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Published in: Pediatric Nephrology 4/2016

01-04-2016 | Original Article

Distinct urinary lipid profile in children with focal segmental glomerulosclerosis

Authors: Elif Erkan, Xueheng Zhao, Kenneth Setchell, Prasad Devarajan

Published in: Pediatric Nephrology | Issue 4/2016

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Abstract

Background

Focal segmental glomerulosclerosis (FSGS) accounts for the majority of new-onset end-stage renal disease (ESRD) during adolescence. FSGS treatment is a great challenge for pediatric nephrologists due to intertwined molecular pathways underlining its complex pathophysiology. There is emerging evidence showing that perturbed lipid metabolism plays a role in the pathophysiology of FSGS.

Methods

We postulate that the nephrotic milieu in FSGS differs from minimal change disease (MCD) and that urinary lipidomics can be used as a tool for early diagnosis of FSGS. We explored the urinary lipid profile of patients with FSGS and MCD using an unbiased metabolomics approach.

Results

We discovered a unique lipid signature characterized by increased concentration of fatty acid (FA) and lysophosphatidylcholines (LPC) and a decrease in urinary concentration of phosphatidylcholine (PC) in patients with FSGS. These findings indicate increased metabolism of membrane phospholipid PC by phospholipase A2 (PLA2), resulting in higher urinary concentrations of LPC and FA.

