Skip to main content

Advertisement

SpringerLink
Log in

Atherogenic dyslipidemia and diabetic nephropathy

  • Review
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Chronic kidney disease is associated with altered lipid metabolism and lipid accumulation. Although it is though that hyperlipemia is a consequence of kidney dysfunction, several lines of evidence support that hyperlipidemia may contribute to the onset and progression of kidney disease, also in diabetes. This review describes the results of recent observational studies supporting the concept that glucose is only partly responsible for kidney damage onset, while a cluster of factors, including hypertriglyceridemia and low HDL-cholesterol, could play a relevant role in inducing onset and progression of DKD. We also report the results of randomized clinical trials investigating in type 2 diabetic patients the role of drug improvement of hypertriglyceridemia on renal outcomes. Finally, we discuss putative mechanisms linking hyperlipidemia (i.e. hypertriglyceridemia or low HDL cholesterol) with kidney disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Saran R, Robinson B, Abbott KC et al (2019) US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 73(3S1):A7–A8

    PubMed Central  PubMed  Google Scholar 

  2. Fioretto P, Mauer M (2007) Histopathology of diabetic nephropathy. Semin Nephrol 27:195–207

    PubMed Central  PubMed  Google Scholar 

  3. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M et al (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375(9731):2073–2081

    Google Scholar 

  4. Nathan DM; DCCT/EDIC Research Group (2014) The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 37(1):9–16

    Google Scholar 

  5. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352(9131):837–853

    Google Scholar 

  6. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358(24):2545–2559

    Google Scholar 

  7. ADVANCE Collaborative Group, Patel A, MacMahon S et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358(24):2560–2572

    Google Scholar 

  8. Duckworth W, Abraira C, Moritz T et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360(2):129–139

    CAS  PubMed  Google Scholar 

  9. Chen SC, Tseng CH (2013) Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud 10(2–3):88–100

    PubMed Central  PubMed  Google Scholar 

  10. Thomas MC, Rosengård-Bärlund M, Mills V et al (2006) Serum lipids and the progression of nephropathy in type 1 diabetes. Diabetes Care 29(2):317–322

    CAS  PubMed  Google Scholar 

  11. Fioretto P, Dodson PM, Ziegler D et al (2010) Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol 6(1):19–25

    PubMed  Google Scholar 

  12. Muntner P, Coresh J, Smith JC et al (2000) Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int 58(1):293–301

    CAS  PubMed  Google Scholar 

  13. Retnakaran R, Cull CA, Thorne KI et al (2006) Risk factors for renal dysfunction in type 2 diabetes: UK Prospective Diabetes Study 74. Diabetes 55(6):1832–1839

    CAS  PubMed  Google Scholar 

  14. Cusick M, Chew EY, Hoogwerf B et al (2004) Risk factors for renal replacement therapy in the Early Treatment Diabetic Retinopathy Study (ETDRS), Early Treatment Diabetic Retinopathy Study Report No. 26. Kidney Int 66(3):1173–1179

    PubMed  Google Scholar 

  15. Morton J, Zoungas S, Li Q et al (2012) Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy: results of the ADVANCE study. Diabetes Care 35(11):2201–2206

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Sacks FM, Hermans MP, Fioretto P et al (2014) Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation 129(9):999–1008

    CAS  PubMed  Google Scholar 

  17. Tsuruya K, Yoshida H, Nagata M et al (2015) Impact of the triglycerides to high-density lipoprotein cholesterol ratio on the incidence and progression of CKD: a longitudinal study in a large Japanese population. Am J Kidney Dis 66(6):972–983

    CAS  PubMed  Google Scholar 

  18. Zoppini G, Negri C, Stoico V et al (2012) Triglyceride-high-density lipoprotein cholesterol is associated with microvascular complications in type 2 diabetes mellitus. Metabolism 61(1):22–29

    CAS  PubMed  Google Scholar 

  19. Russo GT, De Cosmo S, Viazzi F et al (2016) Plasma triglycerides and HDL-C levels predict the development of diabetic kidney disease in subjects with type 2 diabetes: the AMD annals initiative. Diabetes Care 39(12):2278–2287

    CAS  PubMed  Google Scholar 

  20. Penno G, Solini A, Zoppini G et al (2015) Hypertriglyceridemia Is independently associated with renal, but not retinal complications in subjects with type 2 diabetes: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study. PLoS ONE 10(5):e0125512

    PubMed Central  PubMed  Google Scholar 

  21. Tu ST, Chang SJ, Chen JF et al (2010) Prevention of diabetic nephropathy by tight target control in an asian population with type 2 diabetes mellitus: a 4-year prospective analysis. Arch Intern Med 170(2):155–161

