How to live with aging kidney · directly involved in regulation of redox state and is not evolutionarily conserved • Klotho‐deficientdeficient micemice developdevelop aa prematurepremature‐

H t li ith i kidHow to live with aging kidney

Dusit Lumlertgul, MD.

Renal DivisionRenal Division

Department of Internal MedicinehChiang Mai University

การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Aging and kidney disease


Structural change in Aging KidneyStructural change in Aging Kidney

• Reduce in kidney weight ( )(270gm to 200 gm)

• Sclerotic change in the wall of the large renal esselsof the large renal vessels

• Glomerulosclerosis (30‐ 50% reduction in glomerularreduction in glomerular number) and tubulointerstitial fibrosis


Pathological Finding in Aging KidneyPathological Finding in Aging Kidney

Artery of interlobular size Reduplication of the internal elastic Artery of interlobular size showing intimal thickening

p flamina, typical of

hypertension‐related changeการประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล


Hyaline arteriolosclerosis Scanning view of a renal in renal biopsies from older

individuals

g fbiopsy showing



A hypertrophic glomerulus compensating forobsolete glomeruliการประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Aging and the Kidney• Aging is an independence risk factor CKD

Overall

Prevalence of moderate chronic kidney disease by age group in National Health and Nutrition Examination Survey 1988–1994 and 1999–2004

50

60

Overall

30

40

50

20

30

0

10

20 39 yr 45 59 yr 60 69 yr > 70 yr20‐39 yr 45‐59 yr 60‐69 yr > 70 yr

NHANES data, JAMA 2007; 298:2038–2047การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Prevalence of moderate chronic kidney disease by age group in National Health and Nutrition Examination Survey 1988–1994 and 1999–2004and Nutrition Examination Survey 1988–1994 and 1999–2004

CKD stage 1 and 2 CKD stage 3 CKD stage 4

40

50

60

40

50

60

40

50

60

0

10

20

30

0

10

20

30

0

10

20

30

0

20‐39 yr 45‐59 yr 60‐69 yr > 70 yr

0

20‐39 yr 45‐59 yr 60‐69 yr > 70 yr

0

20‐39 yr 45‐59 yr 60‐69 yr > 70 yr

NHANES data, JAMA 2007; 298:2038–2047การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Projection of expected numbers of CKD during 2008-2013

Year Adult Population (x1000)

Expected CKD cases ( )

2008 39,314 5,661,000

2009 39,866 5,741,000

2010 40 433 5 822 0002010 40,433 5,822,000

2011 48,862 7,036,000

2012 49,470 7,124,000

2013 50 098 7 214 0002013 50,098 7,214,000

NST. Thai SEEK project 2009การประชมวิชาการ

Awareness of CKD in ThailandAwareness of CKD in Thailand

Stage 4

Stage 2

NST. Thai SEEK project 2009การประชมวิชาการ

The Progressive Nature of Kidney DiseaseThe Progressive Nature of Kidney Disease

Remuzzi G et al. J. Clin. Invest 2006; 116:288–296 การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Factor Associated with the Pathogenesis of Age‐related Glomerulosclerosis and Tubulointerstitial fibrosis

Angiotensin IIAngiotensin IIAldosterone

LipidsOxidative stress

Advanced glycosylationg y yend products


Schema of Potential Mechanisms of Regression of Glomerulosclerosis

Agnes B. Fogo , Nephrol Dial Tranplant 2006; 21: 281‐284การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Angiotensin II/ Aldosterone

↑ i l b l f di d

Angiotensin II/ Aldosterone

• ↑ Proximal tubular transport of sodium and water → glomerular hypertension

• Glomerular and tubular growth/ immunomodulation/ growth factor induction/ g

• ↓ Nitric oxide synthesis• ↑ Accumulation of extracellular matrix• ↑ Accumulation of extracellular matrix proteins

• Hemodynamic effect → glomerular hypertension


The Multiple Mechanisms Explaining the Potential Detrimental Effects of Angiotensin II/ Aldosterone on the kidney

Remuzzi G et al. J Am Soc Nephrol 2008;19: 1459–1462.การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Angiotensin II/ AldosteroneAngiotensin II/ AldosteroneEffects of Angiotensin converting enzyme on renal aging

Enalapril administered to drinking water mice

25

15

20

10

0

5

0

20 mg 10 mg 3 mg Control

Gl l l i (%) M i l l l l i (%)Glomerulosclerosis (%) Mesangial area per glomerulosclerosis (%)

