Skip to main content
Top
Published in: BMC Nephrology 1/2022

Open Access 01-12-2022 | Diabetic Nephropathy | Research

Association of significantly elevated plasma levels of NGAL and IGFBP4 in patients with diabetic nephropathy

Authors: Hamad Ali, Mohamed Abu-Farha, Eman Alshawaf, Sriraman Devarajan, Yousif Bahbahani, Irina Al-Khairi, Preethi Cherian, Zahra Alsairafi, Vidya Vijayan, Fahd Al-Mulla, Abdulnabi Al Attar, Jehad Abubaker

Published in: BMC Nephrology | Issue 1/2022

Login to get access

Abstract

Background

Diabetic nephropathy (DN) is a type of progressive kidney disease affecting approximately 40% of patients with diabetes. Current DN diagnostic criteria predominantly rely on albuminuria and serum creatinine (sCr) levels. However, the specificity and reliability of both markers are limited. Hence, reliable biomarkers are required for early diagnosis to effectively manage DN progression.

Methods

In this study, a cohort of 159 individuals were clinically evaluated and the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 were determined using Multiplexing Assays. Additionally, the association between the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 in patients with DN were compared to those in patients with T2D without kidney disease and control participants.

Results

Circulating level of NGAL were significantly higher in people with DN compared to people with T2D and non-diabetic groups (92.76 ± 7.5, 57.22 ± 8.7, and 52.47 ± 2.9 mg/L, respectively; p <  0.0001). IGFBP-4 showed a similar pattern, where it was highest in people with DN (795.61 ng/ml ±130.7) compared to T2D and non-diabetic people (374.56 ng/ml ±86.8, 273.06 ng/ml ±27.8 respectively, ANOVA p <  0.01). The data from this study shows a significant positive correlation between NGAL and IGFBP-4 in people with DN (ρ = .620, p <  0.005). IGFBP-4 also correlated positively with creatinine level and negatively with eGFR, in people with DN supporting its involvement in DN.

