasconcelos MA, Miranda DM, Oliveira EA (2013) Interactions between cytokines, congenital anomaliesof kidney and urinary tract and chronic kidney disease. Clin Dev Immunol 2013:Article ID 597920. doi:10.1155/2013/597920
Taha MA, Shokeir AA, Osman HG, El-Aziz A, El-Aziz A, Farahat SE (2007) Pelvi-ureteric junction obstruction in children: the role of urinary transfoming growth factor-beta 1 and epidermal growth factor. BJU Int 99:899–903
Taranta-Janusz K, Wasilewska A, Debek W, Fitonowicz R, Michaluk-Skutnik J (2013) Urinary angiotensinogen as a novel marker of obstructive nephropathy in children. Acta Paediatr 102:e429–e433
Grandaliano G, Gesualdo L, Bartoli F, Ranieri E, Monno R, Leggio A, Paradies G, Caldarulo E, Infante B, Schena FP (2000) MCP-1 and EGF renal expression and urine excretion in human congenital obstructive nephropathy. Kidney Int 58:182–192
Bartoli F, Penza R, Aceto G, Niglio F, D’Addato O, Pastore V, Campanella V, Magaldi S, Lasalandra C, Di BG, Gesualdo L (2011) Urinary epidermal growth factor, monocyte chemotactic protein-1, and 2-microglobulin in children with ureteropelvic junction obstruction. J Pediatr Surg 46:530–536
Madsen MG, Norregaard R, Palmfeldt J, Olsen LH, Frokiaer J, Jorgensen TM (2012) Epidermal growth factor and monocyte chemotactic peptide-1: potential biomarkers of urinary tract obstruction in children with hydronephrosis. J Pediatr Urol 9:838–845
Mohammadjafari H, Rafiei A, Kosaryan M, Yeganeh Y, Hosseinimehr SJ (2014) Determination of the severity of ureteropelvic junction obstruction using urinary epidermal growth factor and kidney injury molecule-1 levels. Biomark Med 20:1199–1206
Taranta-Janusz K, Wasilewska A, Debek W, Waszkiewicz-Stojda M (2012) Urinary cytokine profiles in unilateral congenital hydronephrosis. Pediatr Nephrol 27:2107–2113
Wasilewska A, Taranta-Janusz K, Debek W, Zoch-Zwierz W, Kuroczycka-Saniutycz E (2011) KIM-1 and NGAL: new markers of obstructive nephropathy. Pediatr Nephrol 26:579–586
Decramer S, Wittke S, Mischak H, Zurbig P, Walden M, Bouissou F, Bascands JL, Schanstra JP (2006) Predicting the clinical outcome of congenital unilateral ureteropelvic junction obstruction in newborn by urinary proteome analysis. Nat Med 12:398–400
Drube J, Zurbig P, Schiffer E, Lau E, Ure B, Bluer S, Kirschstein M, Pape L, Decramer S, Bascands JL, Schanstra JP, Mischak H, Ehrich JHH (2010) Urinary proteome analysis identifies infants but not older children requiring pyeloplasty. Pediatr Nephrol 25:1673–1678
Bandin F, Siwy J, Breuil B, Mischak H, Bascands JL, Decramer S, Schanstra JP (2012) Urinary proteome analysis at 5-year followup of patients with nonoperated ureteropelvic junction obstruction suggests ongoing kidney remodeling. J Urol 187:1006–1011
Mesrobian HGO, Kryger JV, Groth TW, Fiscus GE, Mirza SP (2013) Urinary proteome analysis in patients with stable SFU grade 4 ureteropelvic junction obstruction differs from normal. Urology 82:745.e1–745.e10
Morris RK, Malin GL, Khan KS, Kilby MD (2009) Antenatal ultrasound to predict postnatal renal function in congenital lower urinary tract obstruction: systematic review of test accuracy. BJOG 116:1290–1299
Bernardes LS, Aksnes G, Lortat-Jacob S, Benachi A (2011) Ultrasound evaluation of prognosis in fetuses with posterior urethral valves. J Pediatr Surg 46:1412–1418
Yiee J, Wilcox D (2008) Abnormalities of the fetal bladder. Semin Fetal Neonatal Med 13:164–170
Maizels M, Alpert SA, Houston JTB, Sabbagha RE, Parilla BV, MacGregor SN (2004) Fetal bladder sagittal length: a simple monitor to assess normal and enlarged fetal bladder size, and forecast clinical outcome. J Urol 172:1995–1999
