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Erschienen in: Pediatric Nephrology 6/2018

08.01.2018 | Original Article

Klotho G-395A gene polymorphism: impact on progression of end-stage renal disease and development of cardiovascular complications in children on dialysis

verfasst von: Eman A. Elghoroury, Fatina I. Fadel, Manal F. Elshamaa, Dina Kandil, Doaa M. Salah, Marwa M. El-Sonbaty, Hebatallah Farouk, Mona Raafat, Soha Nasr

Erschienen in: Pediatric Nephrology | Ausgabe 6/2018

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Abstract

Background

Klotho G-395-A gene polymorphism may impact children with end-stage renal disease (ESRD). We investigated the relevance of Klotho G-395-A on ESRD development and progression, and its relationship with evolution of cardiovascular complications in pediatric dialysis patients.

Methods

Fifty-five children with chronic kidney disease (CKD) and seventy healthy children were genotyped for Klotho G-395A.

Results

Incidence of GA/AA genotypes and A allele were higher in ESRD patients compared with controls (54.5 vs. 7.1%, P < 0.001; 30.9 vs. 13.6%, P = 0.001, respectively). Also, children with GA/AA genotypes were 15.6 times more likely to develop ESRD than with GG genotype (95% CI 5.4–44.7, P < 0.001). A allele carriers have 2.8 times higher risk of developing ESRD than those with G allele (95% CI 1.5–5.35, P = 0.001). Also, the A allele could be considered a predictor of cardiovascular disease (CVD), as carriers have 161 times higher risk of cardiovascular complications than non-carriers (95% CI 21–1233, P < 0.001). All ESRD patients with CVD presented with left ventricular hypertrophy (LVH) and the frequency of A allele was significantly higher among ESRD children with LVH, whereas G allele frequency was significantly higher among ESRD children without LVH.