Conclusions

We propose that increased PC by-products can be used as a biomarker to diagnose FSGS and shed light on the mechanism of tubular and podocyte damage. Validation of identified urinary lipids as a biomarker in predicting the diagnosis and progression of FSGS in a larger patient population is warranted.
Literature
1.
go back to reference (2003) USRDS: United States Renal Data System. Am J Kidney Dis 42:1–230 (2003) USRDS: United States Renal Data System. Am J Kidney Dis 42:1–230
2.
go back to reference Ferris ME, Gipson DS, Kimmel PL, Eggers PW (2006) Trends in treatment and outcomes of survival of adolescents initiating end-stage renal disease care in the United States of America. Pediatr Nephrol 21:1020–1026CrossRefPubMed Ferris ME, Gipson DS, Kimmel PL, Eggers PW (2006) Trends in treatment and outcomes of survival of adolescents initiating end-stage renal disease care in the United States of America. Pediatr Nephrol 21:1020–1026CrossRefPubMed
3.
go back to reference Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Johansen K, Kasiske B, Kutner N, Liu J, St Peter W, Guo H, Gustafson S, Heubner B, Lamb K, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Thompson B, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Daniels F, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L (2012) United States renal data system 2011 annual data report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis 59(Suppl 1):A7, e1-420CrossRefPubMed Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Johansen K, Kasiske B, Kutner N, Liu J, St Peter W, Guo H, Gustafson S, Heubner B, Lamb K, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Thompson B, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Daniels F, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L (2012) United States renal data system 2011 annual data report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis 59(Suppl 1):A7, e1-420CrossRefPubMed
4.
go back to reference McDonald SP, Craig JC (2004) Long-term survival of children with end-stage renal disease. N Engl J Med 350:2654–2662CrossRefPubMed McDonald SP, Craig JC (2004) Long-term survival of children with end-stage renal disease. N Engl J Med 350:2654–2662CrossRefPubMed
6.
go back to reference Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, Arthur JM (2007) Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol 18:913–922PubMedCentralCrossRefPubMed Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, Arthur JM (2007) Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol 18:913–922PubMedCentralCrossRefPubMed
7.
go back to reference Khurana M, Traum AZ, Aivado M, Wells MP, Guerrero M, Grall F, Libermann TA, Schachter AD (2006) Urine proteomic profiling of pediatric nephrotic syndrome. Pediatr Nephrol 21:1257–1265PubMedCentralCrossRefPubMed Khurana M, Traum AZ, Aivado M, Wells MP, Guerrero M, Grall F, Libermann TA, Schachter AD (2006) Urine proteomic profiling of pediatric nephrotic syndrome. Pediatr Nephrol 21:1257–1265PubMedCentralCrossRefPubMed
9.
go back to reference Merscher S, Fornoni A (2014) Podocyte pathology and nephropathy - sphingolipids in glomerular diseases. Front Endocrinol 5:1–11 Merscher S, Fornoni A (2014) Podocyte pathology and nephropathy - sphingolipids in glomerular diseases. Front Endocrinol 5:1–11
10.
go back to reference Ghiggeri GM, Ginevri F, Candiano G, Oleggini R, Perfumo F, Queirolo C, Gusmano R (1987) Characterization of cationic albumin in minimal change nephropathy. Kidney Int 32:547–553CrossRefPubMed Ghiggeri GM, Ginevri F, Candiano G, Oleggini R, Perfumo F, Queirolo C, Gusmano R (1987) Characterization of cationic albumin in minimal change nephropathy. Kidney Int 32:547–553CrossRefPubMed
11.
go back to reference Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637PubMedCentralCrossRefPubMed Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637PubMedCentralCrossRefPubMed
12.
go back to reference Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D (2008) Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res 49:1137–1146PubMedCentralCrossRefPubMed Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D (2008) Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res 49:1137–1146PubMedCentralCrossRefPubMed
13.
go back to reference Kind T, Liu K-H, Lee DY, DeFelice B, Meissen JK, Fiehn O (2013) LipidBlast in silico tandem mass spectrometry database for lipid identification. Nat Methods 10:755–758PubMedCentralCrossRefPubMed Kind T, Liu K-H, Lee DY, DeFelice B, Meissen JK, Fiehn O (2013) LipidBlast in silico tandem mass spectrometry database for lipid identification. Nat Methods 10:755–758PubMedCentralCrossRefPubMed
14.
