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

30-300

20-200

>300

>200

microalbuminumia

macroalbuminumia

Characteristic of DN 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

Characteristic of DN 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

1387 Others 16%

DM

CGN HT

1438 16%

1550 18%

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 Other 10%

16%

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 DN and DR and CVD Pathology and Pathogenesis Diagnosis and diferential diagnosis Prevention and treatment

Type 1 DM

Natural history of type I diabetic nephropathy

Stage of DN

Time (year)

UAE (mg/d)

GFR

Dx

<30

20-50%

5

<30

20-40%

3. Incipient nephopathy (microalbuminuria)

6-15

30-300

3 mmHg /year

4. overt nephopathy (macroalbuminuria)

15-25

>300

>80%

1. renal hypertrophy and hyperfiltration

2. normoalbuminuria

25-30 5. ESRD

HT

1 mmHg /year

~ 100%

Normo albuminuria

50%

Sustained normoalbuminuria

-Timing - BS control

30% 50%

-BP control - genetic

Micro albuminuria 30%

30%

Sustained microalbuminuria

- BP control - BS control

Overt proteinuria - BP control

ESRD

Type 1 DM

Type 2 DM

Stage of DN

Time (year)

UAE (mg/d)

GFR

Dx

<30

20-50%

5

<30

20-40%

3. Incipient nephopathy (microalbuminuria)

6-15

30-300

3 mmHg /year

4. overt nephopathy (macroalbuminuria)

15-25

>300

>80%

1. renal hypertrophy and hyperfiltration

2. normoalbuminuria

25-30 5. ESRD

HT

1 mmHg /year

~ 100%

No nephropathy

0.1%

1.4%/ years

2.0% / years

Microalbuminuria

0.1%

2.8%

0.3%

Macroalbuminuria

4.6%

2.3%

Rising Cr, RRT

19.2% UKPDS 64: Kidney Int 2003; 63:225-232

DEATH

3.0%

Content • • • • • •

Backgroud Natural history DN and DR and CVD Pathology and Pathogenesis Diagnosis and diferential diagnosis Prevention and treatment

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

0.1%

1.4%

2.0%

Microalbuminuria 3.0%

DEATH

0.1%

2.8%

0.3%

Macroalbuminuria

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 DN and DR and CVD Pathology and Pathogenesis Diagnosis and diferential diagnosis Prevention and treatment

Pathology of DN

Pathology of DN Always present

Usually present

Sometimes

Glomerular -Kimmelstiel-Wilson nodules -GBM thickening -Mesangial matrix expansion -global sclerosis -FSGS

- glomerular microaneurysms - capsular drops - hylaline lesions

Tubulointerstial -TBM thickening - interstial expansion

- Tubular atrophy

Vascular

- Afferent and efferent arteriolar hyalinosis

IF Staining for albumin

- atherosclerosis

Pathology of DN

Pathogenesis of DN

Semin Nephrol 2007; 27: 130-43

Glycemic control

Metabolic factor Hyperglycemia AGEs Polyol Hexosamine Oxidative stress

Genetic factor ACE ID polymorphism Hyperlipidemia Oligonephropathy

Hemodynamic factor Sytemic hypertension Glomerular hypertension vasoactive hormones

Duration Ages at onset

Insulin resistance

Environment factor Dietary protien intake Smoking

Activated of intracellular signaling pathways

Growth factor Inflammatory mediators

Altered vascular permeability

ECM accumulatiom Proteinnuria DN

Content • • • • • •

Backgroud Natural history DN and DR and CVD Pathology and Pathogenesis Diagnosis and diferential diagnosis Prevention and treatment

Diagnosis and DDx

Diagnosis • • • • •

Detail of DM HT DR? LAB ? Bx

Risk factor of DN 1. 2. 3. 4. 5. 6. 7.

Sex : male duration ( mean+SD= 12.8+8.2 years) BP control HbA1C Dyslipidemia DR 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 (ml/min)

CKD

> 60

1+2

At risk

Possible DKN

DKN

30-60

3

Unlike DKN

Possible DKN

DKN

< 30

4+5

Unlike DKN

Unlike DKN

DKN

normoalbuminuria

microalbuminuria macroalbuminuria

Stage

Description

GFR

At increase risk

≥90 (with CKD risk factors)

1

Kidney damage with normal or ↑ GFR

2

Kidney damage with mild ↓GFR

3

Moderate ↓GFR

≥90

Action Screening CKD risk reduction • • • •

Diagnosis and treatment Treatment of co-morbid Slow progression CVD risk reduction

