INTRODUCTION

• 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

• 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.

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

• 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

• 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).

• 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 both the cellular hypertrophy and enhanced collagen synthesis observed in persons with diabetic nephropathy.

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

Figure 1. General features of hyperglycemia-induced tissue damage.

     

Figure 2.  Hyperglycemia increases flux through the polyol pathway. From Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414:813-820, 2001.      

Figure 3.  Increased production of AGE precursors and its pathologic consequences. From Brownlee M: Biochemistry and molecular cell

biology of diabetic complications. Nature 414:813-820, 200

Figure 4. Consequences of hyperglycemia-induced activation of PKC.

     

Figure 5.  Hyperglycemia increases flux through the hexosamine pathway. From Brownlee M: Biochemistry and molecular cell biology of

diabetic complications. Nature 414:813-820, 2001.      

Figure 6. Hyperglycemia-induced production of superoxide by the mitochondrial electron transport chain.

Figure 8.  Mitochondrial overproduction of superoxide activates four major pathways of hyperglycemic damage by inhibiting GAPDH. From

Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414:813-820, 2001.

Figure 9. ROS-induced DNA damage activates PARP and modifies GAPDH

Figure 10. The unifying mechanism of hyperglycemia-induced cellular damage

Figure 11.  Insulin resistance causes mitochondrial overproduction of ROS in macrovascular endothelial cells by increasing FFA flux and oxidation. From Hofmann S,

Brownlee M: Biochemistry and molecular cell biology of diabetic complications: a unifying mechanism. In Diabetes Mellitus: A Fundamental and Clinical Text . 3rd ed. LeRoith D, Taylor SI, Olefsky JM, Eds. Philadelphia, Lippincott Williams & Wilkins, p. 1441-1457,

2004.      

Figure 12. Excess superoxide independently inhibits activity of two critical antiatherogenic enzymes without involvement of the four

pathways of hyperglycemic damage. From refs.[51] and [52]

Frequency: • In the US: 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 declin. 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.

• Internationally: 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 incidences and prevalences 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 • In white persons, the prevalence of progressive

renal disease is generally lower in those with NIDDM than in those with IDDM. This does not apply to persons of all racial groups who have NIDDM, and some have a more ominous renal prognosis. For example, nephropathy develops in as many as 50% of Pima Indians with diabetes at 20 years, with 15% having progressed to ESRD by this time. Additionally, the Pima Indians, among certain other racial or ethnic groups, have a high incidence of diabetic nephropathy, suggesting familial clustering.

• 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 examination

• 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• Evidence of diabetic retinopathy after funduscopy or

fluorescin angiography• Peripheral vascular occlusive disease (decreased

peripheral pulses, carotid bruits)• Evidence for diabetic neuropathy (evidenced by

decreased fine sensations, diminished tendon reflexes)• Evidence for fourth heart sound during cardiac

auscultation• Nonhealing skin ulcers/osteomyelitis

DIFFERENTIALS • Nephritis, Interstitial

Nephrosclerosis Nephrotic Syndrome Renal Artery Stenosis Renal Vein Thrombosis Renovascular Hypertension multiple mylomaOther Problems to be Considered: Diabetic nephropathy must be differentiated from cholesterol embolization, amyloidosis, and other glomerulopathies affecting patients with diabetes.

WORKUP • Lab Studies • Urinalysis

– Regular annual urinalysis is recommended for screening for microalbuminuria Typically, the urinalysis results from a patient with established diabetic nephropathy show proteinuria varying from 150 mg/dL to greater than 300 mg/dL, glucosuria, and occasional hyaline casts.

– Microalbuminuria is defined as albumin excretion of more than 20 mcg/min. This phase indicates incipient diabetic nephropathy and calls for aggressive management, at which stage the disease may be potentially reversible.

– A 24-hour urinalysis for urea, creatinine, and protein is extremely useful in quantifying protein losses and estimating the GFR.

– Perform microscopic urinalysis to help rule out a potentially nephritic picture, which may lead to a workup to rule out other primary glomerulopathies, especially in the setting of rapidly deteriorating renal function (eg, rapidly progressive glomerulonephritis).

Imaging Studies: • Renal ultrasound

– Observe for kidney size, which is usually normal to increased in the initial stages and, later, decreased or shrunken with chronic renal disease.

– Rule out obstruction.– Perform echogenicity studies for chronic renal disease.

• Procedures: Serum and urinary electrophoresis is performed mainly to help exclude multiple myeloma (in the appropriate setting) and to classify the proteinuria (which is predominantly glomerular in diabetic nephropathy).

• Renal biopsy is not routinely indicated in all cases of diabetic nephropathy, especially in persons with a typical history and a progression typical of the disease. It is indicated if the diagnosis is in doubt, if other kidney disease is suggested, or if atypical features are present.

