1887
Volume 2025, Issue 1
  • E-ISSN: 2220-2749

Diabetic nephropathy (DN) represents one of the most severe complications associated with type 2 diabetes (T2D), often leading to kidney failure and significantly affecting patients’ quality of life. Early detection and monitoring of DN are essential to prevent its progression. Midkine and copeptin, two biomarkers associated with inflammatory and metabolic processes, have shown promise in reflecting the underlying changes associated with DN, thus offering hope for improved diagnosis and management. The objective of this study was to investigate the clinical relevance of midkine and copeptin levels in T2D patients and their associations with insulin resistance and albuminuria status, evaluating their potential as predictive tools to detect the progression of DN.

A case–control study was carried out with 360 participants, grouped into 90 healthy controls and T2D patients categorized by different stages of albuminuria (normoalbuminuric, microalbuminuric, and macroalbuminuric, with 90 individuals in each category). Serum levels of midkine, copeptin, fasting insulin, and other biochemical analytes were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR), while renal function was evaluated using the albumin–creatinine ratio (ACR) and the estimated glomerular filtration rate (eGFR).

Elevated levels of midkine and copeptin were found in T2D patients, with the highest levels observed in the macroalbuminuric group ( < 0.001). Both biomarkers were positively correlated with glycemic parameters (fasting glucose, HbA1c), insulin resistance (HOMA-IR), and markers of DN (ACR, eGFR) ( < 0.001). ROC (receiver operating characteristic) analysis showed strong diagnostic performance for both biomarkers, with midkine yielding an area under the curve (AUC) of 0.96 (95% CI: 0.94–0.99, sensitivity: 96.7%, specificity: 91.1%) and copeptin yielding an AUC of 0.98 (95% CI: 0.97–1.0, sensitivity: 97.8%, specificity: 88.9%). Multivariate linear regression analysis identified midkine ( = 0.039) and copeptin ( = 0.027) as significant predictors of albuminuria.

Serum levels of midkine and copeptin are elevated in T2D patients, with a strong association with the onset and progression of DN. These biomarkers may serve as early indicators for diabetic kidney disease, facilitating timely detection and management of renal complications. Their role in predicting insulin resistance and cardiovascular risk further underscores their potential as clinical tools for managing DN.

© 2025 The Author(s), licensee HBKU Press.
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References

