AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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

Diabetic nephropathy is the leading cause of chronic renal failure 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. Although both type 1 diabetes mellitus (insulin-dependent diabetes mellitus [IDDM]) and type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus [NIDDM]) lead to ESRD, the great majority of patients are those with NIDDM. In a prospective study in Germany, the 5-year survival rate was less than 10% in the elderly population with type 2 diabetes, and no more than 40% in the younger population with type 1 diabetes.

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 key change in diabetic glomerulopathy is augmentation of extracellular material.

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. Media file 2 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.

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 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.

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 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 (see Media file 3). 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

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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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
• Evidence of diabetic retinopathy after funduscopy or fluorescein 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

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Diabetic nephropathy must be differentiated from cholesterol embolization, amyloidosis, and other glomerulopathies affecting patients with diabetes.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Urinalysis
• • Regular annual urinalysis is recommended for screening for microalbuminuria (see Media file 4). 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 (ie, microalbuminuria can regress).
  • 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. Pathologic features are described in Pathophysiology.

Histologic Findings

See Pathophysiology.

Staging

See Media file 5.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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
  • Mogensen showed that antihypertensive treatment attenuates the rate of decline in renal function in patients who have IDDM, hypertension, and proteinuria. This is particularly significant when lowering of systemic blood pressure is accompanied with concomitant lessening of glomerular capillary pressure.
  • 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.
  • 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.
• RAS inhibition is effective in treating type 1 and type 2 diabetic nephropathy. ACE-I reduces the risk of progression of overt type 1 diabetic nephropathy to ESRD and in type 1 patients with microalbuminuria to overt nephropathy.
  • It is important to consider type 2 diabetic nephropathy separately from type 1, as there are significant differences between them. Both are characterized by the appearance of microalbuminuria, which leads to overt proteinuria and progressive loss of GFR.
  • A series of renal biopsy samples from patients with type 2 diabetes and proteinuria revealed that a significant proportion of these patients had glomerular lesions other than the classic lesions associated with type 1 diabetic nephropathy. ACE-I, which improves glomerular permeability in patients with type 1 diabetes as assessed by dextran clearances, do not do so in patients with type 2 diabetes. Furthermore, the superior effect of blockade of the RAS has been difficult to prove.
  • Two recent studies (The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] Study and the Irbesartan Diabetic Nephropathy Trial [IDNT]) demonstrated that angiotensin II receptor blockers (ARB) are superior to conventional therapy and amlodipine in slowing the progression of overt nephropathy.
  • These trials were performed with ARB and not ACE-I. This raised the question as to whether such beneficial results in patients with type 2 diabetes would be seen with ACE-I as well. Unfortunately, a large head-to-head comparison of ACE-I and ARB is unlikely to be made.
  • The choice between an ARB and an ACE-I is made more difficult by the results of the Microalbuminuria-Heart Outcomes Prevention Evaluation (MICRO-HOPE) Trial, in which ramipril reduced the risk for myocardial infarction, stroke, or cardiovascular death by 26% after 2 years. Perhaps, the more interesting question is whether the combination of ACE-I and ARB is more effective than either drug alone. Studies are ongoing to address this issue.
• 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.
  • In principle, diabetic patients who require renal replacement therapy have the following 4 options:
    • Refusal of further treatment for uremia, leading to a progressive decline in general health and ultimately leading to death
    • Peritoneal dialysis (eg, machine-assisted intermittent peritoneal dialysis, continuous ambulatory peritoneal dialysis, continuous cyclic peritoneal dialysis)
    • Hemodialysis (eg, facility hemodialysis, home hemodialysis)
    • Renal transplantation (eg, cadaver donor kidney, living related-donor kidney, living unrelated-donor kidney [emotionally related donor], living unrelated-donor kidney [unrelated by family or emotionally; the so-called altruistic donor], pancreas plus kidney transplantation)
  • Except in patients with severe macroangiopathic complications, renal transplantation should be considered a first-line objective because it offers the best degree of medical rehabilitation. This option must be discussed early on with the patient and his or her family. Transplantation even before dialysis (preemptive transplantation) is becoming increasingly popular in some centers.
  • Dialysis treatment partially reverses insulin resistance so that insulin requirements are often reduced. Adequate control of glycemia is important to prevent hyperglycemia-induced thirst, which can lead to volume overload and hyperkalemia. Proper attention must be given to optimizing nutrition, correcting anemia, controlling hypertension and hyperlipidemia, and modifying associated cardiovascular risk factors.
  • Regarding peritoneal dialysis, in a recently completed study, female patients with diabetes mellitus had a better outcome in the first 3 years of requiring renal replacement therapy when they chose peritoneal dialysis over hemodialysis. This positive effect did not continue beyond 3 years.
• Kidney transplantation and kidney-pancreas transplantation
• • Kidney transplantation offers the best medical rehabilitation in patients with uremia and diabetes.
  • Renal transplantation is generally restricted to younger patients with IDDM; this may not be completely justified because good results have also been achieved in patients with NIDDM if high-risk patients with macrovascular disease are excluded. Because of higher cardiovascular mortality, long-term survival of patients with diabetes with renal allografts is definitely inferior to that of those without diabetes.
  • In patients with IDDM, pancreas transplantation is the only treatment that consistently induces insulin independence. Recently, successful reports of islet cell transplantation have been presented.
  • Indications for pancreas transplantation in nonuremic patients have not been established. Generally, it is offered to patients with extremely brittle diabetes and documented episodes of hypoglycemia without preceding symptoms. In patients with IDDM and renal insufficiency, the following 2 options exist: (1) simultaneous kidney and pancreas transplantation and (2) first kidney and then pancreas transplantation (the latter is usually performed when patients receive a live donor graft).
  • Transplantation of the more immunogenic pancreas appears to have a higher risk of biopsy-proven acute kidney graft rejection episodes, but the 1-year graft and patient survival rates are not different from those in patients who had kidney transplantation alone.
  • The major rationale for combined kidney and pancreas transplantation is the increased quality of life and, probably, (controversial) halting or even reversing diabetic complications.

