DIABETIC NEPHROPATHY

Candra WibowoFaculty 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 (15-25 yrs)

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• 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

STAGES 1(very early diabetes = hyperthrophy hyperperfusion)

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• 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 end-stage renal disease (ESRD).

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

STAGES 2(developing diabetes=microalbuminuria=incipient

nephropathy)

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• 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.

STAGES 3(overt = macroalbuminuria – dipstick positive diabetes)

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• 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.

STAGES 4(late stage diabetes)

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

STAGES 5(end stage renal disease)

Progression of Diabetic Renal Diseasein Patients with Diabetes

2000

20

2

200

Albu

min

uria

(µg/

min

)

40%

60%Normoalbuminuria

Overt nephropathy

Microalbuminuria

Time (Years)

Δ GFR2-20:10

Δ GFR1-3

Δ GFR1

2000

20

2

200

Albu

min

uria

(µg/

min

)

Time (Years)

• 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

Progression of Diabetic Renal Diseasein Patients with Diabetes

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:

• Secondary prevention:

• Tertiary prevention:

Progression from normo- to microalbuminuria

Progression from microalbuminuria to DN

Progression from DN to ESRD

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