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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