Diabetic Nephropathy

Question 1

epidemiology of diabetic nephropathy

Answer 1

1/3 of diabetics develop nephropathy

non-caucasians have greater incidence than caucasians (2-5x)

African Americans have the highest risk

number 1 cause of ESRD in the industrialized world

Question 2

What are the criteria for describing clinical stages of diabetic nephropathy?

Answer 2

time from onset of diabetes

functional changes - glomerular filtration rate (GFR), albuminuria/proteinuria, and blood pressure

structural changes - kidney size and microscopic pathology

Question 3

diabetic nephropathy - stage 1

Answer 3

silent phase

hyperfunction and hypertrophy

increased GFR - hyperfiltration and occurs weeks to months

kidney hypertrophy

glomerular and tubular pathology - glomerular enlargement (without cell proliferation), tubular epithelial cell hypertrophy, and thickening of GBM and TBM (onset at 2-3 years)

lasts about a decade

Question 4

diabetic nephropathy - stage 2

Answer 4

incipient nephropathy

microalbuminuria

occurs after 10 years, 1/3 of diabetics enter this stage, beginning of true diabetic nephropathy

the amount of albumin is bout 30-300 per day

blood pressure often starts to rise in type I diabetics

Question 5

pathological findings of stage 2 diabetic nephropathy

Answer 5

further thickening of the GBM and TBM

mesangial matrix expansion is the pathological hallmark

the mesangial space is expanded by excessive amounts of extracellular matrix proteins like collagen and fibronectin

diffuse pattern of glomerulosclerosis (more common) or nodular pattern (less common)

Question 6

diabetic nephropathy - stage 3

Answer 6

overt nephropathy

proteinuria and renal insufficiency

occurs 15 years after onset of diabetes

GFR declines progressively - 6-12 mL.min per year, serum creatinine rises

macroalbuminuria - urine albumin excretion > 300 mg/day, corresponds to overt proteinuria of > 500 mg/day

hypertension (>140/90 mmHg)

~15% get ESRD within 10 years, and ~75% within 15 years

Question 7

diabetic nephropathy - stage 4

Answer 7

advanced nephropathy

renal failure

occurs 15-20 years after onset of disease

albuminuria/proteinuria progresses - may develop nephrotic syndrome, declines when GFR falls low enough

creatinine gets higher

hypertension more severe

pathology worsens

GFR drops - serum creatinine can rise to >6 mg/dL

when GFR <15mL/min/1.73m² - dialysis or transplantation

risk of ESRD ~100% within 5 years

Question 8

What is the structure-function relationship in early hyperfiltraion?

Answer 8

glomerular hypertrophy -> increased surface area of glomerular capillaries

afferent arteriolar vasodilation -> increased renal blood flow into the glomerulus

efferent arteriolar vasoconstriction -> decreased blood flow out of hte glomerulus, increasing the intraglomerular pressure that drives filtration (angiotensin II effect)

Question 9

What are the structure-function relationships that lead to proteinuria in diabetic nephropathy?

Answer 9

filtration barrier becomes more permeable to albumi at first and then plasma proteins in general

loss of cglycocalyx in the endothelium

thickening of the GBM and abnormal composition of the GBM layer leads to albuminuria

podocyte broadening and fusion as well as loss through apoptosis or detachment leads to compensatory attempts in the remaining podocytes to cover the denuded GBM, leading to compromised slit diaphragm integrity and a more porous filter

intraglomerular hypertension pushes plasma proteins across the glomerular filtration barrier

Question 10

How does glomeruloscerlosis lead to renal failure?

Answer 10

expanding matrix impinges on capillary loops and obliterates the surface area available for filtration

increased damage leads to decreased filtration and less creatinine clearance

Question 11

How does tubulointerstitial fibrosis lead to renal failure?

Answer 11

interstitial fibrosis and tubular atrophy in advanced diabetic nephropathy results in the loss of functioning nephrons, contributing to renal failure

Question 12

What is the stimuli in the pathogenesis of diabetic nephropathy?

Answer 12

high glucose and high blood pressure

Question 13

What is the sequelae of the stimuli in diabetic nephropathy?

Answer 13

Amadori modifications and advanced glycation endproducts (AGEs)

high glucose may increase reactive oxygen species that are injurious to the cell

high intra-glomerular pressures may cause mechanical injury to capillary walls, chronically

Question 14

What signaling pathways are involved in the pathogenesis of diabetic nephropathy?

