- Author: Vecihi Batuman, MD, FACP, FASN; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
Diabetic nephropathy is a clinical syndrome characterized by the following :
Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at least 2 occasions 3-6 months apart
Progressive decline in the glomerular filtration rate (GFR)
Elevated arterial blood pressure (see Workup)
Proteinuria was first recognized in diabetes mellitus in the late 18th century. In the 1930s, Kimmelstiel and Wilson described the classic lesions of nodular glomerulosclerosis in diabetes associated with proteinuria and hypertension. (See Pathophysiology.)
By the 1950s, kidney disease was clearly recognized as a common complication of diabetes, with as many as 50% of patients with diabetes of more than 20 years having this complication. (See Epidemiology.)
Currently, diabetic nephropathy is the leading cause of chronic kidney disease in the United States and other Western societies. It is also one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes. Diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States. (See Prognosis.)
Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients may have physical findings associated with long-standing diabetes mellitus. (See Clinical Presentation.)
Good evidence suggests that early treatment delays or prevents the onset of diabetic nephropathy or diabetic kidney disease. This has consistently been shown in both type1 and type 2 diabetes mellitus. (See Treatment and Management).
Regular outpatient follow-up is key in managing diabetic nephropathy successfully. (See Long-term Monitoring.)
Recently, attention has been called to atypical presentations of diabetic nephropathy with dissociation of proteinuria from reduced kidney function. Also noted is that microalbuminuria is not always predictive of diabetic nephropathy. Nevertheless, a majority of the cases of diabetic nephropathy presents with proteinuria, which progressively gets worse as the disease progresses, and is almost uniformly associated with hypertension.
Go to Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2 for more complete information on these topics.
Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycation of matrix proteins. Second, thickening of the glomerular basement membrane (GBM) occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). These different histologic patterns appear to have similar prognostic significance.
The key change in diabetic glomerulopathy is augmentation of extracellular matrix. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix. The image below is a simple schema for the pathogenesis of diabetic nephropathy.
Light microscopy findings show an increase in the solid spaces of the tuft, most frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction) material (diffuse diabetic glomerulopathy). Large acellular accumulations also may be observed within these areas. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules.
Immunofluorescence microscopy may reveal deposition of albumin, immunoglobulins, fibrin, and other plasma proteins along the GBM in a linear pattern, most likely as a result of exudation from the blood vessels, but this is not immunopathogenetic or diagnostic and does not imply an immunologic pathophysiology. The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia and hypertensive arteriosclerosis.
Electron microscopy provides a more detailed definition of the structures involved. In advanced disease, the mesangial regions occupy a large proportion of the tuft, with prominent matrix content. Further, the basement membrane in the capillary walls (ie, the peripheral basement membrane) is thicker than normal.
The severity of diabetic glomerulopathy is estimated by the thickness of the peripheral basement membrane and mesangium and matrix expressed as a fraction of appropriate spaces (eg, volume fraction of mesangium/glomerulus, matrix/mesangium, or matrix/glomerulus).
The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).
In addition to the renal hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing glomerular filtration rate [GFR]) generally develop systemic hypertension. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature.
Evidence suggests that hypertension associated with obesity, metabolic syndrome, and diabetes may play an important role in the pathogenesis of diabetic nephropathy. Central obesity, metabolic syndrome, and diabetes lead to increased blood pressure.
Central obesity induces hypertension initially by increasing renal tubular reabsorption of sodium and causing a hypertensive shift of renal-pressure natriuresis through multiple mechanisms, including activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as physical compression of the kidneys. Hypertension, along with increases in intraglomerular capillary pressure and the metabolic abnormalities (eg, dyslipidemia, hyperglycemia) likely interact to accelerate renal injury.
Similar to obesity-associated glomerular hyperfiltration, renal vasodilation, increases in the glomerular filtration rate and intraglomerular capillary pressure, and increased blood pressure also are characteristics of diabetic nephropathy. Increased systolic blood pressure further exacerbates the disease progression to proteinuria and a decline in the glomerular filtration rate, leading to end-stage kidney disease.
The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycation products, and activation of cytokines. Many investigators now agree that diabetes is an autoimmune disorder, with overlapping pathophysiologies contributing to both type 1 and type 2 diabetes; and recent research highlights the pivotal role of innate immunity (toll-like receptors) and regulatory T-cells (Treg).
