//fpnotebook.com/
Diabetic Nephropathy
Aka: Diabetic Nephropathy, Nephropathy of Diabetes Mellitus, Diabetic Kidney Disease, ACE Inhibitors and ARBs in Diabetic Nephropathy
- See Also
- Diabetes Mellitus
- Prevention of Kidney Disease Progression
- Coronary Artery Disease Prevention in Diabetes
- Acute Kidney Injury
- Intravenous Contrast Related Acute Renal Failure
- Drug Dosing in Chronic Kidney Disease
- Nephrotoxic Drugs
- Renal Osteodystrophy
- Risk Score for Prediction of Contrast-Induced Nephropathy After Percutaneous Coronary Intervention
- Hypertension in Diabetes Mellitus
- Hyperlipidemia in Diabetes Mellitus
- Antiplatelet Management in Diabetes Mellitus
- Epidemiology
- Overall
- Prevalence
- Of the 400 Million with Diabetes Mellitus worldwide, 20% have Diabetic Kidney Disease
- Incidence
- Develops in 2% of those with Diabetes Mellitus per year
- Urine Microalbuminuria and Macroalbuminuria
- Prevalence in Diabetes Mellitus: 35%
- Stage 2-3 Chronic Kidney Disease in Diabetes Mellitus
- Stage 2-3 CKD Prevalence: 29% of those with Diabetes (2010)
- Stage 4-5 Chronic Kidney Disease (ESRD) in Diabetes Mellitus
- Diabetes Mellitus accounts for 44% of all new cases of ESRD in United States (2008)
- Prevalence: Over 200,000 cases of ESRD in Diabetes Mellitus in United States (2008)
- Incidence: Approximately 48,000 new cases of Diabetes related ESRD annually in United States (2008)
- Risk Factors: Microlbuminuria
- Advanced Age
- Male gender
- Hypertension
- Higher average Serum Glucose
- Hyperlipidemia
- Tobacco Abuse
- Alcohol Abuse
- Obesity
- Type II Diabetes Mellitus
- Even more than Type I Diabetes Mellitus
- Ethnic groups with higher risk of developing Microalbuminuria
- Native american
- Asian
- Hispanic
- Black
- Precaution
- Worsening Renal Function may present with sudden improvement in glycemic control or Hypoglycemia
- Pathophysiology: Nephropathy progression
- Step 1: Incipient Nephropathy phase
- Microalbuminuria (30 to 300 mg/day) present
- Urine Albumin levels gradually rise during this phase
- Step 2: Overt Nephropathy phase
- Urine Albumin >300 mg/day
- Hyperfiltration transiently occurs
- Glomerular filtration (Creatinine Clearance) rises
- Step 3: Renal Insufficiency
- Glomerular filtration (Creatinine Clearance) falls
- Ultimately Renal Failure ensues
- Protocol: Monitoring
- Initiating monitoring
- Type I Diabetes Mellitus: 5 years after diagnosis (or at age 10 or Puberty onset if sooner)
- Type II Diabetes Mellitus: Start at time of diagnosis
- Labs
- Spot Urine Albumin to Creatinine Ratio (random Urine Microalbumin)
- Obtain every 12 months
- Serum Creatinine with estimated GFR
- Obtain every 12 months
- Labs: Urine Microalbumin
- See Urine Microalbumin (Urine Albumin to Creatinine Ratio) for diagnostic criteria
- Nephropathy diagnosis
- Microalbuminuria positive on 2 of 3 samples positive
- Macroalbuminuria positive on a single sample
- Spot Urine Albumin to Creatinine Ratio (first morning void preferred)
- Microalbuminuria: 30-300 mg/g Creatinine
- Macroalbuminuria: >300 mg/g Creatinine
- Indications to consider alternative diagnosis for Microalbuminuria
- False Positive (CHF, fever, acute infection, Menses, strenuous Exercise, severe Hyperglycemia)
- Low or rapidly decreasing GFR
- GFR drops >30% within 2-3 months of starting ACE Inhibitor or ARB
- Active urinary sediment
- Nephrotic Syndrome (or rapidly increasing Proteinuria)
- Refractory Hypertension
- Diabetic Retinopathy not present
- Imaging: Renal Ultrasound
- Evaluation for reversible causes of Kidney disease
- Indications
- New onset Chronic Kidney Disease
- New onset Microalbuminuria or Macroalbuminuria
- Diagnostics: Biopsy
- Indications: Unclear diagnosis (see precautions below)
- Findings suggestive of classic Diabetic Nephropathy
- Light microscopy
- Glomerular sclerosis
- Nodular mesangial expansion and proliferation (Kimmelstiel-Wilson Nodules)
