Diabetic Nephropathy

1. See Also
   1. Diabetes Mellitus
   2. Prevention of Kidney Disease Progression
   3. Coronary Artery Disease Prevention in Diabetes
   4. Acute Kidney Injury
   5. Intravenous Contrast Related Acute Renal Failure
   6. Drug Dosing in Chronic Kidney Disease
   7. Nephrotoxic Drugs
   8. Renal Osteodystrophy
   9. Risk Score for Prediction of Contrast-Induced Nephropathy After Percutaneous Coronary Intervention
   10. Hypertension in Diabetes Mellitus
   11. Hyperlipidemia in Diabetes Mellitus
   12. Antiplatelet Management in Diabetes Mellitus
2. Epidemiology
   1. Urine Microalbuminuria and Macroalbuminuria
      1. Prevalence in Diabetes Mellitus: 35%
   2. Stage 2-3 Chronic Kidney Disease in Diabetes Mellitus
      1. Stage 2-3 CKD Prevalence: 29% of those with Diabetes (2010)
   3. Stage 4-5 Chronic Kidney Disease (ESRD) in Diabetes Mellitus
      1. Diabetes Mellitus accounts for 44% of all new cases of ESRD in United States (2008)
      2. Prevalence: Over 200,000 cases of ESRD in Diabetes Mellitus in United States (2008)
      3. Incidence: Approximately 48,000 new cases of Diabetes related ESRD annually in United States (2008)
3. Risk Factors: Microlbuminuria
   1. Hypertension
   2. Higher average Serum Glucose
   3. Hyperlipidemia
   4. Tobacco abuse
   5. Type II Diabetes Mellitus
      1. Even more than Type I Diabetes Mellitus
   6. Ethnic groups with higher risk of developing Microalbuminuria
      1. Native american
      2. Asian
      3. Hispanic
      4. Black
4. Precaution
   1. Worsening Renal Function may present with sudden improvement in glycemic control or Hypoglycemia
5. 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
6. Protocol: Monitoring
   1. Initiating monitoring
      1. Type I Diabetes Mellitus: 5 years after diagnosis
      2. Type II Diabetes Mellitus: Start at time of diagnosis
   2. Labs
      1. Spot Urine Albumin to Creatinine Ratio (random Urine Microalbumin)
         1. Obtain every 6-12 months
      2. Serum Creatinine with estimated GFR
         1. Obtain every 6-12 months
7. Labs: Urine Microalbumin
   1. See Urine Microalbumin (Urine Albumin to Creatinine Ratio) for diagnostic criteria
   2. Nephropathy diagnosis needs 2 of 3 samples positive
   3. Spot Urine Albumin to Creatinine Ratio (first morning void preferred)
      1. Microalbuminuria: 30-300 mcg/mg Creatinine
      2. Macroalbuminuria: >300 mcg/mg Creatinine
8. Imaging: Renal Ultrasound
   1. Evaluation for reversible causes of Kidney disease
   2. Indications
      1. New onset Chronic Kidney Disease
      2. New onset Microalbuminuria or Macroalbuminuria
9. Diagnostics: Biopsy
   1. Indications: Unclear diagnosis (see precautions below)
   2. Findings suggestive of classic Diabetic Nephropathy
      1. Light microscopy
         1. Glomerular sclerosis
         2. Nodular mesangial expansion and proliferation (Kimmelstiel-Wilson Nodules)
      2. Electron microscopy
         1. Glomerular basement membrane thickening
10. Management: General
    1. See Chronic Kidney Disease
    2. See Prevention of Kidney Disease Progression
    3. Avoid Nephrotoxins (e.g. NSAIDs)
    4. Most important modifiable factors (see below)
       1. Diabetes Mellitus glycemic control
       2. Hypertension Control
    5. Other modifiable factors
       1. Hyperlipidemia
11. Management: Diabetes Mellitus
    1. Tight glycemic control is critical to reduce risk of progression in Diabetic Nephropathy
       1. Keep Hemoglobin A1C <7%
       2. Better glycemic control reduces nephropathy risk
       3. Microalbuminuria risk with Hemoglobin A1C > 8.1%
       4. Precaution: ACCORD Study found higher overall mortality with intensive glycemic control in Type II Diabetes
          1. Gerstein (2008) N Engl J Med 358(24): 2545-59 [PubMed]
    2. References
       1. Krolewski (1995) N Engl J Med 332(19):1251-5 [PubMed]
       2. (2011) Diabetes Care 34(Suppl 1): S4-S10 [PubMed]
12. Management: Hypertension
    1. Hypertension goals
       1. Keep Blood Pressure under 130/80
       2. Isolated Systolic Hypertension goals
          1. Keep Systolic Blood Pressure under 140
       3. Avoid overaggressive Blood Pressure lowering to systolic Blood Pressure below 120 mmHg
          1. Associated with more adverse events (e.g. Hypotension, Bradycardia, Azotemia)
          2. Cushman (2010) N Engl J Med 362(17): 1575-85 [PubMed]
    2. First-line Antihypertensives: ACE Inhibitors and ARBs
