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Open Access 01-10-2018 | Original Article

Urinary epidermal growth factor as a prognostic marker for the progression of Alport syndrome in children

Authors: Baihong Li, Yanqin Zhang, Fang Wang, Viji Nair, Fangrui Ding, Huijie Xiao, Yong Yao, Matthias Kretzler, Wenjun Ju, Jie Ding

Published in: Pediatric Nephrology | Issue 10/2018

Abstract

Background

Alport syndrome is a rare hereditary kidney disease manifested with progressive renal failure. Considerable variation exists in terms of disease progression among patients with Alport syndrome. Identification of patients at high risk of rapid progression remains an unmet need. Urinary epidermal growth factor (uEGF) has been shown to be independently associated with risk of progression to adverse kidney outcome in multiple independent adult chronic kidney disease (CKD) cohorts. In this study, we aim to assess if uEGF is associated with kidney impairment and its prognostic value for children with Alport syndrome.

Methods

One hundred and seventeen pediatric patients with Alport syndrome and 146 healthy children (3–18 years old) were included in this study. uEGF was measured in duplicates in baseline urine samples using ELISA (R&D) and concentration was normalized by urine creatinine (uEGF/Cr). In patients with longitudinal follow-up data (n = 38), progression was defined as deteriorated kidney function (CKD stage increase) during follow-up period (follow-up length is about 31 months in average). The association of baseline uEGF/Cr level with estimated glomerular filtration rate (eGFR) slope and Alport syndrome patients’ progression to a more advanced CKD stage during the follow-up period was used to evaluate the prognostic value of the marker.

Results

We found that uEGF/creatinine (uEGF/Cr) decreases with age in pediatric patients with Alport syndrome with a significantly faster rate than in healthy children of the same age group. uEGF/Cr is significantly correlated with eGFR (r = 0.75, p < 0.001), after adjustment for age. In 38 patients with longitudinal follow-up, we observed a significant correlation between uEGF/Cr and eGFR slope (r = 0.58, p < 0.001). Patients with lower uEGF/Cr level were at increased risk of progression to a higher CKD stage. uEGF/Cr was able to distinguish progressors from non-progressors with an AUC of 0.88, versus 0.77 by eGFR and 0.81 by 24-h urinary protein (24-h UP).

Conclusions

Our study suggests that uEGF/Cr is a promising biomarker for accelerated kidney function decline in pediatric patients with Alport syndrome. It may help to identify patients at high risk of progression for targeted clinical care and improve the patients’ stratification in interventional trials.

JKruegel J, Rubel D, Gross O (2013) Alport syndrome-insights from basic and clinical research. Nat Rev Nephrol 9:170–178CrossRef

Dagogo-Jack S, Marshall SM, Kendall-Taylor P, Alberti KG (1989) Urinary excretion of human epidermal growth factor in the various stages of diabetic nephropathy. Clin Endocrinol 31:167–173CrossRef

Kok HM, Falke LL, Goldschmeding R, Nguyen TQ (2014) Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease. Nat Rev Nephrol 10:700–711CrossRefPubMed

Mattila AL, Viinikka L, Saario I, Perheentupa J (1988) Human epidermal growth factor: renal production and absence from plasma. Regul Pept 23:89–93CrossRefPubMed

Jorgensen PE, Hilchey SD, Nexo E, Poulsen SS, Quilley CP (1993) Urinary epidermal growth factor is excreted from the rat isolated perfused kidney in the absence of plasma. J Endocrinol 139:227–234CrossRefPubMed

Mathiesen ER, Nexo E, Hommel E, Parving HH (1989) Reduced urinary excretion of epidermal growth factor in incipient and overt diabetic nephropathy. Diabet Med 6(2):121–126CrossRefPubMed

Safirstein R, Zelent AZ, Price PM (1989) Reduced renal prepro-epidermal growth factor mRNA and decreased EGF excretion in ARF. Kidney Int 36:810–815CrossRefPubMed

Ranieri E, Gesualdo L, Petrarulo F, Schena FP (1996) Urinary IL-6/EGF ratio: a useful prognostic marker for the progression of renal damage in IgA nephropathy. Kidney Int 50:1990–2001CrossRefPubMed

Tsau YK, Chen CH (1999) Urinary epidermal growth factor excretion in children with chronic renal failure. Am J Nephrol 19:400–404CrossRefPubMed

10.