TREATMENT • Medical Care: Several issues are key in the medical care of

patients with diabetic nephropathy

• Glycemic control • In persons with either IDDM or NIDDM, hyperglycemia has

been shown to be a major determinant of the progression of diabetic nephropathy. The evidence is best reported for type 1 diabetes mellitus.

• It has been shown that intensive therapy can partially reverse glomerular hypertrophy and hyperfiltration, delay the development of microalbuminuria, and stabilize or even decrease protein levels in patients with microalbuminuria.

• Results from pancreatic transplant recipients in which true euglycemia is restored suggest that strict glycemic and metabolic control may slow the progression rate of progressive renal injury even after overt dipstick-positive proteinuria has developed.

• In type 2 diabetes, reduction in microvascular complications in patients receiving intensive insulin therapy was of a smaller magnitude than in patients with type 1 diabetes in the Diabetes Control and Complications Trial. In an outcome and cost-effective analysis of the United Kingdom Prospective Diabetes Study, the authors concluded that intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications

Antihypertensive treatment • In general, antihypertensive therapy, irrespective of

the agent used, slows the development of diabetic glomerulopathy; however, ACE inhibitors confer superior long-term protection even compared with triple therapy with reserpine, hydralazine, and hydrochlorothiazide or a calcium (Ca+) channel blocker (nifedipine). In addition to beneficial cardiovascular effects, ACE inhibition has also been demonstrated to have a significant beneficial effect on the progression of diabetic retinopathy and the development of proliferative retinopathy.

• ACE inhibition delays the development of diabetic nephropathy. In the ACE inhibition arm of a large trial, only 7% of patients with microalbuminuria experienced progression to overt nephropathy; however, in the placebo-treated group, 21% of patients experienced progression to overt nephropathy. The beneficial effect of ACE inhibition on preventing progression from microalbuminuria to overt diabetic nephropathy is long-lasting (8 y) and is associated with the preservation of a normal GFR.

• The impact of ACE inhibition in patients with microalbuminuric NIDDM has also been evaluated. Treatment with an ACE inhibitor for 12 months has significantly reduced mean arterial blood pressure and the urinary albumin excretion rate in NIDDM patients who have microalbuminuria.

• Normotensive patients with microalbuminuric NIDDM received enalapril or placebo for 5 years. Of the patients, 12% in the actively treated group experienced diabetic nephropathy, with a rate of decline in kidney function of 13%, and 42% of the patients receiving placebo experienced nephropathy.

• From a therapeutic standpoint, preventing the progression of kidney disease is better achieved with a nonglycemic intervention, such as treatment with ACE inhibition. The antiproteinuric effect of ACE inhibition in patients with diabetic nephropathy varies considerably. Individual differences in the renin-angiotensin system may influence this variation. A potential role may exist for an insertion/deletion polymorphism of the ACE gene on this early antiproteinuric responsiveness in young patients with hypertension and IDDM who have developed diabetic nephropathy.

• Angiotensin receptor blocking (ARB) agents are also believed to exert similar or even additive beneficial effects to the ACE inhibitors, and trials are underway to study this issue.

•

• Long-term treatment with ACE inhibitors, usually combined with diuretics, reduces blood pressure and albuminuria and protects kidney function in patients with hypertension, IDDM, and nephropathy. Beneficial effects on kidney function have also been reported in patients with normotension, IDDM, and nephropathy.

• Meta-analysis has shown that ACE inhibitors are superior to beta-blockers, diuretics, and calcium channel blockers in reducing urinary albumin excretion in normotensive and hypertensive IDDM and NIDDM patients. This superiority is pronounced in the normotensive state, whereas it is diminished progressively with progressive blood pressure reduction. Reduced glomerular capillary hydraulic pressure in combination with diminished size- and charge-selective properties of the glomerular capillary membrane are the most likely mechanisms involved in the antiproteinuric effect of ACE inhibitors

• Dietary protein intake: A meta-analysis examining the effects of dietary protein restriction (0.5-0.85 g/kg/d) in diabetic patients suggested a beneficial effect on the GFR, creatinine clearance, and albuminuria. However, a large, long-term prospective study is needed to establish the safety, efficacy, and compliance with protein restriction in diabetic patients with nephropathy. Limitations include ensuring compliance in the patients.

• Specific therapies: This includes modification and/or treatment of associated risk factors such as hyperlipidemia, smoking, and hypertension.

Renal replacement therapies • As for any other patient with ESRD, diabetic patients

with ESRD can be offered hemodialysis, peritoneal dialysis, kidney transplantation, or combined kidney-pancreas transplantation.