    CAS  PubMed  Google Scholar 

  22. Xu J, Lee ET, Devereux RB et al (2008) A longitudinal study of risk factors for incident albuminuria in diabetic American Indians: the Strong Heart Study. Am J Kidney Dis 51(3):415–424

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Lin J, Hu FB, Mantzoros C et al (2010) Lipid and inflammatory biomarkers and kidney function decline in type 2 diabetes. Diabetologia 53(2):263–267

    CAS  PubMed  Google Scholar 

  24. Keech A, Simes RJ, Barter P et al (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366(9500):1849–1861

    CAS  PubMed  Google Scholar 

  25. ACCORD Study Group, Ginsberg HN, Elam MB et al (2010) Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362(17):1563–1574

    Google Scholar 

  26. Davis TM, Ting R, Best JD et al (2011) Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54(2):280–290

    CAS  PubMed  Google Scholar 

  27. Hirano T (2014) Abnormal lipoprotein metabolism in diabetic nephropathy. Clin Exp Nephrol 18(2):206–209

    CAS  PubMed  Google Scholar 

  28. Hayashi T, Hirano T, Taira T et al (2008) Remarkable increase of apolipoprotein B48 level in diabetic patients with end-stage renal disease. Atherosclerosis 197(1):154–158

    CAS  PubMed  Google Scholar 

  29. Russo GT, Meigs JB, Cupples LA et al (2001) Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study. Atherosclerosis 158(1):173–181

    CAS  PubMed  Google Scholar 

  30. Kanter JE, Shao B, Kramer F et al (2019) Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes. J Clin Invest 130:4165–4179

    Google Scholar 

  31. Hirano T, Sakaue T, Misaki A et al (2003) Very low-density lipoprotein-apoprotein CI is increased in diabetic nephropathy: comparison with apoprotein CIII. Kidney Int 63(6):2171–2177

    CAS  PubMed  Google Scholar 

  32. Mori Y, Hirano T, Nagashima M et al (2007) Decreased peroxisome proliferator-activated receptor alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure. Metabolism 56(12):1714–1718

    CAS  PubMed  Google Scholar 

  33. Hirano T, Hayashi T, Adachi M et al (2007) Marked decrease of apolipoprotein A-V in both diabetic and nondiabetic patients with end-stage renal disease. Metabolism 56(4):462–463

    CAS  PubMed  Google Scholar 

  34. Rye KA, Barter PJ (2014) Cardioprotective functions of HDLs. J Lipid Res 55(2):168–179

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Asztalos BF, Demissie S, Cupples LA et al (2006) LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial. Atherosclerosis 188(1):59–67

    CAS  PubMed  Google Scholar 

  36. Russo GT, Horvath KV, Di Benedetto A et al (2010) Influence of menopause and cholesteryl ester transfer protein (CETP) TaqIB polymorphism on lipid profile and HDL subpopulations distribution in women with and without type 2 diabetes. Atherosclerosis 210(1):294–301

    CAS  PubMed  Google Scholar 

  37. Zhou H, Tan KC, Shiu SW et al (2008) Increased serum advanced glycation end products are associated with impairment in HDL antioxidative capacity in diabetic nephropathy. Nephrol Dial Transplant 23(3):927–933

    CAS  PubMed  Google Scholar 

  38. Russo GT, Giandalia A, Romeo EL et al (2014) Markers of systemic inflammation and Apo-AI containing HDL subpopulations in women with and without diabetes. Int J Endocrinol 2014:607924

    PubMed Central  PubMed  Google Scholar 

  39. Russo GT, Giandalia A, Romeo EL et al (2014) Lipid and non-lipid cardiovascular risk factors in postmenopausal type 2 diabetic women with and without coronary heart disease. J Endocrinol Invest 37(3):261–268

    CAS  PubMed  Google Scholar 

  40. Russo GT, Giandalia A, Romeo EL et al (2017) HDL subclasses and the common CETP TaqIB variant predict the incidence of microangiopatic complications in type 2 diabetic women 9 years follow-up study. Diabetes Res Clin Pract 132:108–117

    CAS  PubMed  Google Scholar 

  41. Izquierdo-Lahuerta A, Martínez-García C, Medina-Gómez G (2016) Lipotoxicity as a trigger factor of renal disease. J Nephrol 29(5):603–610

    CAS  PubMed  Google Scholar 

  42. Takemura T, Yoshioka K, Aya N et al (1993) Apolipoproteins and lipoprotein receptors in glomeruli in human kidney diseases. Kidney Int 43(4):918–927

