Adequacy of peritoneal dialysis
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Transcript Adequacy of peritoneal dialysis
Diabetic Nephropathy
Dinkar Kaw, M.D.,
Division of Nephrology
Objectives
Prevalence of diabetic kidney disease
Pathogenesis of diabetic nephropathy
Clinical course of diabetic nephropathy
Slowing the progression of nephropathy
Screening for early nephropathy
Causes of End Stage Renal Disease
%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Other
Interstit N
Cystic KD
GN
BP
Diabetes
ll
A
USRDS 1993 Annual Data Report
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Diabetic Nephropathy
The most common cause of ESRD in USA.
Accounts for nearly 40% of ESRD in USA. This
proportion of ESRD due to DN is less in Europe
than in USA.
Incidence is increasing, accounted for 10% in
1973 but now around 40% of USRD populations.
However one needs to keep in mind all diabetic
patients with ESRD do not have DN as underlying
cause of ESRD.
Diabetic Nephropathy
Mortality of ESRD patients with Diabetes Mellitus
is higher than in ESRD patients without Diabetes.
This higher mortality is due to increase in
Cardiovascular, cerebro-vascular, peripheral
vascular and infection related morbidity.
In USA the health care cost for diabetic ESRD
patients has approached to $ 2 billion per year.
Patient Survival on Dialysis by Cause of
Renal Failure
From UpToDate v 6.2; Data from USRDS 1995 Annual Report
Diabetic Nephropathy
DN occurs in 35-40% of patients with type I
diabetes (IDDM) whereas it occurs only in 1520% of patients with type II diabetes (NIDDM).
More frequent in Native Americans, Hispanics and
possibly Asian Indians.
Definition or Criteria for diagnosis of DN
Presence
of persistent proteinuria in sterile urine of
diabetic patients with concomitant diabetic retinopathy
and hypertension.
D.N.- Pathogenesis
Familial - Genetic
Only
35-40% patients with IDDM develop DN.
There is an increased risk of DN in a patient with
family member having DN.
Increased predisposition of Native Americans, Hispanic
to DN.
D.N.- Pathogenesis
Glycemic Control-in both expt & human
DN
does not occur in euglycemic patients.
In early 80s some controversy but DCCT confirmed
role of hyperglycemia in pathogenesis of DN.
Renal transplant with early DN showed structural
recovery in euglycemic receipient. (Abouna)
Strict Glycemic Control Prevents
Microalbuminuria in Type 1 Diabetes mellitus
From UpToDate v 6.2; Data from the DCCT Research Group, NEJM(1993) 329:977.
D.N.- Pathogenesis
Glomerular Hyperfiltration
Glomerular Hypertension
Glomerular Hypertrophy
GBM thickening
Mesangial Expansion
D.N.- Pathogenesis
Renal lesions mainly related to
extracellular matrix accumulation
- Occurs in glomerular & tubular basement
membrane
- Principal cause of mesangial expansion
- Contributes to interstitium expansion
D.N.- Pathogenesis
Extracellular matrix accumulation
- Imbalance between synthesis & degradation of
ECM components
- Linkage between glucose concentration & ECM
accumulation
- Transforming growth factor-Beta associated with
increased production of ECM molecules
D.N.- Pathogenesis
Extracellular matrix accumulation
- TGF-B can down regulate synthesis of ECM
degrading enzymes & upregulate inhibitors of
these enzymes
- Angiotensin II can stimulate ECM synthesis
through TGF-B activity
- Hyperglycemia activates protein kinase C,
stimulating ECM production through cyclic AMP
Pathway
Diffuse and Nodular Glomerulosclerosis in Diabetic
Nephropathy
From UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Diabetic Nephropathy
Advanced Diabetic Glomerulosclerosis
From: UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Diabetic Nephropathy
Diabetic Nephropathy
Glomerular Basement Membrane Thickening
From: UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Natural Course of D.N.
