糖尿病腎病變 Diabetic Nephropathy

糖尿病腎病變糖尿病腎病變Diabetic NephropathyDiabetic Nephropathy

蔡宜潔醫師蔡宜潔醫師Feb. 24, 2008Feb. 24, 2008

OutlineOutline

Introduction of diabetic nephropathy Introduction of diabetic nephropathy Manifestations of diabetic nephropathyManifestations of diabetic nephropathy Staging of diabetic nephropathyStaging of diabetic nephropathy MicroalbuminuriaMicroalbuminuria Diagnosis of diabetic nephropathyDiagnosis of diabetic nephropathy Treatment of diabetic nephropathyTreatment of diabetic nephropathy

The leading cause of end-stage renal disease The leading cause of end-stage renal disease Diabetic nephropathy- Diabetic nephropathy-

→ → 30~40% 30~40% type 1 DMtype 1 DM vs. 20% vs. 20% type 2 DMtype 2 DM after years after years

Majority of diabetic p’ts with Majority of diabetic p’ts with ESRDESRD→→Type 2 DM Type 2 DM Prevalence of type 2 DM >> type 1DM (10~15x)Prevalence of type 2 DM >> type 1DM (10~15x)

Susceptibility to DMNSusceptibility to DMN Ethnicity- South Asian, African> CaucasianEthnicity- South Asian, African> Caucasian Gender- ♂>♀(1.7:1)Gender- ♂>♀(1.7:1) Age of DM onset (11~20 y/o in type 1 DM p’t)Age of DM onset (11~20 y/o in type 1 DM p’t)

Cf. >50y/o in type 2 DM p’t: incidence↑Cf. >50y/o in type 2 DM p’t: incidence↑

Introduction ofIntroduction of

Diabetic nephropathyDiabetic nephropathy

Natural history of DM nephropathyNatural history of DM nephropathy→→Better defined in type 1 DMBetter defined in type 1 DM→→5 stages5 stages Clinical and morphologic featuresClinical and morphologic features→→Similar in Similar in type 1 DMtype 1 DM and and type 2 DMtype 2 DM

Glomerular hypertension and hyperfiltrationGlomerular hypertension and hyperfiltration are the earliest renal abnormalitiesare the earliest renal abnormalities

Course of GFR change: more variable in typCourse of GFR change: more variable in type 2 DMe 2 DM

→ → GFR decline: 5~10cc/min/year GFR decline: 5~10cc/min/year (1~20 cc/min/year in type 2 DM)(1~20 cc/min/year in type 2 DM)

Manifestations ofManifestations of


DM nephropathy stagesDM nephropathy stages Stage 1:hyperfiltration phaseStage 1:hyperfiltration phase Stage 2:silent phaseStage 2:silent phase Stage 3:microalbuminuria phaseStage 3:microalbuminuria phase Stage 4:macroalbuminuria phaseStage 4:macroalbuminuria phase Stage 5:ESRDStage 5:ESRD

Describes the renal hypertrophy and hypDescribes the renal hypertrophy and hyperfiltration that present at the time of diagerfiltration that present at the time of diagnosis of type 1 DM .nosis of type 1 DM .

GFR and UAER- elevated by 20-40%GFR and UAER- elevated by 20-40%(UAER: urine albumin excretion rate)(UAER: urine albumin excretion rate)

→→ GFR and UAER↓while insulin therapyGFR and UAER↓while insulin therapy

Stage of Diabetic nephropathy

Stage 1-Hyperfiltration phase

Clinically silent (GFR↑)Clinically silent (GFR↑) Early histologic change (GBM/Matrix ↑)Early histologic change (GBM/Matrix ↑) Hyperfiltration related to Hyperfiltration related to

Degree of hyperglycemia (Degree of hyperglycemia (up to 250 mg/dLup to 250 mg/dL), high), higher levels of glycemia- GFR↓er levels of glycemia- GFR↓

Better glucose control- hyperfiltration↓Better glucose control- hyperfiltration↓

Typically lasts for Typically lasts for 5-15 years 5-15 years


Stage 2- Silent phase

Incipient nephropathyIncipient nephropathy Occurs after Occurs after 6 -15 years6 -15 years of diabetes of diabetes UAER: 30-300mg/dUAER: 30-300mg/d Always Always small but detectable BP↑small but detectable BP↑ Impairment of nocturnal BP “dipping”Impairment of nocturnal BP “dipping”

GFR is elevated or reduced into normal rGFR is elevated or reduced into normal rangeange

Initial hyperfiltration Initial hyperfiltration greater subseque greater subsequent rate of decline in GFR nt rate of decline in GFR


Stage 3- Microalbuminuria phase

24Hr BP Profile in Hypertension (Dipp24Hr BP Profile in Hypertension (Dipper vs non-dipper)er vs non-dipper)

Blood pressure (mm Hg)