    CAS  PubMed  Google Scholar 

  43. Schlondorff D (1993) Cellular mechanisms of lipid injury in the glomerulus. Am J Kidney Dis 22(1):72–82

    CAS  PubMed  Google Scholar 

  44. Sun L, Halaihel N, Zhang W et al (2002) Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus. J Biol Chem 277(21):18919–18927

    CAS  PubMed  Google Scholar 

  45. Zager RA, Johnson A (2001) Renal cortical cholesterol accumulation is an integral component of the systemic stress response. Kidney Int 60(6):2299–2310

    CAS  PubMed  Google Scholar 

  46. Tsun JG, Yung S, Chau MK et al (2014) Cellular cholesterol transport proteins in diabetic nephropathy. PLoS ONE 9(9):e105787

    PubMed Central  PubMed  Google Scholar 

  47. Ducasa GM, Mitrofanova A, Fornoni A (2019) Crosstalk between lipids and mitochondria in diabetic kidney disease. Curr Diab Rep 19(12):144

    CAS  PubMed  Google Scholar 

  48. Kuwabara T, Mori K, Mukoyama M et al (2012) Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice. Diabetologia 55(8):2256–2266

    CAS  PubMed  Google Scholar 

  49. Kuwabara T, Mori K, Mukoyama M et al (2014) Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy. Clin Exp Nephrol 18(4):584–592

    CAS  PubMed  Google Scholar 

  50. Wang Z, Jiang T, Li J, Proctor G et al (2005) Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 54(8):2328–2335

    CAS  PubMed  Google Scholar 

  51. Merscher-Gomez S, Guzman J, Pedigo CE et al (2013) Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes 62(11):3817–3827

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Zhang Y, Ma KL, Liu J et al (2015) Dysregulation of low-density lipoprotein receptor contributes to podocyte injuries in diabetic nephropathy. Am J Physiol Endocrinol Metab 308(12):E1140–1148

    PubMed  Google Scholar 

  53. Gröne HJ, Hohbach J, Gröne EF (1996) Modulation of glomerular sclerosis and interstitial fibrosis by native and modified lipoproteins. Kidney Int Suppl 54:S18–22

    PubMed  Google Scholar 

  54. Moorhead JF, Chan MK, El-Nahas M et al (1982) Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet 2(8311):1309–1311

    CAS  PubMed  Google Scholar 

  55. Jandeleit-Dahm K, Cao Z, Cox AJ et al (1999) Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int Suppl 71:S31–36

    CAS  PubMed  Google Scholar 

  56. De Cosmo S, Menzaghi C, Prudente S et al (2013) Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence. Nephrol Dial Transplant 28(1):29–36

    PubMed  Google Scholar 

  57. Jauregui A, Mintz DH, Mundel P et al (2009) Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria. Curr Opin Nephrol Hypertens 18(6):539–545

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Son JW, Jang EH, Kim MK et al (2011) Diabetic retinopathy is associated with subclinical atherosclerosis in newly diagnosed type 2 diabetes mellitus. Diabetes Res Clin Pract 91(2):253–259

    PubMed  Google Scholar 

  59. Avogaro A, Giorda C, Maggini M et al (2007) Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care 30(5):1241–1247

    PubMed  Google Scholar 

  60. Brownrigg JR, Hughes CO, Burleigh D et al (2016) Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol 4(7):588–597

    PubMed  Google Scholar 

  61. Molitch ME, DeFronzo RA, Franz MJ et al (2003) Diabetic nephropathy. Diabetes Care 26(Suppl 1):S94–98

    PubMed  Google Scholar 

  62. Hirano T (2018) Pathophysiology of diabetic dyslipidemia. J Atheroscler Thromb 25(9):771–782

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Giuseppina Russo & Annalisa Giandalia

  2. Unit of Internal Medicine, Department of Medical Sciences, IRCCS Casa Sollievo Della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, FG, Italy

    Pamela Piscitelli & Salvatore De Cosmo

  3. University of Genova and Ospedale Policlinico San Martino-IST, Genoa, Italy

    Francesca Viazzi & Roberto Pontremoli

  4. Department of Medicine, University of Padova, Padova, Italy

    Paola Fioretto

Authors
  1. Giuseppina Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pamela Piscitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annalisa Giandalia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Viazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberto Pontremoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paola Fioretto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salvatore De Cosmo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore De Cosmo.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Russo, G., Piscitelli, P., Giandalia, A. et al. Atherogenic dyslipidemia and diabetic nephropathy. J Nephrol 33, 1001–1008 (2020). https://doi.org/10.1007/s40620-020-00739-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-020-00739-8

Keywords

Search

Navigation