Conclusion

The data from this study shows a parallel increase in the plasma levels of NGAL and IGFBP-4 in DN. This highlights the potential to use these markers for early diagnosis of DN.
Appendix
Available only for authorised users
Literature
1.
go back to reference Rheinberger M, Boger CA. Diabetic nephropathy: new insights into diagnosis, prevention and treatment. Dtsch Med Wochenschr. 2014;139(14):704–6.CrossRef Rheinberger M, Boger CA. Diabetic nephropathy: new insights into diagnosis, prevention and treatment. Dtsch Med Wochenschr. 2014;139(14):704–6.CrossRef
2.
go back to reference AlSahow A, AlHelal B, Alyousef A, AlQallaf A, Marzouq A, Nawar H, Fanous G, Abdelaty M, Bahbahani Y, AlRajab H, et al. Renal data from the Arab world dialysis in Kuwait: 2013-2019. Saudi J Kidney Dis Transpl. 2020;31(4):826–30.CrossRef AlSahow A, AlHelal B, Alyousef A, AlQallaf A, Marzouq A, Nawar H, Fanous G, Abdelaty M, Bahbahani Y, AlRajab H, et al. Renal data from the Arab world dialysis in Kuwait: 2013-2019. Saudi J Kidney Dis Transpl. 2020;31(4):826–30.CrossRef
3.
go back to reference Rossing P, Persson F, Frimodt-Moller M. Prognosis and treatment of diabetic nephropathy: recent advances and perspectives. Nephrol Ther. 2018;14(Suppl 1):S31–7.CrossRef Rossing P, Persson F, Frimodt-Moller M. Prognosis and treatment of diabetic nephropathy: recent advances and perspectives. Nephrol Ther. 2018;14(Suppl 1):S31–7.CrossRef
4.
go back to reference Satirapoj B. Tubulointerstitial biomarkers for diabetic nephropathy. J Diabetes Res. 2018;2018:2852398–8.CrossRef Satirapoj B. Tubulointerstitial biomarkers for diabetic nephropathy. J Diabetes Res. 2018;2018:2852398–8.CrossRef
5.
go back to reference Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA consensus conference. Am J Kidney Dis. 2014;64(4):510–33.CrossRef Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA consensus conference. Am J Kidney Dis. 2014;64(4):510–33.CrossRef
6.
go back to reference Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev. 2017;33(2). Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev. 2017;33(2).
7.
go back to reference Qiu X, Liu C, Ye Y, Li H, Chen Y, Fu Y, et al. The diagnostic value of serum creatinine and cystatin c in evaluating glomerular filtration rate in patients with chronic kidney disease: a systematic literature review and meta-analysis. Oncotarget. 2017;8(42):72985–99.CrossRef Qiu X, Liu C, Ye Y, Li H, Chen Y, Fu Y, et al. The diagnostic value of serum creatinine and cystatin c in evaluating glomerular filtration rate in patients with chronic kidney disease: a systematic literature review and meta-analysis. Oncotarget. 2017;8(42):72985–99.CrossRef
8.
go back to reference Alaini A, Malhotra D, Rondon-Berrios H, Argyropoulos CP, Khitan ZJ, Raj DSC, et al. Establishing the presence or absence of chronic kidney disease: uses and limitations of formulas estimating the glomerular filtration rate. World J Methodol. 2017;7(3):73–92.CrossRef Alaini A, Malhotra D, Rondon-Berrios H, Argyropoulos CP, Khitan ZJ, Raj DSC, et al. Establishing the presence or absence of chronic kidney disease: uses and limitations of formulas estimating the glomerular filtration rate. World J Methodol. 2017;7(3):73–92.CrossRef
9.
go back to reference Delanaye P, Cavalier E, Pottel H. Serum creatinine: not so simple! Nephron. 2017;136(4):302–8.CrossRef Delanaye P, Cavalier E, Pottel H. Serum creatinine: not so simple! Nephron. 2017;136(4):302–8.CrossRef
10.
go back to reference Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scand J Clin Lab Invest Suppl. 2008;241:89–94.CrossRef Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scand J Clin Lab Invest Suppl. 2008;241:89–94.CrossRef
11.
go back to reference Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 1993;268(14):10425–32.CrossRef Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 1993;268(14):10425–32.CrossRef
12.
