Diabetic Nephropathy

Diabetic Nephropathy (DN)
Dr. naowanit
nata
Content
• Backgroud
• Natural history of DN
• DN and DR and CVD
• Pathology and Pathogenesis
• Diagnosis and diferential diagnosis
• Prevention and treatment
Background
Prevalence Of DM
• World wild 246 million

Internation Diabetes Federation: June 30 2007
• Thailand : 9.6% (adult > 35 years old)

:~ 2.4 million
: type 2 DM 95 %
Diabetes Care 2003;26:2758-63.
Characteristic of DN
1. Albuminuria
2. Hypertension
3. GFR
- hyperfutration
- decrease GFR
Diabetic Nephropathy; albuminuria
Urinary albumin excretion rate
Condition 24 hr (mg/d) Overnight (ug/min)
normoalbuminumia <30 <20
microalbuminumia
30-300 20-200
macroalbuminumia >300 >200

1. Albuminuria
2. Hypertension
3. GFR
- hyperfutration
- decrease GFR
Prevalence of HT in DN
Clinical Prevalence (%)
Type1 DM, microalbuminuria 30-50
Type1 DM, macroalbuminuria 65-88
Type2 DM, microalbuminuria 40-83
Type2 DM, macroalbuminuria 78-96

1. Albuminuria
2. Hypertension
3. GFR
- hyperfutration
- decrease GFR
Prevalence of DN
• World wild (Cross sectional type2 DM n=32,208 : 33
country)
- microalbuminuria 39%
- macroalbuminuria 10%
Kidney Int 2006; 69:2057-63
• Asia (type2 DM n=6,801: 10 country)

- microalbuminuria 39.8%
- macroalbuminuria 18.8%
Diabetologia 2005; 48:17-26
Prevalence of DN in Thailand
• Type2 DM ( big hospital)
- microalbuminuria 18.7 - 43.5%
- macroalbuminuria 1.6 -13.4%
J Med Assoc Thailand 2005; 88: 1624-29
• Type2 DM (community )
- microalbuminuria 30.3%
- macroalbuminuria 15.15%
J Med Assoc Thailand 2005; 88 (suppl 3): S164-S174

Samitivej Sriracha hospital
• DM 380
• Nephropathy 15%
• ESRD on HD 47/98
Etiology of CKD in Thailand
1712
20% 2665
30%
Unknown
DM
1387 Others
16%
CGN HT
1550
1438
18%
16%
TRT Report 2003

Changing in causes of ESRD
Etiology of ESRD in Thailand
HT 26%
DM 34%
1st Qtr
2nd Qtr
3rd Qtr
4th Qtr
5th Qtr
Unknown 14% CGN 16%

Other 10%
TRT Registry 2004
Diabetes Mellitus and Kidney
• Diabetic nephropathy
• Glomerular disease
• Atherosclerotic renal artery stenosis
• UTI
• Renal papillary necrosis
• Renal tubercurosis
• Neurogenic bladder
• Contrast induce nephropathy
• Hyporeninemic hypoaldosteronism
Content
• Backgroud
• Natural history of DN
Type 1 DM
Natural history of type I diabetic nephropathy
Stage of DN Time UAE GFR HT
(year) (mg/d)
1. renal hypertrophy and Dx <30 20-50%
hyperfiltration
5 <30 20-40% 1 mmHg

2. normoalbuminuria /year
3. Incipient nephopathy 6-15 30-300 3 mmHg

(microalbuminuria) /year
4. overt nephopathy 15-25 >300 >80%

(macroalbuminuria)
25-30 ~ 100%
5. ESRD
Normo 50% Sustained
albuminuria normoalbuminuria
-Timing
30% - BS control
50% -BP control
- genetic
Micro 30% Sustained

albuminuria microalbuminuria
- BP control
30% - BS control
Overt
proteinuria
- BP control
Type 1 DM
ESRD
Type 2 DM
Stage of DN Time UAE GFR HT
(year) (mg/d)
1. renal hypertrophy and Dx <30 20-50%
hyperfiltration
5 <30 20-40% 1 mmHg

2. normoalbuminuria /year
3. Incipient nephopathy 6-15 30-300 3 mmHg

(microalbuminuria) /year
4. overt nephopathy 15-25 >300 >80%

(macroalbuminuria)
25-30 ~ 100%
5. ESRD
No nephropathy
1.4%/ years
0.1% 2.0% / years
Microalbuminuria
3.0%
DEATH
0.1%
2.8%
Macroalbuminuria
0.3% 4.6%
2.3%
Rising Cr, RRT

19.2%
UKPDS 64: Kidney Int 2003; 63:225-232
Content
• Backgroud
• Natural history
DR and DN
DN & DR (Type1 DM)
• NPDR 90 – 95%
• PDR 70%
• Most case : > microalbuminuria
• Severity assosiation
Diabetic Retinophathy and Nephropathy: NJ 2006: 473-98
• Some case: advanced DR with normal

renal pathology and normal UAE
Diabetes 1994; 43: 441

DN & DR in Type2 DM
• 56%
- 35 patients : DN 27 patients
: DR 15 patients
Kidney Int 2000; 58: 1719-31
• 45%
- 221 patients : DR 99 patients
- advances DN: DR 90%
Nephron 1998; 80: 171-4
DN and CVD
DN & CVD
• DM type 1
- microalbuminuria RR 1.2 / UAE normal
- macroalbuminuria RR 10.0
• DM type 2
- microalbuminuria RR 2-3
- macroalbuminuria RR 9
J Intern Med 2003; 254:45-66