Glycemic control reflects the balance between dietary intake and gluconeogenesis and tissue uptake or utilization through storage as glycogen or fat and oxidation. This balance is regulated by insulin production from the β cells in the pancreas. Insulin regulates serum glucose through its actions on liver, skeletal muscle, and fat tissue. When there is insulin resistance, insulin cannot suppress hepatic gluconeogenesis, which leads to hyperglycemia. Simultaneously, insulin resistance in the adipose tissue and skeletal muscle leads to increased lipolysis and reduction in disposal of glucose causing hyperlipidemia in addition to hyperglycemia.
Evidence suggests that when there is insulin resistance, the pancreas is forced to increase its insulin output, which stresses the β cells, eventually resulting in β-cell exhaustion. The high blood glucose levels and high levels of saturated fatty acids create an inflammatory medium, resulting in activation of the innate immune system, which results in activation of the nuclear transcription factors-kappa B (NF-κB), and release of inflammatory mediators, including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α, promoting systemic insulin resistance and β-cell damage as a result of autoimmune insulitis. Hyperglycemia and high serum levels of free fatty acids and IL-1 lead to glucotoxicity, lipotoxicity, and IL-1 toxicity, resulting in apoptotic β-cell death.
Hyperglycemia also increases the expression of transforming growth factor-β (TGF-β) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF-β and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy.[6, 7] Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes.
Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes.
It has been argued that the genetic predisposition to diabetes that is so frequent in Western societies, and even more so in minorities, reflects the fact that in the past, insulin resistance conferred a survival advantage (the so-called thrifty genotype hypothesis).
Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. However, definitive genetic markers have yet to be identified. More recently, the role of epigenetic modification in the pathogenesis of diabetic nephropathy has been highlighted.
A study by Bherwani et al suggested that an association exists between decreased serum folic acid levels and diabetic nephropathy. In the study, which involved 100 patients with diabetes mellitus, including 50 with diabetic nephropathy and 50 without it, multivariate logistic regression analysis indicated that reduced folic acid levels increased the risk of diabetic nephropathy by 19.9%.
Since the 1950s, kidney disease has been clearly recognized as a common complication of diabetes mellitus (DM), with as many as 50% of patients with DM of more than 20 years’ duration having this complication.
United States statistics
Diabetic nephropathy rarely develops before 10 years’ duration of type 1 DM (previously known as insulin-dependent diabetes mellitus [IDDM]). Approximately 3% of newly diagnosed patients with type 2 DM (previously known as non–insulin-dependent diabetes mellitus [NIDDM]) have overt nephropathy. The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-20 years, after which the rate progressively declines.
The risk for the development of diabetic nephropathy is low in a normoalbuminuric patient with diabetes’ duration of greater than 30 years. Patients who have no proteinuria after 20-25 years have a risk of developing overt renal disease of only approximately 1% per year.
In terms of diabetic kidney disease in the United States, the prevalence increased from 1988-2008 in proportion to the prevalence of diabetes. Among people with diabetes, the prevalence of diabetic kidney disease remained stable.
Striking epidemiologic differences exist even among European countries. In some European countries, particularly Germany, the proportion of patients admitted for renal replacement therapy exceeds the figures reported from the United States. In Heidelberg (southwest Germany), 59% of patients admitted for renal replacement therapy in 1995 had diabetes and 90% of those had type 2 DM. An increase in end-stage renal disease (ESRD) from type 2 DM has been noted even in countries with notoriously low incidences of type 2 DM, such as Denmark and Australia. Exact incidence and prevalence from Asia are not readily available.
A study from the Netherlands suggested that diabetic nephropathy is underdiagnosed. Using renal tissue specimens from autopsies, Klessens et al found histopathologic changes associated with diabetic nephropathy in 106 of 168 patients with type 1 or type 2 diabetes. However, 20 of the 106 patients did not during their lifetime present with the clinical manifestations of diabetic nephropathy.
Sex distribution for diabetic nephropathy
Diabetic nephropathy affects males and females equally.
Age distribution for diabetic nephropathy
Diabetic nephropathy rarely develops before 10 years’ duration of type 1 DM. The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-20 years. The mean age of patients who reach end-stage kidney disease is about 60 years. Although in general, the incidence of diabetic kidney disease is higher among elderly persons who have had type 2 diabetes for a longer generation, the role of age in the development of diabetic kidney disease is unclear. In Pima Indians with type 2 diabetes, the onset of diabetes at a younger age was associated with a higher risk of progression to end-stage kidney disease.