go back to reference Veselkov KA, Vingara LK, Masson P, Robinette SL, Want E, Li JV, Barton RH, Boursier-Neyret C, Walther B, Ebbels TM, Pelczer I, Holmes E, Lindon JC, Nicholson JK (2011) Optimized preprocessing of ultra-performance liquid chromatography/mass spectrometry urinary metabolic profiles for improved information recovery. Anal Chem 83:5864–5872CrossRefPubMed Veselkov KA, Vingara LK, Masson P, Robinette SL, Want E, Li JV, Barton RH, Boursier-Neyret C, Walther B, Ebbels TM, Pelczer I, Holmes E, Lindon JC, Nicholson JK (2011) Optimized preprocessing of ultra-performance liquid chromatography/mass spectrometry urinary metabolic profiles for improved information recovery. Anal Chem 83:5864–5872CrossRefPubMed
15.
go back to reference Xia J, Mandal R, Sinelnikov IV, Broadhurst D, Wishart DS (2012) MetaboAnalyst 2.0--a comprehensive server for metabolomic data analysis. Nucleic Acids Res 40:W127–W133PubMedCentralCrossRefPubMed Xia J, Mandal R, Sinelnikov IV, Broadhurst D, Wishart DS (2012) MetaboAnalyst 2.0--a comprehensive server for metabolomic data analysis. Nucleic Acids Res 40:W127–W133PubMedCentralCrossRefPubMed
16.
go back to reference Suzuki Y, Fausto A, Hruska KA, Avioli LV (1987) Stimulation of phosphatidylcholine biosynthesis in diabetic hypertrophic kidneys. Endocrinology 120:595–601CrossRefPubMed Suzuki Y, Fausto A, Hruska KA, Avioli LV (1987) Stimulation of phosphatidylcholine biosynthesis in diabetic hypertrophic kidneys. Endocrinology 120:595–601CrossRefPubMed
17.
go back to reference Zhao YY, Cheng XL, Lin RC (2014) Lipidomics applications for discovering biomarkers of diseases in clinical chemistry. Int Rev Cell Mol Biol 313:1–26CrossRefPubMed Zhao YY, Cheng XL, Lin RC (2014) Lipidomics applications for discovering biomarkers of diseases in clinical chemistry. Int Rev Cell Mol Biol 313:1–26CrossRefPubMed
18.
go back to reference Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U (2014) Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 55:561–572PubMedCentralCrossRefPubMed Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U (2014) Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 55:561–572PubMedCentralCrossRefPubMed
19.
go back to reference Stadler K, Goldberg IJ, Susztak K (2015) The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr Diab Rep 15:40CrossRefPubMed Stadler K, Goldberg IJ, Susztak K (2015) The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr Diab Rep 15:40CrossRefPubMed
20.
go back to reference Martinez-Garcia C, Izquierdo A, Velagapudi V, Vivas Y, Velasco I, Campbell M, Burling K, Cava F, Ros M, Oresic M, Vidal-Puig A, Medina-Gomez G (2012) Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model. Dis Model Mech 5:636–648PubMedCentralCrossRefPubMed Martinez-Garcia C, Izquierdo A, Velagapudi V, Vivas Y, Velasco I, Campbell M, Burling K, Cava F, Ros M, Oresic M, Vidal-Puig A, Medina-Gomez G (2012) Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model. Dis Model Mech 5:636–648PubMedCentralCrossRefPubMed
21.
go back to reference Sas KM, Nair V, Byun J, Kayampilly P, Zhang H, Saha J, Brosius FC III, Kretzler M, Pennathur S (2015) Targeted lipidomic and transcriptomic analysis identifies dysregulated renal ceramide metabolism in a mouse model of diabetic kidney disease. J Proteom Bioinform S14 Sas KM, Nair V, Byun J, Kayampilly P, Zhang H, Saha J, Brosius FC III, Kretzler M, Pennathur S (2015) Targeted lipidomic and transcriptomic analysis identifies dysregulated renal ceramide metabolism in a mouse model of diabetic kidney disease. J Proteom Bioinform S14
22.
go back to reference Jia L, Wang C, Zhao S, Lu X, Xu G (2007) Metabolomic identification of potential phospholipid biomarkers for chronic glomerulonephritis by using high performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 860:134–140CrossRefPubMed Jia L, Wang C, Zhao S, Lu X, Xu G (2007) Metabolomic identification of potential phospholipid biomarkers for chronic glomerulonephritis by using high performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 860:134–140CrossRefPubMed
23.
go back to reference Dada N, Kim NW, Wolfert RL (2002) Lp-PLA2: an emerging biomarker of coronary heart disease. Expert Rev Mol Diagn 2:17–22CrossRefPubMed Dada N, Kim NW, Wolfert RL (2002) Lp-PLA2: an emerging biomarker of coronary heart disease. Expert Rev Mol Diagn 2:17–22CrossRefPubMed
24.
go back to reference Suchindran S, Rivedal D, Guyton JR, Milledge T, Gao X, Benjamin A, Rowell J, Ginsburg GS, McCarthy JJ (2010) Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study. PLoS Genet 6:e1000928PubMedCentralCrossRefPubMed Suchindran S, Rivedal D, Guyton JR, Milledge T, Gao X, Benjamin A, Rowell J, Ginsburg GS, McCarthy JJ (2010) Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study. PLoS Genet 6:e1000928PubMedCentralCrossRefPubMed
25.
go back to reference Madesh M, Balasubramanian KA (1997) Activation of liver mitochondrial phospholipase A2 by superoxide. Arch Biochem Biophys 346:187–192CrossRefPubMed Madesh M, Balasubramanian KA (1997) Activation of liver mitochondrial phospholipase A2 by superoxide. Arch Biochem Biophys 346:187–192CrossRefPubMed