Surgical Care

• Surgical care in diabetic nephropathy is usually limited to the management of associated complications such as diabetic foot ulcers or peripheral vascular disease.
• Early creation of a surgical arteriovenous fistula or a graft is also an important part of the pre-ESRD related to diabetic nephropathy, as in any other renal disease.
• Other surgical aspects of diabetic nephropathy treatment are discussed in Renal replacement therapies in Medical Care and Kidney transplantation and kidney-pancreas transplantation in Medical Care.

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.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Major therapeutic interventions include near-normal blood glucose control, antihypertensive treatment, and restriction of dietary proteins.

Drug Category: Hormones

Stimulate proper use of glucose by cells and reduce blood sugar levels.

Drug Category: Sulfonylureas

Act primarily by stimulating release of insulin from beta cells. Extrapancreatic actions include increasing the number of insulin receptors and enhancing insulin-mediated glucose transport independent of increased insulin binding. Use of oral agents has decreased because more emphasis is placed on better control as a means of slowing the development of late complications. Indicated for some patients with relatively mild disease. Commonly used sulfonylureas include chlorpropamide, tolbutamide, glyburide, and glipizide.

Drug Name	Tolazamide (Tolinase)
Description	First-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Adult Dose	100-1000 mg/d PO qd/bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ketoacidosis
Interactions	Clofibrate, fenfluramine, H2 antagonists, androgens, azole antifungals, anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium salts, methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers, and sulfonamides may enhance hypoglycemic effects Nicotinic acid, oral contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids, cholestyramine, beta-blockers, calcium channel blockers, phenothiazines, rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics may decrease hypoglycemic effects; may increase effects of digitalis glycosides
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic and renal impairment; cardiovascular disorders may occur (risk factors include >65 y, malnutrition, irregular eating, impaired renal function, and, possibly, hepatic dysfunction); may cause rash; nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (very rare), intrahepatic cholestasis (very rare), disulfiram reaction, flushing, headache, and SIADH-causing hyponatremia may occur

Drug Name	Tolbutamide (Orinase)
Description	First-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Adult Dose	500-3000 mg/d PO bid/tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; type 1 diabetes; ketoacidosis
Interactions	Clofibrate, fenfluramine, H2 antagonists, androgens, azole antifungals, anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium salts, methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers, and sulfonamides may enhance hypoglycemic effects Nicotinic acid, oral contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids, cholestyramine, beta-blockers, calcium channel blockers, phenothiazines, rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics may decrease hypoglycemic effects; may increase effects of digitalis glycosides
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic and renal impairment; cardiovascular disorders may occur (risk factors include >65 y, malnutrition, irregular eating, impaired renal function, and, possibly, hepatic dysfunction); may cause rash; nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (very rare), intrahepatic cholestasis (very rare), disulfiram reaction, flushing, headache, and SIADH-causing hyponatremia may occur

Drug Name	Glyburide (DiaBeta, Micronase)
Description	Second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Adult Dose	1.25-20 mg/d PO qd/bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; type 1 diabetes; ketoacidosis
Interactions	Clofibrate, fenfluramine, H2 antagonists, androgens, azole antifungals, anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium salts, methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers, and sulfonamides may enhance hypoglycemic effects Nicotinic acid, oral contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids, cholestyramine, beta-blockers, calcium channel blockers, phenothiazines, rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics may decrease hypoglycemic effects; may increase effects of digitalis glycosides
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in hepatic and renal impairment; cardiovascular disorders may occur (risk factors include >65 y, malnutrition, irregular eating, impaired renal function, and, possibly, hepatic dysfunction); may cause rash; nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (very rare), intrahepatic cholestasis (very rare), disulfiram reaction, flushing, headache, and SIADH-causing hyponatremia may occur

Drug Name	Glipizide (Glucotrol)
Description	Second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Adult Dose	2.5-40 mg/d PO qd/bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; type 1 diabetes; ketoacidosis
Interactions	Beta-blockers, phenytoin, corticosteroids, and thiazides decrease hypoglycemic effects; cimetidine may increase hypoglycemic effects; ACE inhibitors enhance hypoglycemic activity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal or liver dysfunction; trauma, infection, surgery, or stress may require use of insulin

Drug Category: Biguanides

Useful in patients with NIDDM who are not responsive to diet and exercise. Usually added as an adjunctive agent in patients whose disease is not controlled by maximal doses of sulfonylureas. Occasionally, may be prescribed as monotherapy in diabetic patients who are obese.

