DIABETIC NEPHROPATHY

Candra Wibowo
Faculty of Medicine of Trisakti University

DEFINITION
DN is microvascular complication Presence of albuminuria Elevated blood pressure Declining glomerular filtration

HISTORY
Rolo (1798) : reported the presence of problem in the urine of diabetic pts Bright (1836) : described the seriousness of protein in the urine of diabetic pts Kimmelstiel, Wilson (1936) : described nodular glomerular lesions in diabetic pts

EPIDEMIOLOGY
DN is the most common cause of ESRD worl wide Accounts for >40% of pts starting RRT in the US in 2002 Increased prevalence of type 2 diabetes
100 million people worldwide have diabeties in 1998 300 million people wil have type 2 diabetes by 2025

Increased life expectancy of diabetics Decrease cv morbidity & mortality Wider acceptance of diabetics in ESRD treatment programs

RISK FACTORS
Genetic predisposition : ACE polymorphism, sodium-lithium counter transport Hyperglycaemia Hypertension Age Gender Smoking Ethnicity (native Americans, Mexican American, African Americans)

CLINICAL STAGES OF DN
Renal enlargement & hyperfiltration Microalbuminuria, incipient nephropathy (10-15 yrs)
30-299 ug/mg creatinine 30-299 mg/24 h collection

Macroalbuminuria, overt nephropathy (11-20 yrs)

300 ug/mg creatinine 300 mg/24 h collection

Progressive renal failure & severe proteinuria (1525 yrs)

STAGES 1
(very early diabetes = hyperthrophy hyperperfusion)
Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate (GFR).
Hyperglycemia leads to increased kidney filtration (see later) This is due to osmotic load and to toxic effects of high sugar levels on kidney cells Increased Glomerular Filtration Rate (GFR) with enlarged kidneys
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(developing diabetes=microalbuminuria=incipient nephropathy)

Clinically silent phase with continued hyper-filtration and hypertrophy The GFR remains elevated or has returned to normal, but glomerular damage has progressed to significant microalbuminuria (small but above-normal level of the protein albumin in the urine). Significant microalbuminuria will progress to endstage renal disease (ESRD).

STAGES 2

Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis.

STAGES 3
(overt = macroalbuminuria dipstick positive diabetes)
Glomerular damage has progressed to clinical albuminuria. Basement membrane thickening due to AGEP The urine is "dipstick positive," containing more than 300 mg of albumin in a 24-hour period.

Hypertension (high blood pressure) typically develops during stage 3.

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STAGES 4
(late stage diabetes)
Glomerular damage continues, with increasing amounts of protein albumin in the urine. The kidneys filtering ability has begun to decline steadily, and blood urea nitrogen (BUN) and creatinine (Cr) has begun to increase. The glomerular filtration rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage 4.
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STAGES 5
(end stage renal disease)

GFR has fallen to <15 ml/min and renal replacement therapy (i.e., haemodialysis, peritoneal dialysis, kidney transplantation) is needed.

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Progression of Diabetic Renal Disease in Patients with Diabetes

2000 2000 (g/min) Albuminuria (g/min) Albuminuria Overt nephropathy 200 200
GFR 2-20:10 GFR 1-3

40%

Microalbuminuria
20 20 Normoalbuminuria 2 2
Time Time (Years) (Years)

GFR 1

60%

Progression of Diabetic Renal Disease in Patients with Diabetes

Diabetic nephropathy is irreversible in humans No cases of recovery or cure have been reported in the literature Once the clinical signs of nephropathy have become manifest, the natural course is inexorably progressive to death The rate of progression is accelerated in the later stages

NATURAL HISTORY

NATURAL COURSE OF DN
This clinical course is well defined in type 1 DM, develops in close to 40% of pts Renal involvement is early in type 2 DM, occurs in 5 to 40 percent of pts In type 2 DM, it is not always clear whether renal failure is due to or caused by diabetes (insidious onset, advanced age, coexisting vascular disease, hypertension)

PATHOGENESIS
Altered renal hemodynamics due to hyperglycaemia
Increased renal blood flow Glomerlar hyperfiltration Altered renal hemodynamics increases the shear stress on endothelial & mesangial cells with increase renal growth factors (A II, TGF-b, IGF-1, PDGF), cytokines & extracellular matrix production

Systemic hypertension Hyperlipidemia Proteinuria Genetic factors

MORPHOLOGIC CHANGES IN DN
Glomerular & tubular hypertrophy Thickening of GBM, TBM Mesangial expansion is the morphological lesion that closely related to the evolution of the GFR Diffuse glomerulosclerosis Arteriosclerosis & hyalinosis of aa & ea Tubulointerstitial fibrosis

SCREENING
Screening for microalbuminuria provided unique window of opportunity for early intrvention, particularly administraion of ACE-I Should be performed annually from the onset in type 2 and 5 yrs after onset of type 1 DM Morning or spot albumin-creatinine ratio is the most reliable test

Prevention and treatment of diabetic nephropathy

Primary prevention: Progression from normo- to microalbuminuria Progression from microalbuminuria to DN Progression from DN to ESRD

Secondary prevention: Tertiary prevention:

PRIMARY PREVENTION
Tight glycemic control Tight blood pressure control

UK PROSPECTIVE DIABETES STUDY

Multi-centre Randomised controlled trial of different therapies of type 2 DM 5102 newly diagnosed type 2 DM pts AIM : to determine whether improved glucose control type 2 DM will prevent clinical complications RESULTS : 0.9% reduction in A1C was associated with 34% reduction in the development of microalbuminuria over 12 yrs in pts w/o retinopathy & 43% in retinopathy Microalbuminuria reduce by 56%

BLOOD PRESSURE CONTROL

ADA (2003), JNC VII (2002) : <130/80 : ACEi/ARB NKF 2000: <130/80; ACEI, ARB if not tolerated

Primary prevention of development of diabetic nephropathy

Strict metabolic control ACE inhibition Lipid lowering drugs? Low protein diet?

SECONDARY PREVENTION
Hypertension control to mid-normal range by ACEI, ARBs (<125/75) Tight glycemic control (A1C <6.5%) Reduce proteinuria to < 1 g/d Smoking cessation Protein restriction Treatment of dyslipidemia Prevention of contrast nephropathy Avoid drug nephrotoxicity

CLASS EFFECT OF ACEI & ARBs

Reduces intraglomerular pressure Antigrowth effect

PROTEIN RESTRICTION
Protein 0.6 g/kg/d in DM with falling GFR 0.8 g/kg/d in overt nephropathy

Secondary prevention of development of DN

Strict metabolic control Antihypertensive treatment
ACE inhibition Angiotensin receptor blockers Both ?

Multifactorial intervention

Tertiary prevention of progression to ESRD

Antihypertensive treatment Strict glucose control Low protein diet ? Lipid lowering drugs ? Stop smoking ?

RRT
Vascular access should be established at GFR 25 ml/min RRT should start at GFR 15-20 ml/min TX should be considered in all type 1 DM pts

OUTCOME OF RRT IN DM
DM on RRT have a 22% higher mortality at one yr & a 15% higher mortality at 5 yrs than pts w/o DM 32% of type 2 DM ESRD pts died in 211 d 80% of type 2 DM with ESRD required emergency dialysis due to late referrals to ghe nephrology service

Late diabetic complications

Prevention is EASIER than cure

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