Diabetic kidney disease

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Diabetic kidney disease is a chronic kidney disease (CKD) caused by chronic hyperglycemia and is a major cause of end-stage renal disease (ESRD). In type 1 diabetes mellitus (T1DM), diabetic kidney disease usually occurs 10 years after diagnosis, whereas it can occur at the time of onset of type 2 diabetes mellitus (T2DM). Patients are usually asymptomatic, and diagnosis is based on the presence of albuminuria and/or reduced eGFR and the exclusion of other causes of CKD. Management includes optimization of glycemic control through lifestyle modifications and pharmacotherapy, and management of CKD, including management of hypertension and ASCVD risk factors as needed.

• Affects up to 40% of adults with diabetes and is a major cause of ESRD ^[2]
• Onset varies depending on the type of diabetes: ^[2]
  • Type 1 DM: Diabetic kidney disease usually occurs approx. 10 years after diagnosis.
  • Type 2 DM: may be present at the time of diagnosis

Epidemiological data refers to the US, unless otherwise specified.

• Risk factors ^[2]
  • Hypertension and blood pressure variability
  • Longstanding diabetes
  • Inadequate glycemic control

Chronic hyperglycemia → glycation (also called non-enzymatic glycosylation or NEG) of the basement membrane (protein glycation) → increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole → hyperfiltration (increase in GFR) → increase in intraglomerular pressure; → progressive glomerular hypertrophy, increase in renal size, and glomerular scarring (glomerulosclerosis) → worsening of filtration capacity ^[3]

Three major histological changes can be seen on light microscopy. ^[4][5]

• Mesangial expansion
• Glomerular basement membrane thickening
• Glomerulosclerosis (later stages)
  • Diffuse hyalinization (most common) or
  • Pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules):
    • Glomerular capillary hypertension and hyperfiltration → increase in mesangial matrix → eosinophilic hyaline material in the area of glomerular capillary loops
    • Can progressively consume the entire glomerulus → hypofiltration (↓ GFR)

• Patients are usually asymptomatic in the early stages; some may report foamy urine. ^[6][7]
• In the later stages, clinical features of chronic kidney disease (e.g., hypertension, volume overload) may be present. ^[6]

Approach ^[2][6]

• Perform diagnostic studies for patients with positive results from screening for diabetic kidney disease.
• Diabetic kidney disease is confirmed through:
  • Laboratory studies showing persistent (≥ 3 months) albuminuria and/or reduced eGFR ^[6]
  • Exclusion of alternative causes of CKD (e.g., hypertensive nephropathy; , nephrotic syndrome); see “Diagnostics for CKD.”
• All patients require CKD staging.
• Refer patients with any of the following to nephrology for further evaluation: ^[2]
  • Diagnostic uncertainty
  • Active urinary sediment
  • Rapidly progressive albuminuria
  • Nephrotic syndrome
  • eGFR that is rapidly decreasing or < 30 mL/min/1.73 m²
  • Indications for renal replacement therapy
  • No concurrent diabetic retinopathy in patients with T1DM

Laboratory studies ^[2][6]

• Glomerular filtration rate (see also “Diagnostics for CKD”)
  • Serum creatinine-based eGFR
    • Calculate using the CKD-EPI equation.
    • Persistent eGFR < 60 mL/min/1.73 m² is considered abnormal. ^[6]
  • Serum cystatin C-based eGFR (alternative); more accurate in transgender patients (see “Principles of transgender health care”) ^[6]
• Urine studies: spot urine albumin to creatinine ratio ^[2]
  • Perform in the morning if possible. ^[6]
  • Urine albumin to creatinine ratio ≥ 30 mg/g is considered abnormal.

Repeat laboratory studies after 3–6 months to confirm persistent albuminuria and/or reduced eGFR. ^[6]

Microalbuminuria may progress to macroalbuminuria. ^[8]

Approach ^[2][6][9]

• Manage patients as part of a multidisciplinary team.
• Reduce the risk of further progression of CKD with:
  • Antihyperglycemic treatment of diabetes
  • Lifestyle recommendations for patients with diabetes mellitus
  • Management of hypertension
• Initiate management of CKD and any associated complications (e.g., electrolyte abnormalities).
• Screen for additional microvascular complications of diabetes because of the high risk of co-occurrence.
• Arrange scheduled follow-up for diabetic kidney disease.
• Refer to nephrology if patients experience worsening renal function or for assistance managing CKD complications.