7:00 11:00 15:00 19:0 23:00 3:00 7:00

Sleep

Dipper

Non-dipper

Time of day

175

135

115

95

75

55

155

Established or overt nephropahtyEstablished or overt nephropahty CharacteristicsCharacteristics

Clear histologic changesClear histologic changes HTN- established in most patientsHTN- established in most patients

Proteinuria→ increase 15~40 % per yearProteinuria→ increase 15~40 % per year GFR decline→10(2~20)mL/min per yearGFR decline→10(2~20)mL/min per year

The rate of decline in GFR is correlated with blThe rate of decline in GFR is correlated with blood pressure levelsood pressure levels

Microscopic hematuriaMicroscopic hematuria: 66% of patient: 66% of patient


Stage 4- Macroalbuminuria phase

Macroproteinuric phaseMacroproteinuric phase→ → a steady decline in renal functiona steady decline in renal function

GFR↓(about 1 mL/min↓per month)GFR↓(about 1 mL/min↓per month) A plot of the reciprocal of the serum creatA plot of the reciprocal of the serum creat

inine level against timeinine level against time usually yields a straight line and allows predusually yields a straight line and allows pred

iction of the rate of deteriorationiction of the rate of deterioration


Stage 4- Macroalbuminuria phase

ESRD developed inESRD developed in 50% of type 1 diabetic patient with overt 50% of type 1 diabetic patient with overt

nephropathy within nephropathy within 10 years10 years Within a median of Within a median of 7 years7 years from the from the

development of persistent proteinuria development of persistent proteinuria


Stage 5- ESRD

Accurate measurement of UAERAccurate measurement of UAER→→Identification of incipient “early” nephropahtyIdentification of incipient “early” nephropahty→→Modify the natural history of DMNModify the natural history of DMN Normal urine contains some albuminNormal urine contains some albumin

< 30 mg/day< 30 mg/day UAER↑- affected byUAER↑- affected by

exerciseexercise feverfever oral protein intake, oral fluid intakeoral protein intake, oral fluid intake pregnancypregnancy time of day (25% higher at daytime than night)time of day (25% higher at daytime than night)

The importance of

Microalbuminuria

Sample: overnight urineSample: overnight urine Microalbiminuria (MicroA): Microalbiminuria (MicroA):

30mg/day< UAER <300mg/day30mg/day< UAER <300mg/day

Persistent microA: Persistent microA: MicroA found inMicroA found in 2/3 2/3 consecutive urine samples consecutive urine samples

within within 3-6 months3-6 months DM DM < 6 years< 6 years: other causes should be suspecte: other causes should be suspecte

dd

Diagnosis of

Microalbuminuria

ScreeningScreening An early morning urine sampleAn early morning urine sample Screening recommendationsScreening recommendations

Type 1 DM: Age >12 y/o, DM Dx >5 yearsType 1 DM: Age >12 y/o, DM Dx >5 years Type 2 DM: At diagnosisType 2 DM: At diagnosis

Both: Annually until 70 y/oBoth: Annually until 70 y/o

Screening of

Microalbuminuria

Microalbiminuria Microalbiminuria

The predictive value of overt DMNThe predictive value of overt DMN A marker of overt nephropathy risk in type 1 DM patA marker of overt nephropathy risk in type 1 DM pat

ients.ients. Type 1 DM> 15 years with microA: 28% developed Type 1 DM> 15 years with microA: 28% developed

overt DMN within 10 years. overt DMN within 10 years.

Systemic hypertensionSystemic hypertension A significant relationship between BP and urine albuA significant relationship between BP and urine albu

min excretion rate(UAE).min excretion rate(UAE).

Microalbiminuria Microalbiminuria

Diabetic retinopathyDiabetic retinopathy Type 1 DM patients: strong association betwType 1 DM patients: strong association betw

een UAE and DMR.een UAE and DMR. Close ophthalmologic monitoring advised.Close ophthalmologic monitoring advised.

Atherosclerosis:Atherosclerosis: DM patients with overt DMN: increased risk DM patients with overt DMN: increased risk

of CV mortality.of CV mortality. Micro A: potentially atherogenic changesMicro A: potentially atherogenic changes

Low systolic blood pressureLow systolic blood pressure BP < 130/80 mmHgBP < 130/80 mmHg

Low cholesterolLow cholesterol Low HbA1CLow HbA1C

HbA1C < 7HbA1C < 7

Regression of

Microalbuminuria

American Familial Physician 72: 96-99, 2005

MicroalbuminuriaMicroalbuminuria

Microalbuminuria

Monitor Creatinine

Investigate forOther Renal

Disease

Screen forHeart Disease

Screen forVascular Disease

Screen forEye Disease

OptimizeLipids

OptimizeGlucose

DiscourageSmoking

OptimizeBP

Usually depend on clinical grounds without a reUsually depend on clinical grounds without a renal biopsynal biopsy

