diabetic nephropathy; diabetic glomerulosclerosis; Kimmelstiel-Wilson disease (DMN)

Introduction

Stages of diabetic nephropathy:

• Stage 1
  • hyperfiltration
  • glomerular filtration rate 20-50% above normal
  • microalbuminuria (30-300 mg/24h)
• Stage 2
  • normalization of glomerular filtration rate
  • early structural damage
• Stage 3
  • early hypertension
• Stage 4
  • progression to proteinuria > 0.5 g/day
  • hypertension
  • declining glomerular filtration rate (GFR)
  • stage 4 lasts 3-15 years
• Stage 5
  • progression to end-stage renal disease (ESRD)
  • heavy proteinuria persists
  • stage 5 lasts 1-7 years

Epidemiology

• 30-40% of insulin-dependent (type-1) diabetics; develops after 10-20 years
• 10-30% of non-insulin-dependent (type-2) diabetics; develops after 5-10 years
• 30% of hospitalized patients with ESRD
• most common cause of ESRD in the USA
• most common cause of overall cause of nephrotic syndrome in adults
• Native Americans, blacks & hispanics especially at risk

Pathology

• non-enzymatic glycosylation
• renal hemodynamic changes
• hypertension
• thickening of the glomerular basement membrane, glomerulosclerosis or Kimmelstiel-Wilson change
• mesangial expansion
• nodular & diffuse glomerular scarring or sclerosis (Kimmelstiel-Wilson nodules)
• capsular drop lesions (pathognomonic)
• fibrin cap lesions (pathognomonic)
• microaneurysms of the glomerular capillaries
• other pathologic manifestations of diabetic nephropathy
  • interstitial fibrosis
  • tubular atrophy
  • papillary necrosis
  • perinephric abscess
  • acute pyelonephritis
  • neurogenic bladder
  • hydronephrosis
  • functional obstruction
  • cystitis
• may be role for AKR1B1 (aldehyde reductase)

Genetics

• susceptibility to diabetic nephropathy associated with defects in HFE protein

Clinical manifestations

• diabetes mellitus of long duration
• evidence of microvascular disease (retinopathy)
• evidence of macrovascular disease (cardiovascular disease)

Laboratory

• urine albumin, urine creatinine (microalbuminuria)
  • primary predictor of renal disease
  • proteinuria precedes decline in glomerular filtration
• urine albumin/creatinine ratio at least annually
  • starting with time of diagnosis type 2 diabetes
  • start witin 5 years of onset for type 1 diabetes
• serum creatinine
  • decline in GFR < 16 mL/min/1.73 m2
• bacteriuria is not uncommon
• low plasma renin

Management

• tight glycemic control
  • delays onset of nephropathy
  • prevents progression of microalbuminuria
  • does not reverse diabetic nephropathy
  • not effective when overt nephropathy is present
  • HgbA1c < 6% or > 9% associated with excess mortality
    • progression to ESRD not associated with glycemic control
  • target hemoglobin A1c of 6.5-8.0% when eGFR > 29 mL/min
• aggressive control of blood pressure (BP)
  • ACE inhibitors vs ARBs
    • ACE inhibitors & ARBs slow progression of diabetic nephropathy
    • ACE inhibitors or ARBs do not prevent or slow progression of diabetic nephropathy in normotensive diabetics with microalbuminuria, but may be a good choice for diabetics with hypertension
    • only ARBs better than placebo for preventing ESRD
    • adequate BP control & use of an ACE inhibitor or ARB slows progression of diabetic nephropathy
  • non-dihydropyridine Ca+2 channel blockers
    • diltiazem
    • verapamil
  • no drug better than placebo in terms of survival
  • may be of benefit in limiting progression of diabetic nephropathy in patients with overt proteinuria
  • decreased sodium intake to < 2 g/day
  • restrict alcohol intake & encourage weight loss
  • goals:
    • BP < 130/80 (mean < 100), < 140/70 mm Hg
    • systolic hypertension: goal is < 160 mm Hg
• ACE inhibitors
  • diminish transglomerular capillary hydrostatic pressure
  • slow progression from microalbuminuria to overt proteinuria & decrease degree of microalbuminuria or proteinuria when present
  • ACE inhibitors do slow progression of diabetic nephropathy in patients with macroalbuminuria
  • tend to decrease increasing creatinine
• angiotensin 2 receptor antagonists (ARB)
  • when ACE inhibitor is not tolerated
  • do not prevent microalbuminuria or progression of microalbuminuria to proteinuria
    • olmesartan may be exception (see microalbuminuria)
  • avoid combination of ACE inhibitor with ARB
  • combination of ARB & direct renin antagonist aliskiren may reduce proteinuria
• non-dihydropyridine Ca+2 channel blockers (diltiazem, verapamil)
  • do not prevent microalbuminuria
  • may slow progression from microalbuminuria to overt proteinuria
• paricalcitol (Zemplar) reduces albuminuria
• aldosterone receptor antagonist finerenone may slow decline in renal function
  • recommended for patients with type 2 diabetes & CKD with eGFR >= 25 mL/min & albuminuria & normal serum potassium
• glycemic control
  • target hemoglobin A1c 6.5-8.0% depending on risk of hypoglycemia
  • metformin & SGLT2 inhibitors (flozins) may be of benefit
    • dapagliflozin + saxagliptin may reduce albuminuria
    • canagliflozin (Invokana) is FDA-approved to reduce risk of ESRD
  • glucagon-like peptide-1 agonist (glutide) if metformin &/or flozin contraindicated or an add-on hypoglycemic agent needed
  • consider glucagon-like peptide-1 agonist (glutide) or SGLT2 inhibitor (flozin) independent of Hgb A1c
  • SGLT2 inhibitor (flozin) if eGFR >= 20 mL/min
    • renoprotective; slow progression of diabetic nephropathy
    • once started, flozin may be continued if eGFR declines < 20 mL/min until renal replacement therapy
• elderly with multiple comorbidities
  • relax glycemic control
  • if insulin needed, use once daily long-acting insulin
• diet
  • dietary protein restriction (0.8 g/kg/day)
  • < 2 grams of sodium/day
• neither vitamin D or omega-3 fatty acid supplementation or both preserve renal function in patients with diabetes mellitus type 2
• kidney or kidney-pancreas transplantation should be considered when creatinine rises above 4 mg/dL
• reduction of formation of advanced glycosylation endproducts (AGE) pigments may be of some benefit
  • aldose reductase inhibitors
  • inhibitors of nonenzymatic glycosylation
• refer to nephrologist when creatinine > 2 mg/dL

More general terms

• glomerulonephropathy; glomerulopathy
• chronic renal failure (CRF)
• microvascular complication of diabetes mellitus

Additional terms

• diabetes mellitus

Patient information

diabetic nephropathy patient information