Diyabetik Nefropati

Prof. Dr. Meltem Pekpak

Internal Medicine/Nephrology

9th-10th Semester

If obesity and immobili-zation increases....

EpidemiologyEpidemiology

• In the year• 2000 151.000.000• 2010 221.000.000• 2025 300.000.000

» Amos,A et al:Diab Med 1997;14(suppl 5):S1-S85» King,H et al: Diabetes Care 1998; 21:1414-1431

Yeni Son Dönem Böbrek Yetersizliği Tanısı KonanHastaların Etiyolojisi (Turkish Society of Nephrology)

n=5656

Diabetes Epidemic

0

50

100

150

200

250

300

350

400

2000 2030

mil

yon

kiş

i

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1

2

3

4

5

6

7

2000 2030

mil

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kişi

Turkey Increase rate %214

World Increase rate: % 209

http://www.who.int/ncd/dia/databases4.htm

Basics

• 1936 Kimmelstiel ve Wilson

• Only %30-40 of all diabetics type 2

Histology

Diabetic renal injurymetabolic and hemodynamic interactions

MetabolikMetabolic Glukose

polyol AGE

İntrasellular signal molekulesPKC, NF- , MAPK

StructurelEkstrasellular matrix

accumulation

Hemodynamicflow/pressure

ET AII

Growth factors-Cytokines

(TGFbeta, VEGF, IL)

Functional Albuminuria

Cooper ME, Diabetologia 2001,44:1957-1972

KısaltmalarAbbrev.:

A II-Diabetic nephropathy pathogenesis

Systemic hypertension

Glomeruler hypertension

Increased glomeruler permability

Increased oxidatifve stress/inflammation

Increased growth factors

Increased TGF-, fibroblasts and fibrozis

Monocyte migration and activation

Glomeruler hypertension

Increase in Albuminuria

Glomerülbasınç

Afferent arterial dilatation

Efferent arterial vasokonstriction

KB

Diabetic nephropathy stages

Type 1-Mogenson

Funktional changes*Funktional changes*

Type 2 Diabetic Nephropathy Type 2 Diabetic Nephropathy

ProteinuriaProteinuria

End stage renal failureEnd stage renal failure

Clinical type 2 diabetesClinical type 2 diabetes

Structural changes†Structural changes†

Increasing BPIncreasing BP

Increasing serum kreatininIncreasing serum kreatinin

Kardiovascular deathKardiovascular death

MicroalbuminuriaMicroalbuminuria

Diyabet başlangıcıDiyabet başlangıcı 22 55 1010 2020 3030YılYıl

*glomerular hypertension† Glomeruler basementl membrane thickeningı , mesangial expansion , microvascular changes +/-.

*glomerular hypertension† Glomeruler basementl membrane thickeningı , mesangial expansion , microvascular changes +/-.

Clinic

• Early signs of nephropathy

–Microalbuminuria

–Hypertension

–Kolesterol ve Triglyseride

Clinic

• Other microangiopathic changes:

• Proliferative fundus ophtalmicus

• Corpus vitreum bleeding

• Blindness

• Polineuropathy

• Coronary microangiyopathy-

Small vessel disease of the heart

• ‘Incipient’ nefphropathy

• REVERSIBLE• Microalbuminuria=

Albumin-excretion

30-300 mg/ 24 saat=

20-200 microgram/dak.• Blood pressure (N)• GFR (N)

• Good control of BP• Exercise• Good control of

blood sugar• Smoking restriction

SLOWS PROGRESSİON

Clinical classification andapproach for treatment

Diabetes Control and Complications Trial Research Group (DCCT)

• Type 1 diabetes• 1. group : Intensive insulin (at least 3 injektion/day)

• 2. group : Conventionel 2 inj./day• HbA1c: mean 1. group :%7 -- 2. group:% 9• 9 years follow-up • Microalbuminuria 1. group <<<< (%35-40)• UKPDS Type 2 diabetes: > 10 years follow-up • Mikroalb.uria, proteinuria in intensive insulin

treatment <<< % 25-30, • creatinine doubling % 50↓↓

Mikroalbuminuria(not only stage 3 in DM)

• Vascular endothelial damage is related with target organ injury• Is a sign of injury in the kidney, vessel wall

and the heart• It is not a potential risk factor like

‘Hyperkolesterolemia’, ‘hypertension’ • It should be diagnosed when still reversibel (in diabetics, hypertensives)

2003 European Society of Hypertension – European Society of Cardiology Guidelines: 2003 European Society of Hypertension – European Society of Cardiology Guidelines: J Hypertens 21J Hypertens 21: : 10111011--10531053, , 20032003

Microalbüminuria

• Shows that there is already a vascular injury !

• Lipids ?

• Blood pressure control ?

• Micro-ve macrovaskular complications ?

