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Diabetic nephropathy is glomerular sclerosis and fibrosis caused by the metabolic and hemodynamic changes of diabetes mellitus. It manifests as slowly progressive albuminuria with worsening hypertension and renal insufficiency. Diagnosis is based on history, physical examination, urinalysis, and urine albumin/creatinine ratio. Treatment is strict glucose control, angiotensin inhibition (using ACE inhibitors or angiotensin II receptor blockers), and control of BP and lipids.
(See also Diabetes Mellitus (DM) : Diabetic nephropathy.)
Diabetic nephropathy (DN) is the most common cause of nephrotic syndrome in adults. Diabetic nephropathy is also the most common cause of end-stage renal disease in the US, accounting for up to 80% of cases. The prevalence of renal failure is probably about 40% among patients with type 1 diabetes mellitus. The prevalence of renal failure among patients with type 2 diabetes mellitus is usually stated as 20 to 30%, but this figure is probably low. Renal failure is particularly common in certain ethnic groups, such as blacks, Mexican-Americans, Polynesians, and Pima Indians. Other risk factors include the following:
Because type 2 diabetes is often present for several years before being recognized, nephropathy often develops < 10 yr after diabetes is diagnosed.
Renal failure usually takes ≥ 10 yr after the onset of nephropathy to develop.
Pathogenesis begins with small vessel disease. Pathophysiology is complex, involving glycosylation of proteins, hormonally influenced cytokine release (eg, transforming growth factor-beta), deposition of mesangial matrix, and alteration of glomerular hemodynamics. Hyperfiltration, an early functional abnormality, is only a relative predictor for the development of renal failure.
Hyperglycemia causes glycosylation of glomerular proteins, which may be responsible for mesangial cell proliferation and matrix expansion and vascular endothelial damage. The glomerular basement membrane classically becomes thickened.
Lesions of diffuse or nodular intercapillary glomerulosclerosis are distinctive; areas of nodular glomerulosclerosis may be referred to as Kimmelstiel-Wilson lesions. There is marked hyalinosis of afferent and efferent arterioles as well as arteriosclerosis; interstitial fibrosis and tubular atrophy may be present. Only mesangial matrix expansion appears to correlate with progression to end-stage renal disease.
DN begins as glomerular hyperfiltration (increased GFR); GFR normalizes with early renal injury and mild hypertension, which worsens over time. Microalbuminuria, urinary excretion of albumin in a range of 30 to 300 mg albumin/day, then occurs. Urinary albumin in these concentrations is called microalbuminuria because detection of proteinuria by dipstick on routine urinalysis usually requires >300 mg albumin/day. Microalbuminuria progresses to macroalbuminuria (proteinuria > 300 mg/day at a variable course, usually over years. Nephrotic syndrome (proteinuria ≥ 3 g/day) precedes end-stage renal disease, on average, by about 3 to 5 yr, but this timing is also highly variable.
Other urinary tract abnormalities commonly occurring with DN that may accelerate the decline of renal function include papillary necrosis, type IV renal tubular acidosis, and UTIs. In DN, the kidneys are usually of normal size or larger (> 10 to 12 cm in length).
DN is asymptomatic in early stages. Sustained microalbuminuria is the earliest warning sign. Hypertension and some measure of dependent edema eventually develop in most untreated patients.
In later stages, patients may develop symptoms and signs of uremia (eg, nausea, vomiting, anorexia) earlier (ie, with higher GFR) than do patients without DN, possibly because the combination of end-organ damage due to diabetes (eg, neuropathy) and renal failure worsens symptoms.
The diagnosis is suspected in patients with diabetes who have proteinuria, particularly if they have diabetic retinopathy (indicating small vessel disease) or risk factors for DN. Other renal disorders should be considered if there are any of the following:
Patients are tested for proteinuria by routine urinalysis; if proteinuria is present, testing for microalbuminuria is unnecessary because the patient already has macroalbuminuria suggestive of diabetic renal disease. In patients without proteinuria on urinalysis, an albumin/creatinine ratio should be calculated from a mid-morning urine specimen. A ratio ≥ 0.03 mg/mg (≥ 30 mg/g) indicates microalbuminuria if it is present on at least 2 of 3 specimens within 3 to 6 mo and if it cannot be explained by infection or exercise.
