Diabetic Nephropathy

1. Pathophysiology: Nephropathy progression
   1. Step 1: Incipient Nephropathy phase
      1. Microalbuminuria (low levels of albumin) present
      2. Urine Albumin levels gradually rise during this phase
   2. Step 2: Overt Nephropathy phase
      1. Urine Albumin >300 mg/24 hours
      2. Hyperfiltration transiently occurs
         1. Glomerular filtration (Creatinine Clearance) rises
   3. Step 3: Renal Insufficiency
      1. Glomerular filtration (Creatinine Clearance) falls
      2. Ultimately Renal Failure ensues
2. Monitoring
   1. Monitor for Microalbuminuria every 6-12 months
   2. Initiating monitoring
      1. Type I Diabetes Mellitus: 5 years after diagnosis
      2. Type II Diabetes Mellitus: Start at time of diagnosis
3. Labs: Urine Protein
   1. General
      1. Nephropathy diagnosis needs 2 of 3 samples positive
   2. Normal
      1. 24h Collection: <30 mg/day
      2. Timed Collection: <20 ug/min
      3. Spot Collection: <30 ug/mg Creatinine
   3. Microalbuminuria
      1. 24h Collection: 30-300 mg/day
      2. Timed Collection: 20-200 ug/min
      3. Spot Collection: 30-300 ug/mg Creatinine
   4. Clinical albuminuria
      1. 24h Collection: >300 mg/day
      2. Timed Collection: >200 ug/min
      3. Spot Collection: >300 ug/mg Creatinine
4. Management
   1. Tight glycemic control
      1. Keep Hemoglobin A1C <7%
      2. Better glycemic control reduces nephropathy risk
      3. Microalbuminuria risk with Hemoglobin A1C > 8.1%
      4. Krolewski (1995) N Engl J Med 332(19):1251-5
   2. Control Hyperlipidemia
   3. Control Hypertension
      1. Antihypertensives
         1. ACE Inhibitors (preferred)
         2. Angiotensin Receptor Blockers (ARB)
            1. Also slows nephropathy progression
            2. Lewis (2001) N Engl J Med 345:851-60
         3. Non-Dihydropyridine Calcium Channel Blockers
            1. Example: Diltiazem
            2. Reduces Proteinuria (less than ACE Inhibitor)
         4. Avoid Dihydropyridine Calcium Channel Blockers
            1. Nifedipine, Amlodipine may increase Proteinuria
      2. Hypertension goals
         1. Keep Blood Pressure under 130/80
         2. Isolated Systolic Hypertension goals
            1. Keep Systolic Blood Pressure under 140
5. Management: Dietary changes (incomplete evidence)
   1. Dietary modification: CR-LIPE
      1. Better than protein restriction in retarding CRI
      2. Components
         1. 50% carbohydrate restricted (CR)
         2. Low Iron available (LI)
         3. Polyphenol enriched (PE)
      3. References
         1. Facchini (2003) Diabetes 52:1204-9
   2. Protein restriction
      1. Near Normal GFR: <0.8g/kg/day Protein
      2. Falling GFR: <0.6g/kg/day Protein
6. Management: Referral to Nephrology Indications
   1. Serum Creatinine over 2.0 mg/dl
   2. Glomerular Filtration Rate (GFR) less than 70 ml/min
7. Precautions: Findings that suggest cause other than typical Diabetic Nephropathy
   1. Albuminuria absent despite stage 3-5 CKD
   2. Diabetic Retinopathy absent despite Diabetic Nephropathy
   3. Active urinary sediment (red cells or casts accompany Proteinuria)
   4. Low GFR estimated at the time of initial diagnosis
   5. GFR reduced >30% within 3 months of starting ACE Inhibitor or ARB
   6. GFR decreases rapidly (4 ml/min/year)
   7. Proteinuria increases rapidly (or Nephrotic Syndrome)
   8. Refractory Hypertension
   9. (2007) Am J Kidney Dis 49(suppl 2): S12-S154
8. Prognosis
   1. Dialysis usually needed when GFR reaches 10 ml/min
   2. GFR decline after onset microalbuminuria
      1. No ACE Inhibitor: 10 ml/min/year
      2. ACE Inhibitor: 4-6 ml/min/year
9. References
   1. Molitch (1997) Am J Med 102:392-8
   2. Cooper (1998) Lancet 352:213-9
   3. Thorp (2005) Am Fam Physician 72:96-99