Answer 14

increased flux of glucose generates precursors of diacylglycerol, endogenous activators of protein kinase C (PKC)

MAPK such as ERK are activated

NF-kappaB and HIF are other important signalling pathways in diabetic nephropathy

Question 15

What are the effector cytokines/chemokines/growth factors involved in diabetic nephropathy?

Answer 15

TGF-beta, MCP-1, and EGF are prominent cytokines

angiotensin II is not just a paracrine vasoactive agent, it is also an inducer of renal cellular responses

TGF-beta is upregulated and has hypertrophic and potent profibrotic effects that leads to renal hypertrophy and glomerulosclerosis/tubulointerstitial fibrosis

Question 16

How are genetics related to diabetic nephropathy?

Answer 16

no single gene has been found to have a large influence on suceptibility

likely a polygenic disease

some racial and familial connections

systemic hypertension and high intrarenal angiotensin II are risk factors

Question 17

What are the strategies for prevention and treatment of diabetic nephropathy?

Answer 17

blood sugar (glycemic) control

blood pressure control - most important/effective

others when applicable (smokin cessation, wieght loss, lipid-lowering, low-protein diet, sleep apnea treatment)

Question 18

Diabetes Control and Complications Trial (DCCT)

Answer 18

enrolled 1,441 type I diabetic patients and randomized them to standard glycemic or tight glycemic control (frequent blood sugar tests and insulin pump)

tiight group achieved a 7% HbA1c over 9% in the standard group

reduced incidence of microalbuminuria by 43% and overt albuminuria by 56% over 10 years

Question 19

Epidemiology of Diabetes Interventions and Complications (EDIC)

Answer 19

DCCT follow-up of type I diabetes

showed that after 22 years of folow-up, the tight group cut its risk of impaired GFR by 50% compared with the standard group

the absolute risk reduction went from 9% to 4.5%

difference of progressing to ESRD also haveld but not statistically significant

rate of GFR decline are very similar

Question 20

United Kingdom Prospective Diabetes Study (UKPDS)

Answer 20

enrolled 3,867 type 2 diabetic patients and made one group have tight control

25% risk reduction in the aggregate microvascular endpoints, retinopathy, and nephropathy

individually, microalbuminuria, proteinuria, and two-fold creatinine increase favored tight control but did not reach statistical significance

Question 21

ADVANCE

Answer 21

study that showed that stringent control of HbA1c to 6.5% could reduce the risk of ESRD anc micro- and macroalbuminuria

Question 22

How effective is pancreas transplant in preventing diabetic nephropathy?

Answer 22

may reverse the established histological lesions of DN due to the true normoglycemia that results

Question 23

What is the target blood pressure, regardless of age?

Answer 23

140/90 mmHg

use any hypertensives to get patients to this goal

Question 24

What are the most effective medications for hypertension treatment and why?

Answer 24

ACE inhibitors and ARBs are the most effective because they have renoprotective abilities beyond the blood pressure reduction

due to hemodynamic effect of these drugs to relax the efferent arterial

GFR decreases slghtly in the short-run because the high intraglomerular pressure was sustaining some of the filtration

also can reduce the renal expression of deleterious TGF-beta

the combination of the two drugs does NOT confer additional benefits, but actually increase risk of AKI and hyperkalemia

Question 25

trade-off hypothesis

Answer 25

when you use ACE I or ARB, you accept a short-term (mild) loss of GFR in exchange for a long-term gain in the preservation of GFR, because the treated patient is not losing GFR as rapidly as the untreated patient

should stick with the therapy because the break even point is a few years away

Question 26

Edmund Leis’s Collaborative Study Grou trial

Answer 26

showed that Captopril outperformed another antihypertensive in reducing the risk of the serum creatinine doubling by 48.5%

study was in type 1 diabetes, but other studies have shown effectiveness in type 2 as well

Question 27

RENAAL

Answer 27

study that found losartan decreased the risks of doubling of serum creatining and reaching ESRD

Question 28

IDNT

Answer 28

study that showed irbesartan decreased the risk of doubling of serum creatinine vs both amlodipine and placebo

P value was 0.07 despite large risk reduction