26.
go back to reference Kohjimoto Y, Honeyman TW, Jonassen J, Gravel K, Kennington L, Scheid CR (2000) Phospholipase A2 mediates immediate early genes in cultured renal epithelial cells: possible role of lysophospholipid. Kidney Int 58:638–646CrossRefPubMed Kohjimoto Y, Honeyman TW, Jonassen J, Gravel K, Kennington L, Scheid CR (2000) Phospholipase A2 mediates immediate early genes in cultured renal epithelial cells: possible role of lysophospholipid. Kidney Int 58:638–646CrossRefPubMed
27.
go back to reference Zager RA, Sacks BM, Burkhart KM, Williams AC (1999) Plasma membrane phospholipid integrity and orientation during hypoxic and toxic proximal tubular attack. Kidney Int 56:104–117CrossRefPubMed Zager RA, Sacks BM, Burkhart KM, Williams AC (1999) Plasma membrane phospholipid integrity and orientation during hypoxic and toxic proximal tubular attack. Kidney Int 56:104–117CrossRefPubMed
28.
go back to reference Nakamura H, Nemenoff RA, Gronich JH, Bonventre JV (1991) Subcellular characteristics of phospholipase A2 activity in the rat kidney. Enhanced cytosolic, mitochondrial, and microsomal phospholipase A2 enzymatic activity after renal ischemia and reperfusion. J Clin Invest 87:1810–1818PubMedCentralCrossRefPubMed Nakamura H, Nemenoff RA, Gronich JH, Bonventre JV (1991) Subcellular characteristics of phospholipase A2 activity in the rat kidney. Enhanced cytosolic, mitochondrial, and microsomal phospholipase A2 enzymatic activity after renal ischemia and reperfusion. J Clin Invest 87:1810–1818PubMedCentralCrossRefPubMed
29.
go back to reference Nguyen VD, Cieslinski DA, Humes HD (1988) Importance of adenosine triphosphate in phospholipase A2-induced rabbit renal proximal tubule cell injury. J Clin Invest 82:1098–1105PubMedCentralCrossRefPubMed Nguyen VD, Cieslinski DA, Humes HD (1988) Importance of adenosine triphosphate in phospholipase A2-induced rabbit renal proximal tubule cell injury. J Clin Invest 82:1098–1105PubMedCentralCrossRefPubMed
30.
go back to reference Matthys E, Patel Y, Kreisberg J, Stewart JH, Venkatachalam M (1984) Lipid alterations induced by renal ischemia: pathogenic factor in membrane damage. Kidney Int 26:153–161CrossRefPubMed Matthys E, Patel Y, Kreisberg J, Stewart JH, Venkatachalam M (1984) Lipid alterations induced by renal ischemia: pathogenic factor in membrane damage. Kidney Int 26:153–161CrossRefPubMed
31.
go back to reference Hara S, Kobayashi N, Sakamoto K, Ueno T, Manabe S, Takashima Y, Hamada J, Pastan I, Fukamizu A, Matsusaka T, Nagata M (2015) Podocyte Injury-Driven Lipid Peroxidation Accelerates the Infiltration of Glomerular Foam Cells in Focal Segmental Glomerulosclerosis. Am J Pathol 185:2118–2131CrossRefPubMed Hara S, Kobayashi N, Sakamoto K, Ueno T, Manabe S, Takashima Y, Hamada J, Pastan I, Fukamizu A, Matsusaka T, Nagata M (2015) Podocyte Injury-Driven Lipid Peroxidation Accelerates the Infiltration of Glomerular Foam Cells in Focal Segmental Glomerulosclerosis. Am J Pathol 185:2118–2131CrossRefPubMed
32.
go back to reference Riederer M, Lechleitner M, Hrzenjak A, Koefeler H, Desoye G, Heinemann A, Frank S (2011) Endothelial lipase (EL) and EL-generated lysophosphatidylcholines promote IL-8 expression in endothelial cells. Atherosclerosis 214:338–344PubMedCentralCrossRefPubMed Riederer M, Lechleitner M, Hrzenjak A, Koefeler H, Desoye G, Heinemann A, Frank S (2011) Endothelial lipase (EL) and EL-generated lysophosphatidylcholines promote IL-8 expression in endothelial cells. Atherosclerosis 214:338–344PubMedCentralCrossRefPubMed
33.
go back to reference Matsumoto T, Kobayashi T, Kamata K (2007) Role of lysophosphatidylcholine (LPC) in atherosclerosis. Curr Med Chem 14:3209–3220CrossRefPubMed Matsumoto T, Kobayashi T, Kamata K (2007) Role of lysophosphatidylcholine (LPC) in atherosclerosis. Curr Med Chem 14:3209–3220CrossRefPubMed
34.
go back to reference Kume N, Gimbrone MA Jr (1994) Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest 93:907–911PubMedCentralCrossRefPubMed Kume N, Gimbrone MA Jr (1994) Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest 93:907–911PubMedCentralCrossRefPubMed
35.
go back to reference Sieber J, Jehle AW (2014) Free Fatty acids and their metabolism affect function and survival of podocytes. Front Endocrinol 5:186CrossRef Sieber J, Jehle AW (2014) Free Fatty acids and their metabolism affect function and survival of podocytes. Front Endocrinol 5:186CrossRef
Metadata
Title
Distinct urinary lipid profile in children with focal segmental glomerulosclerosis
Authors
Elif Erkan
Xueheng Zhao
Kenneth Setchell
Prasad Devarajan
Publication date
01-04-2016
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 4/2016
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-015-3239-7

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