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 58:182–192CrossRefPubMed

11.

Stangou M, Alexopoulos E, Papagianni A, Pantzaki A, Bantis C, Dovas S, Economidou D, Leontsini M, Memmos D (2009) Urinary levels of epidermal growth factor, interleukin-6 and monocyte chemoattractant protein-1 may act as predictor markers of renal function outcome in immunoglobulin A nephropathy. Nephrology 14:613–620CrossRefPubMed

12.

Togashi Y, Miyamoto Y (2013) Urinary cystatin C as a biomarker for diabetic nephropathy and its immunohistochemical localization in kidney in Zucker diabetic fatty (ZDF) rats. Exp Toxicol Pathol 65:615–622CrossRefPubMed

13.

Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PXK, Mariani LH, Eichinger FH, Berthier CC, Randolph A, Lai JY, Zhou Y, Hawkins JJ, Bitzer M, Sampson MG, Thier M, Solier C, Duran-Pacheco GC, Duchateau-Nguyen G, Essioux L, Schott B, Formentini I, Magnone MC, Bobadilla M, Cohen CD, Bagnasco SM, Barisoni L, Lv J, Zhang H, Wang HY, Brosius FC, Gadegbeku CA, Kretzler M, ERCB, C-PROBE, NEPTUNE, and PKU-IgAN Consortium (2015) Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci Transl Med 7:316ra193CrossRefPubMedPubMedCentral

14.

Betz BB, Jenks SJ, Cronshaw AD, Lamont DJ, Cairns C, Manning JR, Goddard J, Webb DJ, Mullins JJ, Hughes J, McLachlan S, Strachan MWJ, Price JF, Conway BR (2016) Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes. Kidney Int 89:1125–1135CrossRefPubMed

15.

Salido EC, Lakshmanan J, Fisher DA, Shapiro LJ, Barajas L (1991) Expression of epidermal growth factor in the rat kidney. Histochemistry 96:65–72CrossRefPubMed

16.

Humes HD, Cieslinski DA, Coimbra TM, Messana JM, Galvao C (1989) Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure. J Clin Invest 84:1757–1761CrossRefPubMedPubMedCentral

17.

Jedlicka J, Soleiman A, Draganovici D, Mandelbaum J, Ziegler U, Regele H, Wüthrich RP, Gross O, Anders HJ, Segerer S (2010) Interstitial inflammation in Alport syndrome. Hum Pathol 41:582–593CrossRefPubMed

18.

Gomez IG, MacKenna DA, Johnson BG, Kaimal V, Roach AM, Ren S, Nakagawa N, Xin C, Newitt R, Pandya S, Xia TH, Liu X, Borza DB, Grafals M, Shankland SJ, Himmelfarb J, Portilla D, Liu S, Chau BN, Duffield JS (2015) Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest 125:141–156CrossRefPubMed

19.

Kim M, Piaia A, Shenoy N, Kagan D, Gapp B, Kueng B, Weber D, Dietrich W, Ksiazek (2015) Progression of Alport kidney disease in Col4a3 knock out mice is independent of sex or macrophage depletion by clodronate treatment. PLoS One 10:e0141231CrossRefPubMedPubMedCentral

20.

Benali SL, Lees GE, Nabity MB, Aricò A, Drigo M, Gallo E, Giantin M, Aresu L (2016) X-linked hereditary nephropathy in Navasota dogs: clinical pathology, morphology, and gene expression during disease progression. Vet Pathol 53:803–812CrossRefPubMed

21.

Gross O, Beirowski B, Marie-Louise Koepke ML, Kuck J, Reiner M, Addicks K, Smyth N, Schulze-Lohoff E, Weber M (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446CrossRefPubMed

22.

Bae EH, Fang F, Williams VR, VR KA, Zhou X, Patel VB, Song X, John R, Oudit GY, Pei Y, Scholey JW (2017) Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome. Kidney Int 91:1347–1361CrossRefPubMed

23.

Hari P, Biswas B, Pandey R, Kalaivani M, Kumar R, Bagga A (2012) Updated height- and creatinine-based equation and its validation for estimation of glomerular filtration rate in children from developing countries. Clin Exp Nephrol 16(5):697–705CrossRefPubMed

24.

Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schröder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2000) X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649–657PubMed

25.

