Diabetic Nephropathy

Aka: Diabetic Nephropathy, Nephropathy of Diabetes Mellitus, Diabetic Kidney Disease, ACE Inhibitors and ARBs in Diabetic Nephropathy

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II. 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)

III. 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

IV. Precaution

  1. Worsening Renal Function may present with sudden improvement in glycemic control or Hypoglycemia

V. 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

VI. 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

VII. 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

VIII. 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

IX. 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

X. 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

XI. 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)
          1. Best evidence of diabetes agents for slowing of CKD progression
          2. May be used if eGFR >=20 ml/min for CKD and cardiac benefits (but low diabetes efficacy at low eGFR)
        2. Glucagon-Like Peptide 1 (GLP-1 Agonist)
          1. Preferred agents are Semaglutide, Dulaglutide and Liraglutide
          2. No dose adjustment needed in reduced eGFR, but not recommended if eGFR <30 ml/min
        3. Dipeptidyl Peptidase-4 Inhibitor (DPP-4 Inhibitor) - least effective
  2. Chronic Kidney Disease Stage 4 to 5 (GFR <30 ml/min/1.73m2)
    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
    2. Many Glucose lowering agents (e.g. Metformin) are contraindicated when GFR is <30 ml/min/1.73m2
      1. Insulin is preferred agent in advanced renal disease
      2. (2012) Am J Kidney Dis 60(5):850-86 +PMID: 23067652 [PubMed]
  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]

XII. 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 (in combination with ACE or ARB)
        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]

XIII. 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)

XIV. 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]

XV. Management: Referral to Nephrology Indications

  1. Serum Creatinine over 2.0 mg/dl
  2. Glomerular Filtration Rate (GFR) less than 70 ml/min

XVI. 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]

XVII. 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

XVIII. Associated Conditions

  1. Diabetic Retinopathy often develops concurrently with Diabetic Kidney Disease

XIX. 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%)

XX. 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]

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Related Studies

Ontology: Diabetic Nephropathy (C0011881)

Definition (MEDLINEPLUS)

If you have diabetes, your blood glucose, or blood sugar, levels are too high. Over time, this can damage your kidneys. Your kidneys clean your blood. If they are damaged, waste and fluids build up in your blood instead of leaving your body.

Kidney damage from diabetes is called diabetic nephropathy. It begins long before you have symptoms. An early sign of it is small amounts of protein in your urine. A urine test can detect it. A blood test can also help determine how well your kidneys are working.

If the damage continues, your kidneys could fail. In fact, diabetes is the most common cause of kidney failure in the United States. People with kidney failure need either dialysis or a kidney transplant.

You can slow down kidney damage or keep it from getting worse. Controlling your blood sugar and blood pressure, taking your medicines and not eating too much protein can help.

