diabetic nephropathy

Question 1

What is diabetic nephropathy?

Answer 1

DN is a glomerular disease with characteristic structural and functional changes. Not all DM pts get DN, and not all diabetic kidney disease is DN.

Question 2

What should I know about the prevalence of DN? What should I know about the natural history of DN?

Answer 2

Very common: leading cause of ESRD in US. Without glycemic control and current proteinuria measurements, 60% of patients develop proteinuria within 25 yrs; 60% of pts with proteinuria develop chronic kidney disease (overall prevalence is 40%)

Question 3

What is the progression of DN?

Answer 3

5 stages:

1. hyperfiltration, renal hypertrophy, and increased GFR
2. GBM thickening, mesangial expansion, normal GFR
3. microalbuminuria and normal GFR
4. albuminuria and renal insufficiency
5. glomerulosclerosis and ESRD

Question 4

What are some risks of DN (think genetics and race)

Answer 4

African americans have higher risk, independent of glycemic control.
genetics- clustering exists for both type I and type II. CNDP-1 gene (carnosinase gene). Some variants have higher carnosinase activity, leading to lower carnosine levels. This is a problem since carnosine is a natural ACE inhibitor.
ACE polymorphisms: severy of disease is assocaited with ACE insertion/deletion polymorphisms.

Question 5

Normal urine protein:creatinine ratio

Answer 5

less than 0.2

Question 6

How does DM lead to kidney disease?

Answer 6

metabolic problems cause functional changes in the nephron like hyperfiltration. Functional changes lead to structural changes like glomerylar hypertrophy. These changes eventually have clinical significance.

Question 7

Early findings of diabetic kidney disease

Answer 7

hyperfiltration and glomerular hypertorphy lead to increased kidney weight (by as much as 15%)

Question 8

Why does hypertrophy develop? (general)

Answer 8

1. stimuation of growth factors in kidney
2. altered hemodynamics
3. altered angiogenesis

Question 9

Why does hypertrophy develop (specific)

Answer 9

1. hyperglycemia stimulates growth factors in the kidney that increase protein synthesis. Cellular prolif is limited by the induction of cell cycle inhibitors.
2. Alterned hemodynamics: hyperglycemia stimulates renin release, partially in response to reactive oxygen species. Increased perfusion leads to shear stress and mechanical strain on the glomerular capillary loops. Increased osmotic pressure increases the oncotic pressure in the post glomerular capilaries and increases proximal reabsoprtion. Also, nephron underdosing.
3. Altered angiogenesis: increased VEGF and uncontrolled vascularization in diabetic nephropathy.

Question 10

What is nephron underdosing?

Answer 10

Hyperglycemia in a pregnant mom leads to decreased nephron formation in the fetus. With low birth weight in particular, we may see compensatory glomerular hypertrophy, increased GFR on a single nephron, and HTN. These babies are at increased risk of nephrotic syndrome and DN.

Question 11

How does hyperglycemia affect AGEs (advanced glycosylation end products)?

Answer 11

AGEs bind macrophages and mesangial cells and cause cellular changes. They also bind to RAGE receptors on tubular cells and podocytes and cause cellular changes. RAGE receptors are upregulated in response to angiotensin II.

Question 12

What are some later structural changes seen in DN?

Answer 12

diffuse mesangial expansion, nodular lesions, GBM thickening, podocyte loss (from direct damage of proteinuria). Diffuse glomerulosclerosis correlates directly with clinical manifestations of worsening renal function.

Question 13

What are some differences between type I and type II GN?

Answer 13

renal disease in type II is more heterogeneous, we see more interstitial fibrosis and glomerulosclerosis without mesangial matrix expansion in type II. Also, there is more arteriosclerosis in type II.

Question 14

Clinical characteristics of DN

Answer 14

1. Hx of DN for at least 10 yrs with evidence of microvascular disease.
2. Retinopathy: 100% of pts with type I DM; 50-60% of pts with type II DM
3. neuropathy: incidence greater for type I DM
4. macrovascular disease: stroke, CAD, PVD. 5X higher in pts with DN than in diabetics w/o kidney probs.
   But, not all proteinuria in a pt with DM = DN.

Question 15

When should you consider a kidney biopsy for DN?

Answer 15

1. neuropathy without retinopathy in a type I diabetic.
2. abrupt onset of proteinuria
3. Type I DM < 5 yrs duration
4. macroscopic hematuria
5. Decrease in renal function without proteinuria.

Question 16

management of DN

Answer 16

for prevention, look at controlling hyperglycemia, proteinuria, and BC

Question 17

hyperglycemia management in DN

Answer 17

Goal: less than 7% of Hb A1C
with tight control, only 9% of type I diabetics develop DN after 25 yrs. Fewer microvascular complications. legacy effect.

Question 18

proteinuria control in DM

Answer 18

ACE-i, ARB, dual therapy decreases progression of CKD in pts with DN for type I and type II. Also, decreased proteinuria reduces mortality. GOAL: less than 500 mg/day total protein and normoalbuminuria. renin/angiotensin/aldo blocks also help even if start in pts with HTN but withOUT proteinuria.

Question 19

BP control in DN

Answer 19

w/o proteinuira, less than 130/80 is a good goal. less than 125/75 in pts with severe proteinuria.

Question 20

Managementent to normotensive, normoalbuminuric pt with DM

Answer 20

yearly microalbuminuria screen.

HbA1C less than 7%

Question 21

management of normotensive pt with microalbuminuria and DM

Answer 21

monitor BP, glycemic control, Uab. Add ACE inhibitor to glycemic control.

Question 22

management of hypertensive pt with microalbuminuria and DM

Answer 22

control bp to 130/80 and titrate ACE-I

Question 23

management of a pt with DM and proteinuria

Answer 23

ACE-I, glycemic control, aggressive bp control to 125/75