199: Diabetic Nephropathy Flashcards
What functional changes occur when a patient is in the microalbuminuria (incipient) stage of diabetic nephropathy?
- 30-300 mg albumin daily
- >300 mg = macroalbuminuria
- GFR remains normal
- Other microvascular complications happen on the same timeline (ex: diabetic retinopathy)
What is the goal blood pressure for diabetic patients?
- <140/90, but probably <130/80 is better
- <130/80 is the target BP for everyone treated for HTN with increased CV risk (which includes all patients with diabetes)
What defines microalbuminuria?
30-300 mg of albumin daily
Describe the steps in the typical natural history of diabetic nephropathy
- Hyperfiltration
- Microalbuminuria
- Macroalbuminuria
- Advanced Nephropathy/Kidney failure
What lesions are present in this biopsy?
Which disease is present?
Kimmelstiel-Wilson nodules
Diabetic nephropathy
Which anti-hypertensives should be prescribed to patients with diabetic nephropathy?
ACE Inhibitor OR ARB
- Renoprotective
- Relaxes the efferent arteriole
- Angiotensin II -> efferent arteriole constriction
- Decrease intraglomerular pressure
- MItigate teh passage of protein into the urine
- Prevent pro-fibrotic effects of angiotensin II
What fraction of patients with diabetes will develop nephropathy?
1/3
Increased risk in African Americans, Native Americans, and Hispanics
What percentage of patients with diabetes will have hyperfiltration?
Probably 100%, but hard to tell because difficult to detect
Not all will progress to diabetic nephropathy - only 1/3 will progress to the microalbuminuria (incipieint) phase
What functional changes occur during the hyperfiltration (silent) phase of diabetic nephropathy?
- Increased GFR (but this is usually not detected in labs)
- Increased kidney size
- Glomerular hypertrophy (without proliferation of cells)
- Glomerular basement membrane thickening
- Usually occurs for 5-10 years
Which drugs are likely to reduce glomerular hypertension specifically?
SGLT2 inhibitors
What is the leading cauuse of end-stage renal disease?
Diabetes
What functional changes are seen in macroalbuminuria (overt) nephropathy?
- >300 mg albuminuria
- May have nephrotic-range (>3g) proteinuria
- GFR declines rapidly
- Almost all patients are hypertensive
- Usually occurs ~15 years after diagnosis of diabetes
What is the goal for glycemic control in patients with diabetic nephropathy?
HbA1c ~7%
What functional changes are present in advanced diabetic nephropathy (renal failure)?
- GFR declines to <15 mL/min
- Hypertension often worsens
- Usually occurs 15-20 years after diagnosis of diabetes
Why is diabetic neprhopathy easier to study in Type 1 Diabetes than Type 2 Diabetes?
Type 1 diabetes is usually diagnosed within weeks or months of onset due to the dramatic physiological changes that follow destruction of the pancreatic islet cells
Type 2 dibaetes develops over years and the time between onset and diagnosis is difficult to determine
Therefore, it is easier to study diabetic nephropathy in type 1 diabetics because we know more about the timeline of development
Why does hypertension worsen with advanced nephropathy?
Sodium and fluid retention
Due to decreased GFR, poor renal function
What are the major long-term consequences of diabetes mellitus?
- Microvascular
- Nephropathy
- Retinopathy
- Neuropathy
- Macrovascular
- Cardiovascular events (MI, Stroke)
- Peripheral vascular disease
- Amputations
What is the classic or almost pathognomonic histologic finding in diabetic nephropathy?
What are 2 other histologic findings in diabetic nephropathy?
Classic = Kimmelstiel-Wilson Nodules
Other = Mesangial matrix expansion, GBM thickening
How long does the hyperfiltration (silent) phase of diabetic nephropathy usually last?
5-10 years
What are the 3 pathogenic factors that contribute to hyperfiltration?
- Glomerular hypertrophy
- -> Increased capillary surface area
- Afferent arteriolar vasodilation
- -> Increased flow into capillaries
- Efferent arteriolar vasoconstriction
- -> Increased pressure within the glomerulus
- Due to the action of Angiotensin II
What are the major strategies for treatment and progression prevention for diabetic nephropathy?
