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Diabetic Nephropathy

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Diabetic Nephropathy
Author: Vecihi Batuman, MD, FACP, FASN; Chief Editor: Vecihi Batuman, MD, FACP, FASN more... Updated: Jun 6, 2012

Background
Diabetic nephropathy is a clinical syndrome characterized by the following: Persistent albuminuria (>300 mg/d or >200 g/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. (See Treatment and Management.) Regular outpatient follow-up is key in managing diabetic nephropathy successfully. (See Long-term Monitoring.) Go to Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2 for more complete information on these topics.

Pathophysiology
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 glycosylation 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
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nephropathy.

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.

Etiology
The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycosylation products, and activation of cytokines. Hyperglycemia increases the expression of transforming growth factor-beta (TGF-beta) in the glomeruli and of matrix proteins specifically stimulated by this cytokine. TGF-beta and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy, enhanced collagen synthesis, and vascular changes observed in persons with diabetic nephropathy.[1, 2] 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 socalled 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
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identified.

Epidemiology
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 (also known as insulin-dependent diabetes mellitus [IDDM]). Approximately 3% of newly diagnosed patients with type 2 DM (also 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.[3] Among people with diabetes, the prevalence of diabetic kidney disease remained stable.

International statistics
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.

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.[4]

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.

Prognosis
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
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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.[5] 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
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 eMedicineHealths Diabetes Center. In addition, see eMedicineHealths patient education article Diabetes Mellitus. For further information, see Mayo Clinic - Kidney Transplant Information.

Contributor Information and Disclosures

Author Vecihi Batuman, MD, FACP, FASN Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology Disclosure: Nothing to disclose. Coauthor(s) Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Anjana S Soman, MD Staff Physician, Department of Pathology, Quest Diagnostics
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Anjana S Soman, MD is a member of the following medical societies: American Society for Clinical Pathology and College of American Pathologists Disclosure: Nothing to disclose. Sandeep S Soman, MBBS, MD, DNB Senior Staff Physician, Department of Internal Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital Sandeep S Soman, MBBS, MD, DNB is a member of the following medical societies: American College of Physicians, American Medical Association, and American Society of Nephrology Disclosure: Nothing to disclose. Chief Editor Vecihi Batuman, MD, FACP, FASN Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology Disclosure: Nothing to disclose. Additional Contributors George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation Disclosure: Nothing to disclose. Sreepada TK Rao, MD, FACP Professor, Department of Medicine, State University of New York Downstate Medical Center Sreepada TK Rao, MD, FACP is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment

References
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26. Jacobsen P, Rossing K, Parving HH. Single versus dual blockade of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers) in diabetic nephropathy. Curr Opin Nephrol Hypertens . May 2004;13(3):319-24. [Medline]. 27. Matsuoka S, Awazu M. Masked hypertension in children and young adults. Pediatr Nephrol. Jun 2004;19(6):651-4. [Medline]. 28. Tanaka Y, Atsumi Y, Matsuoka K, Onuma T, Tohjima T, Kawamori R. Role of glycemic control and blood pressure in the development and progression of nephropathy in elderly Japanese NIDDM patients. Diabetes Care. Jan 1998;21(1):116-20. [Medline]. Medscape Reference 2011 WebMD, LLC

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