Supportive clues areSupportive clues are 1.DM hx >10 years1.DM hx >10 years 2.Presence of normal or enlarged kidneys2.Presence of normal or enlarged kidneys 3.Evidence of proliferative diabetic retinopathy3.Evidence of proliferative diabetic retinopathy 4.A bland urinary sediment.4.A bland urinary sediment. 5.Typical DM nephropathy course 5.Typical DM nephropathy course

Retinopathy is found in Retinopathy is found in 90 and 60 percent90 and 60 percent of patients with type of patients with type 1 DM and type 2 DDM, respectively, who develop nephropathy1 DM and type 2 DDM, respectively, who develop nephropathy

Diagnosis ofDiagnosis of


““Typical “ overt Typical “ overt nephropathynephropathy

Type 1 DM for > 10 yearsType 1 DM for > 10 years RetinopathyRetinopathy Previous microalbuminuriaPrevious microalbuminuria No macroscopic hematuriaNo macroscopic hematuria No RBC castsNo RBC casts Normal renal echoNormal renal echo

No Biopsy

““Atypical“ proteinuriaAtypical“ proteinuria

Type 1 DM for <10 yearsType 1 DM for <10 years No retinopathyNo retinopathy Nephrotic range proteinuria without previNephrotic range proteinuria without previ

ous microalbiminuriaous microalbiminuria Macroscopic hematuriaMacroscopic hematuria Red cell castsRed cell casts

Renal biopsy

The earliest morphologic abnormalities in The earliest morphologic abnormalities in diabetic nephropathy:diabetic nephropathy: Thickening of the glomerular basement membThickening of the glomerular basement memb

rane (rane (GBMGBM)) ExpansionExpansion of the mesangium due to accumula of the mesangium due to accumula

tion of extracellular tion of extracellular matrixmatrix. . With timeWith time

matrix accumulation becomes diffuse and is ematrix accumulation becomes diffuse and is evident as eosinophilic, periodic acid Schiff (+) vident as eosinophilic, periodic acid Schiff (+) glomerulosclerosis on biopsyglomerulosclerosis on biopsy

Pathologic change ofPathologic change of


Prominent areas of nodular matrix expaProminent areas of nodular matrix expansion (nodular glomerulosclerosis)nsion (nodular glomerulosclerosis)

→ → Classic Classic Kimmelstiel-Wilson noduleKimmelstiel-Wilson nodule

Pathologic change ofPathologic change of


Therapy is aimed at Therapy is aimed at retardingretarding the progres the progression of nephropathy throughsion of nephropathy through Blood sugar controlBlood sugar control Systemic blood pressure controlSystemic blood pressure control Glomerular capillary pressure↓(ACE inhibitorGlomerular capillary pressure↓(ACE inhibitor

/ARB)/ARB) Dietary protein intakeDietary protein intake LipidsLipids

Treatments ofTreatments of


NormoalbuminuriaNormoalbuminuria Intensive glycemic control- reduce the risk for dIntensive glycemic control- reduce the risk for d

evelopment of microA at this stageevelopment of microA at this stage Type 1 DM : Strict glycemic control with HbA1C(7% vType 1 DM : Strict glycemic control with HbA1C(7% v

s. 9%)→ risk of microA↓(35~45%)s. 9%)→ risk of microA↓(35~45%) Hypoglycemic episodes↑Hypoglycemic episodes↑ Type 2 DM: HbA1C (7% vs. 7.9%)→ risk of microA↓Type 2 DM: HbA1C (7% vs. 7.9%)→ risk of microA↓

(25~30%)(25~30%)

Microalbuminuria and overt DMNMicroalbuminuria and overt DMN Benefit of strict glycemic control- contraversialBenefit of strict glycemic control- contraversial Concurrence of HTN: confounding factorConcurrence of HTN: confounding factor

Treatment goal (1)Treatment goal (1)

Blood sugar controlBlood sugar control

MDRD studyMDRD study Lower BP (Lower BP (125/75mmHg125/75mmHg)→slower rate )→slower rate

of progression in of progression in proteinuria (>1g/day)proteinuria (>1g/day)

JNC 6JNC 6 Lower target BP for DM patientLower target BP for DM patient Treatment at a BP of 130/85mmHgTreatment at a BP of 130/85mmHg Goal BP of Goal BP of 125/75 in proteinuria125/75 in proteinuria patient patient

JNC 7JNC 7 Goal BP of Goal BP of 130/80 in DM130/80 in DM patient patient


Antihypertensive therapyAntihypertensive therapy

Glomerular pressure↓→Damage↓Glomerular pressure↓→Damage↓ Independent of effects on systemic BPIndependent of effects on systemic BP

