Diabetic Nephropathy

Question 1

What groups have the highest risk of diabetic nephropathy?

Answer 1

African-Americans, Native-Americans, and Hispanics have a greater risk of diabetic nephropathy than Caucasians.

Question 2

What is the first stage in the natural history of diabetic nephropathy?

Answer 2

silent phase
a. During this phase, there are changes happening at the level of the glomeruli but no clinically apparent
disease.
b. Hyperfiltration (an increase in GFR) occurs during this time in addition to kidney hypertrophy (mild increase in kidney size). At the histologic level, basement membrane thickening can be seen.
c. Thought to occur for about 10 years.

Question 3

What is the second stage in diabetic nephropathy?

Answer 3

Microalbuminuria - Incipient Nephropathy
a. As mentioned earlier, only 1/3 of diabetics develop true nephropathy which occurs when entering this phase.
b. The GFR will decrease back down to the “normal range.”
c. This phase is principally defined by the development of microalbuminuria which means that a small
amount of albumin is being “spilled” from the blood into the urine. Although a small amount, this is
abnormal. It is defined as 30-300mg of albumin per day.

Question 4

What pathologic changes occur during the microalbuminuria stage of diabetic nephropathy?

Answer 4

i. Further thickening of the glomerular basement membrane and also the tubular basement membrane
ii. Mesangial matrix expansion, meaning the mesangial space is expanded by excessive amounts of extracellular matrix proteins such as collagen and fibronectin. This is a hallmark of diabetic nephropathy.
iii. Mesangial matrix expansion results in glomerulosclerosis which can be either diffuse or in a nodular pattern. When in a nodular pattern, this is known as Kimmelstiel-Wilson lesion.

Question 5

What is the hallmark of diabetic nephropathy?

Answer 5

mesangial matrix expansion

Question 6

What is a Kimmelsteil Wilson lesion?

Answer 6

Mesangial matrix expansion results in glomerulosclerosis which can be either diffuse or in a nodular pattern. When in a nodular pattern, this is known as Kimmelstiel-Wilson lesion.

Question 7

What should you ask about when trying to evaluate if proteinuria is caused by diabetic nephropathy?

Answer 7

diabetic retinopathy

Question 8

What are the 4 stages of diabetic nephropathy

Answer 8

silent
microalbuminuria
macroalbuminuria
advanced nephropathy/failure

Question 9

What is the 3rd stage of diabetic nephropathy?

Answer 9

a. Macroalbuminuria means that the albumin excretion rate has exceeded 300mg per day.
b. At this point is when GFR start to decline, may happen rather quickly. On average, GFR decline occurs at 6
to 12 ml/min per year.
c. Albuminuria can increase to the point of developing nephrotic-range proteinuria.
d. Without treatment, the risk of progression to ESRD is about 50% within 10 years and 75% within 15 years.

Question 10

What is the fourth stage of diabetic nephropathy

Answer 10

4. Advanced Nephropathy/Failure
   a. GFR continues to fall, serum creatinine rises.
   b. Hypertension tends to become more severe. It is often driven by hypervolemia related to salt and water
   retention in the setting of advanced kidney disease.

Question 11

What causes hyperfiltration in diabetic nephropathy?

Answer 11

Due to glomerular hypertrophy (increased capillary surface area), afferent arteriolar vasodilation, and efferent arteriolar vasoconstriction. These are effects of Angiotensin II.

Question 12

What causes proteinuria in diabetic nephropathy?

Answer 12

in diabetes, the GBM becomes more permeable due to following:

i. GBM thickening – there is more GBM but thought to be of poorer quality and the abnormal composition of the GBM may allow for albuminuria
ii. Podocyte effects – the podocytes can be damaged, undergo apoptosis, or detach from the GBM. The foot processes may become broadened and then fused. All this leads to decreased integrity of the podocyte layer.
iii. Hemodynamic effects – as described above related to effects of Angiotensin II, intraglomerular hypertension can occur which can exacerbate albuminuria and proteinuria.

Question 13

What causes loss of GFR in diabetic nephropathy?

Answer 13

This correlates with increase in mesangial matrix expansion. It is thought this expansion gradually obliterates the glomerular capillary surface area and reduces GFR.

Also, caused by tubulointerstitial fibrosis in advanced stages

Question 14

What is the initial stimulus leading to diabetic nephropathy?

Answer 14

hyperglycemia

Question 15

What are key cytokines in the development of diabetic nephropathy?

Answer 15

Key cytokines in diabetic nephropathy included TGF-beta, VEGF, and Angiotensin II. Of these, TGF-beta is known to have hypertrophic and profibrotic effects that may be responsible for the glomerulosclerosis and tubulointerstitial fibrosis seen in diabetic nephropathy. Angiotensin II is also known to have profibrotic effects.

Question 16

What are the key aspects of treatment for diabetic nephropathy?

Answer 16

glycemic control

blood pressure control

Question 17

What is reduced when glycemic control is tight for diabetic nephropathy?

Answer 17

microalbuminuria

** does not decrease CV events or mortality

Question 18

What is the most important risk factor for progressive decline in GFR in diabetes?

Answer 18

hypertension

Question 19

What is the recommended

BP target for diabetics?

Answer 19

< 130/80

Question 20

What are the BP agents of choice in diabtics?

Answer 20

ACE i or ARBs

Question 21

Why would ACE i or ARB’s be renoprotective?

Answer 21

1. Relieving intraglomerular hypertension due to hemodynamic effects – this ameliorates chronic pressure injury to the glomerulus.
2. May have non-hemodynamic effects of blocking expression of factors that promote fibrosis such as TGF-beta.

Question 22

Should ACE i and

ARB’s ever be combined when treating diabetics?

Answer 22

NO - increased risk of AKI and hyperkalemia with no benefit to GFR

Question 23

What drug class is sued for DM management, reduction of CV risk , and delaying nephropathy?

Answer 23

SGLT2 inhibitors

Question 24

Which patient is most likely to have diabetic nephropathy?
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
b. A 50 year-old Caucasian woman who has been following closely with her primary physician and was
diagnosed with diabetes 3 years ago.
c. 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.

Answer 24

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

Question 25

What is the classic or almost pathognomonic histologic finding in diabetic nephropathy? What are 2 other histologic findings in diabetic nephropathy?

Answer 25

Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules); mesangial matrix expansion, glomerular basement thickening

Question 26

Describe the stages of progression of diabetic nephropathy. What is one key clinical or laboratory finding in each stage of progression?

Answer 26

Silent phase – hyperfiltration (GFR increases in laboratory testing)
Incipient nephropathy – development of microalbuminuria on lab testing, GFR usually normal
Overt nephropathy – microalbuminuria increases to macroalbuminuria (>300mg/day) and GFR starts to decline Advanced nephropoathy – progressive decline in GFR, worsening hypertension, clinical volume overload

Question 27

What is your first-line option to treat:
- A 55 year-old man in your office who has a history of diabetes, his blood pressure is 150/95 and not currently
on any treatment. He is not sure how long he has had diabetes but thinks about 7-10 years. You check a urine dipstick in the office and see that he has a small amount of proteinuria.
- Why did you choose that agent? Describe how it may help preservation of his kidney function in addition to lowering his blood pressure.

Answer 27

ACE-inhibor or ARB. First line blood pressure treatment for any diabetic patient with proteinuria (unless there are contraindications) due to multiple studies that have shown slowing in the progression of diabetic nephropathy using these agents. The effect goes beyond just blood pressure control. It is postulated to be related to reduction in intra-glomerular hypertension and perhaps downstream reduction in pro-fibrotic cytokines.