Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma

IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

See all formats and pricing
More options …
Volume 29, Issue 7


CNDP1 genotype and renal survival in pediatric nephropathies

Verena Peters
  • Corresponding author
  • Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Division of Metabolic Diseases, Heidelberg, Germany
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Moustafa Kebbewar / Bart Janssen / Georg F. Hoffmann
  • Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Division of Metabolic Diseases, Heidelberg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kristina Möller / Simone Wygoda
  • KfH-Nierenzentrum für Kinder und Jugendliche am Städtischen Klinikum „St. Georg“, Leipzig, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Marina Charbit / Ana Fernandes-Teixeira / Nikola Jeck / Johannes Zschocke / Claus Peter Schmitt
  • Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Division of Paediatric Nephrology, Heidelberg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Franz Schäfer
  • Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Division of Paediatric Nephrology, Heidelberg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Elke Wühl
  • Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Division of Paediatric Nephrology, Heidelberg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ for the ESCAPE Trial Group
Published Online: 2016-06-07 | DOI: https://doi.org/10.1515/jpem-2015-0262


Background: The risk of developing type II diabetic nephropathy (DN) is lower in patients carrying the CNDP1 Mannheim polymorphism (homozygosity for the five leucine repeat), resulting in decreased activity of the histidine-dipeptide metabolizing enzyme carnosinase. The role of CNDP1 in other nephropathies is still unknown.

Methods: To evaluate the impact of the CNDP1 Mannheim allele on pediatric chronic kidney disease (CKD), we prospectively followed the long-term clinical outcome of 272 children with non-diabetic kidney disease (glomerulopathies n=32, non-glomerular kidney disease n=240).

Results: Renal failure progression was independent of CNDP1 genotype in the total cohort of CKD children. However, in patients with glomerulopathies, only 39% of patients homozygous for the CNDP1 Mannheim polymorphism attained the primary renal endpoint as compared to 77% of patients with any other CNDP1 genotype (p=0.06).

Conclusions: Our findings in pediatric CKD patients suggest that the nephroprotective effect of the CNDP1 Mannheim variant is not restricted to patients with diabetic nephropathy.

Keywords: carnosinase; CNDP1; non-diabetic glomerulopathies; pediatric kidney disease


  • 1.

    Boldyrev A, Severin SE. The histidine-containing dipeptides, carnosine and anserine: distribution, properties and biological significance. Adv Enzyme Regul 1990;30:175–94.Google Scholar

  • 2.

    Boldyrev AA, Aldini G, Derave W. Physiology and pathophysiology of carnosine. Physiol Rev 2013;93:1803–45.Google Scholar

  • 3.

    Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, et al. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thrombosis Vasc Biol 2013;33:1162–70.Web of ScienceGoogle Scholar

  • 4.

    Negre-Salvayre A, Coatrieux C, Ingueneau C, Salvayre R. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol 2008;153:6–20.Google Scholar

  • 5.

    Vistoli G, Orioli M, Pedretti A, Regazzoni L, Canevotti R, et al. Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species. ChemMedChem 2009;4:967–75.Web of ScienceGoogle Scholar

  • 6.

    Alhamdani M, Al-Azzawie HF, Abbas FK. Decreased formation of advanced glycation end-products in peritoneal fluid by carnosine and related peptides. Perit Dial Int 2007;27:86–9.Google Scholar

  • 7.

    Hou W, Chen HJ, Lin YH. Antioxidant peptides with Angiotensin converting enzyme inhibitory activities and applications for Angiotensin converting enzyme purification. J Agric Food Chem 2003;51:1706–9.Google Scholar

  • 8.

    Nakagawa K, Ueno A, Nishikawa Y. Interactions between carnosine and captopril on free radical scavenging activity and angiotensin-converting enzyme activity in vitro. Yakugaku Zasshi 2006;126:37–42.Google Scholar

  • 9.

    Babizhayev MA, Lankin VZ, Savel’Yeva EL, Deyev AI, Yegorov YE. Diabetes mellitus: novel insights, analysis and interpretation of pathophysiology and complications management with imidazole-containing peptidomimetic antioxidants. Recent Pat Drug Deliv Formul 2013;7:216–56.Google Scholar

  • 10.

    Decker E, Livisay SA, Zhou S. A re-evaluation of the antioxidant activity of purified carnosine. Biochemistry (Mosc) 2000;65:766–70.Google Scholar

  • 11.

