Diabetic Nephropathy - Wall & Nichols Flashcards
What are the classical symptoms of hyperglycemia?
Thirst, polyuria, polydipsia, weight loss, visual burring
What are common occurrences in diabetic nephropathy clinically?
hyperglycemia and a fasting blood glucose concentration of 126 mg/dl or higher, or a random value of 200 mg/dL
Is diabetic nephropathy a considerable portion of diagnoses of ESRD?
yes, 40-50%
What are long term macrovascular complications of Diabetes?
Coronary Artery Disease (myocardial infarction)
Cerebrovascular Disease
Peripheral Vascular Disease (amputations and ulcers)
What are microvascular complications of diabetes?
Diabetic Nephropathy
Diabetic Neuropathy
Diabetic Retinopathy
What percentage of diabetics develop DN?
30-40%, with genetics playing a large factor in who develops DN
What is the first clinical detectable abnormality of DN?
Microalbuminuria, before the dipstick will detect proteinuria, overtime leads to overt proteinuria, reduced GFR and HTN
Histology: increased mesangial matrix, glomerular collapse and glomerulosclerosis
How long do people who develop DN typically have diabetes and retinopathy?
10 yrs
What is the clinical definition of DN?
based on Hx, exam, and urine albumin/creatinine ratio
Longstanding Hx of Diabetes and retinopathy
Macroalbuminuria defined as ratio of Urine Albumin/Creatinine ratio over 300 mg/g
HTN
Describe the first stage of Kidney Disease?
Hyperfiltration or an increase in GFR occurs. Kidneys increase in size. Asymptomatic because the body is compensating. Clearance is 25-50% higher.
Describe the second stage of Kidney Disease.
Glomeruli begin to show damage and microalbuminuria (30-300mg/g of creatinine). Can last for years.
Describe the third stage of kidney disease.
Albumin excretino rate exceeds 200 ugs/min and blood levels f creatinine and BUN rise. Blood pressure may rise during this stage.
Describe the fourth stage of kidney disease?
GFR decreases to less than 75 ml/min, large amounts of protein pass into the urine, and high BP almost always occurs. Levels of Cr and BUN rise
Stage five kidney disease?
Kidney failure, or ESRD, GFR is less than 10ml/min. The average length of time to progress to stage five disease is 23 yrs.
How is diabetes different from other CKDs?
It can lead to an increase in kidney size initially as compensation. Then the kidney will shrink. However, the shrunken state does not go less than the original kidney size
In DN, how are proteinuria and GFR related?
A huge rise in proteinuria correlates with a decreased GFR
In diabetics with macroalbuminuria, how do they relate to numbers of people that develop ESRD?
They usually don’t get to ESRD, because they die of cardiovascular events before development of ESRD.
Describe the glomeruli and kidney in the initial stages of DN, compared to other CKDs.
They are initially increased in size or normal
By what percentage does SNGFR increase?
25%
How do glucose levels in diabetes lead to nephropathy?
The increased glucose provides as osmotic diuretic effect, which increases renal filtration, leading to glomerular hypertrophy.
Glomerular pressure thus increases. The kidneys respond with hypertrophy of the epithelium and endothelium, which accelerates glomerular cell failure.
Result is premature glomerulosclerosis.
What does the glomerular HTN cause the GBM to do?
the GBM because injured as a result of glomerular HTN. Thus, the GBM leaks plasma protein into the urine.
In response to protein leaking into the urine from a damaged GBM, what happens to the proximal tubules?
They try to reabsorb the protein, which leads to injury of the tubular cells, activating an inflammatory response. This is associated with development of lipid metabolic abnormalities that lead to further oxidative stress on the already compromised glomerulus.
The resultant tubular inflammatory response and renal microvascular injury activate pathways that lead to fibrosis and scarring of glomerular and tubular elements/
With the increase in the diuresis due to high glucose levels, how do Angio II respond? What does this cause?
Angio II tries to compensate for the excess water excretion. However, it also leads to efferent arteriole constriction. This increases SNGFR and raises intraglomerular pressure, causing glomerular HTN. Sustained increase in glomerular HTN leads to GBM damage, endothelial dysfunction and ultimately extravasation of protein into Bowman’s Capsule.
In addition to aldosterone and efferent arteriole constriction, what third effect does ang II have? What does this cause?
It triggers the release of TGF-B, which stimulates proliferation of fibroblasts and tubuloepithelial cells. This increases extracellular matrix synthesis. KEY role in glomerular and tubuloepithelial hypertrophy, BM thickening and mesangial matrix expansion. NON-Inflammatory glomerular hypertrophy.
Hyperglycemia directly results in the increased deposition of what on the GBM?
Collagen IV, very early sign, even before microalbuminuria.
In Diabetes, you can non-enzymatic glycosylation of what?
AGEs are deposited in capillary basement membranes, as a consequence of long-term hyperglycemia. This is the same mechanism for ulcer formation on the feet.
Proteins and lipids exposed to _____ sugars go through non-enzymatic changes to make _____, which are then made into AGEs
Aldose
Schiff bases or Amadori products
What did intensive glucose control show in the end result for diabetes and development of microalbuminuria?
THe intensive tx lead to a decreased development of microalbuminuria, even after tx was stopped.
Why are ACEi and ARBs better tx for diabetes mellitus than other BP medicine?
They both lead to a vasodilation of efferent arterioles, reducing glomerular capillary pressure.
What is the tx for DN?
HTN control: bp levels below 130/80
ACEI
ARBs
Beta-Blockers
What is an example of an ACEi that was studied and showed decreased progression of increased creatinine levels?
captopril
When do you want to start tx for diabetic nephropathy?
As early as possible, specifically still during microalbuminuria
What are additional risks for diabetes mellitus in the kidney?
increased risk of pyelonephritis emphasematous pyelonephritis paipillary necrosis type 4 renal tubular acidosis neurogenic bladder increased risk for nephrotoxic agents (NSAIDs and iodianted radio contrast media)
What are the 3 major types of DN?
Glomerular
Papillary
Tubulo-interstitial
What are the most common and second most common forms of glomerular DN?
Diffuse
Nodular (kimmelstiel wilson)
What are the most common and 2nd most common forms of papillary DN?
pyelonephritis
papillary necrosis
What is the most common and 2nd most common types of tubulo-interstitial DN?
tubular BM thickening
Interstitial fibrosis
Describe the diffuse type of glomerular DN.
Earlier, less severe, identical to what happens in HTN and aging. Consists of capillary basement membrane thickening and increased mesangial matrix
What is seen on histology of diffuse glomerular DN?
increased mesangial thickening, purple. Can maybe tell an increase in GBM
Describe the nodular type of glomerular DN.,
Later, usually only after more than 10 yrs with diabetes. Much more characteristic of diabetes, superimposed on diffuse glomerulopathy. Has kimmelstiel wilson nodules and hyaline sclerosos of afferent and efferent artioles.
What do kimmelstiel wilson nodules look like?
ovoid or spherical, hyaline . eventually squeezing capillaries shut
What are fibrin caps?
crescentic deposits of condense leaked plasma proteins overlying peripheral capillaries between endothlial cell and BM or between BM and epithelial cell. along the periphery of the gbm, going to overlie the glomerular capillaries
What are capsular drops
deposits of plasma proteins and partly BM in parietal layer of Bowman’s capsule, protruding into urinoferous space. only occur in diabetic glomerulopathies. specific. going to be right up against the parietal layer of bowmans capsule.
