Diabetic Nephropathy Flashcards
epidemiology of diabetic nephropathy
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
What are the criteria for describing clinical stages of diabetic nephropathy?
time from onset of diabetes
functional changes - glomerular filtration rate (GFR), albuminuria/proteinuria, and blood pressure
structural changes - kidney size and microscopic pathology
diabetic nephropathy - stage 1
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
diabetic nephropathy - stage 2
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
pathological findings of stage 2 diabetic nephropathy
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)
diabetic nephropathy - stage 3
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
diabetic nephropathy - stage 4
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
What is the structure-function relationship in early hyperfiltraion?
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)
What are the structure-function relationships that lead to proteinuria in diabetic nephropathy?
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
How does glomeruloscerlosis lead to renal failure?
expanding matrix impinges on capillary loops and obliterates the surface area available for filtration
increased damage leads to decreased filtration and less creatinine clearance
How does tubulointerstitial fibrosis lead to renal failure?
interstitial fibrosis and tubular atrophy in advanced diabetic nephropathy results in the loss of functioning nephrons, contributing to renal failure
What is the stimuli in the pathogenesis of diabetic nephropathy?
high glucose and high blood pressure
What is the sequelae of the stimuli in diabetic nephropathy?
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
What signaling pathways are involved in the pathogenesis of diabetic nephropathy?
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
What are the effector cytokines/chemokines/growth factors involved in diabetic nephropathy?
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
How are genetics related to diabetic nephropathy?
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
What are the strategies for prevention and treatment of diabetic nephropathy?
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)
Diabetes Control and Complications Trial (DCCT)
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
Epidemiology of Diabetes Interventions and Complications (EDIC)
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
United Kingdom Prospective Diabetes Study (UKPDS)
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
ADVANCE
study that showed that stringent control of HbA1c to 6.5% could reduce the risk of ESRD anc micro- and macroalbuminuria
How effective is pancreas transplant in preventing diabetic nephropathy?
may reverse the established histological lesions of DN due to the true normoglycemia that results
What is the target blood pressure, regardless of age?
140/90 mmHg
use any hypertensives to get patients to this goal
What are the most effective medications for hypertension treatment and why?
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
trade-off hypothesis
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
Edmund Leis’s Collaborative Study Grou trial
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
RENAAL
study that found losartan decreased the risks of doubling of serum creatining and reaching ESRD
IDNT
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