NIH: National Institute of Diabetes and Digestive and Kidney Diseases
Definition (NCI) Progressive kidney disorder caused by vascular damage to the glomerular capillaries, in patients with diabetes mellitus. It is usually manifested with nephritic syndrome and glomerulosclerosis.
Definition (MSH) KIDNEY injuries associated with diabetes mellitus and affecting KIDNEY GLOMERULUS; ARTERIOLES; KIDNEY TUBULES; and the interstitium. Clinical signs include persistent PROTEINURIA, from microalbuminuria progressing to ALBUMINURIA of greater than 300 mg/24 h, leading to reduced GLOMERULAR FILTRATION RATE and END-STAGE RENAL DISEASE.
Definition (CSP) kidney disease and resultant kidney function impairment due to the long standing effects of diabetes on the microvasculature (glomerulus) of the kidney; features include increased urine protein and declining kidney function.
Concepts Disease or Syndrome (T047)
MSH D003928
ICD9 250.4
SnomedCT 127013003, 267470000, 21858001, 190338009, 60009009
LNC LA10570-2
English Diabetic Nephropathies, Nephropathies, Diabetic, Diabetes with renal manifestations, DIABETIC NEPHROPATHY, Nephropathy, Diabetic, Renal disorder associated with diabetes mellitus, diabetic nephropathy, diabetic nephropathy (diagnosis), Diabetic nephropathy NOS, Diabetic Nephropathies [Disease/Finding], Nephropathy;diabetic, diabetic nephropathies, nephropathy diabetic, diabetic renal disease, diabetes with renal manifestations (diagnosis), diabetes with renal manifestations, Diabetic Kidney Problems, Diabetes + nephropathy, Diabetes with renal manifestations (disorder), Nephropathy - diabetic, Diabetic nephropathies, -- Diabetic Kidney Disease, Diabetic nephropathy, Diabetic renal disease, Diabetic renal disease (disorder), diabetes; nephropathy (manifestation), nephropathy; diabetes (manifestation), Diabetic Nephropathy, Diabetic Kidney Diseases, Diabetic Kidney Disease, Kidney Disease, Diabetic, Kidney Diseases, Diabetic
Spanish trastorno renal asociado con diabetes mellitus, Nefropatía diabética NEOM, Enfermedad renal diabética, Diabetes con manifestaciones renales, diabetes con manifestaciones renales (trastorno), diabetes con manifestaciones renales, enfermedad renal diabética, nefropatía diabética (trastorno), nefropatía diabética, Nefropatía diabética, Nefropatías Diabéticas
Dutch diabetische nierziekte, diabetische nefropathie NAO, diabetes met renale manifestaties, diabetes; nefropathie, nefropathie; diabetes, diabetische nefropathie, Diabetische nefropathie, Nefropathie, diabetische, Diabetische nefropathieën, Nefropathieën, diabetische
French Diabète avec manifestations rénales, Néphropathie diabétique SAI, Néphropathie diabétique, Néphropathies diabétiques, Maladie rénale diabétique
German diabetische Nierenerkrankung, Diabetes mit renalen Manifestationen, diabetische Nephropathie NNB, diabetische Nephropathie, Diabetische Nephropathien
Italian Nefropatia diabetica NAS, Diabete con manifestazioni renali, Nefropatia diabetica, Nefropatie diabetiche
Portuguese Nefropatia diabética NE, Doença renal diabética, Diabetes com manifestações renais, Glomeruloesclerose Diabética, Nefropatia diabética, Nefropatias Diabéticas
Japanese 糖尿病性腎症ＮＯＳ, 腎症状をともなう糖尿病, ﾄｳﾆｮｳﾋﾞｮｳｾｲｼﾞﾝｼｮｳNOS, ｼﾞﾝｼｮｳｼﾞｮｳｦﾄﾓﾅｳﾄｳﾆｮｳﾋﾞｮｳ, ﾄｳﾆｮｳﾋﾞｮｳｾｲｼﾞﾝｼｮｳ, 糖尿病性ネフロパシー, 糖尿病性腎障害, 糖尿病ネフロパシー, 糖尿病腎症, 糖尿病性腎症
Swedish Diabetiska njursjukdomar
Czech diabetické nefropatie, Diabetická nefropatie, Diabetes mellitus s postižením ledvin, Diabetická nefropatie NOS, diabetické onemocnění ledvin, diabetická nefropatie
Finnish Diabeettiset nefropatiat
Russian GLOMERULOSKLEROZ DIABETICHESKII, GLOMERULOSKLEROZ INTERKAPILLIARNYI, DIABETICHESKIE NEFROPATII, ГЛОМЕРУЛОСКЛЕРОЗ ДИАБЕТИЧЕСКИЙ, ГЛОМЕРУЛОСКЛЕРОЗ ИНТЕРКАПИЛЛЯРНЫЙ, ДИАБЕТИЧЕСКИЕ НЕФРОПАТИИ
Croatian DIJABETIČNE NEFROPATIJE
Polish Nefropatie cukrzycowe, Nefropatia cukrzycowa, Cukrzycowa choroba nerek, Cukrzycowe choroby nerek
Hungarian diabeteses vesebetegség, Diabetes veseérintettséggel, diabeteses nephropathia k.m.n., diabeteses nephropathia
Norwegian Diabetisk nefropati, Nyresykdommer ved diabetes
Derived from the NIH UMLS (Unified Medical Language System)

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