Ferder L et al. J Am Soc Nephrol 1994; 5: 1147‐1152. การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Angiotensin II/ AldosteroneMWF rats 50 weeks of age 60 weeks of age

Angiotensin II/ AldosteroneMWF rats 50 weeks of age 60 weeks of age

C t lControl

With Lisinoprilp

Remuzzi G et al. Kidney International (2006) 69, 1124–1130 การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

TGF‐βTGF‐β

β i d l f i i• TGF‐β, an active modulator of tissue repair• Associated with the structural change of renal gscaring in the aging kidney

• Induce transcription and production of matrixInduce transcription and production of matrix proteins collagen III, IV, I, fibronectin, tenascin, osteonectin osteopontin thrombospondinosteonectin, osteopontin, thrombospondin , and matrix glycosaminoglycans↑ A l ti f t ll l t i• ↑ Accumulation of extracellular matrix proteins with subsequence glomerulosclerosis


Oxidative StressOxidative StressOxidants

PPKC‐B P66 Shc

P66 Shc‐PPin‐1

P66 Shc P

P66 Shc‐P↑ ROS P66 Shc P↑ ROS

ApoptosisApoptosisChristine JP et al. Nephrology 2008; 13: 147‐152การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Oxidative StressOxidative Stress

Christine JP et al. Nephrology 2008; 13: 147‐152การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

A Putative Role of PPAR‐γ in AgingA Putative Role of PPAR‐γ in Aging

Ruihua Zhang and Feng Zheng Kidney Int 2008; 72: 702‐704การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Functional Changes in Aging KidneyFunctional Changes in Aging Kidney

• Renal plasma flow; ↓ 10% per decade increased from third to ninth decade– Increased renal vascular resistance

Decreased response to vasodilators– Decreased response to vasodilators


Percent Change in Renal RPF, GFR, FF and RVR :Maximal Response to Vasodialtior

Ch t Titl

40

50

Chart Title

20

30

40

0

10

20

-20

-10 RPF GFR FF RVR

-30

younger older

Kidney Int 2001; 59: 1052‐1058.การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Glomerular Filtration RateGlomerular Filtration Rate

• Mean GFR falls from approximately 120 mL/min per 1.73 m2 at the beginning of the fourth decade of life to approximately 90 mL/min per 1 .73 m2 in the sixth decade

• Average, an approximate 1 mL/min per 1 .73 m2 per e age, a app o a e / pe 3 peyr decline in GFR occurs after the age of 50 yr


How to Estimate GFR in the ElderlyHow to Estimate GFR in the Elderly

Methods LimitationsMethods Limitations

Creatinine Clearance;1. Rowe JW, Andrew R, Tobin JD et al.

1. Low muscle mass in the elderly (low Cr) that make over estimated of GRF1. Rowe JW, Andrew R, Tobin JD et al.

formula2. Cockcroff DW, Gaulf MH formula

make over estimated of GRF2. Decrease urinary Cr secretion in the elderly that

make under estimated of GFR

Modification of Diet in Renal Disease (MDRD)

Genetic variation, Race (↓ GFR in aging African American and Japanese >> white)

Routine 24 hr Creatinine Clearance 1. Decrease urinary Cr secretion in the elderly that make under estimated of GFR

2 Volume collected diet2. Volume collected, diet


GFR versus age Estimated GFR percentiles for the US population using NHANES III serum creatinine age sex and race data by age compared to a regression of inulinserum creatinine,age, sex, and race data by age compared to a regression of inulin

clearance measurement of GFR on age among 70 healthy male participants.


Aging and Renal DiseaseAging and Renal Disease

l ilAcute Renal Failure• 3.5 times more common over age 70 yearsg y• Pre‐renal azothemia

– More common; vomiting diarrhea over use of– More common; vomiting, diarrhea, over use of diuretics, bleeding, medication, sepsis, hypoperfusion, low cardiac outputhypoperfusion, low cardiac output

• ATN ; more common than younger patients (23% versus 15%) FeNa may be less than 1(23% versus 15%), FeNa may be less than 1 due to underlying hypoperfusion


Elderly is the Risk for AKIElderly is the Risk for AKI



Aging and Renal DiseaseAging and Renal DiseaseEnd stage Renal Diseaseg


Relationship between age and renal perfusionrates in 207 healthy human subjects

500

600

300

400

200

0

100

<30 yr 30‐40 yr 40‐50 yr 50‐60 yr > 60 yr

Rapid‐component flow rate(QI) Mean renal blood flow (QM)