Drug Category: Thiazolidinedione derivatives

Only active in presence of insulin. Approved for use in patients who are obese, have NIDDM, and whose diabetes is poorly controlled on insulin. Administered by some physicians as an add-on agent in patients with NIDDM who are on maximal doses of other oral agents.

Drug Category: Angiotensin-converting enzyme inhibitors

All except fosinopril are excreted primarily by the kidney. Have similar actions and adverse effects, including severe hypotension, acute renal failure (especially in bilateral renal artery stenosis), hyperkalemia, dry cough (sometimes accompanied by wheezing), and angioedema. Cough and angioedema are believed to be mediated by bradykinin.

Drug Name	Enalapril (Vasotec)
Description	Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.
Adult Dose	10-20 mg PO qd/bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; renal impairment, bilateral RAS or solitary kidney with RAS
Interactions	NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects may be enhanced when administered concurrently with diuretics; concurrent use of potassium supplements or potassium-sparing diuretics can result in hyperkalemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; caution in renal impairment, valvular stenosis, or severe congestive heart failure

Drug Name	Lisinopril (Monopril)
Description	Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.
Adult Dose	10-80 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects may be enhanced when administered concurrently with diuretics; concurrent use of potassium supplements or potassium-sparing diuretics can result in hyperkalemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; caution in valvular stenosis or severe congestive heart failure

Drug Category: Angiotensin receptor blockers

Specific and selective angiotensin II receptor antagonists. Compared with ACE inhibitors, ARBs are associated with a lower incidence of drug-induced cough, rash, and/or taste disturbances.

Drug Category: Beta-adrenergic blocking agents

Affect blood pressure via multiple mechanisms. Actions include negative chronotropic effect that decreases heart rate at rest and after exercise, negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from CNS, and suppression of renin release from kidneys.

Drug Category: Calcium channel blockers

Inhibit influx of extracellular calcium across both myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. Resultant decrease in intracellular calcium inhibits contractile processes of myocardial smooth muscle cells, resulting in dilation of coronary and systemic arteries and improved oxygen delivery to myocardial tissue. In addition, total peripheral resistance, systemic blood pressure, and afterload are decreased.

Provide control of hypertension associated with less impairment of function of the ischemic kidney. Calcium channel blockers may have beneficial long-term effects, but this remains uncertain.

Drug Category: Diuretics

Furosemide and bumetanide are loop diuretics that appear primarily to inhibit reabsorption of sodium and chloride in ascending limb of loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Following administration, renal vasodilation occurs, renal vascular resistance decreases, and renal blood flow is enhanced.

Hydrochlorothiazide is a thiazide diuretic that inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water and potassium and hydrogen ions.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 (Hba1c <7%)
• Control of hypertension (BP <120/70)
• 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.
• For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article Diabetes.
• For further information, see Mayo Clinic - Kidney Transplant Information.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Excluding the presence of other glomerular and nonglomerular diseases in a patient who is diabetic is important, especially if the diabetes is not of long-standing duration or no other typical features, such as proteinuria, or other associated manifestations of diabetes, such as retinopathy, are present.

Special Concerns

• 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.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Diabetic nephropathy. Rate of decline in glomerular filtration rate in various stages of type 1 and type 2 diabetes.
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Media file 2:  Simple schema for the pathogenesis of diabetic nephropathy.
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Media file 3:  Diabetic nephropathy. The prevalence, incidence, and cumulative incidence of microalbuminuria and nephropathy in diabetes mellitus.
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Media file 4:  Diabetic nephropathy. Screening for and prevention of the progression of microalbuminuria in diabetes mellitus, in which ACE-I is angiotensin-converting enzyme inhibitor.
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Media file 5:  Stages in the development of diabetic nephropathy.
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Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet. Jul 18 1998;352(9123):213-9. [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. Kidney Int. Jun 1995;47(6):1703-20. [Medline].
• 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].
• Matsuoka S, Awazu M. Masked hypertension in children and young adults. Pediatr Nephrol. Apr 8 2004;[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].
• Tanaka Y, Atsumi Y, Matsuoka K, et al. 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].
• 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). Lancet. Sep 12 1998;352(9131):837-53. [Medline].

Article Last Updated: Aug 23, 2006