NormoalbuminuriaNormoalbuminuria EUCLID study- no benefit (Lisinopril)EUCLID study- no benefit (Lisinopril) Other recent studies- benefit(+)Other recent studies- benefit(+)

Microalbuminuria with normal BPMicroalbuminuria with normal BP Progression to proteinuria↓(type 1&2)Progression to proteinuria↓(type 1&2)

Microalbuminria/proteinuria with HTNMicroalbuminria/proteinuria with HTN Most study: proteinuria↓(type 1&2)Most study: proteinuria↓(type 1&2) Slow the deterioration of renal functionSlow the deterioration of renal function


ACEI in DMNACEI in DMN

Many studies clearly document the benefit Many studies clearly document the benefit of ACEI in normotensive and hypertensive of ACEI in normotensive and hypertensive microalbuminuric patient with type1 & type microalbuminuric patient with type1 & type 2 DM2 DM

→→All diabetic patients should receive an ACE All diabetic patients should receive an ACE inhibitor upon the development of microalbinhibitor upon the development of microalbuminuria, even in the absence of systemic uminuria, even in the absence of systemic hypertension unless contraindicatedhypertension unless contraindicated

ARB have the similar beneficial effects as ARB have the similar beneficial effects as ACEI (RENNAL, IDNT, IRMAII)ACEI (RENNAL, IDNT, IRMAII)


ACEI in DMNACEI in DMN

Low protein diet 0.6g/kg/day (c/w 1g/kLow protein diet 0.6g/kg/day (c/w 1g/kg/day) was associated with a 75% redg/day) was associated with a 75% reduction in the rate of decline of the GFuction in the rate of decline of the GFR in type 1 DMR in type 1 DM

MDRD: the effects of dietary protein rMDRD: the effects of dietary protein restriction were inconclusive estriction were inconclusive

American Diabetes AssociationAmerican Diabetes Association: nonp: nonpregnant diabetic --- restrict protein to regnant diabetic --- restrict protein to 0.8 g/kg0.8 g/kg ideal body weight /day ideal body weight /day


Dietary protein intake Dietary protein intake

Lipids may accelerate renal injury via Lipids may accelerate renal injury via cytokine-dependent pathwayscytokine-dependent pathways

HMG CoA reductase inhibitors retard HMG CoA reductase inhibitors retard the progression of diabetic nephropatthe progression of diabetic nephropathy --- controversial nowhy --- controversial now


LipidsLipids

Management of Stage VManagement of Stage V

The nephrotic stage transforms almost imperceThe nephrotic stage transforms almost imperceptibly into the azotemic stage.ptibly into the azotemic stage.

The interval between diagnosis of DM and devThe interval between diagnosis of DM and development of ESRD: elopment of ESRD: type 1 DM 22 yrs, type 2 Dtype 1 DM 22 yrs, type 2 DM 10-12 yrs. M 10-12 yrs.

Early dialysis if ESRD- consensus Early dialysis if ESRD- consensus (not evidence base(not evidence based)d) Serum Cre: 5.5mg/dL or GFR 10~20cc/minSerum Cre: 5.5mg/dL or GFR 10~20cc/min DM more vulnerable to uremic symptoms, fluid retenDM more vulnerable to uremic symptoms, fluid reten

tion, hyperkalemia at an earlier stage than non DM stion, hyperkalemia at an earlier stage than non DM subjectsubjects

STAGES OF DM nephSTAGES OF DM nephropahtyropahty

STAGE-1 STAGE-1 HYPERFILTRATIONHYPERFILTRATION

STAGE-2STAGE-2SILENT STAGESILENT STAGE

STAGE-3STAGE-3INCIPIENT INCIPIENT NEPHROPATHYNEPHROPATHY

STAGE-4STAGE-4OVERT OVERT NEPHROPATHYNEPHROPATHY

STAGE-5STAGE-5CHRONIC RENAL CHRONIC RENAL FAILURE → ESRDFAILURE → ESRD

高血壓腎病變高血壓腎病變 HypertensiHypertensive Kidney Diseaseve Kidney Disease

OutlineOutline

IntroductionIntroduction Definition of HypertensionDefinition of Hypertension Risk factors of Hypertensive nephrosclerosisRisk factors of Hypertensive nephrosclerosis Pathogenesis of hypertensive nephrosclerosis Pathogenesis of hypertensive nephrosclerosis Diagnosis of hypertensive kidney diseaseDiagnosis of hypertensive kidney disease PrognosisPrognosis TherapyTherapy

Introduction of Hypertensive Kidney Disease

Chronic Kidney DiseaseChronic Kidney Disease

雞生蛋雞生蛋 ? ?

蛋生雞蛋生雞 ??