Hollenberg NK et al. Circ Res 1974; 34:309‐316.การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Adjusted hazard for death associated with an eGFR 50–59 ml/min/1 73m2 compared with an eGFR > 60eGFR 50–59 ml/min/1.73m2 compared with an eGFR > 60

among a national cohort of Veterans Affairs patients

O Hare AM et al. J Am Soc Nephrol 2006;17: 846‐853การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดุสิต ล้ําเลิศกุล

Predictors of Death in AKIResults from Multicenter O bservational Studies

BEST Kidney Invest.(Uchino et al. JAMA 2005)

PICARD (Chertow Kidney Int 2006)

• O verall mortality 60%– Age

• O verall mortality 37%, over 60% for AKI‐RRT

– Duration between admission and AKI

– Mechanical ventilation

– Age– Higher BUN

Liver failureMechanical ventilation– Vasopressor use– Sepsis

– Liver failure– Sepsis– CKD stage IV

– Cardiogenic shock– Hepatorenal syndrome

g


KlothoKlotho

• A newly identified anti‐aging factor that is not directly involved in regulation of redox state y gand is not evolutionarily conserved

• Klotho deficient mice develop a premature• Klotho‐deficient mice develop a premature‐aging phenotype that includes a drastically h l f k l hshortened life span, skin and muscle atrophy, osteoporosis, pulmonary emphysema, and extensive ectopic calcification


การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดสุิต

ล้ําเลิศกลุ

1.4

1.6

1

1.2

Doxorubicin hydrochloride (DXR)

0.6

0.8 Control

With rhEPORh-EPO 200 iu x 3/week

0 2

0.4

0

0.2

Klotho expression

Doxorubicin hydrochloride (DXR)

Klotho expression

Hidekazu Sugiura, abstract ASN 2007การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดสุิต


Gouva C., et al. Kidney International,Gouva C., et al. Kidney International,การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดสุิต




Eto et al. Kidney Inter.การประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดสุิต


Oxidative StressStress

CVS Immunogenicity of HLA presentation

Remodelingpresentation

Tissue Injury

Chronic All ft AtherosclerosiREJECTION Allograft nephropathy

sREJECTION

yการประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดสุิต


Z Aydin etการประชุมวิชาการแหงชาติฯ โดย ศ.นพ.ดสุิต


Ischemic injury

Hypoxia inducible factor (HIF 1)Hypoxia-inducible factor (HIF-1)

EPO receptorEPO receptorJAX-2 kinaseSTATs and NF-kB

Upregulation of Bcl-XL and XIAP (antiapoptotic protients)Prevent activation of caspase-3

Semin Nephrol 2006; 26 325 331



EPO actions Antioxidative effectsEPO actions Antioxidative effectsDirect

I h 1 D d d bili d hIncrease heme oxygenase-1 Degrade destabilized hemeproteinProduce biliverdin and bilirubin

Increase antioxidative enzymes Enhance cellular antioxidativecapacity

I diIndirectDeplete body iron Reduce iron-dependent oxidative

injuryinjury

Increase young red blood cells Increase circulating antioxidants

P Katavetin et al, KI 2007



Preventive NephrologyPreventive Nephrology

Primary PreventionAims at preventing kidney disease from occurring at allCalls for knowledge of ○ risk factors that predispose to renal disease○ risk factors that initiate renal damage.○ modification, removal, or avoidance of factors.○ development of a positive health seeking attitude and behavior○ development of a positive health seeking attitude and behavior

Secondary PreventionAims at identifying factors that aid or hasten progressionAims at identifying factors that aid or hasten progression of kidney disease and/or accelerate loss of kidney function, and preventing or removing such factors.function, and preventing or removing such factors.

Tertiary Preventionการประชมวิชาการ

What do we need for CKD program?(Education programs)

Wh t ? T iWhat ? ….TopicIntroduction to CKDAnemiaHypertensionDiabetes melitusNutrition Renal replacement therapyIntroductionHemodialysisPeritoneal dialysisKidney transplantation

Worawon Chailimpamontree, MD.การประชมวิชาการ

การประชมวิชาการ



Documents

How to live with aging kidney · directly involved in regulation of redox state and is not evolutionarily conserved • Klotho‐deficientdeficient micemice developdevelop aa prematurepremature‐