Am J Physiol Renal Physiol 2004;286:F442-F450
No nephropathy
1.4%
0.1% 2.0%
Microalbuminuria
3.0%
DEATH
0.1%
2.8%
Macroalbuminuria
0.3% 4.6%
2.3%
Rising Cr, RRT

19.2%
UKPDS 64: Kidney Int 2003; 63:225-232
Machanism increase CVD
• Severity of traditional cardiovascular
Risk factors ( BS, BP, DLD, Smoking)
• Nontraditional risk factor

( fribinogen, homocysteine)
• Endothelial dysfuction,RAS, basement

membrane
J Intern Med 2003; 254:45-66

Am J Physiol Renal Physiol 2004;286:F442-F450
Content
• Backgroud
• Natural history
Pathology of DN
Pathology of DN
Always present Usually present Sometimes
Glomerular
-Kimmelstiel-Wilson - glomerular
-GBM thickening nodules microaneurysms
-Mesangial matrix expansion -global sclerosis - capsular drops
-FSGS - hylaline lesions
Tubulointerstial
-TBM thickening - Tubular atrophy

- interstial expansion
Vascular - Afferent and efferent - atherosclerosis

arteriolar hyalinosis
IF
Staining for albumin
Pathology of DN
Pathogenesis of DN
Semin Nephrol 2007; 27: 130-43

Glycemic Duration Insulin
control Ages at onset resistance
Metabolic factor Environment factor

Hyperglycemia Dietary protien intake
AGEs Smoking
Polyol
Hexosamine
Oxidative stress
Activated of intracellular
signaling pathways
Genetic factor
ACE ID polymorphism Growth factor
Hyperlipidemia Inflammatory mediators
Oligonephropathy
ECM Altered vascular

accumulatiom permeability
Hemodynamic factor
Sytemic hypertension
Glomerular hypertension Proteinnuria
vasoactive hormones DN
Content
• Backgroud
• Natural history
Diagnosis and DDx
Diagnosis
• Detail of DM
• HT
• DR?
• LAB
• ? Bx
Risk factor of DN
1. Sex : male
2. duration ( mean+SD= 12.8+8.2 years)
3. BP control
4. HbA1C
5. Dyslipidemia
6. DR
7. Smoking
J Med Assoc Thai Vol.89 Suppl.1: 2006

LAB
• UA
• plain KUB, ultrasonography
• Selology (ANA, ANCA, complement)
Association of DN and CKD
Albuminuria
GFR CKD
(ml/min) normoalbuminuria microalbuminuria macroalbuminuria
> 60 1+2 At risk Possible DKN DKN
30-60 3 Unlike DKN Possible DKN DKN
< 30 4+5 Unlike DKN Unlike DKN DKN

Stage Description GFR Action
At increase risk ≥90 Screening CKD risk

(with CKD risk factors) reduction
• Diagnosis and treatment

Kidney damage with • Treatment of co-morbid
1 ≥90
normal or ↑ GFR • Slow progression
• CVD risk reduction
Kidney damage with Estimation of CKD
2 60-89 progression
mild ↓GFR
Evaluation and treatment

3 Moderate ↓GFR 30-59 of complications
Preparation for kidney

4 Severe ↓GFR 15-29 replacement therapy
5 ESRD <15 RRT

Kidney Bx or further investigation
1. proteinuria without DR in type 1 DM

2. acute onset of proteinuria
3. GFR without proteinuria
4. ARF after ACEI, ARB
5. Unexplaint cause ARF
6. gross hematuria
7. Differential size of both kidney
8. Symptom and sing secondary glomerular disease
9. Refractory HT

6. gross hematuria
9. Refractory HT

5. gross hematuria
8. Refractory HT

6. gross hematuria
9. Refractory HT

5. gross hematuria
8. Refractory HT

6. gross hematuria
9. Refractory HT

6. gross hematuria
9. Refractory HT

6. gross hematuria
9. Refractory HT

6. gross hematuria
9. Refractory HT
Content
• Backgroud
• Natural history
Prevention and treatment
Prevention and Treatment DN
1. Screening high risk, early detection

2. Prevention, slow progression DKD
3. Detect risk CVD and treatment
4. Prevent, treatment complication of CKD



Screening and early detection
Screening and early detection
• History and PE
• Lab
-UAE
-GFR
Urine Albumin Excretion (UAE)
• Yearly ( type 1 DM after Dx 5 yrs, type 2 at Dx)
• Urine dipstick (trace = macroalbuminuria 2/3 in 6 mo)
• UPCR (urine albumin/creatinine ratio)
• Urine dipstick negative : microalbuminuria

: positive 2/3 in 6 mo
GFR measurment
• Yearly
• Serum creatinine
• GFR by calculated
Cockcroft-Gault equation (ml/min)

[(140-age)*weight(*0.85 if female)]/72*SCr
MDRD equation (mL/min/1.73m2)

186.3*(serum creatinine)-1.154*age-0.203
*(0.742 if woman)*(1.21 if black)
Prevention
slow progression DKD
Treatment and Prevention
• Glycemic control
• BP control
• RAS blockade
• Stop smoking
• Protein restriction
• Lipid control
• TZD
• New therapy
• Multifactorial
Glycemic control
Glycemic control
• Both DM type 1, 2
1. prevent microalbuminuria
2. slow progression microalbuminuria
to macroalbuminuria
3. prevent DR
•N Eng J Med: 1993; 329: 977-986 (DCCT)