- Electron microscopy
- Glomerular basement membrane thickening
- Management: General
- See Chronic Kidney Disease
- See Prevention of Kidney Disease Progression
- Avoid Nephrotoxins (e.g. NSAIDs)
- Most important modifiable factors (see below)
- Diabetes Mellitus glycemic control
- Hypertension Control
- Management: Diabetes Mellitus
- Multifactorial approach
- See Intensive Lifestyle Change In Type II Diabetes Mellitus
- See Type II Diabetes Medications
- See Exercise in Diabetes Mellitus
- Type II DM Glucose lowering medications preferred in renal disease prevention
- Metformin is a first-line agent for optimal Glucose management
- Second-line agents associated with reduced Kidney disease progression
- Glucagon-Like Peptide 1 (GLP-1 Agonist)
- Dipeptidyl Peptidase-4 Inhibitor (DPP-4 Inhibitor)
- Sodium-Glucose Co-Transporter-2 Inhibitor (SGLT2 Inhibitor)
- Precautions
- Hemoglobin A1C is falsely lower in advanced Kidney disease due to Anemia
- Serum Glucose measurement log may be more accurate than A1C in CKD 4-5
- Ideal glycemic control is critical to reduce risk of progression in Diabetic Nephropathy
- Keep Hemoglobin A1C <7-8%
- Better glycemic control reduces nephropathy risk
- Microalbuminuria risk with Hemoglobin A1C > 8.1%
- Precaution: ACCORD Study found higher overall mortality with intensive glycemic control in Type II Diabetes
- Lead to goal targeting Hemoglobin A1C <8%
- Gerstein (2008) N Engl J Med 358(24): 2545-59 [PubMed]
- References
- Krolewski (1995) N Engl J Med 332(19):1251-5 [PubMed]
- (2011) Diabetes Care 34(Suppl 1): S4-S10 [PubMed]
- Management: Hypertension
- Hypertension goals
- Blood Pressure targets
- Target <140/90 (U.S. standard target as of 2019)
- JNC-8
- ADA (if patient WITHOUT multiple risk factors)
- Target <130/80
- ACC/AHA
- ADA (if patient WITH multiple risk factors)
- Isolated Systolic Hypertension goals
- Keep Systolic Blood Pressure under 140
- Avoid overaggressive Blood Pressure lowering to systolic Blood Pressure below 120 mmHg
- Associated with more adverse events (e.g. Hypotension, Bradycardia, Azotemia)
- Cushman (2010) N Engl J Med 362(17): 1575-85 [PubMed]
- Lifestyle measures
- See Lifestyle Modification in Hypertension
- First-line Antihypertensives: ACE Inhibitors and ARBs
- ACE Inhibitors and ARBs are preferred first-line agents for Hypertension and Proteinuria
- Best evidence is for Macroalbuminuria
- ACE Inhibitors and ARBs are indicated even without Hypertension
- However evidence does not support ACE Inhibitor use for Microalbuminuria without Hypertension
- Microalbuminuria alone is not a good marker for renal disease
- (2012) Prescr Lett 19(4): 24
- Do not use ACE Inhibitors in combination with Angiotensin Receptor Blockers
- Higher rate of progression to ESRD
- Mann (2008) Lancet 372(9638): 547-53 [PubMed]
- Recent trials suggest ACE Inhibitors and ARBs are equivalent in renal outcomes
- Mann (2008) Lancet 372(9638): 547-53 [PubMed]
- Lewis (2001) N Engl J Med 345:851-60 [PubMed]
- All-cause mortality is reduced with ACE Inhibitors, but not with Angiotensin Receptor Blockers
- Strippoli (2004) BMJ 329(7470): 828 [PubMed]
- Indications to stop ACE Inhibitors or Angiotensin Receptor Blockers
- Serum Creatinine rises 30% or more above baseline in first 2 months of starting medication or
- Hyperkalemia persists with Serum Potassium >5.6 mEq/L
- Other considerations
- Do not use if risk of pregnancy (Teratogenic)
- May be used in adolescents with Microalbuminuria
- Agents
- ACE Inhibitors (preferred - see above)
- Angiotensin Receptor Blockers (ARB)
- Second-line Antihypertensives
- Thiazide Diuretics (especially in combination with ACE Inhibitors or ARB agents above)
- Hydrochlorothiazide
- Chlorthalidone
- Bakris (2008) Kidney Int 73(11); 1303-9 [PubMed]
- Calcium Channel Blockers
- Renal protection
- Calcium Channel Blockers in general appear to be effective in maintaining Renal Function