  1. Reda S, Fawzy O, Sayed D, Mohamed G, Khidr EG. Inactive matrix gla protein in relation to renal and cardiac functions and cardiac valvular calcification among type 2 diabetes patients. Clin Med Insights Endocrinol Diabetes .2023Oct 14;(16):11795514231203862. https://doi.org/10.1177/11795514231203862
    [Google الباحث العلمي]
  2. Natesan V, Kim S-J. Diabetic nephropathy – a review of risk factors, progression, mechanism, and dietary management. Biomol Ther (Seoul) .2021Jul 1; 29:(4):365–72. https://doi.org/10.4062/biomolther.2020.204
    [Google الباحث العلمي]
  3. International Diabetes Federation. IDF Diabetes Atlas .9th ed. Brussels,Belgium:International Diabetes Federation;2019.Available from: https://diabetesatlas.org
    [Google الباحث العلمي]
  4. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol .2018Feb; 14:(2):88–98. https://doi.org/10.1038/nrendo.2017.151
    [Google الباحث العلمي]
  5. Nagib SN, Abdelwahab S, Amin GEE-D, Allam MF. What is the prevalence of chronic kidney disease among hypertensive non-diabetic Egyptian patients attending primary healthcare? Clin Exp Hypertens .2023Dec 31; 45:(1):2203411. https://doi.org/10.1080/10641963.2023.2203411
    [Google الباحث العلمي]
  6. Thipsawat S. Early detection of diabetic nephropathy in patient with type 2 diabetes mellitus: A review of the literature. Diab Vasc Dis Res .2021Nov-Dec; 18:(6):14791641211058856. https://doi.org/10.1177/14791641211058856
    [Google الباحث العلمي]
  7. Yang J, Liu Z. Mechanistic pathogenesis of endothelial dysfunction in diabetic nephropathy and retinopathy. Front Endocrinol (Lausanne) .2022May 25; 13:816400. https://doi.org/10.3389/fendo.2022.816400
    [Google الباحث العلمي]
  8. Viggiano D. Mechanisms of diabetic nephropathy not mediated by hyperglycemia. J Clin Med .2023Oct 30; 12:(21):6848. https://doi.org/10.3390/jcm12216848
    [Google الباحث العلمي]
  9. Carmichael J, Fadavi H, Ishibashi F, Shore AC, Tavakoli M. Advances in screening, early diagnosis and accurate staging of diabetic neuropathy. Front Endocrinol (Lausanne) .2021May 26; 12:671257. https://doi.org/10.3389/fendo.2021.671257
    [Google الباحث العلمي]
  10. Cai Y-Q, Lv Y, Mo Z-C, Lei J, Zhu J-L, Zhong Q-Q. Multiple pathophysiological roles of midkine in human disease. Cytokine .2020Nov; 135:155242. https://doi.org/10.1016/j.cyto.2020.155242
    [Google الباحث العلمي]
  11. Campbell VK, Gately RP, Krishnasamy R, Burg D, Robertson GR, Gray NA. Midkine and chronic kidney disease-associated multisystem organ dysfunctions. Nephrol Dial Transplant .2021Aug 27; 36:(9):1577–84. https://doi.org/10.1093/ndt/gfaa084
    [Google الباحث العلمي]
  12. Elshafei A, Abdalla G, El-Motaal OA, Salman T. Copeptin: A neuroendocrine biomarker in acute myocardial infarction. Ann Res Rev Biol .2013Jan; 3:(4):1040–54.Available from: https://www.researchgate.net/publication/309546591_Copeptin_A_neuroendocrine_biomarker_in_acute_myocardial_infarction
    [Google الباحث العلمي]
  13. Hammad R, Elshafei A, Khidr EG, El-Husseiny AA, Gomaa MH, Kotb HG, et al. Copeptin: A neuroendocrine biomarker of COVID-19 severity. Biomark Med .2022Jun; 16:(8):589–97. https://doi.org/10.2217/bmm-2021-1100
    [Google الباحث العلمي]
  14. Jalleh R, Torpy DJ. The emerging role of copeptin. Clin Biochem Rev .2021Feb; 42:(1):17–25. https://doi.org/10.33176/AACB-20-00001
    [Google الباحث العلمي]
  15. El-Soudany NN, Bessa SSE-D, Morad HA, Selim AAM. Plasma copeptin level in type 2 diabetic patients and its role in diabetic nephropathy. Egypt J Intern Med .2023Apr; 35:(1):31. https://doi.org/10.1186/s43162-023-00207-2
    [Google الباحث العلمي]