•Diabetes Res Clin Pract 1995; 28: 103-117 (Kumamoto)
•Lancet 1998; 352: 837-853 (UKPDS 33)
The effect of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control
and Complications Trial Research Group.
BACKGROUND. Long-term microvascular and neurologic complications cause major morbidity and mortality
in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with
the goal of maintaining blood glucose concentrations close to the normal range could decrease the
frequency and severity of these complications.
METHODS. A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention
cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to
intensive therapy administered either with an external insulin pump or by three or more daily insulin injections
and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin
injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of
retinopathy and other complications were assessed regularly.
RESULTS. In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the
development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared
with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of
retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of
proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67
percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria
(urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval,
21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54
percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent
(95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy
was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS. Intensive therapy effectively delays the onset and slows the progression of diabetic
retinopathy, nephropathy, and neuropathy in patients with IDDM.
DCCT: N Engl J Med 1993 Sep 30;329(14):977-86.

The Diabetes Control and Complications Trial
Research Group
• Long term : microvascular and neurological

Complication mean F/U 6.5 years
• Number : 1441 intensive insulin therapy
• Result :
- risk develop DR 76%
- slow progression DR 54%
- progression to severe DR 47 %
- microalbuminuria 39%
- macroalbuminuria 54%
- neuropathy 60%
DCCT: N Engl J Med 1993 Sep 30;329(14):977-86.
Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2
diabetes
BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect
on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in
patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects
of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular
and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months'
diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned
intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with
diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable
FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three
aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related
endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart
failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation,
blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral
vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical
endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of
hypoglycaemia was also analysed by actual therapy.
FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8)
in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group.
Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-
related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause
mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40,
p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the
three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the
intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both
p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with
chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group
(mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than
those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).
INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of
microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.
UKPDS 33: Lancet 1998 Sep 12;352(9131):837-53.

Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications
in patients with type 2 diabetes
• Number : 3867 newly Type 2 DM, F/U 10 ys
• 3 End point :
- diabetes-related endpoint : sudden death, death from hyper or
hypoglycaemia, MI , CHF,stroke, renal failure, amputation , complication DR
- diabetes-related death : MI, stroke, peripheral diabetes-related

death (death from myocardial infarction, stroke, peripheral vascular disease,
renal disease, hyperglycaemia or hypoglycaemia, and sudden death)
-all-cause mortality
UKPDS 33: Lancet 1998 Sep 12;352(9131):837-53.

Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications
in patients with type 2 diabetes
• RESULT:
- HbA1C = 7:7.9% intensive / conventional gr.

- Diabetes-related endpoint 12 %
- Diabetes-related death 10 %
- All-cause mortality 6%
- Microvascular end point 25 %
UKPDS 33: Lancet 1998 Sep 12;352(9131):837-53.

Long-term results of the Kumamoto Study on optimal diabetes control
in type 2 diabetic patients
OBJECTIVE: To examine whether intensive glycemic control could decrease the frequency or
severity of diabetic microvascular complications, an 8-year prospective study of Japanese
patients with type 2 diabetes was performed.
METHODS: A total of 110 patients with type 2 diabetes (55 with no retinopathy [the primary
prevention cohort] and 55 with simple retinopathy [the secondary intervention cohort]) were
randomly assigned to multiple insulin injection therapy (MIT) groups and administered three or
more daily insulin injections or assigned to conventional insulin injection therapy (CIT) groups
and administered one or two daily intermediate-acting insulin injections. Worsening of
microvascular complications was regularly assessed during 8 years. Two or more steps up in
the 19 stages of the modified Early Treatment of Diabetic Retinopathy Study classification in
retinopathy and one or more stages up among three stages in nephropathy (normoalbuminuria,
microalbuminuria, and albuminuria) were defined as worsening of complications.
RESULTS: In both primary prevention and secondary intervention cohorts, the cumulative
percentages of worsening in retinopathy and nephropathy were significantly lower (P < 0.05) in
the MIT group than in the CIT group. In neurological tests after 8 years, the MIT group showed
significant improvement (P < 0.05) in the median nerve conduction velocities (motor and
sensory nerves), whereas the CIT group showed significant deterioration (P < 0.05) in the nerve
conduction velocities and vibration threshold. From this study, the glycemic threshold to prevent
the onset and progression of diabetic microvascular complications was as follows: HbA1c <
6.5%, fasting blood glucose concentration < 110 mg/dl, and 2-h postprandial blood glucose
concentration < 180 mg/dl.
CONCLUSIONS: Intensive glycemic control can delay the onset and progression of the early
stages of diabetic microvascular complications in Japanese patients with type 2 diabetes.
Diabetes Care 2000 Apr;23 Suppl 2:B21-9.