- Segura (2005) JASN 16(3):S64-6 [PubMed]
- Proteinuria
- Non-Dihydropyridine Calcium Channel Blockers (e.g. Verapamil, Diltiazem)
- Reduce Proteinuria (less than ACE Inhibitor)
- Dihydropyridine Calcium Channel Blockers (mixed results)
- Amlodipine appears to also reduce Microalbuminuria
- Bakris (2008) Kidney Int 73(11); 1303-9 [PubMed]
- Nifedipine may increase Proteinuria
- Aldosterone Antagonists (e.g. Spironolactone, Eplerenone)
- Beneficial in reducing Kidney disease progression when used in combination with ACE Inhibitors or ARBs
- However, risk of Hyperkalemia and requires close Potassium monitoring
- Currie (2016) BMC Nephrol 17(1): 127 [PubMed]
- Management: Hyperlipidemia
- Lipid lowering does not directly reduce renal disease progression
- However, Hyperlipidemia Management (esp. Statin) reduces cardiovascular mortality
- Cardiovascular mortality is among the highest risks for those with Diabetic Nephropathy
- Mortality benefit for those with ESRD on Dialysis is reduced
- Statin drugs
- Most Statins are renally excreted
- Renal Dosing is reduced for most Statins (except Atorvastatin)
- Management: Dietary changes (incomplete evidence)
- Protein restriction
- Efficacy
- Decreases Microalbuminuria
- Decreases progression to Macroalbuminuria
- Protocol
- Near Normal GFR: <0.8g/kg/day Protein
- Falling GFR: <0.6g/kg/day Protein
- Mediterranean Diet or DASH Diet
- Avoid high sugar, high saturated fat and highly processed carbohydrates
- Emphasize whole grains, fiber, fresh fruits and vegetables
- Encourage omega 3 Fatty Acids (and omega-9 fats)
- Limit Sodium to <2300 mg/day
- (2019) Diabetes Care 42(suppl 1):S46-60 [PubMed]
- Dietary modification: CR-LIPE
- Better than protein restriction in retarding CRI
- Components
- 50% carbohydrate restricted (CR)
- Low Iron available (LI)
- Polyphenol enriched (PE)
- References
- Facchini (2003) Diabetes 52:1204-9 [PubMed]
- Management: Referral to Nephrology Indications
- Serum Creatinine over 2.0 mg/dl
- Glomerular Filtration Rate (GFR) less than 70 ml/min
- Precautions: Findings that suggest cause other than typical Diabetic Nephropathy
- See Proteinuria Causes
- Albuminuria absent despite stage 3-5 CKD
- Diabetic Retinopathy absent despite Diabetic Nephropathy
- Active urinary sediment (red cells or casts accompany Proteinuria)
- Low GFR estimated at the time of initial diagnosis
- GFR reduced >30% within 3 months of starting ACE Inhibitor or Angiotensin Receptor Blocker (ARB)
- GFR decreases rapidly (4 ml/min/year)
- Proteinuria increases rapidly (or Nephrotic Syndrome)
- Refractory Hypertension
- (2007) Am J Kidney Dis 49(suppl 2): S12-S154 [PubMed]
- Prognosis
- Dialysis usually needed when GFR reaches 10 ml/min
- Onset of Proteinuria after diagnosis of Diabetes Mellitus
- Microalbuminuria develops in 2.0% of patients with diabetes per year
- Macroalbuminuria develops in 2.8% of diabetic patients with Microalbuminuria per year
- Increased Serum Creatinine develops in 2.3% of diabetic patients with Macroalbuminuria per year
- Adler (2003) Kidney Int 63(1): 225-32 [PubMed]
- GFR decline after onset Microalbuminuria
- No ACE Inhibitor: 10 ml/min/year
- ACE Inhibitor: 4-6 ml/min/year
- Blood Pressure <130/80: 1-4 ml/min/year
- Associated Conditions
- Diabetic Retinopathy often develops concurrently with Diabetic Kidney Disease
- Complications
- Microalbuminuria (and Macroalbuminuria) are associated with an increased cardiovascular mortality and overall mortality
- Macroalbuminuria is a higher mortality risk per year (4.6%) than end-stage renal disease progression per year (2.3%)
- References
- McGrath (2019) Am Fam Physician 99(12): 751-9 [PubMed]
- Molitch (1997) Am J Med 102:392-8 [PubMed]
- Cooper (1998) Lancet 352:213-9 [PubMed]
- Thorp (2005) Am Fam Physician 72:96-99 [PubMed]
- Roett (2012) Am Fam Physician 85(9): 883-9 [PubMed]