go back to reference Ntrinias T, Papasotiriou M, Balta L, Kalavrizioti D, Vamvakas S, Papachristou E, et al. Biomarkers in progressive chronic kidney disease. Still a long way to go. PRILOZI. 2019;40(3):27–39.CrossRef Ntrinias T, Papasotiriou M, Balta L, Kalavrizioti D, Vamvakas S, Papachristou E, et al. Biomarkers in progressive chronic kidney disease. Still a long way to go. PRILOZI. 2019;40(3):27–39.CrossRef
13.
go back to reference Moschen AR, Adolph TE, Gerner RR, Wieser V, Tilg H. Lipocalin-2: a master mediator of intestinal and metabolic inflammation. Trends Endocrinol Metab. 2017;28(5):388–97.CrossRef Moschen AR, Adolph TE, Gerner RR, Wieser V, Tilg H. Lipocalin-2: a master mediator of intestinal and metabolic inflammation. Trends Endocrinol Metab. 2017;28(5):388–97.CrossRef
14.
go back to reference Parmar T, Parmar VM, Perusek L, Georges A, Takahashi M, Crabb JW, et al. Lipocalin 2 plays an important role in regulating inflammation in retinal degeneration. J Immunol. 2018;200(9):3128–41.CrossRef Parmar T, Parmar VM, Perusek L, Georges A, Takahashi M, Crabb JW, et al. Lipocalin 2 plays an important role in regulating inflammation in retinal degeneration. J Immunol. 2018;200(9):3128–41.CrossRef
15.
go back to reference Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, Chrousos GP, Papassotiriou I. Biomarkers of diabetic nephropathy: a 2017 update. Crit Rev Clin Lab Sci. 2017;54(5):326–42.CrossRef Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, Chrousos GP, Papassotiriou I. Biomarkers of diabetic nephropathy: a 2017 update. Crit Rev Clin Lab Sci. 2017;54(5):326–42.CrossRef
16.
go back to reference Wu J, Shao X, Lu K, Zhou J, Ren M, Xie X, et al. Urinary RBP and NGAL levels are associated with nephropathy in patients with type 2 diabetes. Cell Physiol Biochem. 2017;42(2):594–602.CrossRef Wu J, Shao X, Lu K, Zhou J, Ren M, Xie X, et al. Urinary RBP and NGAL levels are associated with nephropathy in patients with type 2 diabetes. Cell Physiol Biochem. 2017;42(2):594–602.CrossRef
17.
go back to reference Papadopoulou-Marketou N, Margeli A, Papassotiriou I, Chrousos GP, Kanaka-Gantenbein C, Wahlberg J. NGAL as an early predictive marker of diabetic nephropathy in children and young adults with type 1 diabetes mellitus. J Diabetes Res. 2017;2017:7526919.CrossRef Papadopoulou-Marketou N, Margeli A, Papassotiriou I, Chrousos GP, Kanaka-Gantenbein C, Wahlberg J. NGAL as an early predictive marker of diabetic nephropathy in children and young adults with type 1 diabetes mellitus. J Diabetes Res. 2017;2017:7526919.CrossRef
18.
go back to reference Oh Y. The insulin-like growth factor system in chronic kidney disease: pathophysiology and therapeutic opportunities. Kidney Res Clin Pract. 2012;31(1):26–37.CrossRef Oh Y. The insulin-like growth factor system in chronic kidney disease: pathophysiology and therapeutic opportunities. Kidney Res Clin Pract. 2012;31(1):26–37.CrossRef
19.
go back to reference Vasylyeva TL, Ferry RJ Jr. Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy. Diabetes Res Clin Pract. 2007;76(2):177–86.CrossRef Vasylyeva TL, Ferry RJ Jr. Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy. Diabetes Res Clin Pract. 2007;76(2):177–86.CrossRef
20.
go back to reference Wedrychowicz A, Dziatkowiak H, Nazim J, Sztefko K. Insulin-like growth factor-1 and its binding proteins, IGFBP-1 and IGFBP-3, in adolescents with type-1 diabetes mellitus and microalbuminuria. Horm Res. 2005;63(5):245–51.PubMed Wedrychowicz A, Dziatkowiak H, Nazim J, Sztefko K. Insulin-like growth factor-1 and its binding proteins, IGFBP-1 and IGFBP-3, in adolescents with type-1 diabetes mellitus and microalbuminuria. Horm Res. 2005;63(5):245–51.PubMed
21.
go back to reference Haneda M, Utsunomiya K, Koya D, Babazono T, Moriya T, Makino H, et al. A new classification of diabetic nephropathy 2014: a report from joint committee on diabetic nephropathy. J Diabetes Invest. 2015;6(2):242–6.CrossRef Haneda M, Utsunomiya K, Koya D, Babazono T, Moriya T, Makino H, et al. A new classification of diabetic nephropathy 2014: a report from joint committee on diabetic nephropathy. J Diabetes Invest. 2015;6(2):242–6.CrossRef