    Hipkiss AR. Energy metabolism, proteotoxic stress and age-related dysfunction – protection by carnosine. Mol Aspects Med 2011;32:267–78.Web of ScienceGoogle Scholar

  • 12.

    Mozdan M, Szemraj J, Rysz J, Nowak D. Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. Basic Clin Pharmacol Toxicol 2005;96: 352–60.Google Scholar

  • 13.

    Velez S, Nair NG, Reddy VP. Transition metal ion binding studies of carnosine and histidine: biologically relevant antioxidants. Colloids Surf B Biointerfaces 2008;66:291–4.Google Scholar

  • 14.

    Aydogan S, Yapislar H, Artis S, Aydogan B. Impaired erythrocytes deformability in H[2]O[2]-induced oxidative stress: protective effect of L-carnosine. Clin Hemorheol Microcirc 2008;39:93–8.Google Scholar

  • 15.

    Hipkiss AR. Carnosine, a protective, anti-ageing peptide? Int J Biochem Cell Biol 1998;30:863–8.Google Scholar

  • 16.

    McFarland GA, Holliday R. Retardation of the senescence in cultured human diploid fibroblasts by carnosine. Exp Cell Res 1994;212:167–75.Google Scholar

  • 17.

    Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, et al. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosine gene CNDP1. Diabetes 2005;54:2320–7.Google Scholar

  • 18.

    Tanida M, Shen J, Kubomura D, Nagai K. Effects of anserine on the renal sympathetic nerve activity and blood pressure in urethane-anesthetized rats. Physiol Res 2010;59:177–85.Google Scholar

  • 19.

    Peters V, Schmitt CP, Zschocke J, Gross ML, Brismar K, et al. Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice. Amino Acids 2012;42:2411–6.Web of ScienceGoogle Scholar

  • 20.

    Ansurudeen I, Sunkari VG, Grunler J, Peters V, Schmitt CP, et al. Carnosine enhances diabetic wound healing in the db/db mouse model of type 2 diabetes. Amino Acids 2012;43:127–34.Web of ScienceGoogle Scholar

  • 21.

    Peters V, Riedl E, Braunagel M, Hoger S, Hauske S, et al. Carnosine treatment in combination with ACE inhibition in diabetic rats. Regul Pept 2014;194–195:36–40.Web of ScienceGoogle Scholar

  • 22.

    Riedl E, Pfister F, Braunagel M, Brinkkotter P, Sternik P, et al. Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats. Cell Physiol Biochem 2011;28:279–88.Web of ScienceGoogle Scholar

  • 23.

    Pfister F, Riedl E, Wang Q, vom Hagen F, Deinzer M, et al. Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy. Cell Physiol Biochem 2011;28: 125–36.Google Scholar

  • 24.

    Alkhalaf A, Bakker SJ, Bilo HJ, Gans RO, Navis GJ, et al. A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus. Diabetologia 2010;53:2562–8.Web of ScienceGoogle Scholar

  • 25.

    Teufel M, Saudek V, Ledig JP, Bernhardt A, Boularand S, et al. Sequence identification and characterization of human carnosine and a closely related non-specific dipeptidase. J Biol Chem 2003;278:6521–31.Google Scholar

  • 26.

    Mooyaart AL, Zutinic A, Bakker SJ, Grootendorst DC, Kleefstra N, et al. Association between CNDP1 genotype and diabetic nephropathy is sex specific. Diabetes 2010;59:1555–9.Google Scholar

  • 27.

    Freedman BI, Hicks PJ, Sale MM, Pierson ED, Langefeld CD, et al. A leucine repeat in the carnosine gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol Dial Transplant 2007;22:1131–5.Google Scholar

  • 28.

    Mooyaart AL, van Valkengoed IG, Shaw PK, Peters V, Baelde HJ, et al. Lower frequency of the 5/5 homocygous CNDP1 genotype in South Asian Surinamese. Diabetes Res Clin Pract 2009;85:272–8.Google Scholar

  • 29.

    McDonough C, Hicks PJ, Lu L, Langefeld CD, Freedman BI, et al. The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans. Human Genetics 2009;126:265–75.Web of ScienceGoogle Scholar

  • 30.

    Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, et al. Strict blood pressure control and renal failure progression in children. The ESCAPE Trial Group. N Engl J Med 2009;361: 1639–50.Google Scholar

  • 31.

    Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children and adolescents. Pediatr Clin North Am 1987;34: 571–90.Google Scholar

  • 32.

    Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–54.Google Scholar

  • 33.

    Grenda R, Wuhl E, Litwin M, Janas R, Sladowska J, et al. Urinary excretion of endothelin-1 (ET-1), transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial. Nephrol Dial Transplant 2007;22:3487–94.Google Scholar

  • 34.

    Kiliś-Pstrusińska K, Zwolińska D, Grzeszczak W, Study Group. Is carnosinase 1 gene (CNDP1) polymorphism associated with chronic kidney disease progression in children and young adults? results of a family-based study. Arch Med Res 2010;41:356–62.Web of ScienceGoogle Scholar

  • 35.

    Ardissino G, Dacco V, Testa S, Bonaudo R, Claris-Appiani A, et al. Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics 2003;111:e382–7.Google Scholar

  • 36.

    Warady BA, Abraham AG, Schwartz GJ, Wong CS, Munoz A, et al. Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the chronic kidney disease in children (CKiD) cohort. Am J Kidney Dis 2015;65:878–88.Web of ScienceGoogle Scholar

  • 37.

    Li JJ, Kwag SJ, Jung DS, Kim JJ, Yoo TH, et al. Podocyte biology in diabetic nephropathy. Kidney Int 2007;72:S36–42.Web of ScienceGoogle Scholar

  • 38.

    Kriz W, Gretz N, Lemley KV. Progression of glomerular disease: is the podocyte the culprit? Kidney Int 1998;54:687–97.Google Scholar

  • 39.

    Mooyaart A, van Valkengoed IG, Shaw PK, Peters V, Baelde HJ, et al. Lower frequency of the 5/5 homozygous CNDP1 genotype in South Asian Surinamese. Diabetes Res Clin Pract 2009;85:272–8.Google Scholar

  • 40.

    Peters V, Klessens CQ, Baelde HJ, Singler B, Veraar KA, et al. Intrinsic carnosine metabolism in the human kidney. Amino Acids 2015;47:2541–50.Web of ScienceGoogle Scholar

  • 41.

    Modlinger PS, Wilcox CS, Aslam S. Nitric oxide, oxidative stress, and progression of chronic failure. Semin Nephrol 2004;24:354–65.Google Scholar

About the article

Corresponding author: Dr. Verena Peters, Center for Pediatrics and Adolescent Medicine, Im Neuenheimer Feld 669, 69120 Heidelberg, Germany, Phone: +49-6221-5631715, Fax: +49-6221-565565

Received: 2015-07-01

Accepted: 2016-04-22

Published Online: 2016-06-07

Published in Print: 2016-07-01

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: The ESCAPE trial was supported by grants of the Boehringer Ingelheim Stiftung, the European Commission (5th Framework Program QLRT-2001-00908, the Kuratorium für Dialyse und Nierentransplantation e.V., Neu-Isenburg, and the Baxter Extramural Grant Program. Part of this study was supported by grants of the Deutsche Forschungsgemeinschaft (SFB 1118) and the Doktor Pfleger Foundation, Bamberg, Germany.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 29, Issue 7, Pages 827–833, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2015-0262.

Export Citation

©2016 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Harvest F. Gu
Frontiers in Genetics, 2019, Volume 10
Jiedong Qiu, Sibylle J. Hauske, Shiqi Zhang, Angelica Rodriguez-Niño, Thomas Albrecht, Diego O. Pastene, Jacob van den Born, Harry van Goor, Sven Ruf, Markus Kohlmann, Michael Teufel, Bernhard K. Krämer, Hans-Peter Hammes, Verena Peters, Benito A. Yard, and Aimo Kannt
Amino Acids, 2018
Verena Peters, Johannes Zschocke, and Claus P. Schmitt
Journal of Inherited Metabolic Disease, 2017
Franck Boizard, Valérie Brunchault, Panagiotis Moulos, Benjamin Breuil, Julie Klein, Nadia Lounis, Cécile Caubet, Stéphanie Tellier, Jean-Loup Bascands, Stéphane Decramer, Joost P. Schanstra, and Bénédicte Buffin-Meyer
Scientific Reports, 2016, Volume 6, Number 1

Comments (0)

Please log in or register to comment.
Log in