AIM glycemic control
• HbA1C < 7.0%
• Preprandial capillary plasma glucose
90-130 mg/dl
• Peak postprandial capillary plasma glucose
< 180 mg/dl
ADA: Diabetes care 2007; 30 : s4-s41

AIM glycemic control
• HbA1C < 6.5 %
• Preprandial capillary plasma glucose
< 110 mg/dl
• Peak postprandial capillary plasma glucose
< 145 mg/dl
IDF GGT2D: International Diabetes Federation,

Global Guideline for Type 2 Diabetes
IDF WPRT2D: Internation Diabetes Federation

Asian-Pacific Type 2 Diabetes Policy
Group
• BP control
• RAS blockade
• Stop smoking
• Lipid control
• TZD
• New therapy
• Multifactorial
BP control
Blood pressure control
• Importance of BP control ?
• Level of blood pressure?
• Type of antihypertension?
Any DM Microvascul
Strok Diabetic Death ar
0 e Endpoint s Complicatio
% Reduction in Relative Risk
5% n
10
-1 12 %
0 %
-2
0 24
%
-3 32 32
0 % % 37
**P < %
-4 44
0 %
0.05
Tight Glucose Tight BP Control
Control Average 144/82
-5 Goal < 108 mg/dl mmHg
0
UKPDS 38: BMJ 1998; 317:
703-13
SBP (mm
Hg)
13 13 13 14 14 15 15 17 18
00 4 8 2 6 0 4 0 0
-2
r = 0.39; P <
GFR (ml/min/year)
-4 0.05
-6
-8 Untreated
HTN
-1
0
-1
2
-1
•Parving HH et al. Br Med J, •Bakris GL : Hypertension, 1997
4
1989 •Estacio R et al. Diabetes Care,
•Viberti GC et al. JAMA, 1993 2000
•Lewis EJ et al. N Engl J Med, •Bakris, GL et al. Arch Intern Med,
1993 2003
•Lebovitz H et al. Kidnek Int,
1994
•Bakris GL et al.KDOQI:
KidneyAm J Kidney Disease 2007; 49 (Suppl 2): S1-S179
Int,
1996
Level of BP
• CVD increase x2 : every 20/10 mmHg (BP 115/75 mmHg)
Am J Kidney dis 2004; 43:

s1-s290
s1-s179
• RCT (end point: Scr x2, ESRD) : GFR decrease < 1 cc/min/y
: SBP < 130 mmHg
s1-s290
s1-s179
• Mean BP 128/75 mmHg : 137/81 mmHg
- slow progression to microalbuminuria and macroalbuminuria
- diabetic retinopathy, stroke
ABCD: Kidney Int 2002; 61:

1086-97
Aim of BP control
• BP < 130/80 mmHg
• Treatment : life style modification

: low salt diet (Nacl < 6 g/d)
: antihypertensive drug
•Am J Kidney dis 2004; 43: s1-

s290
•Am J Kidney dis 2007; 49: s1-
Type of antihypertension
Type of antihypertenstion
• RAS blockade
- ACEI, ARB, renin antagonist
- aldosterone antagonist
- combination
• CCB
• B-blocker
• Other: diuretic, central-acting a- agonists,
A1-blockers, vasodilatators
RAS blockade
RAS blockade
• ACEI, ARB, renin antagonist
• Aldosterone antagonist
• Combination
Terminology
Primary prevention:
normoalbuminuria microalbuminuria
Secondary prevention:
microalbuminuria macroalbuminuria
Tertiary prevention:
macroalbuminuria progression CKD,ESRD
Type 1 DM and RAS blockade
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy
The Collaborative Study Group
BACKGROUND. Renal function declines progressively in patients who have diabetic nephropathy, and
the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine
whether captopril has kidney-protecting properties independent of its effect on blood pressure in
diabetic nephropathy.
METHODS. We performed a randomized, controlled trial comparing captopril with placebo in patients
with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day
and the serum creatinine concentration was < or = 2.5 mg per deciliter (221 mumol per liter). Blood-
pressure goals were defined to achieve control during a median follow-up of three years. The primary
end point was a doubling of the base-line serum creatinine concentration.
RESULTS. 207 patients received captopril, and 202 placebo. Serum creatinine concentrations doubled
in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0.007).
The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent
in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine
concentration of 2.0 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a
concentration of 1.5 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a
concentration of 1.0 mg per deciliter (88.4 mumol per liter). The mean (+/- SD) rate of decline in
creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per
year in the placebo group (P = 0.03). Among the patients whose base-line serum creatinine
concentration was > or = 1.5 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25
percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group
(P = 0.01). Captopril treatment was associated with a 50 percent reduction in the risk of the combined
end points of death, dialysis, and transplantation that was independent of the small disparity in blood
pressure between the groups.
CONCLUSIONS. Captopril protects against deterioration in renal function in insulin-dependent diabetic
nephropathy and is significantly more effective than blood-pressure control alone.
N Engl J Med 1993 Nov 11;329(20):1456-62.

The Collaborative Study Group
• RCT : captopril / placebo, mean F/U 3 ys
• Type 1 DM : albuminuria > 500 mg/d
: Scr < 2.5 mg/dl
• Number : 207 captopril / 202 placebo
• Result
- mean (+SD) rate of decline : captopril group - CrCl 11 +/- 21 %/y
: placebo group - CrCl 17 +/- 20
%/y
- reductions in risk 2xScr :48 % in the captopril gr.
- reduction in risk combined end points (death,

dialysis,transplantationand ) Captopril : 50 %
N Engl J Med 1993 Nov 11;329(20):1456-62.
Primary prevention
Primary prevention:
normoalbuminuria microalbuminuria
BENEDICT: N Engl J Med: 2004; 351: 1941-51
Preventing Microalbuminuria
in Type 2 Diabetes
• Multicenter double-blind RCT
• Compare N-CCB, ACEI, N-CCB+ACEI, placebo
• N= 1204, Type2 DM+HTN+normoalbuminuria
• Time: F/U 3 years
• Primary end point: microalbuminuria