Pulido JE, Furth SL, Zderic SA, Canning DA, Tasian GE (2014) Renal parenchymal area and risk of ESRD in boys with posterior urethral valves. Clin J Am Soc Nephrol 9:499–505
Chevalier RL (2012) Obstructive uropathy: assessment of renal function in the fetus. In: Oh W, Guignard J-P, Baumgart S (eds) Nephrology and fluid/electrolyte physiology: neonatology questions and controversies, 2nd edn. Elsevier-Saunders, Philadelphia, pp 335–359
Nicolini U, Fisk NM, Rodeck CH, Beacham J (1992) Fetal urine biochemistry: an index of renal maturation and dysfunction. Br J Obstet Gynaecol 99:46–50
Morris RK, Quinlan-Jones E, Kilby MD, Khan KS (2007) Systematic review of accuracy of fetal urine analysis to predict poor postnatal renal function in cases of congenital urinary tract obstruction. Prenat Diagn 27:900–911
Morris RK, Malin GL, Khan KS, Kilby MD (2010) Systematic review of the effectiveness of antenatal intervention for the treatment of congenital lower urinary tract obstruction. BJOG 117:382–390
Klein J, Lacroix C, Caubet C, Siwy J, Zurbig P, Dakna M, Muller F, Breuil B, Stalmach A, Mullen W, Mischak H, Bandin F, Monsarrat B, Bascands JL, Decramer S, Schanstra JP (2013) Fetal urinary peptides to predict postnatal outcome of renal disease in fetuses with posterior urethral valves (PUV). Sci Transl Med 5:1–10
Trnka P, Ivanova L, Hiatt MJ, Matsell DG (2012) Urinary biomarkers in obstructive nephropathy. Clin J Am Soc Nephrol 7:1567–1575
Salih M, Zietse R, Hoorn EJ (2014) Urinary extracellular vesicles and the kidney: biomarkers and beyond. Am J Physiol Ren Physiol 306:F1251–F1259
Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, Hager HD, Abdel-Bakky MS, Gutwein P, Altevogt P (2007) CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int 72:1095–1102
Hohenfellner K, Wingen A-M, Nauroth O, Wuhl E, Mehls O, Schaefer F (2001) Impact of ACE I/D gene polymorphism on congenital renal malformations. Pediatr Nephrol 16:356–361
Noiri E, Satoh H, Taguchi J, Brodsky WV, Nakao A, Ogawa Y, Nishijima S, Yokomizo T, Tokunaga K, Fujita T (2002) Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension 40:535–540
Hughson MD, Farris AB, Douglas-Denton R, Hoy WE, Bertram JF (2003) Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int 63:2113–2122
Bueters RRG, Van de Kar NCAJ, Schreuder MF (2013) Adult renal size is not a suitable marker for nephron numbers: an individual patient data meta-analysis. Kidney Blood Press Res 37:540–546
Beeman SC, Cullen-McEwen LA, Puelles VG, Zhang M, Wu T, Baldelomar EJ, Dowling J, Charlton JR, Forbes MS, Ng A, Wu Q, Armitage JA, Egan GF, Bertram JF, Bennett KM (2014) MRI-based glomerular morphology and pathology in whole human kidneys. Am J Physiol Ren Physiol 306:F381–F390
Forbes MS, Thornhill BA, Galarreta CI, Chevalier RL (2015) A population of mitochondrion-rich cells in pars recta of mouse kidney. Cell Tissue Res. doi:10.1007/s00441-015-2273-x
Ivanova L, Hiatt MJ, Yoder MC, Tarantal AF, Matsell DG (2010) Ontogeny of CD24 in the human kidney. Kidney Int 77:1123–1131
Hiatt MJ, Ivanova L, Toran N, Tarantal AF, Matsell DG (2010) Remodeling of the fetal collecting duct epithelium. Am J Pathol 176:630–637
Zurbig P, Decramer S, Dakna M, Jantos J, Good DM, Coon JJ, Bandin F, Mischak H, Bascands JL, Schanstra JP (2009) The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease. Proteomics 9:2108–2117
Rappaport SM, Smith MT (2010) Environment and disease risks. Science 330:460–461
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Chevalier, R.L. Prognostic factors and biomarkers of congenital obstructive nephropathy. Pediatr Nephrol 31, 1411–1420 (2016). https://doi.org/10.1007/s00467-015-3291-3
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DOI: https://doi.org/10.1007/s00467-015-3291-3