Stage 1: Renal hypertrophy - hyperfunction
Stage 2 : Presence of detectable glomerular
lesion with normal albumin excretion rate &
normal blood pressure
Stage 3 : Microalbuminuria
Stage 4 : Dipstick positive proteinuria
Stage 5 : End stage renal disease
Natural History of IDDM
Clinical type 1 diabetes
Functional changes*
Structural changes†
Microalbuminuria
Proteinuria
Rising
blood pressure
Proteinuria
Rising serum
creatinine levels
End-stage
renal disease
CV events
2
5
10
Onset of
diabetes
Years
* Kidney size , GFR .
† GBM thickening , mesangial expansion
20
30
Natural History of NIDDM
Clinical type 2 diabetes
Functional changes*
Structural changes†
Rising blood pressure
Microalbuminuria
Proteinuria
Rising serum
creatinine levels
End-stage
renal disease
Cardiovascular death
Onset of
diabetes
2
5
* Kidney size , GFR .
† GBM thickening , mesangial expansion
10
Years
20
3
0
D.N.- Pathogenesis
Hypertension - in both expt & human
Hypertension
follows 8-10 years of hyperglycemia
in IDDM patients but it is frequently present at the
diagnosis of NIDDM.
Many experimental & human studies have shown
HTN accelerating progressive renal injury in DN.
Effect of Angiotensin Blockade
Glomerulus
Bowman’s Capsule
Afferent arteriole
Proteinuria
Efferent arteriole
Angiotensin II
A II blockade: Glomerular pressure
AER
( GFR)
ACE-I Is More Renoprotective Than Conventional Therapy
in Type 1 Diabetes
100
% with
doubling of
baseline
creatinine
Baseline creatinine >1.5
mg/dL
75
Placebo
n=202
50
P<.001
25
Captopril
n=207
0
0
1
2
Years of followup
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
3
4
RENAAL
Primary Composite End Point: Doubling of Serum Creatinine,
ESRD or Death (Kaplan – Meier Curve)
Brenner BM et al. N Engl J Med 345:861-869, 2001
RENAAL
dl/mg/yr
Rate of Progression of Renal Disease
(median 1/s Cr slope)
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
Losartan
Placebo
Losartan could delay ESRD by 1.5-2 years.
Brenner BM et al. N Engl J Med 345:861-869, 2001
Irbesartan in patients with type 2 diabetes &
microalbuminuria study
590 NIDDM patients with HTN and microalbuminuria
with nearly normal GFR.
Randomly assigned to placebo, 150 mg or 300 mg of
irbesartan for 2 years.
Primary outcome was time to the onset of diabetic
nephropathy (urinary albumin excretion rate >200
mcg/min and at least 30% greater albuminuria)
14.9% patients on placebo group, 9.7% of irbesartan
150mg group and 5.2% of irbesartan 300 mg group
reached the primary point.
–
(Parving et al, NEJM, 2001)
ARBs in NIDDM,HTN & microalbuminuria-Parving 2001
Lewis et al NEJM 2001
ACE-I + Verapamil: Additive Reduction of Proteinuria in
Type 2 Diabetes at 1 Year
Trandolapril
Verapamil
(315 mg/d)
Trandolapril (2.9 mg/d)
+ Verapamil (219 mg/d)
n=12
n=11
n=14
(5.5 mg/d)
Percent reduction
0
-10
-27%
-20
-33%
-30
-40
-62%
-50
-60
-70
MAP
Proteinuria
*p <0.001 combination vs either
monotherapy
Bakris GL, et al. Kidney Int. 1998;54:1283-1289.
Reprinted by permission, Blackwell Science, Inc.
*
D.N.-Management
ACEI or AII RB- in both expt & human
Reduce
glomerular hypertension
Reduce proteinuria independent of
hemodynamic effects
Reduce glomerular hypertrophy
well tolerated apart from hyperkalemia &
worsening of anemia in severe CRF
Cautious use in presence of severe renovascular
disease
DN: ADA Position Statement
Screening:
Perform an annual test for the presence of microalbuminuria in
1)
type 1 diabetic patients who have had diabetes > 5 years and
2)
all type 2 diabetics patients starting at diagnosis.