BENEDICT: N Engl J Med: 2004; 351: 1941-
51
No ACEI
CCB
No CCB
ACEI

Result: primary end point
• Tradorapril 5.7%
• Tradorapril + Verapamil 6%
• Verapamil 11.9%
• Placebo 10%

secondary prevention
Secondary prevention:
microalbuminuria macroalbuminuria
IRMA-2: N Engl J Med: 2001; 345: 870-78
IRMA-2 study
• Multinational double-blind RCT (compare:

irbesartan 150 mg, 300 mg, placebo)
• N=590, Type2 DM + HTN + microalbuminuria
• Time: 2 years
• Primary outcome: UAE > 200 mg/d

: > 30% baseline
IRMA-2: N Engl J Med: 2001; 345: 870-78

IRMA-2: N Engl J Med: 2001; 345: 870-78
Urine albumin excretion (UAE)
Months of follow-
up
IRMA-2: N Engl J Med: 2001; 345: 870-78

Creatinine clearance (CrCl)
Months of follow-
up
IRMA-2: N Engl J Med: 2001; 345: 870-78

Mean Arterial Blood Pressure
IRMA-2: N Engl J Med: 2001; 345: 870-78

Tertiary prevention
Tertiary prevention:
macroalbuminuria progression CKD,ESRD
IDNT : N Engl J Med : 2001 ; 345:851-60
IDNT study
• Multicentor double-blind RCT ( compare:

Irbesartan 300 mg, Amlopine 10 mg, Placebo)
• N = 1715, Type2 DM + HTN + macroalbuminuria
• Time: mean F/U 2.6 years
• Primary end point: X2 Scr, ESRD, death
IDNT : N Engl J Med : 2001 ; 345:851-60

IDNT : N Engl J Med : 2001 ; 345:851-60
Cumulative Proportions of Patients with the Primary
Composite End Point (Panel A)
Relative
risk
< placebo 20%
< amlopine
23%
IDNT : N Engl J Med : 2001 ; 345:851-60

Doubling of the Base-Line Serum Creatinine
Concentration (Panel B)
Relative
risk
< placebo 33%
< amlopine
37%
IDNT : N Engl J Med : 2001 ; 345:851-60

End-Stage Renal Disease (Panel C)
Relative
risk
< placebo 23%
< amlopine
23%
IDNT : N Engl J Med : 2001 ; 345:851-60

Death from Any Cause (Panel D)
Relative
risk
= placebo
=amlopine
IDNT : N Engl J Med : 2001 ; 345:851-60

RENAAL: N Engl J Med: 2001; 345: 861-69
RENAAL Study
• Double-blind RCT, Compare Losartan:placebo
• N = 1513, mean F/U 3.4 years
• Primary end point: x2 Scr, ESRD, death
• Secondary end point

: CVD, proteinuria, rate progression renal

Kaplan–Meier Curves of the Percentage of Patients with the
Primary Composite End Point (Panel A)
RR 16%
P=
0.02

Doubling of the serum creatinine
(Panel B)
RR 25%
P=
0.006

End-Stage Renal Disease (Panel C)
RR 28%
P=
0.002

Combinde end point of ESRD or Death
(Panel D)
RR 20%
P = 0.01

Median Changes from Base Line in the Level of
Proteinuria

Type 1 DM
RAS
prevention study blockade result
primary Small study ACEI No significant
secondary Meta- ACEI Risk microalbuminuria

analysis Regression to
normoalbuminuria
tertiary Collaborative ACEI Risk dialysis, KT, death 50%

study
Type 2 DM
prevention study RAS Result

blockade
primary BENEDICT ACEI Risk microalbuminuria 50%
Micro-HOPE ACEI Risk macroalbuminuria 24%
IRMA-2 ARB Risk macroalbuminuria

secondary
MARVAL ARB Regression to
normoalbuminuria
IDNT ARB Risk macroalbuminuria 33%

tertiary
RENAAL ARB Risk macroalbuminuria 35%
ARB versus ACEI
Type 2 DM
DETAIL: N Engl J Med: 2004; 351:1952-61
DETAIL Study
• Multicenter double-blind RCT
• Telmisartan 80 mg : Enalapril 20 mg
• N = 250 pateins, treatment 5 years
• Primary end point : change GFR 5 years

• Second end point : annual change GFR
: Scr, UAE, BP
: ESRD, CVD, death

Changes from Baseline GFR (Panel A)

Changes from Baseline GFR
complete Five-Year data (Panel B)

Changes from Baseline in Systolic Blood
Pressure (Panel A)

Changes from Baseline Diastolic Blood
Pressure (Panel B)

RESULT: DETAIL Study
• Primary end point :change in GFR 5 years
Telmisartan - 17.9 ml/min/1.73 mm3
Enalapril - 14.9 ml/min/1.73 mm
( CI -7.6 – 1.6)
• Secondary end point : no significant

Combination
antihypertensive drugs
Combination antihypertensive drugs
• Mean 3.2 type

• For control SBP 129-144 mm Hg
Am J Kidney Dis 2000; 36:

646-61
Calcium-channel blockers (CCB)
UAE (small study, short term F/U )

• Non-dihydropyridine = ACEI > dihydropyridine
Arch Intern Med 1995; 155:
1073-80
Kidney Int 2004; 65; 1991-2002
• Non-dihydropyridine + ACEI > ACEI
Diabetes Care 2004; 27: 1688-91
• Type 2 DM, N= 436 (normo, microalbuminuria)

Enalapril = nifedipine retard
Diabetes Res Clin Pract 2001; 54:
B-blockers
• + proteinuria
• + slow progression CKD
BMJ 1982; 285: 685-