HypertensionHypertension


About About 6%6% essential HTN have CKD and essential HTN have CKD and are at risk for progression to ESRDare at risk for progression to ESRD

Hypertension is as a cause of Hypertension is as a cause of 30%30% ESRD patients in USESRD patients in US

The incidence of ESRD attributed to HTN The incidence of ESRD attributed to HTN is is 5x5x higher in higher in African AmericansAfrican Americans than in than in non-African Americannon-African American

Kidney Int 64: 2331-2341, 2003


Hypertensive kidney diseaseHypertensive kidney disease= Nephrosclerosis = Nephrosclerosis = benign nephrosclerosis= benign nephrosclerosis= nephroangiosclerosis= nephroangiosclerosis

Renal damage is thought secondary to eRenal damage is thought secondary to essential hypertension which affecting ssential hypertension which affecting prepreglomerularglomerular microvasculature microvasculature

Kidney Int 68: S52-S56, 2005

Definition of Definition of HypertensionHypertension

BP ClassificationBP Classification Systolic BPSystolic BP mmHg mmHg

Diastolic BP Diastolic BP mmHg mmHg

NormalNormal <120<120 andand < 80< 80

PreHTNPreHTN 120-139120-139 oror 80-8980-89

Stage 1Stage 1 140-159140-159 oror 90-9990-99

Stage 2Stage 2 >>160160 oror >> 100 100

JAMA 289: 2561, 2003

From JNC 7

Risk factors forRisk factors for

Hypertensive NephrosclerosisHypertensive Nephrosclerosis Systolic blood pressureSystolic blood pressure ProteinuriaProteinuria Decreased glomerular filtration rateDecreased glomerular filtration rate RaceRace AgeAge SexSex Lipid abnormalitiesLipid abnormalities Insulin resistanceInsulin resistance HyperuricemiaHyperuricemia HyperhomocysteinemiaHyperhomocysteinemia SmokingSmoking OthersOthers

Kidney Blood Press Res 25: 341-353, 2002


Hypertensive NephrosclerosisHypertensive Nephrosclerosis SBPSBP

Systolic blood pressure was an independent risk factor for Systolic blood pressure was an independent risk factor for all-cause ESRDall-cause ESRD

ProteinuriaProteinuria In AASK study: Urine protein/Cr ratio > 0.22 In AASK study: Urine protein/Cr ratio > 0.22 2x higher 2x higher

rate of decline in GFRrate of decline in GFR Every Every 1g/24h1g/24h increase in urinary protein increased the risk increase in urinary protein increased the risk

by by 1.4 times1.4 times Decreased glomerular filtration rateDecreased glomerular filtration rate

In AASK study:In AASK study: In patients with GFR < 40 ml/min/1.73m2 and proteinuria > In patients with GFR < 40 ml/min/1.73m2 and proteinuria >

300mg/day, despite BP < 122/77 mmHg, renal disease continued to 300mg/day, despite BP < 122/77 mmHg, renal disease continued to progressed progressed

Each Each doubling of the serum Crdoubling of the serum Cr concentration increased the concentration increased the risk risk 2.6 times2.6 times

Kidney Int 64: 2331-2341, 2003 Nephrol Dial Transplant 28: 517-523, 2003


Hypertensive NephrosclerosisHypertensive Nephrosclerosis RaceRace

Prevalence is higher in Prevalence is higher in blackblack with more severe histology with more severe histology The incidence of hypertension induced renal failure: The incidence of hypertension induced renal failure:

Black: 33.8% Black: 33.8% White: 21%White: 21%

AgeAge Age was the factor most closely associated with HN among Age was the factor most closely associated with HN among white white

patientspatients The incidence of HN as a cause of ESRD:The incidence of HN as a cause of ESRD:

>64 years old: 31%>64 years old: 31% <64 years old: 19.2%<64 years old: 19.2%

The The histologicalhistological change is similar in aging process and hypertension- change is similar in aging process and hypertension-related injuryrelated injury

Starting from the Starting from the age of 30-40age of 30-40, kidney manifest significant functional , kidney manifest significant functional changeschanges



Hypertensive NephrosclerosisHypertensive Nephrosclerosis SexSex

HN is more common in maleHN is more common in male The role of androgens in mediating renal injury in renin-dependent hypThe role of androgens in mediating renal injury in renin-dependent hyp

ertension? ertension? But in black, female?But in black, female?