22.
go back to reference Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med. 1999;130(6):461–70.CrossRef Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med. 1999;130(6):461–70.CrossRef
23.
go back to reference Pennemans V, Rigo JM, Faes C, Reynders C, Penders J, Swennen Q. Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue? Clin Chem Lab Med. 2013 Sep;51(9):1795–802. https://doi.org/10.1515/cclm-2013-0157 PMID: 23648635.)10.1515/cclm-2013-0157. PMID: 23648635.).CrossRefPubMed Pennemans V, Rigo JM, Faes C, Reynders C, Penders J, Swennen Q. Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue? Clin Chem Lab Med. 2013 Sep;51(9):1795–802. https://​doi.​org/​10.​1515/​cclm-2013-0157 PMID: 23648635.)10.1515/cclm-2013-0157. PMID: 23648635.).CrossRefPubMed
24.
25.
go back to reference Cao Z, Cooper ME. Pathogenesis of diabetic nephropathy. J Diabetes Invest. 2011;2(4):243–7.CrossRef Cao Z, Cooper ME. Pathogenesis of diabetic nephropathy. J Diabetes Invest. 2011;2(4):243–7.CrossRef
26.
go back to reference Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008;3(3):665–73.CrossRef Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008;3(3):665–73.CrossRef
27.
go back to reference Khawaja S, Jafri L, Siddiqui I, Hashmi M, Ghani F. The utility of neutrophil gelatinase-associated Lipocalin (NGAL) as a marker of acute kidney injury (AKI) in critically ill patients. Biomarker Res. 2019;7:4.CrossRef Khawaja S, Jafri L, Siddiqui I, Hashmi M, Ghani F. The utility of neutrophil gelatinase-associated Lipocalin (NGAL) as a marker of acute kidney injury (AKI) in critically ill patients. Biomarker Res. 2019;7:4.CrossRef
28.
go back to reference Wasung ME, Chawla LS, Madero M. Biomarkers of renal function, which and when? Clin Chim Acta. 2015;438:350–7.CrossRef Wasung ME, Chawla LS, Madero M. Biomarkers of renal function, which and when? Clin Chim Acta. 2015;438:350–7.CrossRef
29.
go back to reference Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(2):337–44.CrossRef Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(2):337–44.CrossRef
30.
go back to reference Ulinski T, Mohan S, Kiepe D, Blum WF, Wingen AM, Mehls O, et al. Members of the German study group for growth hormone treatment in chronic renal F: serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. Pediatr Nephrol. 2000;14(7):589–97.CrossRef Ulinski T, Mohan S, Kiepe D, Blum WF, Wingen AM, Mehls O, et al. Members of the German study group for growth hormone treatment in chronic renal F: serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. Pediatr Nephrol. 2000;14(7):589–97.CrossRef
31.
go back to reference Al Shawaf E, Abu-Farha M, Devarajan S, Alsairafi Z, Al-Khairi I, Cherian P, et al. ANGPTL4: a predictive marker for diabetic nephropathy. J Diabetes Res. 2019;2019:4943191–1.CrossRef Al Shawaf E, Abu-Farha M, Devarajan S, Alsairafi Z, Al-Khairi I, Cherian P, et al. ANGPTL4: a predictive marker for diabetic nephropathy. J Diabetes Res. 2019;2019:4943191–1.CrossRef
32.
go back to reference Wu T, Xie C, Han J, Ye Y, Singh S, Zhou J, et al. Insulin-like growth factor binding Protein-4 as a marker of chronic lupus nephritis. PLoS One. 2016;11(3):e0151491.CrossRef Wu T, Xie C, Han J, Ye Y, Singh S, Zhou J, et al. Insulin-like growth factor binding Protein-4 as a marker of chronic lupus nephritis. PLoS One. 2016;11(3):e0151491.CrossRef
Metadata
Title
Association of significantly elevated plasma levels of NGAL and IGFBP4 in patients with diabetic nephropathy
Authors
Hamad Ali
Mohamed Abu-Farha
Eman Alshawaf
Sriraman Devarajan
Yousif Bahbahani
Irina Al-Khairi
Preethi Cherian
Zahra Alsairafi
Vidya Vijayan
Fahd Al-Mulla
Abdulnabi Al Attar
Jehad Abubaker
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2022
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-022-02692-z

Other articles of this Issue 1/2022

BMC Nephrology 1/2022 Go to the issue