8
Aim of BP control
• BP < 130/80 mmHg
• UAE < 0.5-1 g/d (g/g creatinine)
KDOQI: Am J Kidney Disease 2007; 49 (Suppl 2): S1-S179

• BP control
• RAS blockade
• Stop smoking
• Lipid control
• TZD
• New therapy
• Multifactorial
Protein Restriction
Effect of dietary protein restriction
on prognosis in patients with DN
BACKGROUND: Recent data suggest that dietary protein restriction improves survival and
delays the progression to end-stage renal disease (ESRD) in non-diabetic nephropathies.
The purpose of our study was to determine the effect of dietary protein restriction on
survival and progression to ESRD in diabetic nephropathy.
METHODS: A four-year prospective, controlled trial with concealed randomization was
performed comparing the effects of a low-protein diet (0.6 g/kg/day) with a usual-protein
diet. The study included 82 type 1 diabetic patients with progressive diabetic nephropathy
[pre-study mean decline in glomerular filtration rate (GFR) 7.1 mL/min/year (95% CI, 5.8 to
8.5)]. The main outcome measures were decline in GFR and development of ESRD or
death.
RESULTS: During the follow-up period the usual-protein diet group consumed 1.02
g/kg/day (95% CI; 0.95 to 1.10) as compared with 0.89 (0.83 to 0.95) in the low-protein diet
group (P = 0.005). The mean declines in GFR were 3.9 mL/min/year (2.7 to 5.2) in the
usual-protein diet group and 3.8 (2.8 to 4.8) in the low-protein diet group. ESRD or death
occurred in 27% of patients on a usual-protein diet as compared with 10% on a low-protein
diet (log-rank test; P = 0.042). The relative risk of ESRD or death was 0.23 (0.07 to 0.72)
for patients assigned to a low-protein diet, after an adjustment at baseline for the presence
of cardiovascular disease (P = 0.01). Blood pressure and glycemic control were
comparable in the two diet groups during the follow-up period.
CONCLUSION: Moderate dietary protein restriction improves prognosis in type 1 diabetic
patients with progressive diabetic nephropathy in addition to the beneficial effect of
antihypertensive treatment.
Kidney Int 2002 Jul;62(1):220-8.

Effect of dietary protein restriction
on prognosis in patients with DN
• Type1 DM 82 patiens, F/U 4 years

• Compare : usual protein, low (0.6g/kg/d)
• Outcome: GFR, ESRD, death
• Result: usual protein/ low protein

- protein 1.02 / 0.89 (g/kg/d)
- GFR 3.9 / 3.8 (ml/min/years)
- ESRD 27% / 10%
Kidney Int 2002 Jul;62(1):220-8.
Restriction of dietary protein and progression
of renal failure in DN
In a study of the effect of a low-protein diet on the progression of renal disease 19

insulin-dependent diabetic patients with persistent clinical proteinuria were observed
for 12-39 (mean 29) months while they were on a normal-protein diet (1.13 [0.06]
g/kg per day), then for 12-49 (mean 33) months on a low-protein diet (0.67 [0.03]
g/kg per day). The low-protein diet had no adverse effect on nutrition or glycosylated
haemoglobin concentration. Mean supine blood pressure (BP) fell slightly on the low-
protein diet and was probably due to the start or modification of antihypertensive
medication in 9 patients. The mean rate of decline in glomerular filtration rate fell
from 0.61 (SEM 0.14) ml/min per month with the normal-protein diet to 0.14 (0.08)
with the low-protein diet, and this effect remained highly significant after adjustment
for blood pressure, energy intake, and glycosylated haemoglobin. The rise in the
fractional clearance of albumin during a normal-protein diet stopped with the low-
protein diet, and there was a significant fall in albumin excretion from 467 (95% CI
234-895) micrograms/24 h on the normal-protein to 340 (138-719) on the low-protein
diet. a low-protein diet, with its reduction in protein and possibly other dietary
components such as phosphate or fat, seems to retard the rate of decline of
glomerular filtration rate in diabetic nephropathy independently of blood pressure
changes and glycaemic control.
Lancet 1989 Dec 16;2(8677):1411-5.

Restriction of dietary protein and progression
of renal failure in DN
• Type1 DM 19 pateins
• Normal protein 1.13 g/kg/d, F/U 29 mo
• Low protein 0.67 g/kg/d, F/U 33 mo
• Result : normal / low protein

- GFR 0.61 / 0.14 (ml/min/mo)
- UAE 467 / 340 (mg/d)
Lancet 1989 Dec 16;2(8677):1411-5.

Effect of restricting dietary protein on the
progression of renal failure in IDDM
BACKGROUND. Restriction of dietary protein may slow the progression of renal failure in
diverse renal diseases, but the extent to which such a diet is beneficial in patients with diabetic
nephropathy is uncertain.
METHODS. We studied the effect of reduced intake of protein and phosphorus on the
progression of renal disease in 35 patients with insulin-dependent (Type I) diabetes mellitus and
clinically evident nephropathy. The low-protein, low-phosphorus diet contained 0.6 g of protein
per kilogram of ideal body weight per day, 500 to 1000 mg of phosphorus, and 2000 mg of
sodium. The control diet consisted of the patient's prestudy diet with the stipulation that it
contain 2000 mg of sodium and at least 1 g of protein per kilogram per day and 1000 mg of
phosphorus. Renal function was assessed by measurement of iothalamate and creatinine
clearances at intervals of 3 to 6 months, and the patients were followed for a minimum of 12
months (mean, 34.7). The declines in mean glomerular filtration rates were compared between
groups by linear-regression analysis of the glomerular filtration rate as a function of time.
RESULTS. The patients who followed the study diet for a mean of 37.1 months had declines in
iothalamate clearance of 0.0043 ml per second per month and in creatinine clearance of 0.0055
ml per second per month. The comparable values in the control group were 0.0168 and 0.0135,
respectively (P less than 0.05). Blood pressure was well controlled, and the degree of glycemic
control was comparable in both groups.
CONCLUSION. Dietary restriction of protein and phosphorus can retard the progression of
renal failure in patients with Type I diabetes mellitus who have nephropathy. We believe that
wider use of this treatment is indicated.
N Engl J Med 1991 Jan 10;324(2):78-84.