Lipid abnormalitiesLipid abnormalities ParticularlyParticularly hypercholesterolemia hypercholesterolemia, may play a role in the development , may play a role in the development

of glomerulosclerosisof glomerulosclerosis Lipid related renal injuryLipid related renal injury

GlomerulosclerosisGlomerulosclerosis Interstitial inflammation and fibrosisInterstitial inflammation and fibrosis Impair both arterial and artiolar endothelial functionImpair both arterial and artiolar endothelial function

Lipid abnormalities seem to be a Lipid abnormalities seem to be a modulatormodulator of progressive renal disea of progressive renal disease rather than a primary initiator, se rather than a primary initiator, synergistic effectsynergistic effect with HTN with HTN



Hypertensive NephrosclerosisHypertensive Nephrosclerosis Insulin resistanceInsulin resistance

Hypertensive patients with hyperinsulinemia excrete greater aHypertensive patients with hyperinsulinemia excrete greater amounts of urinary albuminmounts of urinary albumin

Mechanism of renal injury: unclearMechanism of renal injury: unclear Enhance sympathetic activityEnhance sympathetic activity Increased renal Na retentionIncreased renal Na retention Increase cholesterol and TG synthesisIncrease cholesterol and TG synthesis Direct injury on endothelial cellsDirect injury on endothelial cells

HyperuricemiaHyperuricemia Hyperuricemia is believed to influence the development of Hyperuricemia is believed to influence the development of protprot

einuria einuria and to have a worse renal outcome in hypertensivesand to have a worse renal outcome in hypertensives Postmortem examination of kidney with hypertension showed Postmortem examination of kidney with hypertension showed ii

nterstitial uric acid depositsnterstitial uric acid deposits similar to gout nephropathy similar to gout nephropathy



Hypertensive NephrosclerosisHypertensive Nephrosclerosis HyperhomocysteinemiaHyperhomocysteinemia

Hyperhomocysteinemia is considered a new risk factor for cardHyperhomocysteinemia is considered a new risk factor for cardiovascular diseaseiovascular disease

More frequently in essential hypertension than withoutMore frequently in essential hypertension than without Mechanism is not fully understoodMechanism is not fully understood

Induced oxidative stressInduced oxidative stress Endothelial injuryEndothelial injury Enhancement of vascular monocyte adhesionEnhancement of vascular monocyte adhesion

SmokingSmoking MicroalbuminuriaMicroalbuminuria is twice as prevalent in smoking as nonsmok is twice as prevalent in smoking as nonsmok

ers with primary HTNers with primary HTN Smoking related Smoking related vascular renal injuryvascular renal injury make smokers more vuln make smokers more vuln

erable to hypertensive renal involvementerable to hypertensive renal involvement



Hypertensive NephrosclerosisHypertensive Nephrosclerosis OthersOthers

Heavy metals:Heavy metals: lead lead Salt intakeSalt intake::

SaltSalt↑↑ ↓ renal plasma flow, ↑glomerular capillary pressure ↓ renal plasma flow, ↑glomerular capillary pressure SaltSalt↑↑glomerular TGFglomerular TGFββ1 ↑1 ↑ promotes glomerulosclerosis promotes glomerulosclerosis

Genes: candidate genes linked to the Genes: candidate genes linked to the renin-angiotenrenin-angiotensin systemsin system

Perinatal programming: Perinatal programming: low birth weightlow birth weight may be rela may be related to low nephron numbersted to low nephron numbers


PathogenesisPathogenesis

Incompletely understoodIncompletely understood Genetic predisposing factors may contribGenetic predisposing factors may contrib

uteute Angiotensin IIAngiotensin II plays an important role plays an important role

Kidney Int 64: 2331-2341, 2003

PathologyPathology

Benign nephrosclerosis: essential hypertension Benign nephrosclerosis: essential hypertension relatedrelated Microvascular changes with hyalinosis of Microvascular changes with hyalinosis of preglomerpreglomer

ularular vessel ( vessel (arcuate and interlobulararcuate and interlobular arteries) walls arteries) walls afferent arteriole vasconstriction afferent arteriole vasconstriction glomerular inj glomerular injury ury renal scarring renal scarring

As a form of intrarenal renovascular disase As a form of intrarenal renovascular disase Malignant nephrosclerosis: malignant hypertenMalignant nephrosclerosis: malignant hyperten

sion relatedsion related Fibrinoid necrosisFibrinoid necrosis Myointimal hyperplasiaMyointimal hyperplasia

Kidney Int 68: S52-S56, 2005

Diagnosis of Diagnosis of

Hypertensive NephrosclerosisHypertensive Nephrosclerosis PresumptivePresumptive, due to , due to rare biopsyrare biopsy data data Clinical criteria (Clinical criteria (Schlessinger et alSchlessinger et al. 1994). 1994)

