Diabetic nephropathy

Approximately 20% to 40% of patients with type 1 or type 2 diabetes mellitus develop diabetic kidney disease.

This clinical syndrome characterized by:

  • Persistent albuminuria (> 300 mg/24 h, or > 300 mg/g creatinine)
  • Relentless decline in glomerular filtration rate (GFR)
  • Raised arterial blood pressure
  • Enhanced cardiovascular morbidity and mortality.
  • There is a characteristic histopathology.

    In classical diabetic nephropathy:

  • the first clinical sign is moderately increased urine albumin excretion (microalbuminuria: 30–300 mg/24 h, or 30–300 mg/g creatinine; albuminuria grade A2).
  • Untreated microalbuminuria will gradually worsen, reaching clinical proteinuria or severely increased albuminuria (albuminuria grade A3) over 5 to 15 years.
  • The GFR then begins to decline, and without treatment, end stage kidney failure is likely to result in 5 to 7 years.
  • Although albuminuria is the first sign of diabetic nephropathy, the first symptom is usually peripheral edema, which occurs at a very late stage.
  • Regular, systematic screening for diabetic kidney disease is needed in order to identify patients at risk of or with presymptomatic diabetic kidney disease.
  • Annual monitoring of urinary albumin-to-creatinine ratio, estimated GFR, and blood pressure is recommended.

    Stage of diabetic nephropathy

    1. Stage One
      • manifests by renal hyperperfusion and hypertrophy
      • This stage starts with the onset of diabetes before insulin treatment.
      • Changes are at least partly reversible by insulin treatment.
      • Glomerular filtration rate is increased due to hyperperfusion
    2. Stage Two
      • Characterized by clinical silence and morphologic changes characteristic of diabetic glomerulosclerosis.
      • Glomerular filtration rate (GFR) is still higher than normal during this stage.
      • During good diabetes control, abumin excretion is normal
      • physical exercise unmasks changes in albuminuria not demonstrable in the resting situation.
      • During poor diabetes control albumin excretion goes up both at rest and during exercise
      • Some diabetic patients continue in this stage throughout their lives.
    3. Stage Three
      • Microalbuminuria is the salient feature, also called the stage of incipient nephropathy
      • It defined as UAE >30 mg/d, >20 μg/min, or albumin:creatinine ratio (ACR) >30 mg/g creatinine.
      • This stage is initially associated with increased GFR.
      • GFR starts a consistent decline that becomes more evident with the continuous increase of UAE above 300 mg/d, 200 μg/min, or when ACR exceeds 300 mg/g.
    4. Stage Four
      • This is the stage of overt nephropathy.
      • Progressive increase in blood pressure is usually associated with these renal changes.
      • When the associated high blood pressure is left untreated, renal function declines,
      • the mean fall rate being around 1 ml/min/mo.
      • Long-term antihypertensive treatment reduces the fall rate by about 60% 7 and thus postpones uremia considerably.
    5. Stage Five
      • Itis End Stage Kidney Failure with uremia due to diabetic nephropathy.
      • As many as 25% of the population presently have end-stage kidney failure

    stage of dn.jpg

    Management of diabetic nephropathy

    1. Control of blood pressure
    2. Control of blood sugar
    3. Quitting smoking
    4. Diet control: Dietary salt restriction
    5. Hypolipidemic treatment
    6. Treatment of hyperuricemia
    7. Phosphate handling

    Approved interventions that can prevent development and progression of diabetic nephropathy

    Drug class On-target action Off-target actions Remarks
    Antihypertensive RAS blockers Blood pressure control UAE↓, GTP↓, K+ ↑, AT1-7↑, cytokines↓, Klotho↑ Failed to prevent DN, can accelerate progression in advanced CKD & old age
    Blood Sugar control Normalize blood sugar UAE↓, incident CKD↓, CKD progression ↓ Hypoglycemia increases morbidity & mortality risk esp with SU & insulin
    • Metformin ‘’ AMPK↑, mTOR↓ ↓ dose by 50% if GFR<60 mL/min, stop if GFR<30
    • Pioglitazone ‘’ UAE↓, NF-κB↓, CKD progression ↓ Salt and water retension, osteopenia, BW↑
    • GLP-1 agonists ‘’ BW↓, UAE↓, ROS↓, TGF-β1↓, CCN2↓ Nausea, vomiting, stop if GFR<30
    • DPP-4 inhibitors ‘’ UAE↓, ROS↓, CCN2↓,EndM T↓, CKD progression ↓ Hypoglycemia less likely, dose adjustment with CKD progression except Linagliptin
    • SGLT2 inhibitors ‘’ Hyperfiltration ↓, BW↓, BP↓,UA↓, ROS↓. stop if GFR<30
    Statins ↓Serum Cholesterol ↓CVD No effect on stroke, CKD progession or mortality
    Quitting smoking ‘’ ↓DN progress ‘’
    Diet control• salt restriction ↓BP, ↓UAE, ↓DN progress Salt paradox in very low salt
    • ptn restriction ↓DN progress Of value only in T1DM
    Hypouricemic agents ↓UA ↓UAE, ↓DN progress
    Phosphate handling • ↓P intake +sevelamer ↓Serum P ↓DN progress, ↓mortality
    HCO3 supplement Treat acidosis ↓DN progress May↑BP, may ↑edema
    Pentoxifylline RBCs rheology ↓UAE, ↓DN progress 1200 mg/day
    Sarpogrelate ↓thromboxane A2 ↓UAE, ↓MCP1
    Paricalcitol ↓PTH ↓UAE