Aim of protein restriction
• Protein 0.8 g/kg/d
• Malnutrition survilance
KDOQI: Am J Kidney Disease 2007; 49 ( Suppl 2 ): S1-S179

• BP control
• RAS blockade
• Stop smoking
• Lipid control
• TZD
• New therapy
• Multifactorial
Lipid Control
J Am Soc Nephrol: 2006;17:2006-16
Statins for Improving Renal
Outcomes: A Meta-Analysis
• Medline, EMBASE, Cochrane …
• Published or unpublished RCT
• 27 studies, N=39,704
J Am Soc Nephrol: 2006;17:2006-16

Change in GFR for statin versus placebo
J Am Soc Nephrol: 2006;17:2006-16

Statins for Improving Renal
Outcomes: A Meta-Analysis
• Change GFR (1.22 ml/min/1.73 mm3 /y

Slower in statin (CI 0.44-2.0)
• Reduction albuminuria (CI 0.17-0.98)
J Am Soc Nephrol: 2006;17:2006-16

Aim of lipid control
• LDL-cholesterol < 100 mg/dl

< 70 mg/dl High risk
• HDL-cholesterol > 40 mg/dl
• Triglyceride < 150 mg/dl
• DM with CKD stage 1-4

if LDL > 100 mg/dl start statin
• J Am Coll Cardiol 2004; 44: 720-32

• KDOQI: Am J Kidney Disease 2007; 49:
s1-s179
• BP control
• RAS blockade
• Stop smoking
• Lipid control
• TZD
• New therapy
• Multifactorial
Thaiazolidinediones
Thaiazolidinediones
• Animal study : albuminuria

: mesangial expansion
: glomerular sclerosis
: interstitial fribosis
• Type 2 DM with microalbuminuria

: UAE 30 %
•Diabetes Care 1998; 21: 2135-9

•J Diabetes Complications 2000; 14:
250-4
•Diabet Med 2001; 18: 308-13
•Metabolism 2001; 50: 1193-6
•J Clin Endocrinol Metab 2001; 86:
• BP control
• RAS blockade
• Lipid control
• TZD
• Stop smoking
• New therapy
• Multifactorial
Stop smoking
J Am Soc Nephrol 2002; 13: 1663-1672
Renal hemodynamic in smoker
Afferent Efferent
arteriole arteriole
Normal RA PGC RE
RA PGC
AII RE
Glomerular
hypertension
Proteinuria
J Am Soc Nephrol 2002; 13: 1663-1672
Smoking and DN in Type 1 DM
• Risk for microalbuminuria

Acta Med Scand 1984; 215: 63-8
• Incident proteinuria 13% smoking< 10/d

25% smoking >30/d
JAMA 1991; 256: 614-7
• UAE : 2.8 times

BMJ 1993; 306: 1235-9
• Decrease GFR 1.21 cc/min/mo : 0.86

cc/min/mo Nephrol Dial Transplant 1994; 9: 1097 - 102
Smoking and DN in Type 1 DM
• Progression microalbuminuria to
macroalbuminuria 2-2.5 times
Diabetes 1993; 42: 381-9
• Decrease GFR 1.21 cc/min/mo: 0.73

cc/min/mo
Nephrol Dial Transplant 1994; 9: 1097 - 102
• Stop smoking decrease UAE

Am J Med Sci 2004; 327: 57-67
• BP control
• RAS blockade
• Stop smoking
• Lipid control
• TZD
• Multifactorial intervention
• New therapy
Multifactorial Intervention
Intensified multifactorial intervention in patient
with type 2 DM and microalbuminuria
2. Lipid diet control

3. Exercise
4. Stop smoking
5. HbA1c < 6.5 %
6. ACEI or ARB
7. BP < 130/80 mm Hg
8. CHO < 175 mg/dl, TG < 150 mg/dl
9. ASA
10. Vitamin-mineral suplement ( Vit C, E, folic)
Steno-2: Lancet 1999; 353:

617-22
Intensified multifactorial intervention in patient
with type 2 DM and microalbuminuria
• Time: F/U 3.8 years

• Macroalbuminuria 73%
• DR 55%
• Autonomic neuropathy 68%
Steno-2: Lancet 1999; 353:

617-22
N Engl J Med: 2003; 348: 383-93
• Randomized, open, parallel trial
• N = 160 pateins
• Multifactorial Intervention : conventional
• Time: 7.8 years
N Engl J Med: 2003; 348: 383-93

N Engl J Med: 2003; 348: 383-93
N Engl J Med: 2003; 348: 383-93
N Engl J Med: 2003; 348: 383-93
Multifactorial Intervention and Cardiovascular
Disease in Type 2 DM
• CVD : hazard ratio = 0.45 (CI 0.24-0.73)
• Nephropathy : hazard ratio = 0.39 (CI 0.17-0.87)
• Retinopathy : hazard ratio = 0.42 (CI 0.21-0.86)
• Neuropathy : hazard ratio = 0.37 (CI 0.18-0.79)
N Engl J Med: 2003; 348: 383-93