60-89

Estimation of CKD progression

30-59

Evaluation and treatment of complications Preparation for kidney replacement therapy

4

Severe ↓GFR

15-29

5

ESRD

<15

RRT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 5. 6. 7. 8.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 5. 6. 7. 8.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Kidney Bx or further investigation 1. 2. 3. 4. 5. 6. 7. 8. 9.

proteinuria without DR in type 1 DM acute onset of proteinuria GFR without proteinuria ARF after ACEI, ARB Unexplaint cause ARF gross hematuria Differential size of both kidney Symptom and sing secondary glomerular disease Refractory HT

Content • • • • • •

Backgroud Natural history DN and DR and CVD Pathology and Pathogenesis Diagnosis and diferential diagnosis Prevention and treatment

Prevention and treatment

Prevention and Treatment DN 1. 2. 3. 4.

Screening high risk, early detection Prevention, slow progression DKD Detect risk CVD and treatment Prevent, treatment complication of CKD

Prevention and Treatment DN 1. 2. 3. 4.

Screening high risk, early detection Prevention, slow progression DKD Detect risk CVD and treatment Prevent, treatment complication of CKD

Prevention and Treatment DN 1. 2. 3. 4.

Screening high risk, early detection Prevention, slow progression DKD Detect risk CVD and treatment Prevent, treatment complication of CKD

Prevention and Treatment DN 1. 2. 3. 4.

Screening high risk, early detection Prevention, slow progression DKD Detect risk CVD and treatment 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 diabetesrelated 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

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Stop smoking Protein restriction Lipid control TZD New therapy Multifactorial

BP control

Blood pressure control • Importance of BP control ? • Level of blood pressure? • Type of antihypertension?

% Reduction in Relative Risk

0

Strok e

Any Diabetic Endpoint

DM Death s

5% -1 0

10 %

12 %

-2 0

24 % 32 %

-3 0 -4 0 -5 0

Microvascul ar Complicatio n

44 %

**P < 0.05

Tight Glucose Control Goal < 108 mg/dl

32 %

37 %

Tight BP Control Average 144/82 mmHg

UKPDS 38: BMJ 1998; 317: 703-13

SBP (mm 13 00

GFR (ml/min/year)

-2 -4

13 4

13 8

Hg)

14 2

14 6

15 0

15 4

17 0

18 0

r = 0.39; P < 0.05

-6 -8 -1 0 -1 2 -1 4

Untreated HTN

•Parving HH et al. Br Med J, •Bakris GL : Hypertension, 1997 •Estacio R et al. Diabetes Care, 1989 •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 J Kidney Disease 2007; 49 (Suppl 2): S1-S179 •Bakris GL et al.KDOQI: KidneyAm Int, 1996

Level of BP •

•

•

CVD increase x2 : every 20/10 mmHg (BP 115/75 mmHg) Am J Kidney dis 2004; 43: s1-s290 Am J Kidney dis 2007; 49: s1-s179

RCT (end point: Scr x2, ESRD) : GFR decrease < 1 cc/min/y : SBP < 130 mmHg

Am J Kidney dis 2004; 43: s1-s290 Am J Kidney dis 2007; 49: 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: s1s290 •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). Bloodpressure 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.

Type 2 DM and RAS blockade

Type 2 DM and RAS blockade

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

BENEDICT: N Engl J Med: 2004; 351: 194151

No ACEI CCB ACEI

No CCB

BENEDICT: N Engl J Med: 2004; 351: 1941-51

BENEDICT: N Engl J Med: 2004; 351: 1941-51

Result: primary end point • Tradorapril

5.7%

• Tradorapril + Verapamil 6% • Verapamil

11.9%

• Placebo

10% BENEDICT: N Engl J Med: 2004; 351: 1941-51

Type 2 DM and RAS blockade

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 followup IRMA-2: N Engl J Med: 2001; 345: 870-78

Creatinine clearance (CrCl)

Months of followup IRMA-2: N Engl J Med: 2001; 345: 870-78

Mean Arterial Blood Pressure

IRMA-2: N Engl J Med: 2001; 345: 870-78

Type 2 DM and RAS blockade

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 RENAAL: N Engl J Med: 2001; 345: 861-69

Kaplan–Meier Curves of the Percentage of Patients with the Primary Composite End Point (Panel A)

