(See also Complications of Diabetes Mellitus: Diabetic nephropathy Diabetic Nephropathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular)... read more .)
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 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:
Duration and degree of hyperglycemia
Certain polymorphisms affecting the renin-angiotensin-aldosterone axis
Family history of diabetic nephropathy
Genetic variables (decreased number of glomeruli)
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 .
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 , 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.
Other urinary tract abnormalities commonly occurring with diabetic nephropathy that may accelerate the decline of renal function include papillary necrosis, type IV renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is acidosis and electrolyte disturbances due to impaired renal hydrogen ion excretion (type 1), impaired bicarbonate resorption (type 2), or abnormal aldosterone... read more , and urinary tract infections Introduction to Urinary Tract Infections (UTIs) Urinary tract infections (UTIs) can be divided into upper tract infections, which involve the kidneys ( pyelonephritis), and lower tract infections, which involve the bladder ( cystitis), urethra... read more . In diabetic nephropathy, the kidneys are usually of normal size or larger (> 10 to 12 cm in length).
Symptoms and Signs of Diabetic Nephropathy
Diabetic nephropathy is asymptomatic in early stages. Sustained microalbuminuria is the earliest warning sign. 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 and some measure of dependent edema Edema Edema is swelling of soft tissues due to increased interstitial fluid. The fluid is predominantly water, but protein and cell-rich fluid can accumulate if there is infection or lymphatic obstruction... read more 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 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)
The diagnosis is suspected in patients with diabetes 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 who have proteinuria, particularly if they have diabetic retinopathy Diabetic Retinopathy Manifestations of diabetic retinopathy include microaneurysms, intraretinal hemorrhage, exudates, macular edema, macular ischemia, neovascularization, vitreous hemorrhage, and traction retinal... read more (indicating small vessel disease) or risk factors for diabetic nephropathy. Other renal disorders should be considered if there are any of the following:
Heavy proteinuria with only a brief history of diabetes
Absence of diabetic retinopathy
Rapid onset of heavy proteinuria
Rapid decline in glomerular filtration rate (GFR)
Small kidney size
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.
For most patients with diabetes who have proteinuria, the diagnosis is clinical. Renal biopsy Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more 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 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.
Dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more should also be treated.
Statins should be used as first-line therapy for dyslipidemia treatment in patients with diabetic nephropathy because they reduce cardiovascular mortality and urinary protein.
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 ).
Vitamin D supplementation, typically with cholecalciferol (vitamin D3).
Sodium bicarbonate, given to maintain a serum bicarbonate concentration > 22 mEq/L (22 mmol/L), may slow disease progression in patients with chronic 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 and metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more .
Treatments for edema can include the following:
Dietary sodium restriction (eg, < 2 g/day)
Loop diuretics, as needed, with careful titration to avoid hypovolemia
Kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more with or without simultaneous or subsequent pancreas transplantation Pancreas Transplantation Pancreas transplantation is a form of pancreatic beta-cell replacement that can restore normoglycemia in diabetic patients. (See also Overview of Transplantation.) Because the recipient exchanges... read more is an option for patients with 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 . The 5-year survival rate for patients with type 2 diabetes receiving a kidney transplant is almost 77%, compared with 88% for patients who do not have diabetes. Kidney allograft survival rates are > 97% and 77% among living and deceased donor transplant recipients, respectively, at 5 years (4, 5 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 ).
1. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al: Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383(15):1436-1446, 2020. doi: 10.1056/NEJMoa202481
2. Perkovic V, Jardine MJ, Neal B, et al: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 13;380(24):2295-2306, 2019. doi: 10.1056/NEJMoa1811744
3. Zinman B, Wanner C, Lachin JM, et al: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117-2128, 2015. doi: 10.1056/NEJMoa1504720
4. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Transplantation. Accessed May 19, 2023.
5. Harding JL, Pavkov M, Wang Z, et al: Long-term mortality among kidney transplant recipients with and without diabetes: A nationwide cohort study in the USA. BMJ Open Diabetes Res Care 9(1):e001962, 2021. doi: 10.1136/bmjdrc-2020-001962
Prognosis for Diabetic Nephropathy
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 Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries. The plaques contain lipids, inflammatory cells, smooth muscle... read more (stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more , myocardial infarction Acute Myocardial Infarction (MI) Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and/or diaphoresis... read more , peripheral arterial disease Peripheral Arterial Disease Peripheral arterial disease (PAD) is atherosclerosis of the extremities (virtually always lower) causing ischemia. Mild PAD may be asymptomatic or cause intermittent claudication; severe PAD... read more ) predicts an increase in mortality.
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.
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.
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