Prevalence of diabetic nephropathy by race
The severity and incidence of diabetic nephropathy are especially great in blacks (the frequency being 3- to 6-fold higher than it is in whites), Mexican Americans, and Pima Indians with type 2 DM. The relatively high frequency of the condition in these genetically disparate populations suggests that socioeconomic factors, such as diet, poor control of hyperglycemia, hypertension, and obesity, have a primary role in the development of diabetic nephropathy. It also indicates that familial clustering may be occurring in these populations.
By age 20 years, as many as half of all Pima Indians with diabetes have developed diabetic nephropathy, with 15% of these individuals having progressed to ESRD.
Diabetic nephropathy accounts for significant morbidity and mortality.
Proteinuria is a predictor of morbidity and mortality. (See Workup.) The overall prevalence of microalbuminuria and macroalbuminuria in both types of diabetes is approximately 30-35%. Microalbuminuria independently predicts cardiovascular morbidity, and microalbuminuria and macroalbuminuria increase mortality from any cause in diabetes mellitus. Microalbuminuria is also associated with increased risk of coronary and peripheral vascular disease and death from cardiovascular disease in the general nondiabetic population.
Patients in whom proteinuria did not develop have a low and stable relative mortality rate, whereas patients with proteinuria have a 40-fold higher relative mortality rate. Patients with type 1 DM and proteinuria have the characteristic bell-shaped relationship between diabetes duration/age and relative mortality, with maximal relative mortality in the age interval of 34-38 years (as reported in 110 females and 80 males).
ESRD is the major cause of death, accounting for 59-66% of deaths in patients with type 1 DM and nephropathy. In a prospective study in Germany, the 5-year survival rate was less than 10% in the elderly population with type 2 DM and no more than 40% in the younger population with type 1 DM.
The cumulative incidence of ESRD in patients with proteinuria and type 1 DM is 50% 10 years after the onset of proteinuria, compared with 3-11% 10 years after the onset of proteinuria in European patients with type 2 DM.
A study by Rosolowsky et al found that despite renoprotective treatment, including transplantation and dialysis, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD.
Although both type 1 and type 2 DM lead to ESRD, the great majority of patients are those with type 2 diabetes. The fraction of patients with type 1 DM who develop renal failure seems to have declined over the past several decades. However, 20-40% still have this complication. On the other hand, only 10-20% of patients with type 2 DM develop uremia due to diabetes. Their nearly equal contribution to the total number of patients with diabetes who develop kidney failure results from the higher prevalence of type 2 DM (5- to 10-fold).
Cardiovascular disease is also a major cause of death (15-25%) in persons with nephropathy and type 1 DM, despite their relatively young age at death.
Patient education is key in trying to prevent diabetic nephropathy. Appropriate education, follow-up, and regular doctor visits are important in prevention and early recognition and management of diabetic nephropathy.
For excellent patient education resources, visit eMedicineHealth’s Diabetes Center. In addition, see eMedicineHealth’s patient education article Diabetes Mellitus.
For further information, see Mayo Clinic - Kidney Transplant Information.
Tang SC, Chan GC, Lai KN. Recent advances in managing and understanding diabetic nephropathy. F1000Res. 2016. 5:[Medline]. [Full Text].
Ekinci EI, Jerums G, Skene A, Crammer P, Power D, Cheong KY. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care. 2013 Nov. 36(11):3620-6. [Medline].
Hall JE, Henegar JR, Dwyer TM, Liu J, Da Silva AA, Kuo JJ. Is obesity a major cause of chronic kidney disease?. Adv Ren Replace Ther. 2004 Jan. 11(1):41-54. [Medline].
Yip JW, Jones SL, Wiseman MJ, Hill C, Viberti G. Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes. 1996 Dec. 45(12):1729-33. [Medline].
Odegaard JI, Chawla A. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb Perspect Med. 2012 Mar. 2(3):a007724. [Medline]. [Full Text].
Chiarelli F, Gaspari S, Marcovecchio ML. Role of growth factors in diabetic kidney disease. Horm Metab Res. 2009 Aug. 41(8):585-93. [Medline].
Rask-Madsen C, King GL. Kidney complications: factors that protect the diabetic vasculature. Nat Med. 2010 Jan. 16(1):40-1. [Medline].
Ziyadeh FN. Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J Am Soc Nephrol. 2004 Jan. 15 Suppl 1:S55-7. [Medline].