Family history of hypertension (first-degree relative)Family history of hypertension (first-degree relative) Left ventricular hypertensive hypertrophy (or hypertenLeft ventricular hypertensive hypertrophy (or hyperten

sive retinopathy)sive retinopathy) Minimal proteinuria (Minimal proteinuria (commonly less than 0.5g/daycommonly less than 0.5g/day)) Long-standing hypertension preceding any evidence oLong-standing hypertension preceding any evidence o

f renal diseasef renal disease Absence of nephrotoxin exposureAbsence of nephrotoxin exposure Absence of congenital or intrinsic renal diseaseAbsence of congenital or intrinsic renal disease Absence of systemic illness associated with renal diseAbsence of systemic illness associated with renal dise

asease

Am J Kidney Dis 23: 655-660, 1994

Diagnosis of Diagnosis of

Hypertensive NephrosclerosisHypertensive Nephrosclerosis Hints of diagnosis nephrosclerosis as the Hints of diagnosis nephrosclerosis as the

cause of renal dysfunctioncause of renal dysfunction Long-standing HTNLong-standing HTN Male sexMale sex Age > 55 y/oAge > 55 y/o Family history of HTNFamily history of HTN Signs of HTN damage in other organs (LVH, Signs of HTN damage in other organs (LVH,

retinopathy…)retinopathy…) Extrarenal manifestations of atherosclerosisExtrarenal manifestations of atherosclerosis

Kidney Int 68: S52-S56, 2005

Mis-DiagnosisMis-Diagnosis

46%-50%46%-50% remained the original diagnosi remained the original diagnosis after angiography or biopsys after angiography or biopsy Misdiagnosis: renovascular diseaseMisdiagnosis: renovascular disease

85%85% agreement between clinical diagnosi agreement between clinical diagnosis and histological diagnosis in s and histological diagnosis in African-AAfrican-Americansmericans

Kidney Int 54(S68): S55-59, 1998Nephrol Dial Transplant 15: 1801-1807, 2000Kidney Int 51: 244-252, 1997

Prognosis ofPrognosis of Hypertension nephrosclerosisHypertension nephrosclerosis

Progression is relatively slowProgression is relatively slow In non-proteinuric patients: 5-6 ml/min/yearIn non-proteinuric patients: 5-6 ml/min/year In proteinuric patients: 6-8 ml/min/yearIn proteinuric patients: 6-8 ml/min/year Treated HN: 1-2 ml/min/year Treated HN: 1-2 ml/min/year

Percentage of ESRD (with biopsy provePercentage of ESRD (with biopsy proved)d) In 3 years: 18%In 3 years: 18% In 13 years: 32%In 13 years: 32%

Nephrol Dial Transplant 28: 517-523, 2003

Kidney Int 64: 2331-2341, 2003

Unfavorable renal outcome FactorsUnfavorable renal outcome Factors AgeAge African descentAfrican descent Systolic blood pressureSystolic blood pressure ProteinuriaProteinuria Concomitant cardiovascular diseaseConcomitant cardiovascular disease

Kidney Int 68: S52-S56, 2005



非非 African AmericanAfrican American 之患者之患者 , essential HTN, essential HTN 治療治療與否和與否和 renal dysfunctionrenal dysfunction 沒有直接關係沒有直接關係 ; ; 但若合併但若合併intrarenal atherosclerotic vascular disease, intrarenal atherosclerotic vascular disease, 則有則有可能會影響腎功能可能會影響腎功能 . .

In non-African Americans:In non-African Americans:Nephrosclerosis = aging + diffuse atherosclerosisNephrosclerosis = aging + diffuse atherosclerosis

Nephrosclerosis could be the Nephrosclerosis could be the renal expression of renal expression of a systemic disordera systemic disorder causing other vascular alterat causing other vascular alterations such as coronary heart disease or cerebrovaions such as coronary heart disease or cerebrovascular diseasescular disease

Nephrol Dial Transplant 28: 517-523, 2003

Therapy ofTherapy of Hypertensive nephrosclerosis Hypertensive nephrosclerosis

In African American Study of Kidney Disease aIn African American Study of Kidney Disease and Hypertensionnd Hypertension 1094 African Americans with hypertensive renal dise1094 African Americans with hypertensive renal dise

ase (GFR 20-65 ml/min) ase (GFR 20-65 ml/min) Randomly into 2 mean BP goalsRandomly into 2 mean BP goals

102-107 mmHg102-107 mmHg < 92 mmHg< 92 mmHg

MedicationsMedications ββ-blocker (metoprolol 50-200 mg/d)-blocker (metoprolol 50-200 mg/d) ACEI (ramipril 2.5-10 mg/d)ACEI (ramipril 2.5-10 mg/d) DHP CCB (amlodipine 5-10 mg/d)DHP CCB (amlodipine 5-10 mg/d)

JAMA 288: 2421-2431, 2002


Main outcomeMain outcome Rate of change in GFRRate of change in GFR Clinical composite outcome of reduction in GFR Clinical composite outcome of reduction in GFR

by 50% or more, ESRD, or deathby 50% or more, ESRD, or death

2 comparisons2 comparisons Lower vs usual BP goalLower vs usual BP goal Ramipril vs metoprololRamipril vs metoprolol Amlodipine vs metoprololAmlodipine vs metoprolol Amlodipine vs ramiprilAmlodipine vs ramipril