  16. Salgado ALFdA, de Carvalho L, Oliveira AC, dos Santos VN, Vieira JG, Parise ER. Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals. Arq Gastroenterol .2010Apr-Jun; 47:(2):165–9. https://doi.org/10.1590/s0004-28032010000200009
    [Google الباحث العلمي]
  17. Levin A, Ahmed SB, Carrero JJ, Foster B, Francis A, Hall RK, et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: Known knowns and known unknowns. Kidney Int .2024Apr; 105:(4):684–701. https://doi.org/10.1016/j.kint.2023.10.016
    [Google الباحث العلمي]
  18. van den Brand JAJG, van Boekel GAJ, Willems HL, Kiemeney LALM, den Heijer M, Wetzels JFM. Introduction of the CKD-EPI equation to estimate glomerular filtration rate in a Caucasian population. Nephrol Dial Transplant .2011Oct; 26:(10):3176–81. https://doi.org/10.1093/ndt/gfr003
    [Google الباحث العلمي]
  19. Zhu F-X, Wu H-L, Tu K-S, Chen J-X, Zhang M, Shi C. Serum levels of copeptin are associated with type 2 diabetes and diabetic complications in Chinese population. J Diabetes Complications .2016Nov–Dec; 30:(8):1566–70. https://doi.org/10.1016/j.jdiacomp.2016.07.017
    [Google الباحث العلمي]
  20. Asferg CL, Andersen UB, Linneberg A, Goetze JP, Jeppesen JL. Copeptin, a surrogate marker for arginine vasopressin secretion, is associated with higher glucose and insulin concentrations but not higher blood pressure in obese men. Diabet Med .2014Jun; 31:(6):728–32. https://doi.org/10.1111/dme.12411
    [Google الباحث العلمي]
  21. Metwalley KA, Farghaly HS, Gabri MF, Abdel-Aziz SM, Ismail AM, Raafat DM, et al. Midkine: Utility as a predictor of early diabetic nephropathy in children with type 1 diabetes mellitus. J Clin Res Pediatr Endocrinol .2021Aug 23; 13:(3):293–99. https://doi.org/10.4274/jcrpe.galenos.2021.2020.0303
    [Google الباحث العلمي]
  22. Harkin C, Cobice D, Brockbank S, Bolton S, Johnston F, Strzelecka A, et al. Biomarkers for detecting kidney dysfunction in type-2 diabetics and diabetic nephropathy subjects: A case–control study to identify potential biomarkers of DN to stratify risk of progression in T2D patients. Front Endocrinol (Lausanne) .2022Jun 29: 13:887237. https://doi.org/10.3389/fendo.2022.887237
    [Google الباحث العلمي]
  23. Mohamed ON, Mohamed MI, Kamel SF, Dardeer AM, Shehata S, Mohammed HMH, et al. Serum midkine level and its association with subclinical coronary artery calcification and carotid atherosclerosis in chronic kidney disease. BMC Nephrol .2025Apr 10; 26:(1):185. https://doi.org/10.1186/s12882-025-04066-7
    [Google الباحث العلمي]
  24. Arroyo JP, Akwo EA, Terker AS, Alsouqi A, Bhave G, Harris RC, et al. Peripheral insulin resistance is associated with copeptin in patients with chronic kidney disease. Kidney 360 .2021Jul 8; 2:(9):1434–40. https://doi.org/10.34067/KID.0002622021
    [Google الباحث العلمي]
  25. Murat B, Devost D, Andrés M, Mion J, Boulay V, Corbani M, et al. V1b and CRHR1 receptor heterodimerization mediates synergistic biological actions of vasopressin and CRH. Mol Endocrinol .2012Mar; 26:(3):502–20. https://doi.org/10.1210/me.2011-1202
    [Google الباحث العلمي]
  26. Tanoue A, Ito S, Honda K, Oshikawa S, Kitagawa Y, Koshimizu T-A, et al. The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. J Clin Invest .2004Jan; 113:(2):302–9. https://doi.org/10.1172/JCI19656
    [Google الباحث العلمي]
  27. Watts JA, Arroyo JP. Rethinking vasopressin: New insights into vasopressin signaling and its implications. Kidney 360 .2023Aug 1; 4:(8):1174–80. https://doi.org/10.34067/KID.0000000000000194
    [Google الباحث العلمي]
  28. Student J, Sowers J, Lockette W. Thirsty for fructose: Arginine vasopressin, fructose, and the pathogenesis of metabolic and renal disease. Front Cardiovasc Med .2022May 17; 9:883365. https://doi.org/10.3389/fcvm.2022.883365
    [Google الباحث العلمي]
