DIABETIC NEPHROPATHY

Luthfan Budi Purnomo Division of Endocrinology Internal Medicine Department School of Medicne Gadjah Mada University Dr Sardjito Hospital Jogjakarta

INTRODUCTION

Prevalence of diabetes increases: 14.7% in urban area and 7.2% in rural area (PERKENI, 2006) Diabetes has become the number one cause of endstage renal disease (ESRD) Early diagnosis of diabetes and early intervention are critical in preventing the normal progression to renal failure

Definition of diabetic nephropathy

Diabetic nephropathy (DN) is defined by either macroalbuminria (a urinary albumin excretion of greater than 300 mg/day or urinary albumin: creatinine ratio/ACR >30 mg/mmol) or by abnormal renal function and with existing diabetic retinopathy Microalbuminuria (earliest sign of DN or incipient DN) is defined by a urinary albumin excretion of 30300 mg/day or ACR >2,5 mg/mmol in men and >3,5 in women
(DeFronzo, 2005; Augustine and Vidt, 2003)

Flowchart for diagnosis of diabetic nephropathy

Annual dipstick Positive
Previously positive on 2 occasions over previous 12 months YES Retinopathy + YES NO Retest over next 12 months Positive

Urinalysis for protein Negative

Test for microalbuminria Positive YES NO

ACR >2,5 mg/mmol or >3,5 mg/mmol

YES Confirm with 2 samples if 2/3 positive NO Microalbuminuria NO

Clinical nephropathy

YES

Retest over next 6 months

Jones et. al., 2006

Prevalence of type 1 and type 2 diabetes in United States and progression of microalbuminuria and diabeticnephropathy
Type 1 Prevalence of disease Prevalence of microalbuinuria at 15 years Prevalence of macroalbuminuria at 15 years Progression to end-stage renal disease 10 years after onset of macroalbuminuria Type 2 0.85-1.7 million 15,3-16,2 million 21% 28% 21% 50% 14% 10%

(Augustine and Vidt, 2003)

Pathogenesis of diabetic nephropathy

METABOLIC METABOLIC Glucose
PKC-II HEMODYNAMIC Flow/Pressure

Vasoactive hormones (A-II, Endothelin)

Vascular permeability Proteinuria

AGEs

Cytokines Vascular TGF- VEGF

Extra-cellular matrix Cross-linking Extra-cellular matrix

Extra-cellular matrix accumulation

Natural course of diabetic nephropathy

-3 120 0 150 3 150 Time (years) GFR (mL/mnt) 15 120 20 60 25 <10

1.0
15

0.8
10

0.8
10

Serum creatinine (mg/dL)

Serum urea nitrogen (mg/dL)

1.0
15

>2.0
>30

>10
>100

Microalbuminuria -3 0 3 Prior to Onset of Onset of onset of diabetes diabetic diabetes glomerulosclerosis 10 15 Onset of proteiuria 20 25 Onset ESRD of azotemia

(DeFronzo, 2005)

Features that suggest non-diabetic kidney disease

Rapid deterioration in renal function Sudden development of nephrotic syndrome Heavy hematuria/red cell casts Absence of diabetic retinopathy Short duration of type 1 diabetes Clinical or laboratory evidence of non-diabetic systemic disease Blood pressure higher than expected for degree of proteinuria
Jones et. al., 2004

Risk factors of diabetic nephropathy

Blood glucose level Blood pressure Male sex Duration of diabetes Total cholesterol level

Treatment of diabetic nephropathy

Blood glucose control Blood pressure control Protein restriction Cholesterol lowering
(Steele, 2001)

The role of glycemic control

DCCT: A1c 7.2% vs 9.2% 39% risk reduction in the development of microalbuminuria and 54% risk reduction in the development of macroalbuminuria UKPDS: A1c 7% vs 7.9% 0.76 relative risk (24% risk reduction) for the development of microalbuminuria (Jones et. al., 2004; Augustine and Vidt, 2003) Good glycemic control (A1c<8%) was associated with a slower rate of decline in renal function (Jones et al., 2004)

The role of blood pressure control

Normotensive, normoalbuminuric T1D patients: There is no evidence that antihypertensive treatment prevents or delays the onset of microalbuminuria (Jones et al., 2004) T2D patients: Blood pressure control reduces the development of microalbuminuria (Jones et al., 2004) ACEIs reduce 75% UAER after 1 year treatment in T1D patients Irbesartan 300 mg in 2 years treatment reduces 32% the development of clinical nephropathy (in T2D patients) Target of blood pressure 130/80 mmHg. Once renal function starts to decline and proteinuria reaches 1 g/d T 125/75 mmHg Each 10 mmHg reduction improves the relative decline in renal function by 0.18 ml/min/mo (Steele, 2001)

Blood pressure goal and recommended agents

Goal blood pressure
T1DM <130/80

Blood pressure agents of choice

ACEI, ARB if ACEI not tolerated; diuretic as secondline agent ARB, ACEI as alternative, diuretic as second-line agent ARB in conjunction with diuretic, beta blocker or CCB as third-line agent ACEI, beta blocker as secondline agent Beta blocker followed by ACEI, diuretic as third-line agent
(Augustine and Vidt, 2003)

T2DM DM with macroalb. DM with CHF

<130/80 <130/80 <130/80

DM with CAD

<130/80

The role of protein restriction

Protein restriction (0.8-1.0 g/kg body weight/d) reduces the decline in glomerular filtration rate (relative risk of the decline in GFR: 0.56) (Steele, 2001) Dietary protein intake amounting to >20% of total energy was linked to the presence of microalbuminuria (Jones et al., 2004) Protein and phosphate restricted diet reduced a decline of GFR of only 0,26 ml/min/mo (Evants and Capell, 2000) RDA protein of 0.8 g/kg body weight/d or 10% of total calories (Evants and Capell, 2000)