RR 16% P= 0.02

RENAAL: N Engl J Med: 2001; 345: 861-69

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

RENAAL: N Engl J Med: 2001; 345: 861-69

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

RENAAL: N Engl J Med: 2001; 345: 861-69

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

RENAAL: N Engl J Med: 2001; 345: 861-69

Median Changes from Base Line in the Level of Proteinuria

RENAAL: N Engl J Med: 2001; 345: 861-69

Type 1 DM

prevention

study

RAS blockade

primary

Small study

ACEI

No significant

secondary

Metaanalysis

ACEI

Risk microalbuminuria Regression to normoalbuminuria

tertiary

Collaborative study

ACEI

Risk dialysis, KT, death 50%

result

Type 2 DM prevention

study

RAS blockade

primary

BENEDICT

ACEI

Risk microalbuminuria 50%

Micro-HOPE

ACEI

Risk macroalbuminuria 24%

IRMA-2

ARB

Risk macroalbuminuria

MARVAL

ARB

Regression to normoalbuminuria

IDNT

ARB

Risk macroalbuminuria 33%

RENAAL

ARB

Risk macroalbuminuria 35%

secondary

tertiary

Result

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 DETAIL: N Engl J Med: 2004; 351:1952-61

Changes from Baseline GFR (Panel A)

DETAIL: N Engl J Med: 2004; 351:1952-61

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

DETAIL: N Engl J Med: 2004; 351:1952-61

DETAIL: N Engl J Med: 2004; 351:1952-61

Changes from Baseline in Systolic Blood Pressure (Panel A)

DETAIL: N Engl J Med: 2004; 351:1952-61

Changes from Baseline Diastolic Blood Pressure (Panel B)

DETAIL: N Engl J Med: 2004; 351:1952-61

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 DETAIL: N Engl J Med: 2004; 351:1952-61

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: 6858

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

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Protein restriction 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 lowprotein 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 lowprotein 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

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Stop smoking Protein restriction 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

< < • HDL-cholesterol > • Triglyceride <

100 mg/dl 70 mg/dl High risk 40 mg/dl 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

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Stop smoking Protein restriction 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:

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Lipid control Protein restriction TZD Stop smoking New therapy Multifactorial

Stop smoking

J Am Soc Nephrol 2002; 13: 1663-1672

Renal hemodynamic in smoker Efferent arteriole

Afferent arteriole

Normal

RA

PGC

AII

RA

PGC

RE

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

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Stop smoking Protein restriction 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

Treatment and Prevention • • • • • • • • •

Glycemic control BP control RAS blockade Stop smoking Protein restriction 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 Glucose & Proteins

Glucose Lowering Agents

AGEs

AGE Formation inhibitors Pimagedine Pyridoxami ne

Crosslin k AGEs

AGE Crosslin k Breaker s

RAGE

Receptor Blocker

Advances in Chronic KidneyDisease, Vol 12, No 2, 2005: pp 212-222

Impacting the AGE Cascade Glucose & Proteins

Glucose Lowering Agents

AGEs

AGE Formation inhibitors Pimagedine Pyridoxami ne

Crosslin k AGEs

AGE Crosslin k Breaker s

RAGE

Receptor Blocker

Advances in Chronic KidneyDisease, Vol 12, No 2, 2005: pp 212-222

Impacting the AGE Cascade Glucose & Proteins

Glucose Lowering Agents

AGEs

AGE Formation inhibitors Pimagedine Pyridoxami ne

Crosslin k AGEs

AGE Crosslin k Breaker s

RAGE

Receptor Blocker

Advances in Chronic KidneyDisease, Vol 12, No 2, 2005: pp 212-222

New therapeutic Agents undergoing clinical development for DN Agent

Action

Status

Replace GAGs

Phase II in progress Phase III planned

Pyridorin (pyridoxamine)

AGE inhibitor

Phase II completed Phase III planned

Alagebrium (ALT-711)

Cross-link breaker

Cardiovascular trials

PKC-B inhibitor

Phase II completed Phase III planned

Sulodexide (KRX-101)

Ruboxistaurin (LY333531)

Advances in Chronic KidneyDisease, Vol 12, No 2, 2005:

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

Stage

Normo albuminuria

Micro albuminuria

Macro albuminuria

aim

-Primary prevention

-secondary prevention - Prevent CVD

-Slow progression -Prevent CKD complication

BS control

- HbA1c < 7%

- HbA1c < 7%

- Prevent non renal complication

BP control

-BP < 130/80 - ACEI

-BP < 130/80 - ACEI, ARB

-BP < 130/80 - ACEI, ARB

Other Rx

-Stop smoking - LDL < 100

-Stop smoking - protein 0.8 g/kg/d - LDL < 100

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

11 october 2007