- Tight glycemic control
- Reduces microalbuminuria, but may not slow GFR decline
- Treat hypertension
- Perhaps the most important risk factor for the progressive decline in GFR in diabetes
- Goal is <140/90, but <130/80 is probably better
- Use ACEI or ARB
- SGLT-2 inhibitors
- Inhibt Na+ and glucose uptake in the PCT
- -> Urinary glucose loss
- -> Prevent activation of RAAs
What is the main cause of decreased GFR in patients with diabetic neprophathy?
Mesangial matrix expansion
- Impinges on capillary loops
- Obliterates the surface area available for filtration
- -> Tubulointerstitial fibrosis
- -> Nephron loss
What structural changes are seen when a patient has microalbuminuria (incipient) nephropathy?
- Basement membrane thickening
- Mesangial matrix expansion (pictured)
- Leads to glomerulosclerosis in a diffuse patter
- May be nodular
- This eventually leads to Kimmelstiel-Wilson nodules
What are the pathogenic factors that drive diabetic nephropathy?
Altered hemodynamics
+
Metabolic stimuli (hyperglycemia)
+
Genetic predisposition
->
- Hyperfiltration
- Proteinuria development
- Intraglomerular hypertension
- Mesangial matrix expansion
What percentage of patients will progress to ESRD after developing macroalbuminuria in 10 years?
15 years?
50% in 10 years
75% in 15 years
If a paitnet lives long enough after deveopint macroalbuminuria, they will progress to ESRD
Which patient is most likely to have diabetic nephropathy?
- A 50 year-old African American man with type 2 diabetes for 15 years who is being treated with laser photocoagulation therapy for diabetic retinopathy
- A 50 year-old Caucasian woman who has been following closely with her primary physician and was diagnosed with diabetes 3 years ago.
- A 50 year-old Caucasian man with type 1 diabetes for 30 years who follows with his ophthalmologist yearly and has no evidence of diabetic retinopathy.
a. A 50 year-old African American man with type 2 diabetes for 15 years who is being treated with laser photocoagulation therapy for diabetic retinopathy
Why do diabetic patients develop proteinuria?
- Basement membrane abnormalities
- Get thicker, but the integrity of the membrane is compromised
- Podocyte abnormalities
- Damage
- Foot processes fuse and detach from the GBM -> Apoptosis
- Hemodynamic effects
- Intraglomerular hypertension -> Worse albuminuria
- Due to efferent arteriolar vasoconstriction
- Increased glucose in the filtrate
- -> Afferent arteriolar vasodilation
- -> Increased SGLT2 channels in the PCT
- -> Increased Na+ and glucose reabsorption
- -> Decreaed Na+ delivery to the macula densa
- -> Renin release, increased angiotensin II
- -> efferent arteriolar constriction
- -> Hyperfiltration and intra-glomerular hypertension
What is the difference between microalbuminuria and proteinuria?
Up to 150 mg/day of general proteinuria is not concerning
However, any albumin in the urin is abnormal
Microalbuminuria is not always detected on a urine dipstick because the amount is very small (30-300 mg/day)
=> use urinary albumin / urinary creatinine rato to determine albuminuria
How does hyperglycemia lead to diabetic nephropathy?
Hyperglycemia ->
- Activation of signaling pathways + Generation of ROS
- -> Cytokine release
- TGF-beta, VEGF, Angiotensin II
- Cytokine release is profibrotic
- -> Sclerosis
- Cytokine release contributes to altered hemodynamics
- -> Albuminuria
Describe the changes in GFR and proteinuria as diabetic nephropathy progresses
-
Hyperfiltration: Pre diabetic nephropathy
- Usually we don’t detect this stage
- No albuminuria
- Increased GFR is not typically concerning
- Usually we don’t detect this stage
-
Microalbuminuria: Incipient diabetic nephropathy
- GFR normal
- Albuminuria begins (30-300 mg/day)
-
Macroalbuminuria: Overt diabetic nephropathy
- 15+ years after onset)
- Decline in GFR
- Steep rise in albuminuria
-
End stage renal disease
- GFR < 15 mL/min
