Nephropathy

• Affects up to 40% of adults with diabetes and is a major cause of ESRD [1]

• Onset varies depending on the type of diabetes: [1]

  • Type 1 DM: Diabetic kidney disease usually occurs approx. 10 years after diagnosis.

  • Type 2 DM: may be present at the time of diagnosis

• Risk factors

  • 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

Three major histological changes can be seen on light microscopy.

• 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.

• In the later stages, clinical features of chronic kidney disease (e.g., hypertension, volume overload) may be present.

• 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

  • 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: [1]

  • 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

• Glomerular filtration rate (

  • Serum creatinine-based eGFR

    • Calculate using the CKD-EPI equation.

    • Persistent eGFR < 60 mL/min/1.73 m2 is considered abnormal.

  • Serum cystatin C-based eGFR (alternative); more accurate in transgender patients (see “Principles of transgender health care”)

• Urine studies: spot urine albumin to creatinine ratio

  • Perform in the morning if possible.

  • 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.

Microalbuminuria may progress to macroalbuminuria.

• Glycemic targets

  • Measure HbA1c at least twice yearly.

  • An HbA1c of < 6.5–8% is generally recommended.

• Pharmacotherapy

  • T1DM: Insulin dosage may need to be reduced as eGFR declines ; monitor patients for hypoglycemia. [5]

  • T2DM

    • Choice of treatment depends on eGFR; dosages may need to be adjusted or medications stopped as eGFR declines.

    • SGLT-2 inhibitors should be prescribed when possible, as they slow the progression of CKD.

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.

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.

Patients should undergo management of ASCVD risk factors in CKD with the following modifications for hypertension management:

• Patients with albuminuria

  • First-line: RAS inhibitors (ACE inhibitors or angiotensin receptor blockers)

  • Combination antihypertensive therapy: Consider if blood pressure is not controlled with an RAS inhibitor.

• Patients without albuminuria: Initiate first-line antihypertensive medication (i.e., RAS inhibitors, thiazide diuretics, or calcium channel blockers).

• Educate patients on diabetic kidney disease.

• Provide nutritional advice; consider dietitian consultation.

• Adjust the dosage of renally cleared medications based on eGFR and avoid nephrotoxins.

• Ensure patients are up-to-date on vaccinations (see “Immunization schedule”).

• Educate patients on diabetic kidney disease and the importance of attending screenings.

• Optimize management of diabetes to reach glycemic targets for DM.

• Treat underlying hypertension.

• Avoid prescribing nephrotoxic medications.

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

Screening for diabetic kidney disease

• Onset

  • T1DM: 5 years after diagnosis

  • T2DM: from the time of diagnosis

• Recommended assessment

  • 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.”