       1. ACE Inhibitors and ARBs are preferred first-line agents for Hypertension and Proteinuria
          1. Best evidence is for Macroalbuminuria, in which case these agents are indicated even without Hypertension
          2. However evidence does not support ACE Inhibitor use for Microalbuminuria without Hypertension
             1. Microalbuminuria alone is not a good marker for renal disease
             2. (2012) Prescr Lett 19(4): 24
          3. Do not use ACE Inhibitors in combination with Angiotensin Receptor Blockers
             1. Higher rate of progression to ESRD
             2. Mann (2008) Lancet 372(9638): 547-53 [PubMed]
          4. Recent trials suggest ACE Inhibitors and ARBs are equivalent in renal outcomes
             1. Mann (2008) Lancet 372(9638): 547-53 [PubMed]
             2. Lewis (2001) N Engl J Med 345:851-60 [PubMed]
          5. All-cause mortality is reduced with ACE Inhibitors, but not with Angiotensin Receptor Blockers
             1. Strippoli (2004) BMJ 329(7470): 828 [PubMed]
          6. Indications to stop ACE Inhibitors or Angiotensin Receptor Blockers
             1. Serum Creatinine rises 30% or more above baseline in first 2 months of starting medication or
             2. Hyperkalemia persists with Serum Potassium >5.6 mEq/L
       2. Agents
          1. ACE Inhibitors (preferred - see above)
          2. Angiotensin Receptor Blockers (ARB)
    3. Second-line Antihypertensives
       1. Thiazide Diuretics (especially in combination with ACE Inhibitors or ARB agents above)
          1. Hydrochlorothiazide
          2. Chlorthalidone
          3. Bakris (2008) Kidney Int 73(11); 1303-9 [PubMed]
       2. Calcium Channel Blockers
          1. Renal protection
             1. Calcium Channel Blockers in general appear to be effective in maintaining Renal Function
             2. Segura (2005) JASN 16(3):S64-6 [PubMed]
          2. Proteinuria
             1. Non-Dihydropyridine Calcium Channel Blockers (e.g. Verapamil, Diltiazem)
                1. Reduce Proteinuria (less than ACE Inhibitor)
             2. Dihydropyridine Calcium Channel Blockers (mixed results)
                1. Amlodipine appears to also reduce Microalbuminuria
                   1. Bakris (2008) Kidney Int 73(11); 1303-9 [PubMed]
                2. Nifedipine may increase Proteinuria
13. 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 [PubMed]
    2. Protein restriction
       1. Efficacy
          1. Decreases Microalbuminuria
          2. Decreases progression to Macroalbuminuria
       2. Protocol
          1. Near Normal GFR: <0.8g/kg/day Protein
          2. Falling GFR: <0.6g/kg/day Protein
14. Management: Referral to Nephrology Indications
    1. Serum Creatinine over 2.0 mg/dl
    2. Glomerular Filtration Rate (GFR) less than 70 ml/min
15. Precautions: Findings that suggest cause other than typical Diabetic Nephropathy
    1. See Proteinuria Causes
    2. Albuminuria absent despite stage 3-5 CKD
    3. Diabetic Retinopathy absent despite Diabetic Nephropathy
    4. Active urinary sediment (red cells or casts accompany Proteinuria)
    5. Low GFR estimated at the time of initial diagnosis
    6. GFR reduced >30% within 3 months of starting ACE Inhibitor or Angiotensin Receptor Blocker (ARB)
    7. GFR decreases rapidly (4 ml/min/year)
    8. Proteinuria increases rapidly (or Nephrotic Syndrome)
    9. Refractory Hypertension
    10. (2007) Am J Kidney Dis 49(suppl 2): S12-S154 [PubMed]
16. Prognosis
    1. Dialysis usually needed when GFR reaches 10 ml/min
    2. Onset of Proteinuria after diagnosis of Diabetes Mellitus
       1. Microalbuminuria develops in 2.0% of patients with diabetes per year
       2. Macroalbuminuria develops in 2.8% of diabetic patients with Microalbuminuria per year
       3. Increased Serum Creatinine develops in 2.3% of diabetic patients with Macroalbuminuria per year
       4. Adler (2003) Kidney Int 63(1): 225-32 [PubMed]
    3. GFR decline after onset Microalbuminuria
       1. No ACE Inhibitor: 10 ml/min/year
       2. ACE Inhibitor: 4-6 ml/min/year
       3. Blood Pressure <130/80: 1-4 ml/min/year
17. Complications
    1. Microalbuminuria (and Macroalbuminuria) are associated with an increased cardiovascular mortality and overall mortality
18. References
    1. Molitch (1997) Am J Med 102:392-8 [PubMed]
    2. Cooper (1998) Lancet 352:213-9 [PubMed]
    3. Thorp (2005) Am Fam Physician 72:96-99 [PubMed]
    4. Roett (2012) Am Fam Physician 85(9): 883-9 [PubMed]