diabetic nephropahty by syed rizwan, md. 19841986198819901992199419961998200020022004200620082010 0...
TRANSCRIPT
DIABETIC NEPHROPAHTY
BY
Syed Rizwan, MD
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 20100
100
200
300
400
500
600
700
IncidenceR2 = 99.8%
Point prevalenceR2 = 99.7%
Projection
Number of Patients
95% Confidence Interval
326,217
372,407
661,330
86,82598,953
172,667
Adjusted for age, gender, race350
300
250
200
150
100
50
0
AII
Diabetes
Hypertension
Cystic Kidney
1992 1994 1996 1998 2000
Chronic Kidney Disease
• Increase in incidence due to,– age of population– increase in diabetes– Decrease in Cardiovascular Mortality
Diabetic Nephropathy
• will increase with more Diabetics all over world.
• Higher morbididty and mortality compared to non-Diabetics.
• Higher cost of health care
Diabetic Nephropathy
• What to do?– prevent or slow progression of disease– decrease morbidity/ mortality– Prepare for RRT(renal replacement
Therapy
prevent or slow progression of Diabetic Nephropahty
– diet,exercise, life style modifications– Glycemic control– HTN control– ACEI/ARBs– Protein restriction– Hyperlipidemia management
Glycemic control in DN
• Stage- earlier the better
• Degree- tighter the better
• Renal disease in Type1 Diabetic may be decreasing.
Glycemic control in DN
• Is game over once Proteinuric?
• Pancreatic Transplantation can reverse proteinuria and establised Glomerular pathology.
HTN control in DN
• Most important
• Most practical
For Individuals With: BP Goal:
Hypertension(no diabetes or renal disease)
Diabetes Mellitus
Renal Diseasewith proteinuria >1 gram/24 hours or diabetic kidney disease
<140/90 mmHg(JNC 7)
<130/80 mmHg(ADA, JNC 7)
<135/85 mmHg<125/75 mmHg
(NKF)
Target Blood Pressure
Chobanian AV et al. JAMA. 2003;289:2560–2571. American Diabetes Association. Diabetes Care. 2002;25:134–147.National Kidney Foundatrion. Am J Kidn Dis.
2002;39(suppl 1):S1–S266.
ACEI/ARBs in DN
• RAS activated in Diabetic Kidney.
• Strict Glycemic contron in overt Nephropathy- not as helpful in DN.
• Glomerular Hyperfiltration injures kidney.
• Lowering intraglomerular pressure is beneficial
ACEI/ARBs in DN
• Is ACEI effective in slowing DN in Type 2 Diabetics?
• No clear evidence that ACEIs are renoprotective in Type 2 Diabetics
• Drug companies would not research on generic medicine.
ACEI/ARBs in DN
• ACE escape phenomenon.
• Biological action of Ang11 are not completley prevented by ACEI.
• Biological actions of Ang11 are mediated by AT-1 receptor.
Acronym Diagnosis Randomization PrimaryEndpoint Duration
IDNT1
N = 1,715Type 2 DM with nephropathy
Irbesartan/amlodipine/placebo + AHT*
•ESRD•2x creatinine•mortality
2.6 yrs
*AHT = other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs).†AHT = other antihypertensive therapy (excluding ACEIs and ARBs).
RENAAL Type 2 DM with nephropathy
Losartan/placebo + AHT†
•ESRD•2x creatinine•mortality
3.4 yrs
N = 1,513
Effect of ARBs on Diabetic Nephropathy
Multicenter (210 sites), prospective, randomized, double-blind trial in 1,715 hypertensive patients with nephropathy due to type 2 diabetes
Composite of doubling of serum creatinine, onset of ESRD, or death from any cause
Usual AHT* + placebo
Usual AHT* + irbesartan 300 mg/day
Usual AHT* + amlodipine 10 mg/day
2.6 yrs
135/85 mmHg
*Antihypertensive therapy (excluding ACEIs, ARBs, CCBs).
Design:
Duration:
Primary Endpoint:
Randomization:
Target BP:
IDNT: Study Design
Doubling of Serum Creatinine, ESRD, and/or Death
32.6%
41.1%39.0%
20
25
30
35
40
45
Irbesartan Amlodipine Placebo
*
*P = 0.02 vs placebo; P = 0.006 vs amlodipine.
20% - irb vs pbo
23% - irb vs aml
Pat
ien
ts, %
IDNT: Primary Composite Endpoint
Multicenter, randomized, double-blind, placebo-controlled trial in 1,513 patients with type 2 diabetes and nephropathy
Composite of doubling of serum creatinine, onset of ESRD, or death from any cause
Usual AHT* + placebo
Usual AHT* + losartan 50–100 mg/day
3.4 yrs
SBP <140 mmHg
DBP <90 mmHg
Brenner BM et al. N Engl J Med. 2001;345:861–869.
*Antihypertensive therapy (excluding ACEIs or other ARBs).
Design:
Duration:
Primary Endpoint:
Target BP:
RENAAL: Study Design
Doubling of Serum Creatinine, ESRD, and/or Death
43.5%
47.1%
30
34
38
42
46
50
Losartan Placebo
(16% )
P = 0.02.
Pat
ien
ts, %
RENAAL: Primary Composite Endpoint
Brenner BM et al. N Engl J Med. 2001;345:861–869
ACEI/ARBs in DN
• Stronger evidence to use ARBs than ACEI in type2 Diabetic Nephropahty.
• ACEI use is warranted because of cost, BP control and beneficial effects on CVS.