Diabetic kidney disease usually occurs together with retinopathy in T1DM. ^[6][10]

Glycemic control and antihypertensive treatment can delay the progression of diabetic kidney disease. ^[2]

Management of underlying risk factors

Modifications to antihyperglycemic treatment in diabetic kidney disease ^[2][6][9]

• Glycemic targets ^[9]
  • Measure HbA1c at least twice yearly. ^[6]
  • An HbA1c of < 6.5–8% is generally recommended. ^[6]
  • HbA1c may not be an accurate method of glucose monitoring in patients with an eGFR < 30 mL/min/1.73 m²; consider continuous glucose monitoring.
• Pharmacotherapy ^[6]
  • T1DM: Insulin dosage may need to be reduced as eGFR declines ; monitor patients for hypoglycemia. ^[6]
  • T2DM
    • Choice of treatment depends on eGFR; dosages may need to be adjusted or medications stopped as eGFR declines. ^[2]
    • SGLT-2 inhibitors should be prescribed when possible, as they slow the progression of CKD. ^[6]
    • For dosages, see “Noninsulin antidiabetics for T2DM.”

SGLT-2 inhibitors improve renal and cardiovascular outcomes in patients with T2DM and CKD; their use is even recommended for patients who meet HbA1c targets. ^[6]

Adjust the dosing of antihyperglycemic medications in patients with reduced eGFR as needed. Metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m². ^[6]

Management of ASCVD risk factors for patients with diabetic kidney disease ^[6]

Patients should undergo management of ASCVD risk factors in CKD with the following modifications for hypertension management: ^[2][6]

• Patients with albuminuria: for dosages see “Antihypertensive therapy.”
  • First-line: RAS inhibitors (ACE inhibitors or angiotensin receptor blockers)
    • Titrate up gradually to the maximum tolerated dose. ^[6]
    • Monitor serum potassium and creatinine; do not discontinue until creatinine levels increase by > 30% from baseline.^[2]
  • Combination antihypertensive therapy: Consider if blood pressure is not controlled with an RAS inhibitor. ^[6]
  • Nonsteroidal mineralocorticoid receptor antagonists PLUS RAS inhibitor: for patients with persistent albuminuria refractory to therapy ^[6][10]
• Patients without albuminuria: : Initiate first-line antihypertensive medication (i.e., RAS inhibitors, thiazide diuretics, or calcium channel blockers). ^[6]

RAS inhibitors should not be prescribed to normotensive patients as trials have not shown a renoprotective effect in this cohort. ^[10]

Nonsteroidal mineralocorticoid receptor antagonists are associated with improved cardiovascular and renal outcomes. ^[6]

ACE inhibitors and angiotensin receptor blockers are potential teratogens and should not be used in pregnant patients. Avoid use in women of childbearing age who do not use contraception. ^[11][12]

Management of CKD in patients with diabetes ^[2][6][9]

• Educate patients on diabetic kidney disease. ^[6]
  • Advise patients that some treatments may cause an initial decline in eGFR.
  • Encourage patients to attend all recommended follow-up appointments.
  • See also “Managing chronic conditions.”
• Provide nutritional advice; consider dietitian consultation. ^[10]
  • Adjust protein intake based on CKD stage. ^[2][6]
  • Consider sodium restriction (below 2–2.3 g/day) and potassium restriction , if necessary. ^[6]
• Adjust the dosage of renally cleared medications based on eGFR and avoid nephrotoxins.
• Ensure patients are up-to-date on vaccinations (see “Immunization schedule”). ^[2]

Follow-up for diabetic kidney disease

• Reassess ASCVD risk factors every 3–6 months. ^[6]
• Patients with eGFR ≥ 60 mL/min/1.73 m^{2 [2]}
  • Mild to moderate albuminuria: Monitor annually (see “Screening for diabetic kidney disease”).
  • Severe albuminuria: Perform screening for diabetic kidney disease twice yearly.
• Patients with eGFR < 60 mL/min/1.73 m²: Regularly assess for complications of CKD. ^[2]
  • Check BP and assess for signs of fluid overload at each visit.
  • Check eGFR, urinary albumin, serum electrolytes, CBC, and markers for metabolic bone disease:
    • Every 6–12 months in stage 3 CKD
    • Every 3–5 months for stage 4 CKD
    • Every 1–3 months in stage 5 CKD

• Educate patients on diabetic kidney disease and the importance of attending screenings.
• Optimize management of diabetes to reach glycemic targets for DM. ^[2]
• Treat underlying hypertension. ^[2]
• Avoid prescribing nephrotoxic medications. ^[2]

RAS inhibitors slow the progression of diabetic kidney disease but do not prevent its development. ^[2]

Screening for diabetic kidney disease ^[2][6]

• Onset ^[6]
  • T1DM: 5 years after diagnosis
  • T2DM: from the time of diagnosis
• Recommended assessment ^[2]
  • eGFR ≥ 60 mL/min/1.73 m²: Check urine albumin levels and eGFR once a year.
  • eGFR < 60 mL/min/1.73 m²: more frequent assessment is required; see “Follow-up for diabetic kidney disease.”

Educate patients on the importance of regular screening; fewer than half of patients with diabetes have been screened for albuminuria in the past year. ^[6]