Deshpande SD, Putta S, Wang M, Lai JY, Bitzer M, Nelson RG. Transforming growth factor-ß-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy. Diabetes. 2013 Sep. 62(9):3151-62. [Medline].
Bherwani S, Saumya AS, Ahirwar AK, et al. The association of folic acid deficiency and diabetic nephropathy in patients with type 2 diabetes mellitus. Endocr Metab Immune Disord Drug Targets. 2016 Apr 15. [Medline].
de Boer IH, Rue TC, Hall YN, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011 Jun 22. 305(24):2532-9. [Medline].
Klessens CQ, Woutman TD, Veraar KA, et al. An autopsy study suggests that diabetic nephropathy is underdiagnosed. Kidney Int. 2016 Jul. 90 (1):149-56. [Medline].
Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. 2006 Jul 26. 296(4):421-6. [Medline].
Rosolowsky ET, Skupien J, Smiles AM, et al. Risk for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol. 2011 Mar. 22(3):545-53. [Medline]. [Full Text].
Kostadaras A. Risk Factors for Diabetic Nephropathy. Astoria Hypertension Clinic. Available at http://www.kidneydoctor.com/dm.htm.
Iliadis F, Didangelos T, Ntemka A, et al. Glomerular filtration rate estimation in patients with type 2 diabetes: creatinine- or cystatin C-based equations?. Diabetologia. 2011 Dec. 54(12):2987-94. [Medline].
Shlipak M. Diabetic nephropathy. Clin Evid (Online). 2009 Jan 14. 2009:[Medline].
Burney BO, Kalaitzidis RG, Bakris GL. Novel therapies of diabetic nephropathy. Curr Opin Nephrol Hypertens. 2009 Mar. 18(2):107-11. [Medline].
Suckling RJ, He FJ, Macgregor GA. Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst Rev. 2010 Dec 8. 12:CD006763. [Medline].
Heerspink HJ, Holtkamp FA, Parving HH, Navis GJ, Lewis JB, Ritz E, et al. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int. 2012 Mar 21. [Medline].
Diabetes Control and Complications Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int. 1995 Jun. 47(6):1703-20. [Medline].
UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12. 352(9131):837-53. [Medline].
Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007 Jul. 30(7):1862-4. [Medline].
Scheen AJ. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol. 2013 May. 9(5):529-50. [Medline].
Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial. 2004 Sep-Oct. 17(5):365-70. [Medline].
Lamos EM, Younk LM, Davis SN. Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013 Jun. 9(6):763-75. [Medline].
Linnebjerg H, Kothare PA, Park S, Mace K, Reddy S, Mitchell M. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. 2007 Sep. 64(3):317-27. [Medline].
Davidson JA, Brett J, Falahati A, Scott D. Mild renal impairment and the efficacy and safety of liraglutide. Endocr Pract. 2011 May-Jun. 17(3):345-55. [Medline].
Young A. Clinical studies. Adv Pharmacol. 2005. 52:289-320. [Medline].
Mogensen CE. The effect of blood pressure intervention on renal function in insulin-dependent diabetes. Diabete Metab. 1989. 15(5 Pt 2):343-51. [Medline].
Diabetes Guidelines. Royal Free Hampstead NHS Trust. Available at http://royalfree.org.uk/default.aspx?top_nav_id=1&sel_left_nav=25&tab_id=403. Accessed: 7/2/09.
Laight DW. Therapeutic inhibition of the renin angiotensin aldosterone system. Expert Opin Ther Pat. 2009 Jun. 19(6):753-9. [Medline].
Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis. Diabet Med. 2007 May. 24(5):486-93. [Medline].
Imai E, Chan JC, Ito S, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. 2011 Dec. 54(12):2978-2986. [Medline].
Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14. 369(20):1892-903. [Medline].
Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, et al. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care. 2009 Oct. 32(10):1873-9. [Medline]. [Full Text].
[Guideline] National Kidney Foundation. NKF-KDOQI Guidelines. Available at http://www.kidney.org/professionals/kdoqi/guidelines.cfm.
Agarwal R. Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol. 2009 Sep. 4(9):1523-8. [Medline].
de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010 Nov 6. 376(9752):1543-51. [Medline].
Wenzel RR, Littke T, Kuranoff S, Jürgens C, Bruck H, Ritz E, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol. 2009 Mar. 20(3):655-64. [Medline]. [Full Text].
Suckling RJ, He FJ, Macgregor GA. Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst Rev. 2010 Dec 8. 12:CD006763. [Medline].