Effect of ARBs on Type 2 Diabetic Nephropathy: Conclusions
• Losartan/irbesartan significantly slow deterioration of renal function in nephropathy
• ARBs significantly reduce the risk of doubling serum creatinine or progressing to ESRD
• In type 2 diabetics with nephropathy, ARBs provide renal benefits independent of their BP-lowering effect
Lewis EJ et al. N Engl J Med. 2001;345:851–860. Brenner BM et al. N Engl J Med. 2001;345:861–869.
Mogensen CE et al. BMJ. 2000;321:1440–1444.
CALM: Study Design
Primary OutcomeMeasures:
Multicenter, randomized, double-blind, placebo-controlled trial in 199 patients with type 2 diabetes, hypertension, and microalbuminuria
BP and urinary albumin:creatinine ratio
Group 1: candesartan 16 mg for 24 weeks (n = 66)
Group 2: lisinopril 20 mg for 24 weeks (n = 64)
Group 3: C16 for 12 weeks with add-on L20 for 2 weeks (n = 34)
Group 4: L20 for 12 weeks with add-on C16 for 12 weeks (n = 35)
Design:
Randomization:
Ch
an
ge
in U
rin
ary
Alb
um
in:
Cre
ati
nin
e R
atio
, %
Candesartan 16 mg
Lisinopril 20 mg
Both
*P = 0.05 from baseline.†P < 0.001 from baseline.
–60
–50
–40
–30
–20
–10
0
*
†
†
Mogensen CE et al. BMJ. 2000;321:1440–1444.
CALM: Reductions From Baseline in Urinary Albumin:Creatinine Ratio (Week 24)
*P = 0.05 from baseline.†P < 0.001 from baseline.
Mogensen CE et al. BMJ. 2000;321:1440–1444.
Ch
an
ge
in B
P, m
mH
g
Candesartan 16 mg
Lisinopril 20 mg
Both–30
–25
–20
–15
–10
–5
0
†
SBPDBP
†
*
† †
†
CALM: Reductions From Baseline in BP
Design: Randomized, double-blind trial in 263 patients with nondiabetic renal
disease
Primary Composite of time to doubling of serum Endpoint: creatinine concentration or ESRD
Randomization: Losartan 100 mg/day + AHT* as neededTrandolapril 3 mg/day + AHT* as
needed
Duration: 3 yrs
Target BP: SBP <130 mmHgDBP <80 mmHg
Nakao N et al. Lancet. 2003;361:117–124.
*Antihypertensive therapy (excluding other ACEIs or other ARBs).
COOPERATE: Study Design
Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124.
Doubling of Serum Creatinine or Progression to ESRD
0
5
10
15
0 5 12 18 24 30 36
20
25
30
Pro
po
rtio
n R
each
ing
En
dp
oin
t, %
Months After Randomization
737683868788Combination
637275838586Trandolapril
596579848889Losartan
Number at Risk
Trandolapril
Losartan
Combination
P = 0.02
COOPERATE: Primary Endpoint
0
1
2
3
0 5 15 20 30 35
Trandolapril
Losartan
Combination
Months After Randomization
Med
ian
Uri
nar
y P
rote
in E
xcre
tio
n,
g/d
ay
Baseline
10 25 40
COOPERATE: UAER
Management of Hyperkalemia in Patients Treated With ACEIs or ARBs
•Discontinue other meds that interfere in K excretion•Low K diet (70 mEq/d)•Effective diuretic therapy: loop diuretics when creatinine >1.8 mg/dl•NaHCO3 tablets (650-mg tablet, 8 mEq)•Decrease dose of ACEI•Consider change to ARB
Palmer BF. N Engl J Med. 2002;347:1256–1261.
ACEI and ARB combination
• No good study in Diabetic Nephropathy.
• Overall use is safer and seems beneficial
• Hyperkalemia is a major concern.
• Benefit proven in Non-Diabetic CKD Pts.
Protein restriction in DN
• Unproven.
• Uncertain.
• Problems with compliance.
• Risk of Malnutrition.
• Avoid High Protein diet.
• About 1gm/kg/day.
Hyperlipidemia and DN
• Common in Diabetics.
• Can cause Glomerular injury.
• Lowering lipid can slow renal disease
Proteinuria in DN
• Proteinuria in Diabetes means more than Glomerular damage.
• Proteinuria in DM points to widespread endothelial and epithelial cell injury.
• High association with,– Retinopathy– Neuropathy– Coronary Artery disease
ANEMIA
AND
DIABETIC NEPHROPATHY
Anemia
• Independent risk factor for ESRD.
• Associated with higher mortality & moebidity.
• Correcting anemia could delay progression of DM.
• Do not ignore ANEMIA in your Diabetic Patients.
Cardiovascular Disease
and
Diabetic Nephropathy
Renal Osteodystrophy
• Almost all Patient with advanced CKD have Renal Bone disease.
• Vitamin D3 deficiency
• Hypocalcemia
• Hyperphosphatemia
• Hyperparathyroidism
• Phosphate Binders used for years are Calcium(PhosLo=Ca acetate)
Diabetic Nephropathy
• What to do?– prevent or slow progression of disease– decrease morbidity/ mortality– Prepare for RRT(renal replacement
Therapy
Vascular Access Placement
As early as possible and indicated
CKD and Diabetes
• Outcome(Morbididty and Mortality) is better if Patient wirh DN started on dilalysis earlier.
• Indication for Dialysis,• Diabetics- Cr. Cl < 15 cc/min.
• Non- Diabetics- Cr.Cl < 10cc/min
Transplantation
• Renal Transplant- graft survival> 90%- 1yr.• Simultaneous Kid./Pancrease(SKP) 92%• Pancease after Kid. TX(PAK) 93%
• Pancrease Transplant alone(PTA) 97%
• Islet Transplant- results encouraging