Diabetic Nephropathy

Question 0

2 “major clinical manifestations” of diabetic nephropathy? (i.e. broad problems you can determine from usual lab studies)

Answer 0

Albuminuria

Chronic kidney disease (CKD)

Question 1

3 characteristic structural changes in diabetic nephropathy?

Answer 1

GBM thickening.
Mesangial thickening.
Glomerular sclerosis.

Question 2

The 4 clinical stages of diabetic nephropathy are defined by what 2 parameters?

Answer 2

GFR and albuminuria/proteinuria

Question 3

In stage 1 diabetic nephropathy, what are GFR and urine albumin?

Answer 3

GFR is actually increasing, but the urine albumin has not yet increased.

Question 4

What’s the deal with the increased GFR in diabetic pre-nephropathy?

Answer 4

Cause, probably, by increased renal blood flow… but it’s not beneficial.
The kidneys can also enlarge at this point.

Question 5

What structural change is already happening in diabetic pre-nephropathy?

Answer 5

Increased GBM thickness.

Question 6

What are the GFR and urine albumin like stage 2 of diabetic nephropathy?

Answer 6

GFR is still high.

Urine albumin begins to rise - “microalbuminuria”

Question 7

What levels of urine albumin are typical for stage 2 diabetic nephropathy?

Answer 7

30-300mg/24hrs (normal is about 15mg/24hrs)

Don’t confuse this with total urine protein, which is normally <150mg/24hrs. Lots of that is Tam-Horsfall protein.

Question 8

What’s the natural history for untreated stage 2 diabetic nephropathy?

Answer 8

Depends on T1DM vs. T2DM:
T1DM: 80% progress to overt nephropathy.
T2DM: 25-40% progress to over nephropathy.

Question 9

What do you see on light microscopy of Stage 2 diabetic nephropathy?

Answer 9

Continued GBM (and tubular basement membrane) thickening.
Mesangial expansion (there's less Bowman's space visible in the glomeruli).

Question 10

Stage 4 diabetic nephropathy.. what happens to GFR and urine albumin?

Answer 10

Overt nephropathy with high urine albumin and low, progressively declining GFR.

Question 11

2 clinical findings (other than GFR and urine albumin) that change in stage 3 diabetic nephropathy?
How about kidney size?

Answer 11

Microscopic hematuria is sometimes present.
Hypertension is common.
Kidney size is reduced to normal due to fibrosis/scarring.

Question 12

Histological findings in the glomeruli in stage 3 diabetic nephropathy? (there are 2 different patterns)

Answer 12

Usually: Diffuse mesangial sclerosis.

Less common, but pathognomonic: Nodular glomerulosclerosis (aka Kimmelstiel-Wilson lesions)

Question 13

What are some extra-glomerular histologic findings in stage 3 diabetic nephropathy?

Answer 13

Arteriolar hyalinosis (perhaps largely responsible for the HTN)
Tubular atrophy
Interstitial fibrosis

Question 14

Stage 4 diabetic nephropathy?

Answer 14

Is really bad. Decreasing GFR, urine albumin might reach nephrotic levels.
Nephrotic syndrome (proteinuria, edema, hypoalbuminemia, hyperlipidemia) might occur.
Well on the way to ESRD.

Question 15

3 aspects of a diagnosis of diabetic glomerulopathy?

Answer 15

Persistent proteinuria.
Absence of other causes of renal disease.
Other evidence of microvascular disease, esp retinopathy.

Question 16

When would you do a biopsy when working up a patient with suspected diabetic nephropathy?

Answer 16

When there are funny things in the history / lab results that aren’t consistent with diabetic nephropathy or point to other possible causes.

Question 17

What are 5 modifiable risk factors for diabetic nephropathy?

Answer 17

Hyperglycemia
Hyperfiltration 
HTN
Soluble mediators
Smoking/obesity

Question 18

What are 2 proposed mechanisms by which hyperglycemia causes damage that leads to diabetic nephropathy?

Answer 18

Hyperglycemia -> non-enzymatic glycation -> advanced glycation end products (AGEs) -> inflammation.
High glucose gets converted to sorbitol, consuming NADPH -> NADPH depletion -> less glutathione activity to neutralize bad stuff like free radicals.

Question 19

How can the hyperfiltration of early diabetic nephropathy be reduced?

Answer 19

With an ACE inhibitor or ARB.
A-II causes constriction of efferent arteriole -> increased filtration pressure.
ACE inhibitor -> efferent arteriole relaxation.

Question 20

What’s a soluble mediator of sclerosis that you might be able to inhibit to slow progression of diabetic nephropathy?

Answer 20

TGF-beta