  29. Wannamethee SG, Welsh P, Papacosta O, Lennon L, Whincup PH, Sattar N. Copeptin, insulin resistance, and risk of incident diabetes in older men. J Clin Endocrinol Metab .2015Sep; 100:(9):3332–9. https://doi.org/10.1210/JC.2015-2362
    [Google الباحث العلمي]
  30. Majaj M, Weckbach LT. Midkine—A novel player in cardiovascular diseases. Front Cardiovasc Med .2022Sep 20: 9:1003104. https://doi.org/10.3389/fcvm.2022.1003104
    [Google الباحث العلمي]
  31. Fan N, Sun H, Wang Y, Zhang L, Xia Z, Peng L, et al. Midkine, a potential link between obesity and insulin resistance. PLoS One .2014Feb 7; 9:(2):e88299. https://doi.org/10.1371/journal.pone.0088299
    [Google الباحث العلمي]
  32. Karadeniz Z, Aynacioglu AS, Bilir A, Tuna MY. Inhibition of midkine by metformin can contribute to its anticancer effects in malignancies: A proposal mechanism of action of metformin in context of endometrial cancer prevention and therapy. Med Hypotheses .2020Jan: 134:109420. https://doi.org/10.1016/j.mehy.2019.109420
    [Google الباحث العلمي]
  33. Divya, Khan S, Khan MM, Khare R, Ahmad MK, Ahmad A, et al. Role of serum copeptin as potential biomarkers for chronic kidney disease patients with and without type 2 diabetes mellitus. Int J Chem Biochem Sci .2024; 25:(15):386–94.Available from: https://www.researchgate.net/publication/379341079_Role_of_Serum_Copeptin_as_Potential_Biomarkers_for_Chronic_Kidney_Disease_Patients_with_and_without_Type_2_Diabetes_Mellitus
    [Google الباحث العلمي]
  34. El Boustany R, Tasevska I, Meijer E, Kieneker LM, Enhörning S, Lefèvre G, et al. Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population. JCI Insight .2018Jul 12; 3:(13):e121479. https://doi.org/10.1172/jci.insight.121479
    [Google الباحث العلمي]
  35. Parizadeh SM, Ghandehari M, Parizadeh MR, Ferns GA, Ghayour-Mobarhan M, Avan A, et al. The diagnostic and prognostic value of copeptin in cardiovascular disease, current status, and prospective. J Cell Biochem .2018Nov; 119:(10):7913–23. https://doi.org/10.1002/jcb.27093
    [Google الباحث العلمي]
  36. Velho G, Bouby N, Hadjadj S, Matallah N, Mohammedi K, Fumeron F, et al. Plasma copeptin and renal outcomes in patients with type 2 diabetes and albuminuria. Diabetes Care .2013Nov; 36:(11):3639–45. https://doi.org/10.2337/dc13-0683
    [Google الباحث العلمي]
  37. Liu G, Ren X, Li Y, Li H. Midkine promotes kidney injury in diabetic kidney disease by increasing neutrophil extracellular traps formation. Ann Transl Med .2022Jun; 10:(12):693. https://doi.org/10.21037/atm-22-2382
    [Google الباحث العلمي]
  38. Salaru DL, Albert C, Königsmark U, Brandt S, Halloul Z, Heller A, et al. Serum levels for midkine, a heparin-binding growth factor, inversely correlate with angiotensin and endothelin receptor autoantibody titers in patients with macroangiopathy. Int Angiol .2014Aug; 33:(4):372–8.Available from: https://pubmed.ncbi.nlm.nih.gov/25056169/
    [Google الباحث العلمي]
  39. Guzel S, Cinemre FBS, Guzel EC, Kucukyalcin V, Kiziler AR, Cavusoglu C, et al. Midkine levels and its relationship with atherosclerotic risk factors in essential hypertensive patients. Niger J Clin Pract .2018Jul; 21:(7):894–900. https://doi.org/10.4103/njcp.njcp_309_17
    [Google الباحث العلمي]
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Serum midkine and copeptin as predictive biomarkers for diabetic nephropathy progression in type 2 diabetes mellitus
Avicenna 2025, 7 (٢٠٢٥); https://doi.org/10.5339/avi.2025.7
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  • نوع المستند: Research Article
الموضوعات الرئيسية albuminuria, copeptin, Diabetic nephropathy, insulin resistance and midkine

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