(See also Complications of Diabetes Mellitus: Diabetic nephropathy.)
Diabetic nephropathy is the most common cause of nephrotic syndrome in adults. Diabetic nephropathy is also the most common cause of end-stage 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. 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.
Mesangial cell proliferation and matrix expansion with endothelial damage are manifest here as thickened glomerular basement membranes without evident immune complex deposits (periodic acid-Schiff stain, ×400).
Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).
Formation of acellular nodules within mesangial matrix is a distinctive feature of diabetic nephropathy (periodic acid-Schiff stain, ×200).
Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).
Hyalinosis of both afferent and efferent arterioles.
Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).
Mesangial cell proliferation and matrix expansion with endothelial damage are manifest here as thickened glomerular basement membranes without evident immune complex deposits (periodic acid-Schiff stain, ×400).
Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).
Formation of acellular nodules within mesangial matrix is a distinctive feature of diabetic nephropathy (periodic acid-Schiff stain, ×200).
Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).
Hyalinosis of both afferent and efferent arterioles.
Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).
Diabetic nephropathy begins as glomerular hyperfiltration (increased glomerular filtration rate [GFR]); GFR normalizes with early renal injury and mild hypertension>> 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, and urinary tract infections. 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 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 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
Urinalysis for signs of other renal disorders (eg, hematuria, red blood cell [RBC] casts)
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 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
Gross hematuria
RBC casts
Rapid decline in glomerular filtration rate (GFR)
Small kidney size
Urinary protein
≥ 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.
> 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.
Screening
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
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 blockershyperkalemia or other contraindications to ACE inhibitors or ARBs.
Dyslipidemia
Dyslipidemia 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.
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).
typically with cholecalciferol (vitamin D3).
, given to maintain a serum bicarbonate concentration > 22 mEq/L (22 mmol/L), may slow disease progression in patients with chronic kidney disease and metabolic acidosis.
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
Kidney transplantation with or without simultaneous or subsequent pancreas transplantation is an option for patients with end-stage kidney disease. 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
1. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et alN Engl J Med 383(15):1436-1446, 2020. doi: 10.1056/NEJMoa202481
2. Perkovic V, Jardine MJ, Neal B, et alN Engl J Med 13;380(24):2295-2306, 2019. doi: 10.1056/NEJMoa1811744
3. Zinman B, Wanner C, Lachin JM, et alN 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 (stroke, myocardial infarction, peripheral arterial disease) predicts an increase in mortality.
Key Points
Diabetic nephropathy is very common, asymptomatic until late, and should be considered in all patients with diabetes.
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.