• Goal = Normoalbuminuria

Overt proteinuria:

• Albuminuria: • >300 mg/ 24 h• GFR: normal or • Blood pressure:

• Good control of BP• Good control of

blood sugar• Little protein

restriction

Clinical classification andapproach for treatment

• Dialysis • (or other Renal

Replacement Therapy) Albuminuria:

• >1000 mg/ 24 saat• GFR: <15- 10 ml/min• Blood pressure :

Intervention: • Hemodialysis• Contineous

Ambulatory Peritoneal Dialysis

• Kidney Tx • Pankreas and kidney

Tx

Clinical classification andapproach for treatment

-40

-35

-30

-25

-20

-15

-10

-5

0

MICRO-HOPE TrialMICRO-HOPE Trial((MMiicroalbuminuria croalbuminuria CCardiovascular and ardiovascular and RRenal enal OOutcomes in utcomes in HHope ope SStudytudy))

Lancet 355:253-259, 2000

Stroke MICardiovaskular

Mortality

P < 0.01P = 0.0001

P = 0.01

-33-37

-22

Nefropathy

-24

P = 0.027

Ris

k R

educ

tion

(%)

Ris

k R

educ

tion

(%)

Diabetes mellitus (n=3577) ramipril treatmentDiabetes mellitus (n=3577) ramipril treatment

0

2

4

6

8

10

12

14

16

18

20

Overt NEFROPATHY ManifestationOvert NEFROPATHY Manifestation

%%

PlaseboPlasebo IrbesartanIrbesartan(150 mg)(150 mg)

IrbesartanIrbesartan(300 mg)(300 mg)

Risk reduction: %39Risk reduction: %39P=0.08P=0.08

Risk reduction: %70Risk reduction: %70P<0.001P<0.001

14.9

9.7

5.2

Parving et al.: N Engl J MedParving et al.: N Engl J Med 345345::870-878870-878, 200, 20011

IRMA 2IRMA 2(The (The IrIrbesartan in Patients with Type 2 Diabetes and besartan in Patients with Type 2 Diabetes and MMicroicroaalbuminuria Study)lbuminuria Study)

590 hypertensive, diabetic,microalb,crea<1.5-1.1,plasebo,150mg-300mg İrbes., 2y)

RENAAL TrialRENAAL TrialSerum Ceatinine doubling

End stage renal failure End stage renal failure,death

All

% 16 %25

%20

P=0.02 P=0.002

P=0.002 P=0.01

%28

(1513 diabetics, Urinary Alb. Excretion>500mg/gün, 42 months)(1513 diabetics, Urinary Alb. Excretion>500mg/gün, 42 months)

IDNTIDNT((IIrbesartan rbesartan DDiabetic iabetic NNephropathy ephropathy TTrial)rial)

İrbesartan vs. Plaseboİrbesartan vs. PlaseboRisk azalması: %33 (P=0.003)Risk azalması: %33 (P=0.003)

İrbesartan vs. Amlodipinİrbesartan vs. AmlodipinRisk azalması: %37 (P<0.001)Risk azalması: %37 (P<0.001)

İrbesartan vs. Plaseboİrbesartan vs. PlaseboRisk azalması: %20 (P=0.02)Risk azalması: %20 (P=0.02)

İrbesartan vs. Amlodipinİrbesartan vs. AmlodipinRisk azalması: %23 (P=0.006)Risk azalması: %23 (P=0.006)

Kreat.x2

(Macroalbuminuria== End stage renal failure(Macroalbuminuria== End stage renal failure

n=1715İrbesartan 75-300mgAmlodipine 2.5-10 mgPlasebo

Follow- up

• Fundus ophtalmicus diagnostic• Kidney biopsy:especially if proteinuria is too

high and you can not diagnose any eye background signs

• Urine for microalbuminuria twice a year• Blood tests for Cholesterol (HDL and LDL-

fractions) triglyceride • Every visit: ECG, blood pressure control,

education for self assessment of BP, 24 hours blood pressure records if necessary

Treatment and Progression

• Increase of cardiovascular mortality to % 40

Prognosis can be changed by:• Early and good blood pressure control

• Goal : BP <120/80 mm Hg

• Good glycemic control (HbA1c = < %7)• Exercise• Moderate protein restriction (0.8 g/kg)• STOP smoking

Blood pressure control

• Teach self assessment

• Microalbuminuria- Antihypertensives

• Angiotensin Converting Enzyme Inh., Angiotension-Reseptor Antag., Beta-Blockerler, Alpha-Blockers, Vasodilataters

(ACE, ARB)+ Diuretics (Hydrochlorothiazide comb., later Loop-Diuretics)

Blood sugar control

• Renal insulin clearence is reduced: RISK: HYPOGLYSEMIA !

• Reduce insulin latest in overt proteinurics

• Regular HbA1c control

• Self assessment ! Records

Renal Replacement Therapy Preperation

• Creatinine >2 mg/dl every month control

• Creatinine, urea, Na, K, phos., calcium and hemoglobin control

• Feet ulcerations ? • Oftalmologic control• Education for RRT alternatives !

Renal Replacement Therapy

• Hemodialysis (arterio-venous fistula = creatinine-clearance <20 ml/min),

• CAPD ( transperitoneal katheter implantation and education,

• Transplantation (cadaveric or from living donor)

Be careful !!• Contrast dye may precipitate acute renal

failure (good hydration !)

• Renal replacement therapy should be started earlier (Serum-creatinine 4-6 mg/dl, Creatinine-clearance < 20 ml/min

• The patient should not be severe hypertensive or hypo- and hypervolemic before starting RRT!!