Conclusions

The A allele of the G-395A Klotho gene polymorphism shows a significantly higher frequency among children with CKD and those with CVD and LVH. This mutant allele could be used as a risk marker for the development of ESRD as well as a predictor of CVD in these children.
Literatur
1.
Zurück zum Zitat McDonald S, Craig J (2004) Long-term survival of children with end-stage. Renal disease. N Engl J Med 350:2654–2662CrossRefPubMed McDonald S, Craig J (2004) Long-term survival of children with end-stage. Renal disease. N Engl J Med 350:2654–2662CrossRefPubMed
2.
Zurück zum Zitat Marchelek-Myśliwiec M, Różański J, Ogrodowczyk A, Dutkiewicz G, Dołęgowska B, Sałata D, Budkowska M, Safranow K, Stępniewska J, Wiśniewska M, Ciechanowski K (2016) The association of the Klotho polymorphism rs9536314 with parameters of calcium-phosphate metabolism in patients on long-term hemodialysis. Ren Fail 38:776–780CrossRefPubMed Marchelek-Myśliwiec M, Różański J, Ogrodowczyk A, Dutkiewicz G, Dołęgowska B, Sałata D, Budkowska M, Safranow K, Stępniewska J, Wiśniewska M, Ciechanowski K (2016) The association of the Klotho polymorphism rs9536314 with parameters of calcium-phosphate metabolism in patients on long-term hemodialysis. Ren Fail 38:776–780CrossRefPubMed
3.
Zurück zum Zitat Albaramki J, Al-Ammouri I, Akl K (2016) Neurological and cardiac complications in a cohort of children with end-stage renal disease. Saudi J Kidney Dis Transpl 27:507–511CrossRefPubMed Albaramki J, Al-Ammouri I, Akl K (2016) Neurological and cardiac complications in a cohort of children with end-stage renal disease. Saudi J Kidney Dis Transpl 27:507–511CrossRefPubMed
4.
Zurück zum Zitat Karsli Ceppioğlu S, Yurdun T, Canbakan M (2011) Assessment of matrix Gla protein, Klotho gene polymorphisms, and oxidative stress in chronic kidney disease. Ren Fail 33:866–874CrossRefPubMed Karsli Ceppioğlu S, Yurdun T, Canbakan M (2011) Assessment of matrix Gla protein, Klotho gene polymorphisms, and oxidative stress in chronic kidney disease. Ren Fail 33:866–874CrossRefPubMed
5.
Zurück zum Zitat MC H, Kuro-o M, Moe OW (2013) Klotho and chronic kidney disease. Contrib Nephrol 180:47–63CrossRef MC H, Kuro-o M, Moe OW (2013) Klotho and chronic kidney disease. Contrib Nephrol 180:47–63CrossRef
6.
Zurück zum Zitat Donate-Correa J, Martín-Núñez E, Martínez-Sanz R, Muros-de-Fuentes M, Mora-Fernández C, Pérez-Delgado N, Navarro-González JF (2016) Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease. J Cell Mol Med 20:128–133CrossRefPubMed Donate-Correa J, Martín-Núñez E, Martínez-Sanz R, Muros-de-Fuentes M, Mora-Fernández C, Pérez-Delgado N, Navarro-González JF (2016) Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease. J Cell Mol Med 20:128–133CrossRefPubMed
7.
Zurück zum Zitat MC H, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136CrossRef MC H, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136CrossRef
8.
Zurück zum Zitat Majumdar V, Nagaraja D, Christopher R (2010) Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke. Biochem Biophys Res Commun 403:412–416CrossRefPubMed Majumdar V, Nagaraja D, Christopher R (2010) Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke. Biochem Biophys Res Commun 403:412–416CrossRefPubMed
9.
Zurück zum Zitat Hoa Q, Ding X, Goa L, Yang M, Dong B (2016) G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old. Age (Dordr) 38:7CrossRef Hoa Q, Ding X, Goa L, Yang M, Dong B (2016) G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old. Age (Dordr) 38:7CrossRef
10.
Zurück zum Zitat Mula-Abed WA, Al Rasadi K, Al-Riyami D (2012) Estimated glomerular filtration rate (eGFR): a serum creatinine-based test for the detection of chronic kidney disease and its impact on clinical practice. Oman Med J 27:108–113CrossRefPubMedPubMedCentral Mula-Abed WA, Al Rasadi K, Al-Riyami D (2012) Estimated glomerular filtration rate (eGFR): a serum creatinine-based test for the detection of chronic kidney disease and its impact on clinical practice. Oman Med J 27:108–113CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57:450–458CrossRefPubMed Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57:450–458CrossRefPubMed
12.
Zurück zum Zitat de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH (1992) Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 20:1251–1260CrossRefPubMed de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH (1992) Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 20:1251–1260CrossRefPubMed
13.
Zurück zum Zitat de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH (1995) Effect of growth on variability of left ventricular mass assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 25:1056–1062CrossRefPubMed de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH (1995) Effect of growth on variability of left ventricular mass assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 25:1056–1062CrossRefPubMed
14.
Zurück zum Zitat Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H (2010) A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population. Clin Chim Acta 411:386–390CrossRefPubMed Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H (2010) A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population. Clin Chim Acta 411:386–390CrossRefPubMed
15.
Zurück zum Zitat MC H, Kuro-o M, Moe OW (2013) Renal and extrarenal actions of Klotho. Semin Nephrol 33:118–129CrossRef MC H, Kuro-o M, Moe OW (2013) Renal and extrarenal actions of Klotho. Semin Nephrol 33:118–129CrossRef
16.
Zurück zum Zitat Sugiura H, Yoshida T, Mitobe M, Yoshida S, Shiohira S, Nitta K, Tsuchiya K (2010) Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70. Nephrol Dial Transplant 25:60–68CrossRefPubMed Sugiura H, Yoshida T, Mitobe M, Yoshida S, Shiohira S, Nitta K, Tsuchiya K (2010) Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70. Nephrol Dial Transplant 25:60–68CrossRefPubMed
17.
Zurück zum Zitat Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806CrossRefPubMed Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806CrossRefPubMed
18.