JAMA 288: 2421-2431, 2002


JAMA 288: 2421-2431, 2002


JAMA 288: 2421-2431, 2002


JAMA 288: 2421-2431, 2002

Clinical composite outcome (reduction in GFR Clinical composite outcome (reduction in GFR by 50% or more, ESRD, or death)by 50% or more, ESRD, or death) Lower vs Usual BP: no differenceLower vs Usual BP: no difference Ramipril vs metoprolol: all risk reduction was 22% Ramipril vs metoprolol: all risk reduction was 22%

(P=0.04)(P=0.04) Metoprolol vs Amlodipine: risk reduction 59% risk for Metoprolol vs Amlodipine: risk reduction 59% risk for

ESRD alone (P<0.001)ESRD alone (P<0.001) Ramipril vs amlodipine: all risk reduction was 38% Ramipril vs amlodipine: all risk reduction was 38%

(P=0.004); 59% for ESRD alone (P<0.001)(P=0.004); 59% for ESRD alone (P<0.001)


JAMA 288: 2421-2431, 2002

Effects on Effects on proteinuriaproteinuria Drug effect is different according to Drug effect is different according to

proteinuria levelproteinuria level Baseline proteinuria < 300 mg/dBaseline proteinuria < 300 mg/d Baseline proteinuria > 300 mg/dBaseline proteinuria > 300 mg/d

<300 mg/day >300 mg/day

Change in proteinuriaChange in proteinuria

Kidney Int 64: 2331-2341, 2003

Blocking RAAS –ACEI/ARB Blocking RAAS –ACEI/ARB

ACEI and ARBACEI and ARB

The antiproteinuric and nephroprotective The antiproteinuric and nephroprotective effect of ACEI and ARB is effect of ACEI and ARB is dose dependedose dependentnt

J Am Soc Nephrol 17: S250-254, 2006

Dual BlockadeDual Blockade

45 patients with primary proteinuric nephr45 patients with primary proteinuric nephropathies opathies After 6 months of medicationAfter 6 months of medication

Lisinopril 40 mg Lisinopril 40 mg ↓proteinuria 50%↓proteinuria 50% Candesartan 32mg Candesartan 32mg ↓proteinuria 48% ↓proteinuria 48% Lisinopril 20 mg + Candesartan 16mg Lisinopril 20 mg + Candesartan 16mg ↓protein ↓protein

uria 70%uria 70% BP was reduced significantly but no differenBP was reduced significantly but no differen

ce between groupsce between groups

Kidney Int Suppl 82: S47-52, 2002

Dual BlockadeDual Blockade

Combination therapy Combination therapy reducedreduced proteinuria proteinuria more effectively than monotherapymore effectively than monotherapy

Dual blockade reduced the Dual blockade reduced the risk of ESRDrisk of ESRD more effectively than monotherapy more effectively than monotherapy (a study (a study with 263 Japanese in 2003)with 263 Japanese in 2003)

Adverse effectsAdverse effects Hyperkalemia: most frequentHyperkalemia: most frequent Anemia: RAS stimulates erythropoietin synthAnemia: RAS stimulates erythropoietin synth

esis esis

J Am Soc Nephrol 17: S250-254, 2006

Thanks for your attentions !Thanks for your attentions !

慢性腎病分為哪幾期慢性腎病分為哪幾期 ?? 依腎絲球濾過率依腎絲球濾過率 (GFR)(GFR) 分為五期分為五期

分期分期敘述敘述 GFRGFR(ml/min/(ml/min/1.73m)1.73m)

第一期第一期腎損傷但腎損傷但 GFRGFR 正常或增加正常或增加 9090第二期第二期腎損傷併腎損傷併 GFRGFR 輕度減少輕度減少 60-8960-89

第三期第三期 GFRGFR 中度減少中度減少 30-5930-59

第四期第四期 GFRGFR 嚴重減少嚴重減少 15-2915-29

第五期第五期腎衰竭腎衰竭 <15 (<15 ( 或透析或透析治療治療 ))

African African AmericansAmericans

CaucasiansCaucasians

At the time of At the time of biopsybiopsy

YoungerYounger

Higher serum CrHigher serum Cr

OlderOlder

Lower serum CrLower serum Cr

Pronounced gloPronounced glomerulosclerosis merulosclerosis and interstitial fiand interstitial fibrosisbrosis

Mimic agingMimic aging

Essential HTN Essential HTN ESRD ?ESRD ?

TreatedTreated Untreated Untreated

CaucasiansCaucasians XX X?X?

African AmericanAfrican American OO OO

Kidney Int 68: S52-S56, 2005

AASK study wanted to ask?AASK study wanted to ask? Does aggressive lowering BP result in sloweDoes aggressive lowering BP result in slowe

r declines in kidney function? r declines in kidney function? NoNo Does the type of antiHTN agents with regard Does the type of antiHTN agents with regard

to kidney disease outcomes? to kidney disease outcomes? YesYes

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