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. Overall
      1. Prevalence
         1. Of the 400 Million with Diabetes Mellitus worldwide, 20% have Diabetic Kidney Disease
      2. Incidence
         1. Develops in 2% of those with Diabetes Mellitus per year
   2. Urine Microalbuminuria and Macroalbuminuria
      1. Prevalence in Diabetes Mellitus: 35%
   3. Stage 2-3 Chronic Kidney Disease in Diabetes Mellitus
      1. Stage 2-3 CKD Prevalence: 29% of those with Diabetes (2010)
   4. 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. Advanced Age
   2. Male gender
   3. Hypertension
   4. Higher average Serum Glucose
   5. Hyperlipidemia
   6. Tobacco Abuse
   7. Alcohol Abuse
   8. Obesity
   9. Type II Diabetes Mellitus
      1. Even more than Type I Diabetes Mellitus
   10. 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 (30 to 300 mg/day) present
      2. Urine Albumin levels gradually rise during this phase
   2. Step 2: Overt Nephropathy phase
      1. Urine Albumin >300 mg/day
      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 (or at age 10 or Puberty onset if sooner)
      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 12 months
      2. Serum Creatinine with estimated GFR
         1. Obtain every 12 months
7. Labs: Urine Microalbumin
   1. See Urine Microalbumin (Urine Albumin to Creatinine Ratio) for diagnostic criteria
   2. Nephropathy diagnosis
      1. Microalbuminuria positive on 2 of 3 samples positive
      2. Macroalbuminuria positive on a single sample
   3. Spot Urine Albumin to Creatinine Ratio (first morning void preferred)
      1. Microalbuminuria: 30-300 mg/g Creatinine
      2. Macroalbuminuria: >300 mg/g Creatinine
   4. Indications to consider alternative diagnosis for Microalbuminuria
      1. False Positive (CHF, fever, acute infection, Menses, strenuous Exercise, severe Hyperglycemia)
      2. Low or rapidly decreasing GFR
      3. GFR drops >30% within 2-3 months of starting ACE Inhibitor or ARB
      4. Active urinary sediment
      5. Nephrotic Syndrome (or rapidly increasing Proteinuria)
      6. Refractory Hypertension
      7. Diabetic Retinopathy not present
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
11. Management: Diabetes Mellitus
    1. Multifactorial approach
       1. See Intensive Lifestyle Change In Type II Diabetes Mellitus
       2. See Type II Diabetes Medications
       3. See Exercise in Diabetes Mellitus
       4. Type II DM Glucose lowering medications preferred in renal disease prevention
          1. Metformin is a first-line agent for optimal Glucose management
          2. Second-line agents associated with reduced Kidney disease progression
             1. Sodium-Glucose Co-Transporter-2 Inhibitor (SGLT2 Inhibitor) - best evidence
             2. Glucagon-Like Peptide 1 (GLP-1 Agonist)
             3. Dipeptidyl Peptidase-4 Inhibitor (DPP-4 Inhibitor) - least effective
    2. Precautions
       1. Hemoglobin A1C is falsely lower in advanced Kidney disease due to Anemia
          1. Serum Glucose measurement log may be more accurate than A1C in CKD 4-5
    3. Ideal glycemic control is critical to reduce risk of progression in Diabetic Nephropathy
       1. Keep Hemoglobin A1C <7-8%
       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. Lead to goal targeting Hemoglobin A1C <8%
          2. Gerstein (2008) N Engl J Med 358(24): 2545-59 [PubMed]
    4. 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. Blood Pressure targets
          1. Target <140/90 (U.S. standard target as of 2019)
             1. JNC-8
             2. ADA (if patient WITHOUT multiple risk factors)
          2. Target <130/80
             1. ACC/AHA
             2. ADA (if patient WITH multiple risk factors)
       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. Lifestyle measures
       1. See Lifestyle Modification in Hypertension
    3. 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
             1. ACE Inhibitors and ARBs 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
          7. Other considerations
             1. Do not use if risk of pregnancy (Teratogenic)
             2. May be used in adolescents with Microalbuminuria
       2. Agents
          1. ACE Inhibitors (preferred - see above)
          2. Angiotensin Receptor Blockers (ARB)
    4. 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
    5. Third-Line Antihypertensives - Aldosterone Blockers
       1. Steroidal Aldosterone Antagonists (e.g. Spironolactone, Eplerenone)
          1. Beneficial in reducing Kidney disease progression when used in combination with ACE Inhibitors or ARBs
          2. However, risk of Hyperkalemia and requires close Potassium monitoring
          3. Currie (2016) BMC Nephrol 17(1): 127 [PubMed]
       2. Non-Steroidal Aldosterone Antagonists
          1. Finerenone (Kerendia)
             1. Nonsteroidal mineralcorticoid receptor antagonist released in 2021 at $570/month
             2. May limit renal fibrosis and inflammation and may decrease CKD progression
             3. Avoid in eGFR <25 ml/min, with risk of Hyperkalemia
             4. (2021) Presc Lett 28(10): 58-9
             5. Bakris (2020) N Engl J Med 383:2219-29 [PubMed]
13. Management: Hyperlipidemia
    1. Lipid lowering does not directly reduce renal disease progression
       1. However, Hyperlipidemia Management (esp. Statin) reduces cardiovascular mortality
       2. Cardiovascular mortality is among the highest risks for those with Diabetic Nephropathy
       3. Mortality benefit for those with ESRD on Dialysis is reduced
    2. Statin drugs
       1. Most Statins are renally excreted
       2. Renal Dosing is reduced for most Statins (except Atorvastatin)
14. Management: Dietary changes (incomplete evidence)
    1. 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
    2. Mediterranean Diet or DASH Diet
       1. Avoid high sugar, high saturated fat and highly processed carbohydrates
       2. Emphasize whole grains, fiber, fresh fruits and vegetables
       3. Encourage omega 3 Fatty Acids (and omega-9 fats)
       4. Limit Sodium to <2300 mg/day
       5. (2019) Diabetes Care 42(suppl 1):S46-60 [PubMed]
    3. 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]
15. Management: Referral to Nephrology Indications
    1. Serum Creatinine over 2.0 mg/dl
    2. Glomerular Filtration Rate (GFR) less than 70 ml/min
16. 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]
17. 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
18. Associated Conditions
    1. Diabetic Retinopathy often develops concurrently with Diabetic Kidney Disease
19. Complications
    1. Microalbuminuria (and Macroalbuminuria) are associated with an increased cardiovascular mortality and overall mortality
    2. Macroalbuminuria is a higher mortality risk per year (4.6%) than end-stage renal disease progression per year (2.3%)
20. References
    1. McGrath (2019) Am Fam Physician 99(12): 751-9 [PubMed]
    2. Molitch (1997) Am J Med 102:392-8 [PubMed]
    3. Cooper (1998) Lancet 352:213-9 [PubMed]
    4. Thorp (2005) Am Fam Physician 72:96-99 [PubMed]
    5. Roett (2012) Am Fam Physician 85(9): 883-9 [PubMed]