• In patients with uremia of any cause, starting at a creatinine clearance of 10-15 mL/min is wise. In diabetic patients, starting earlier is useful when hypervolemia renders blood pressure uncontrollable, when the patient experiences anorexia and cachexia or other uremic symptoms, and when severe vomiting is the combined result of uremia and gastroparesis.

• Carefully explain the therapeutic options and modalities of renal replacement therapy to patients, their partners, and their families in an early stage of renal failure. In chronically ill patients with diabetes, this tends to be much more important than in those renal patients who do not have diabetes.

• As for any other patient with ESRD, diabetic patients with ESRD can be offered hemodialysis, peritoneal dialysis, kidney transplantation, or combined kidney-pancreas transplantation.

• In patients with uremia of any cause, starting at a creatinine clearance of 10-15 mL/min is wise. In diabetic patients, starting earlier is useful when hypervolemia renders blood pressure uncontrollable, when the patient experiences anorexia and cachexia or other uremic symptoms, and when severe vomiting is the combined result of uremia and gastroparesis.

• Carefully explain the therapeutic options and modalities of renal replacement therapy to patients, their partners, and their families in an early stage of renal failure. In chronically ill patients with diabetes, this tends to be much more important than in those renal patients who do not have diabetes.

Diet:

• The American Diabetic Association suggests diets of various energy intake (caloric values), depending on the patient. With advancing renal disease, protein restriction of as much as 0.8-1 g/kg/d may retard the progression of nephropathy.

• When nephropathy is advanced, the diet should reflect the need for phosphorus and potassium restriction, with the use of phosphate binders.

• Activity: • No restriction in activity is necessary for persons

with diabetic nephropathy, unless warranted by other associated complications of diabetes, such as associated coronary disease or peripheral vascular disease.

• Further Inpatient Care:

• Inpatient care is usually restricted to managing complications of diabetic nephropathy, such as volume overload, renal vein thrombosis, uremia complications (eg, pericarditis), and problems related to access.

• Further Outpatient Care:

• Regular outpatient follow-up is key in managing diabetic mellitum nephropathy successfully, with screening regularly for microalbuminuria, ensuring optimal glucose control, optimizing blood pressure, and screening for other associated complications of diabetes (eg, retinopathy, diabetic foot, cardiovascular disease).

• Pre-ESRD clinic referral is appropriate if the patient has overt diabetic nephropathy

Deterrence/Prevention • Optimal blood glucose control

• Control of hypertension

• Avoidance of potentially nephrotoxic substances such as nonsteroidal anti-inflammatory medications and aminoglycosides

• Early detection and optimal management of diabetes, especially in the setting of family history of diabetes

Complications: • Diabetic retinopathy is present in virtually all persons with IDDM who

have nephropathy, whereas only 50-60% of patients with proteinuric NIDDM have retinopathy. An absence of retinopathy requires further investigation for nondiabetic glomerulopathies. Blindness due to severe proliferative retinopathy or maculopathy is approximately 5 times more common in persons with IDDM or NIDDM and nephropathy than in persons who are normoalbuminuric.

• Macroangiopathy (eg, stroke, carotid artery stenosis, coronary heart disease, peripheral vascular disease) is 2-5 times more common in patients who are nephropathic.

• Peripheral neuropathy is present in almost all patients with advanced nephropathy. Foot ulcers with associated sepsis, which leads to amputation, occur frequently (>25%), probably because of a combination of neural and arterial disease.

• Autonomic neuropathy may be asymptomatic and simply manifest as abnormal cardiovascular reflexes, or it may result in debilitating symptoms.

• Nearly all patients have grossly abnormal results from autonomic function tests, with more than half the patients with advanced nephropathy having symptoms of autonomic neuropathy (ie, gustatory sweating, impotence, postural hypotension, and diarrhea in one study).

• Diabetic cystopathy is also a frequent (>30%) problem in these patients.

Prognosis: • The overall prevalence of microalbuminuria and macroalbuminuria in both

types of diabetes is approximately 30-35%. Diabetic nephropathy rarely develops before patients have had IDDM for at least 10 years, whereas approximately 3% of patients with newly diagnosed NIDDM 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.

• Microalbuminuria independently predicts cardiovascular morbidity, and both microalbuminuria and macroalbuminuria increase mortality from any cause in diabetes mellitus. Microalbuminuria also predicts 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 IDDM 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 IDDM and nephropathy. The cumulative incidence rate of ESRD in patients with proteinuria and IDDM is 50% 10 years after the onset of proteinuria, compared with 3-11% 10 years after the onset of proteinuria in European patients with NIDDM.

• Cardiovascular disease is also a major cause of death (15-25%) in persons with nephropathy and IDDM, 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.

• Pregnancy in a patient with diabetic nephropathy does not seem to accelerate functional loss. More overt bacteruria, increased range of proteinuria, and hypertension may occur after mid gestation