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Diabetic Nephropathy

(End-Stage Renal Disease)


Frank O'Brien

, MD, Washington University in St. Louis

Reviewed/Revised Jun 2023
Topic Resources

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 angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs]), and control of blood pressure and lipids.

Diabetic nephropathy is the most common cause of nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more in adults. Diabetic nephropathy is also the most common cause of end-stage kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more Chronic Kidney Disease in the United States, accounting for up to 80% of cases. The prevalence of renal failure is probably about 40% among patients with type 1 diabetes mellitus Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more . 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 people who are Black, Mexican-American, Polynesian, and Pima Indian. Other risk factors include the following:

Because type 2 diabetes is often present for several years before being recognized, nephropathy often develops < 10 years after diabetes is diagnosed.

End-stage kidney disease (ESKD) usually takes 10 years after the onset of nephropathy to develop.

Pathophysiology of Diabetic Nephropathy

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 kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more Chronic Kidney Disease .

Depictions of Diabetic Nephropathy

Diabetic nephropathy begins as glomerular hyperfiltration (increased glomerular filtration rate [GFR]); GFR normalizes with early renal injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more and mild hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more 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 kidney disease, on average, by about 3 to 5 years, but this timing is also highly variable.

Symptoms and Signs of Diabetic Nephropathy

In later stages, patients may develop symptoms and signs of uremia (eg, nausea, vomiting, anorexia) earlier (ie, with higher glomerular filtration rate [GFR]) than do patients without diabetic nephropathy, possibly because the combination of end-organ damage due to diabetes (eg, neuropathy) and renal failure worsens symptoms.

Diagnosis of Diabetic Nephropathy

  • Yearly screening of all patients with diabetes with random urine albumin/creatinine ratio

  • Urinalysis for signs of other renal disorders (eg, hematuria, red blood cell [RBC] casts)

  • Heavy proteinuria with only a brief history of diabetes

  • Absence of diabetic retinopathy

  • Rapid onset of heavy proteinuria

  • Gross hematuria

  • RBC casts

  • Rapid decline in glomerular filtration rate (GFR)

  • Small kidney size

Urinary protein

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 30 mg/g ( 34 mg/mmol) indicates microalbuminuria if it is present on at least 2 of 3 specimens within 3 to 6 months and if it cannot be explained by infection or exercise.

Some experts recommend that microalbuminuria be measured from a 24-hour 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-hour 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.


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 years after diagnosis and at least annually thereafter.

Patients with type 2 diabetes should be screened at the time of diagnosis and annually thereafter.

Treatment of Diabetic Nephropathy

  • Maintenance of glycosylated Hb (HbA1C) 7.0

  • Aggressive blood pressure (BP) control, beginning with angiotensin inhibition

  • Treatment of dyslipidemia

Blood glucose control

Primary treatment is strict glucose control to maintain HbA1C 7.0; maintenance of euglycemia reduces microalbuminuria but may not retard disease progression once diabetic nephropathy is well-established.

Blood pressure control

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, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are the antihypertensives of choice; they reduce BP and proteinuria and slow the progression of diabetic nephropathy. ACE inhibitors are usually less expensive, but ARBs 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 medications 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 Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There... read more or other contraindications to ACE inhibitors or ARBs.

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.


Statins should be used as first-line therapy for dyslipidemia treatment in patients with diabetic nephropathy because they reduce cardiovascular mortality and urinary protein.

Other treatments

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.

SGLT 2 inhibitors should also be given to patients with type 2 diabetes, but not those with type 1 diabetes or those with an eGFR of < 20 mL/minute. Inhibition of the sodium glucose transporter has been shown to reduce the progression of kidney disease (1, 2, 3 Treatment references 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... read more Treatment references ).

Vitamin D supplementation, typically with cholecalciferol (vitamin D3).

Treatments for edema can include the following:

  • Dietary sodium restriction (eg, < 2 g/day)

  • Fluid restriction

  • Loop diuretics, as needed, with careful titration to avoid hypovolemia

Kidney transplantation

Treatment references

Prognosis for Diabetic Nephropathy

Key Points

  • 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 blood pressure aggressively, usually beginning with angiotensin inhibition.

  • Treat increased albuminuria with angiotensin inhibition.

  • Control glucose to maintain HbA1C at ≤ 7.0.

  • Treat dyslipidemia with a statin.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

  • American Diabetes Association: Information about diabetes, from risk assessment to advocacy for adequate and affordable health care for everyone who is at risk of diabetes.

Drugs Mentioned In This Article

Drug Name Select Trade
Albuked , Albumarc, Albuminar, Albuminex, AlbuRx , Albutein, Buminate, Flexbumin, Kedbumin, Macrotec, Plasbumin, Plasbumin-20
Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT , Dilacor XR, Dilt-CD , Diltia XT, Diltzac, Matzim LA, Taztia XT, TIADYLT ER, Tiamate, Tiazac
Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM
Adalat, Adalat CC, Afeditab CR, Nifediac CC, Nifedical XL, Procardia, Procardia XL
Katerzia, Norliqva, Norvasc
Calcidol, Calciferol, D3 Vitamin, DECARA, Deltalin, Dialyvite Vitamin D, Dialyvite Vitamin D3, Drisdol, D-Vita, Enfamil D-Vi-Sol, Ergo D, Fiber with Vitamin D3 Gummies Gluten-Free, Happy Sunshine Vitamin D3, MAXIMUM D3, PureMark Naturals Vitamin D, Replesta, Replesta Children's, Super Happy SUNSHINE Vitamin D3, Thera-D 2000, Thera-D 4000, Thera-D Rapid Repletion, THERA-D SPORT, UpSpring Baby Vitamin D, UpSpring Baby Vitamin D3, YumVs, YumVs Kids ZERO, YumVs ZERO
Alka-Seltzer Heartburn Relief, Baros, Neut
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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