Some experts recommend that microalbuminuria be measured from a 24-h urine collection, but this approach is less convenient, and many patients have difficulty accurately collecting a specimen. The random urine albumin/creatinine ratio overestimates 24-h collection of microalbuminuria in up to 30% of patients > 65 due to reduced creatinine production from reduced muscle mass. Inaccurate results can also occur in very muscular patients or if vigorous exercise precedes urine collection.
For most patients with diabetes who have proteinuria, the diagnosis is clinical. Renal biopsy can confirm the diagnosis but is rarely necessary.
Patients with type 1 diabetes without known renal disease should be screened for proteinuria and, if proteinuria is absent on routine urinalysis, for microalbuminuria, beginning 5 yr after diagnosis and at least annually thereafter.
Patients with type 2 diabetes should be screened at the time of diagnosis and annually thereafter.
Prognosis is good for patients who are meticulously treated and monitored. Such care is often difficult in practice, however, and most patients slowly lose renal function; even prehypertension (BP 120 to 139/80 to 89 mm Hg) or stage 1 hypertension (BP 140 to 159/90 to 99 mm Hg) may accelerate injury. Systemic atherosclerotic disease (stroke, MI, peripheral arterial disease) predicts an increase in mortality.
Glucose control must also be accompanied by strict control of BP to < 130/80 mm Hg, although some experts now recommend BP < 140/90 mm Hg. Some suggest BP should be 110 to 120/65 to 80 mm Hg, particularly in patients with protein excretion of > 1 g/day; however, others claim that BP values < 120/85 mm Hg are associated with increased cardiovascular mortality and heart failure.
Angiotensin inhibition is first-line therapy. Thus, ACE inhibitors or angiotensin II receptor blockers are the antihypertensives of choice; they reduce BP and proteinuria and slow the progression of DN. ACE inhibitors are usually less expensive, but angiotensin II receptor blockers can be used instead if ACE inhibitors cause persistent cough. Treatment should be started when microalbuminuria is detected regardless of whether hypertension is present; some experts recommend drugs be used even before signs of renal disease appear.
Diuretics are required by most patients in addition to angiotensin inhibition to reach target BP levels. Dose should be decreased if symptoms of orthostatic hypotension develop or serum creatinine increases by more than 30%.
Nondihydropyridine calcium channel blockers (diltiazem and verapamil) are also antiproteinuric and renoprotective and can be used if proteinuria does not meaningfully decrease when target BP is reached or as alternatives for patients with hyperkalemia or other contraindications to ACE inhibitors or angiotensin II receptor blockers.
In contrast, dihydropyridine calcium channel blockers (eg, nifedipine, felodipine, amlodipine) do not reduce proteinuria, although they are useful adjuncts for BP control and may be cardioprotective in combination with ACE inhibitors. ACE inhibitors and nondihydropyridine calcium channel blockers have greater antiproteinuric and renoprotective effects when used together, and their antiproteinuric effect is enhanced by sodium restriction. Nondihydropyridine calcium channel blockers should be used with caution in patients taking beta-blockers because of the potential to worsen bradycardia.
Dietary protein restriction yields mixed results. The American Diabetes Association recommends that people with diabetes and overt nephropathy be restricted to 0.8 to 1.2 g protein/kg/day. Significant protein restriction is not recommended.
Vitamin D supplementation, typically with cholecalciferol (vitamin D3).
Sodium bicarbonate, given to maintain a serum bicarbonate concentration > 22 mEq/L, may slow disease progression in patients with chronic kidney disease and metabolic acidosis.
Treatments for edema can include the following:
Kidney transplantation with or without simultaneous or subsequent pancreas transplantation is an option for patients with end-stage renal disease. The 5-yr survival rate for patients with type 2 diabetes receiving a kidney transplant is almost 60%, compared with 2% for dialysis-dependent patients who do not undergo transplantation (though this statistic probably represents significant selection bias). Kidney allograft survival rate is > 85% at 2 yr.
Diabetic nephropathy is very common, asymptomatic until late, and should be considered in all patients with diabetes.
Periodically screen all patients with diabetes with urinalysis and, if proteinuria is absent, albumin/creatinine ratio calculated from a mid-morning urine specimen.
Treat BP aggressively, usually beginning with angiotensin inhibition.
Control glucose to maintain HbA1cat ≤ 7.0.
Drug NameSelect Trade
cholecalciferolNo US brand name
diltiazemCARDIZEM, CARTIA XT, DILACOR XR
nifedipineADALAT CC, PROCARDIA
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