CNDP1 genotype and renal survival in pediatric nephropathies

Peters, Verena; Kebbewar, Moustafa; Janssen, Bart; Hoffmann, Georg F.; Möller, Kristina; Wygoda, Simone; Charbit, Marina; Fernandes-Teixeira, Ana; Jeck, Nikola; Zschocke, Johannes; Schmitt, Claus Peter; Schäfer, Franz; Wühl, Elke; Group, for the ESCAPE Trial

doi:10.1515/jpem-2015-0262

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…The dipeptide possesses also strong antioxidant and free radical scavenging activities 58 . Interestingly, protective effects of carnosine have been demonstrated in rodent models of kidney disease 60 61 62 and in patients with diabetic nephropathy 63 or children with glomerulopathies 64 . Thus, increased urinary excretion of carnosine in UPJ obstruction could be an adaptive rather than a deteriorating mechanism.…”

Section: Discussionmentioning

confidence: 99%

A capillary electrophoresis coupled to mass spectrometry pipeline for long term comparable assessment of the urinary metabolome

Boizard

Brunchault

Moulos³

et al. 2016

Sci Rep

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Although capillary electrophoresis coupled to mass spectrometry (CE-MS) has potential application in the field of metabolite profiling, very few studies actually used CE-MS to identify clinically useful body fluid metabolites. Here we present an optimized CE-MS setup and analysis pipeline to reproducibly explore the metabolite content of urine. We show that the use of a beveled tip capillary improves the sensitivity of detection over a flat tip. We also present a novel normalization procedure based on the use of endogenous stable urinary metabolites identified in the combined metabolome of 75 different urine samples from healthy and diseased individuals. This method allows a highly reproducible comparison of the same sample analyzed nearly 130 times over a range of 4 years. To demonstrate the use of this pipeline in clinical research we compared the urinary metabolome of 34 newborns with ureteropelvic junction (UPJ) obstruction and 15 healthy newborns. We identified 32 features with differential urinary abundance. Combination of the 32 compounds in a SVM classifier predicted with 76% sensitivity and 86% specificity UPJ obstruction in a separate validation cohort of 24 individuals. Thus, this study demonstrates the feasibility to use CE-MS as a tool for the identification of clinically relevant urinary metabolites.

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Section: Discussionmentioning

confidence: 99%

A capillary electrophoresis coupled to mass spectrometry pipeline for long term comparable assessment of the urinary metabolome

Boizard

Brunchault

Moulos³

et al. 2016

Sci Rep

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“…The influence of the CNDP1 Mannheim allele has also been investigated in nondiabetic nephropathies, where it was found to be associated with a slower progression to CKD and to correlate with renal survival in patients with glomerulopathies, but not in patients with tubulointerstitial disease [22,23]. Notwithstanding the foregoing, there is compelling evidence that carnosine, a major substrate of CN-1, has renoprotective properties in animal models of diabetes [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Serum Carnosinase-1 and Albuminuria Rather than theCNDP1Genotype Correlate with Urinary Carnosinase-1 in Diabetic and Nondiabetic Patients with Chronic Kidney Disease

Rodriguez-Niño

Hauske

et al. 2019

Journal of Diabetes Research

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Background. Carnosinase-1 (CN-1) can be detected in 24 h urine of healthy individuals and patients with type 2 diabetes (T2DM). We aimed to assess whether urinary CN-1 is also reliably measured in spot urine and investigated its association with renal function and the albumin/creatinine ratio (ACR). We also assessed associations between the CNDP1 (CTG)n genotype and CN-1 concentrations in serum and urine. Methods. Patients with T2DM (n=85) and nondiabetic patients with chronic kidney disease (CKD) (n=26) stratified by albuminuria (ACR≤300 mg/g or ACR>300 mg/g) recruited from the nephrology clinic and healthy subjects (n=24) were studied. Results. Urinary CN-1 was more frequently detected and displayed higher concentrations in patients with ACR>300 mg/g as compared to those with ACR≤300 mg/g irrespective of the baseline disease (T2DM: 554 ng/ml [IQR 212-934 ng/ml] vs. 31 ng/ml [IQR 31-63 ng/ml] (p<0.0001) and nondiabetic CKD: 197 ng/ml [IQR 112-739] vs. 31 ng/ml [IQR 31-226 ng/ml] (p=0.015)). A positive correlation between urinary CN-1 and ACR was found (r=0.68, p<0.0001). Multivariate linear regression analysis revealed that ACR and serum CN-1 concentrations but not eGFR or the CNDP1 genotype are independent predictors of urinary CN-1, explaining 47% of variation of urinary CN-1 concentrations (R2=0.47, p<0.0001). Conclusion. These results confirm and extend previous findings on urinary CN-1 concentrations, suggesting that assessment of CN-1 in spot urine is as reliable as in 24 h urine and may indicate that urinary CN-1 in macroalbuminuric patients is primarily serum-derived and not locally produced.

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“…The leucine repeat in the signal sequence of CNDP1 gene is essential for CN1 secretion with the short allelic variant (CTG) 5 associated with low-serum CN1 concentrations. Importantly, patients with T2D without DN are significantly more frequently homozygous for the (CTG) 5 allele (Freedman et al 2007;Riedl et al 2007;Alkhalaf et al 2010;Peters et al 2016). It was postulated that low CN1 activity might favour high circulating carnosine concentrations.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

et al. 2018

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Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a K i of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.

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CNDP1 genotype and renal survival in pediatric nephropathies

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

Cited by 13 publications

References 37 publications

A capillary electrophoresis coupled to mass spectrometry pipeline for long term comparable assessment of the urinary metabolome

A capillary electrophoresis coupled to mass spectrometry pipeline for long term comparable assessment of the urinary metabolome

Serum Carnosinase-1 and Albuminuria Rather than theCNDP1Genotype Correlate with Urinary Carnosinase-1 in Diabetic and Nondiabetic Patients with Chronic Kidney Disease

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

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