Treatment:
•
•
•
•
In the treatment of albuminuria/nephropathy both ACE inhibitors and
ARBs can be used:
In hypertensive and nonhypertensive type 1 diabetic patients with
microalbuminuria or clinical albuminuria, ACE inhibitors are the initial
agents of choice
In hypertensive type 2 diabetic patients with microalbuminuria or
clinical albuminuria, ARBs are the initial agents of choice.
If one class is not tolerated, the other should be substituted
American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002
UK Prospective Diabetes Study (UKPDS) Major Results:
Powerful Risk Reductions
Better blood pressure control reduces…
Strokes by > one third
Serious deterioration of vision by > one third
Death related to diabetes by one third
Better glucose control reduces…
Early kidney damage by one third
Major diabetic eye disease by one fourth
Turner RC, et al. BMJ. 1998;317:703713.
Hazard ratio
UKPDS: Relationship Between BP Control And DiabetesRelated Deaths
5
1
p<0.0001
17% decrease per 10 mmHg decrement in
0.5 BP
110 120 130 140 150 160 170
Mean systolic blood pressure (mmHg)
Adler AI, et al. BMJ. 2000;321:412-419.
Reprinted by permission, BMJ Publishing Group.
Diabetes: Tight Glucose vs Tight BP Control and CV
Outcomes in UKPDS
% Reduction In Relative Risk
0
Stroke
Any Diabetic
Endpoint
DM
Deaths
Microvascular
Complications
5%
-10
10%
12%
-20
24%
*
-30
32%
*
-40
-50
32%
*P <0.05 compared to tight glucose control
44%
*
37%
*
Tight Glucose Control Tight BP Control
(Goal <6.0 mmol/l or 108 mg/dL) (Average 144/82 mmHg)
Bakris GL, et al. Am J Kidney Dis.
2000;36(3):646-661.
Reprinted by permission, Harcourt Inc.
National Kidney Foundation Recommendations on
Treatment of HTN and Diabetes
Blood pressure goal: 130/80 mmHg
Target blood pressure: 125/75 for patients
with >1 gram/day proteinuria
Blood pressure lowering medications
should reduce both blood pressure +
proteinuria
Therapies that reduce both blood pressure
and proteinuria have been known to reduce
renal disease progression and incidence of
ischemic heart disease
Bakris GL, et al. Am J Kidney Dis.
2000;36(3):646-661.
Cholesterol Lowering Therapy and
Diabetic Nephropathy
Randomized singleblinded study
34 NIDDM patients
Lovastatin or PlaceboGFR
ml/mi
n
Followed for 2 years
86
84
82
80
78
76
74
72
70
68
placeb
o
lovasta
tn
0
12
24
Months
Lam, etal. Diabetologia (1995) 38:604-609
Management of ESRD due to DN
Early planning of Vascular Access
Both HD & PD could be appropriate modalities.
Early initiation of Dialysis at GFR 18-20 mls/min.
Renal Transplantation
CHD
very common even in absence of symptoms.
Coronary Angiogram in diabetics under 40 years age.
Combined Renal & Pancreatic Transplantation for
IDDM.
Comparison of Patient Survival on Hemodialysis
and CAPD by Cause of Renal Failure
From UpToDate v 6.2; Data from Nelson, et al JASN(1992)3:1147.
Simultaneous Pancreas-Kidney Transplantation
Patient and Graft Survival
From:
UpToDate
v 6.2
Screening for microalbuminuria in diabetes
Treatment Objectives to Prevent Macrovascular Disease in
Diabetic Patients
Hypertension
BP < 130/80 mmHg
Hypercholesterolemia
LDL < 100 mg/dL
Hyperglycemia
Hgb A1C < 7.0 %
American Diabetes Association Clinical Practice
Recommendations. Diabetes Care. 2001;24(suppl1):S1S133.
Management of HTN and Chronic Renal Disease (CRD) in
Diabetics
Reduce BP to <130/80 mmHg
Use multiple antihypertensive drugs (ACEI, ARB,
diuretic, CCB, beta-blocker)
Maximal reduction of proteinuria
Treat hyperlipidemia (LDL <100 mg/dL)
Control Hgb A1C to <7%
Low salt diet (<2 gm NaCl/day)
Stop cigarette smoking
Thanks for your attention