Zurück zum Zitat Li L, Wang Y, Gao W, Yuan C, Zhang S, Zhou H, Huang M, Yao X (2015) Klotho reduction in alveolar macrophages contributes to cigarette smoke extract-induced inflammation in chronic obstructive pulmonary disease. J Biol Chem 290:890–900 Li L, Wang Y, Gao W, Yuan C, Zhang S, Zhou H, Huang M, Yao X (2015) Klotho reduction in alveolar macrophages contributes to cigarette smoke extract-induced inflammation in chronic obstructive pulmonary disease. J Biol Chem 290:890–900
19.
Zurück zum Zitat MC H, Shi M, Gillings N, Flores B, Takahashi M, Kuro OM, Moe OW (2017) Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 91:1104–1114CrossRef MC H, Shi M, Gillings N, Flores B, Takahashi M, Kuro OM, Moe OW (2017) Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 91:1104–1114CrossRef
20.
Zurück zum Zitat Farouk H, Kandil D, Kamel S, Elghoroury E, Elshamaa M, Sabry S, Galal A (2013) Effect of GSTM1 and GSTT1 deletions in the development of oxidative stress in children with chronic kidney disease. J Clin Basic Cardiol 16:1–5 Farouk H, Kandil D, Kamel S, Elghoroury E, Elshamaa M, Sabry S, Galal A (2013) Effect of GSTM1 and GSTT1 deletions in the development of oxidative stress in children with chronic kidney disease. J Clin Basic Cardiol 16:1–5
21.
Zurück zum Zitat Zhang H, Shi Y, Ma F, Wang I, Hou Y, Zhu Z (2017) Association of Klotho single nucleotide polymorphisms with cardiovascular diseases: a systematic review and meta-analysis. Int J Clin Exp Med 10:5721–5741 Zhang H, Shi Y, Ma F, Wang I, Hou Y, Zhu Z (2017) Association of Klotho single nucleotide polymorphisms with cardiovascular diseases: a systematic review and meta-analysis. Int J Clin Exp Med 10:5721–5741
22.
Zurück zum Zitat MC H, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, Shelton J, Amaral AP, Faul C, Taniguchi M, Wolf M, Brand M, Takahashi M, Kuro OM, Hill JA, Moe OW (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26:1290–1302CrossRef MC H, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, Shelton J, Amaral AP, Faul C, Taniguchi M, Wolf M, Brand M, Takahashi M, Kuro OM, Hill JA, Moe OW (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26:1290–1302CrossRef
23.
Zurück zum Zitat Liu F, Wu S, Ren H, Gu J (2011) Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 13:254–262CrossRefPubMed Liu F, Wu S, Ren H, Gu J (2011) Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 13:254–262CrossRefPubMed
24.
Zurück zum Zitat Elshamaa M, Sabry S, Badr A, El-Ahmady M, Elghoroury EA, Thabet EH, Kandil D, Kamel S (2011) Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with chronic kidney disease. Blood Coagul Fibrinolysis 22:487–492CrossRefPubMed Elshamaa M, Sabry S, Badr A, El-Ahmady M, Elghoroury EA, Thabet EH, Kandil D, Kamel S (2011) Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with chronic kidney disease. Blood Coagul Fibrinolysis 22:487–492CrossRefPubMed
25.
Zurück zum Zitat Kobayashi S (2016) Cardiovascular events in chronic kidney disease (CKD)—an importance of vascular calcification and microcirculatory impairment. Ren Replace Ther 2:55CrossRef Kobayashi S (2016) Cardiovascular events in chronic kidney disease (CKD)—an importance of vascular calcification and microcirculatory impairment. Ren Replace Ther 2:55CrossRef
26.
Zurück zum Zitat Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL (2012) Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3:1238CrossRefPubMedPubMedCentral Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL (2012) Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3:1238CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, Olson EN (2006) TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest 116:3114–3126CrossRefPubMedPubMedCentral Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, Olson EN (2006) TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest 116:3114–3126CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Zou Q, Zhang C, Guo Y (2015) TRPC3 and TRPC6 contribute to the pathogenesis of hypertension. Am J Mol Biol 5:124–133CrossRef Zou Q, Zhang C, Guo Y (2015) TRPC3 and TRPC6 contribute to the pathogenesis of hypertension. Am J Mol Biol 5:124–133CrossRef
29.
Zurück zum Zitat Agabiti-Rosei E, Muiesan ML (2005) Pathophysiology and treatment of hypertensive left ventricular hypertrophy. Dialogues Cardiovasc Med 10:3–18 Agabiti-Rosei E, Muiesan ML (2005) Pathophysiology and treatment of hypertensive left ventricular hypertrophy. Dialogues Cardiovasc Med 10:3–18
30.
Zurück zum Zitat Rhee EJ, KW O, Yun EJ, Jung CH, Lee WY, Kim SW, Baek KH, Kang MI, Park SW (2006) Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. J Endocrinol Investig 29:613–618CrossRef Rhee EJ, KW O, Yun EJ, Jung CH, Lee WY, Kim SW, Baek KH, Kang MI, Park SW (2006) Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. J Endocrinol Investig 29:613–618CrossRef
31.
Zurück zum Zitat Ko GJ, Lee YM, Lee EA, Lee JE, Bae SY, Park SW, Park MS, Pyo HJ, Kwon YJ, WDPA (2013) The association of Klotho gene polymorphism with the mortality of patients on maintenance dialysis. Clin Nephrol 80:263–269CrossRefPubMed Ko GJ, Lee YM, Lee EA, Lee JE, Bae SY, Park SW, Park MS, Pyo HJ, Kwon YJ, WDPA (2013) The association of Klotho gene polymorphism with the mortality of patients on maintenance dialysis. Clin Nephrol 80:263–269CrossRefPubMed
32.
Zurück zum Zitat Ko GJ, Lee EA, Jeon US, Pyo HJ, Chin HJ, Chae DW, Kim S, Kwon YJ (2012) The association of Klotho polymorphism with disease progression and mortality in IgA nephropathy. Kidney Blood Press Res 36:191–199CrossRefPubMed Ko GJ, Lee EA, Jeon US, Pyo HJ, Chin HJ, Chae DW, Kim S, Kwon YJ (2012) The association of Klotho polymorphism with disease progression and mortality in IgA nephropathy. Kidney Blood Press Res 36:191–199CrossRefPubMed
Metadaten
Titel
Klotho G-395A gene polymorphism: impact on progression of end-stage renal disease and development of cardiovascular complications in children on dialysis
verfasst von
Eman A. Elghoroury
Fatina I. Fadel
Manal F. Elshamaa
Dina Kandil
Doaa M. Salah
Marwa M. El-Sonbaty
Hebatallah Farouk
Mona Raafat
Soha Nasr
Publikationsdatum
08.01.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
Pediatric Nephrology / Ausgabe 6/2018
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-017-3877-z

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