Hashimura Y, Nozu K, Kaito H, Nakanishi K, Fu XJ, Ohtsubo H, Hashimoto F, Oka M, Ninchoji T, Ishimori S, Morisada N, Matsunoshita N, Kamiyoshi N, Yoshikawa N, Iijima K (2014) Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV α5 chain. Kidney Int 85:1208–1213CrossRefPubMed

26.

Temme J, Kramer A, Jager KJ, Lange K, Peters F, Müller GA, Kramar R, Heaf JG, Finne P, Palsson R, Reisæter AV, Hoitsma AJ, Metcalfe W, Postorino M, Zurriaga O, Santos JP, Ravani P, Jarraya F, Verrina E, Dekker FW, Gross O (2012) Outcomes of male patients with Alport syndrome undergoing renal replacement therapy. Clin J Am Soc Nephrol 7:1969–1976CrossRefPubMedPubMedCentral

27.

Lamattina JC, Foley DP, Mezrich JD, Fernandez LA, Vidyasagar V, D’Alessandro AM, Musat AI, Samaniego-Picota MD, Pascual J, Alejandro MD, Leverson GE, Pirsch JD, Djamali A (2011) Chronic kidney disease stage progression in liver transplant recipients. Clin J Am Soc Nephrol 6:1851–1857CrossRefPubMedPubMedCentral

28.

Kukla A, Adulla M, Pascual J, Samaniego M, Nanovic L, Becker BN, Djamali A (2008) CKD stage-to-stage progression in native and transplant kidney disease. Nephrol Dial Transplant 23:693–700CrossRefPubMed

29.

Lee CC, Sun CY, Wu IW, Wang SY, Wu MS (2011) Metabolic syndrome loses its predictive power in late-stage chronic kidney disease progression—a paradoxical phenomenon. Clin Nephrol 75:141–149CrossRefPubMed

30.

Marks A, Fluck N, Prescott GJ, Robertson LM, Simpson WG, Smith WC, Black C (2014) Definitions of progression in chronic kidney disease—predictors and relationship to renal replacement therapy in a population cohort with a 6-year follow-up. Nephrol Dial Transplant 29:333–341CrossRefPubMed

31.

Gross O, Perin L, Deltas C (2014) Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol Dial Transplant 29:iv124–iv130CrossRefPubMed

32.

Mattila AL, Perheentupa J, Pesonen K, Viinikka L (1985) Epidermal growth factor in human urine from birth to puberty. J Clin Endocrinol Metab 61:997–1000CrossRefPubMed

33.

Uchihashi M, Hirata Y, Fujita T, Matsukura S (1982) Age-related decrease of urinary excretion of human epidermal growth factor (hEGF). Life Sci 31:679–683CrossRefPubMed

34.

Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schröder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2003) X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a “European Community Alport Syndrome Concerted Action” study. J Am Soc Nephrol 14:2603–2610CrossRefPubMed

35.

Yamamura T, Nozu K, Fu XJ, Nozu Y, Ye MJ, Shono A, Yamanouchi S, Minamikawa S, Morisada N, Nakanishi K, Shima Y, Yoshikawa N, Ninchoji T, Morioka I, Kaito H, Iijima K (2017) Natural history and genotype-phenotype correlation in female X-linked Alport syndrome. Kidney Int Rep 2:850–855CrossRefPubMedPubMedCentral

36.

Marcocci E, Uliana V, Bruttini M, Artuso R, Silengo MC, Zerial M, Bergesio F, Amoroso A, Savoldi S, Pennesi M, Giachino D, Rombolà G, Fogazzi GB, Rosatelli C, Martinhago CD, Carmellini M, Mancini R, Di Costanzo G, Longo I, Renieri A, Mari F (2009) Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome. Nephrol Dial Transplant 24:1464–1471CrossRefPubMed

37.

Pescucci C, Mari F, Longo I, Vogiatzi P, Caselli R, Scala E, Abaterusso C, Gusmano R, Seri M, Miglietti N, Bresin E, Renieri A (2004) Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int 65:1598–1603CrossRefPubMed

Title: Urinary epidermal growth factor as a prognostic marker for the progression of Alport syndrome in children
Authors: Baihong Li
Yanqin Zhang
Fang Wang
Viji Nair
Fangrui Ding
Huijie Xiao
Yong Yao
Matthias Kretzler
Wenjun Ju
Jie Ding
Publication date: 01-10-2018
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 10/2018
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-018-3988-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Urinary epidermal growth factor as a prognostic marker for the progression of Alport syndrome in children

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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