eMedicine Specialties > Nephrology > The Kidney in Systemic Diseases

Diabetic Nephropathy

Author: Sandeep S Soman, MBBS, MD, DNB, Senior Staff Physician, Department of Internal Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital
Coauthor(s): Anjana S Soman, MD, Staff Physician, Department of Pathology, Quest Diagnostics
Contributor Information and Disclosures

Updated: Nov 19, 2009

Introduction

Background

Diabetes is a metabolic disorder of multiple causes characterized by chronic hyperglycemia and disorders of carbohydrate, fat, and protein metabolism. It results from defects in insulin secretion (type 1), insulin action (type 2), or a combination of these factors.

Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/d or >200 mcg/min) that is confirmed on at least 2 occasions 3-6 months apart, a relentless decline in the glomerular filtration rate (GFR), and elevated arterial blood pressure. The rate of decline in the GFR in various stages of type 1 and type 2 diabetes is shown in the image below.

There is good evidence that early treatment delays or prevents the onset of diabetic nephropathy or diabetic kidney disease.

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).

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.

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.

World Health Organization and American Diabetes Association diagnostic criteria are as follows:

• Fasting plasma glucose >126 mg/dL (>7.0 mmol/L) or fasting whole-blood glucose level >110 mg/dL (>6.1 mmol/L), or a 2-hour post-glucose-load plasma glucose >200 mg/dL (>11.1 mmol/L; 180 mg/dL [10.0 mmol/L] if whole blood), or a random plasma glucose >200 mg/dL (>11.1 mmol/L) on more than 1 occasion
• Prediabetic stage - Fasting plasma glucose 100-126 mg/dL (5.6-7.0 mmol/L) increasingly recognized as a risk factor for end-organ complications; evidence supports lifestyle interventions to prevent or delay onset of diabetes

Pathophysiology

The earliest morphologic abnormality in diabetic nephropathy is the thickening of the glomerular basement membrane (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.

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).

Immunofluorescence microscopy may reveal deposition of immunoglobulin G along the GBM in a linear pattern, but this is not immunopathogenetic or diagnostic. Immune deposits are not observed. 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).

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, GBM thickening occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by renal vasodilatation 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 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 may contribute to the cellular hypertrophy and enhanced collagen synthesis observed in persons with diabetic nephropathy.¹

Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes.

In addition to the renal hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing 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.

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.

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.

Frequency

United States

Diabetic nephropathy rarely develops before 10 years' duration of IDDM. Approximately 3% of newly diagnosed NIDDM patients have overt nephropathy. The peak incidence rate (3%/y) is usually found in persons who have had diabetes for 10-20 years, after which the rate progressively declines (as seen in the image below). The risk for the development of diabetic nephropathy is low in a normoalbuminuric patient with diabetes' duration of greater than 30. The peak onset of nephropathy in those with IDDM is 10-15 years after disease onset. Patients who have no proteinuria after 20-25 years have a risk of developing overt renal disease of only approximately 1% per year.

International

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 NIDDM. An increase in ESRD from NIDDM has been noted even in countries with notoriously low incidences of NIDDM, such as Denmark and Australia. Exact incidence and prevalence from Asia are not readily available.

Mortality/Morbidity

Diabetic nephropathy accounts for significant morbidity and mortality. The fraction of patients with IDDM 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 NIDDM 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 NIDDM (5- to 10-fold).

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 diabetes. 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.

Sex

Diabetic nephropathy affects males and females.

Age

Diabetic nephropathy rarely develops before 10 years' duration of IDDM. The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-20 years.

Clinical

History

• Diabetes
• Passing of foamy urine
• Otherwise unexplained proteinuria in a patient with diabetes
• Diabetic retinopathy
• Fatigue and foot edema secondary to hypoalbuminemia (if nephrotic syndrome is present)
• Other associated disorders such as peripheral vascular occlusive disease, hypertension, or coronary artery disease

Physical

Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients usually have physical findings associated with long-standing diabetes mellitus.

• Hypertension
• Peripheral vascular occlusive disease (decreased peripheral pulses, carotid bruits)
• Evidence of diabetic neuropathy in the form of decreased fine sensations and diminished tendon reflexes
• Evidence of fourth heart sound during cardiac auscultation
• Nonhealing skin ulcers/osteomyelitis

Almost all patients with nephropathy and type 1 diabetes demonstrate signs of diabetic microvascular disease, such as retinopathy and neuropathy.² Clinical detection of the retinopathy is easy, and in these patients the condition typically precedes the onset of overt nephropathy. The converse is not true. Only a minority of patients with advanced retinopathy have histologic changes in the glomeruli and increased protein excretion that is at least in the microalbuminuric range, and most have little or no renal disease (as assessed by renal biopsy and protein excretion).
 
Patients with type 2 diabetes who have marked proteinuria and retinopathy typically have diabetic nephropathy, while those persons who do not have retinopathy frequently exhibit nondiabetic glomerular disease.

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