• BP control
• RAS blockade
• Stop smoking
• Lipid control
• TZD
• Multifactorial intervention
• New therapy
New Therapy
New Therapy
• Inhibitors of growth factors and vasopeptides
- IGF-1
- GH
-TGF-b
- VEGF
- ET-1 antagonist
• Biological
- PKC inhitors
- inhibition of AGE formation
- AGE cross link breakers
- Blockade of receptor for AGE
Ruboxistaurin (LY333531)
Impacting the AGE Cascade
Crosslin
Glucose & AGEs RAGE
k
Proteins
AGEs
Glucose Lowering AGE AGE Receptor

Agents Formation Crosslin Blocker
inhibitors k
Pimagedine Breaker
s
Pyridoxami
ne
Advances in Chronic KidneyDisease, Vol 12, No 2, 2005:

pp 212-222
Crosslin
Glucose & AGEs RAGE
k
Proteins
AGEs

inhibitors k
Pimagedine Breaker
s
Pyridoxami
ne

pp 212-222
Crosslin
Glucose & AGEs RAGE
k
Proteins
AGEs

inhibitors k
Pimagedine Breaker
s
Pyridoxami
ne

pp 212-222
New therapeutic Agents undergoing clinical
development for DN
Agent Action Status

Phase II in progress
Sulodexide Replace GAGs Phase III planned
(KRX-101)
Phase II completed
Pyridorin AGE inhibitor Phase III planned
(pyridoxamine)
Alagebrium Cross-link breaker Cardiovascular trials

(ALT-711)
Phase II completed
Ruboxistaurin PKC-B inhibitor Phase III planned
(LY333531)

conclusion
Slow progression DKD
treatment Aim
1. ACEI, ARB Proteinuria < 0.5-1.0 g/d
2. Combination drugs BP < 130/80 mm Hg
3. Control BS HbA1C <7%
4.Protein restriction 0.8 g/kg/d
5.Low salt diet 3-5 gram NaCl/d
6. Lipid control LDL < 100 mg/dl
7. Smoking Stop smoking
Semin Nephrol 2004; 24: 141-6

Diabet Med 2004; 21: 4-17
Normo Micro Macro
Stage albuminuria albuminuria albuminuria
-Primary -secondary -Slow progression

aim prevention prevention -Prevent CKD
- Prevent CVD complication
BS control - HbA1c < 7% - HbA1c < 7% - Prevent non renal

complication
BP control -BP < 130/80 -BP < 130/80 -BP < 130/80
- ACEI - ACEI, ARB - ACEI, ARB
Other Rx -Stop smoking -Stop smoking -Stop smoking

- LDL < 100 - protein 0.8 g/kg/d - protein 0.8 g/kg/d
- LDL < 100 - LDL < 100
- Hb 11-13g/dl
-Prevent HPT
11 october 2007

Diabetic Nephropathy

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Diabetic Nephropathy

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Diabetic Nephropathy (DN)

• World wild 246 million

• Thailand : 9.6% (adult > 35 years old)

Urinary albumin excretion rate

Condition 24 hr (mg/d) Overnight (ug/min)

normoalbuminumia <30 <20

macroalbuminumia >300 >200

Clinical Prevalence (%)

Type1 DM, microalbuminuria 30-50

Type1 DM, macroalbuminuria 65-88

Type2 DM, microalbuminuria 40-83

Type2 DM, macroalbuminuria 78-96

• Asia (type2 DM n=6,801: 10 country)

J Med Assoc Thailand 2005; 88: 1624-29

J Med Assoc Thailand 2005; 88 (suppl 3): S164-S174

TRT Report 2003

Unknown 14% CGN 16%

5 <30 20-40% 1 mmHg

3. Incipient nephopathy 6-15 30-300 3 mmHg

4. overt nephopathy 15-25 >300 >80%

Micro 30% Sustained

5 <30 20-40% 1 mmHg

3. Incipient nephopathy 6-15 30-300 3 mmHg

4. overt nephopathy 15-25 >300 >80%

0.1% 2.0% / years

Rising Cr, RRT

• Some case: advanced DR with normal

Diabetes 1994; 43: 441

Kidney Int 2000; 58: 1719-31

J Intern Med 2003; 254:45-66

Rising Cr, RRT

• Nontraditional risk factor

• Endothelial dysfuction,RAS, basement

J Intern Med 2003; 254:45-66

-TBM thickening - Tubular atrophy

Vascular - Afferent and efferent - atherosclerosis

Semin Nephrol 2007; 27: 130-43

Metabolic factor Environment factor

ECM Altered vascular

J Med Assoc Thai Vol.89 Suppl.1: 2006

> 60 1+2 At risk Possible DKN DKN

30-60 3 Unlike DKN Possible DKN DKN

< 30 4+5 Unlike DKN Unlike DKN DKN

At increase risk ≥90 Screening CKD risk

• Diagnosis and treatment

Evaluation and treatment

Preparation for kidney

5 ESRD <15 RRT

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. proteinuria without DR in type 1 DM

1. Screening high risk, early detection

1. Screening high risk, early detection

1. Screening high risk, early detection

1. Screening high risk, early detection

• Yearly ( type 1 DM after Dx 5 yrs, type 2 at Dx)

• Urine dipstick (trace = macroalbuminuria 2/3 in 6 mo)