childhood ckd prevention program in taiwan: what are we going to do?

CHILDHOOD CKD PREVENTION PROGRAM IN TAIWAN:

WHAT ARE WE GOING TO DO?

You-Lin Tain MD, PhD, Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung, Taiwan

Purposes

(1)Intervention ： which, when, and why？ (2)CV measurement (3)Efficiency of ACEI/ARB in CKD

progression (4)Cerebral accident in ESRD children:

marker (5) Primary prevention:

1. Identify high risk group 2. how to maintain GFR

(6) Early detection: how and why? (7) Steering committee?

CKD prevention program is intended to raise awareness and increase detection of CKD, but most emphasis is placed on adults rather than children.

Prevalence of complications in children with CKD CKD Stage I 57% II 29% III 10.4% IV+V 4.1%

Wang et al., KI, 2006

Screening for kidney disease in children on World Kidney Day in Jalisco, Mexico 240 children: 8.9 ± 4.1 years; 44.2% male

Proteinuria: 16.1% Hematuria:17.5% BMI > 95th percentile for age: 15% Systolic hypertension: ~7% Reduced GFR (<60ml/min; CKD stage 3): 1.7%

CKD1-3 ~15-20%

Koshy et al., PN, 2009

CriteriaHow to screen? What kinds of screen?Which population?Intervention OR preventionSubcommittee

Iseki K, Int Med, 2008

Outlines Cr-based eGFR Questionnaire design

Which phenotype: High risk group CKD screen: which parameter(s) Global status of CKD prevention programs in children

Intervention: ACEi, ARB, OR? CVD in CKD Sub-committee OR interesting topic

林 : FGF-23, Ghrelin 邱 : Solitary kidney outcome/LN/Cystic kidney 田 : ADMA and SDMA

Outlines Cr-based eGFR Questionnaire design

Which phenotype: High risk group CKD screen: which parameter(s) Global status of CKD prevention programs in children

Intervention: ACEi, ARB, OR? CVD in CKD Sub-committee OR interesting topic

林 : FGF-23, Ghrelin 邱 : Solitary kidney outcome/LN/Cystic kidney 田 : ADMA and SDMA

CKD Staging

Stage 1 ：腎功能正常但有①病理學檢查異常 ; ②腎損傷的指標：包括血、尿成分異常或影像學檢查異常。 eGFR：≧ 90 ml/min/1.73 m2。

Stage 2 ：輕度慢性腎衰竭 eGFR ： 60~89 ml/min/1.73 m2

。 Stage 3 ：中度慢性腎衰竭 eGFR ： 30~59 ml/min/1.73 m2

。 Stage 4 ：重度慢性腎衰竭 eGFR ： 15~29 ml/min/1.73 m2

。 Stage 5 ：末期腎臟病變 eGFR ：＜ 15 ml/min/1.73 m2。

Estimated GFR in children (NKF K/DOQI )

Schwartz Formula

GFR (mL/min/1.73 m2) = k (Height) / Serum Creatinine

k = Constant k = 0.33 in premature infants k = 0.45 for infant k = 0.70 for pubertal males k = 0.55 for all other children

Height in cm Serum Creatinine in mg/dL

Schwartz et al, Pediatrics 58:259,1976

Creatinine Standardization Recommendations by NKDEP Jaffe Cr assay Enzymatic Cr assay HPLC IDMS: Cr assays that are traceable to an

isotope dilution mass spectroscopy (IDMS) reference measurement procedure.

IDMS-traceable Cr << Jaffe Cr overestimate GFR by 20% to 40%

Clinical Chemistry 2006;52(1):5-18.

K=0.41

Calculating eGFR for children The older equations for eGFR in children and

infants will no longer be valid. Blood creatinine values will generally be lower for

methods that have been calibrated to be traceable to an IDMS reference-measurement procedure.

Not to estimate GFR for children when using an alkaline picrate (“Jaffe”) method with calibration traceable to IDMS.

The interim Schwartz equation (k=0.41) is intended only for enzymatic creatinine methods with calibration traceable to IDMS.

http://www.nkdep.nih.gov/labprofessionals/labgfr_children.htm

K=0.435

Not Cinulin?

Outlines Cr-based eGFR Questionnaire design

Which phenotype: High risk group CKD screen: which parameter(s) Global status of CKD prevention programs in children

Intervention: ACEi, ARB, OR? CVD in CKD Sub-committee OR interesting topic

林 : FGF-23, Ghrelin 邱 : Solitary kidney outcome/LN/Cystic kidney 田 : ADMA and SDMA

High Risk Group

遺傳性腎臟病家族史 ( 例如多囊腎 ) 單一腎臟 ( 任何原因 ) 雙側腎發育異常 (hypoplasia/dysplasia) 低出生體重兒於6 個月大以上超音波腎 /肝強度超過 1 嚴重腎水腫或阻塞性水腎 雙側重度膀胱輸尿管逆流 (grade IV-V) 尿道及膀胱頸之閉鎖及狹窄 神經性膀胱 除 steroid-sensitive nephrotic syndrome外之中重度蛋白尿 (≧1公

克 /天 ) 紅班性狼瘡 溶血性尿毒症候群 高血壓 (≧同年齡 95%之血壓 )

High Risk Groups (1)Hogg et al., Pediatrics, 2003

High Risk Groups

Hypodysplastic renal disease, VUR ItalKid

Hematuria, albuminuria, obesity, hypertension Haysom et al., AJKD, 2009 (Australia)

Low birth weight, nephron number, and kidney disease. Brenner et al., AJKD, 1994 ~7% LBW per year in Taiwan

DM type 1 &2 ~10/100,000 children in Taiwan

SCreening for Occult REnal Disease (SCORED)

Arch Intern Med. 2007;167(4):374-381

Ca, P?

Status of CKD Prevention Programs International Federation of Kidney Foundations

(IFKF) survey: 28 countries response (56%) Most countries are not focused on children

KEEP - Kidney Early Evaluation Program - USA KEY - Kidney Evaluation for You - Australia IKEAJ - International Kdiney Early Evaluation Program – Japan NICE guideline – UK ……..

Mass Urinary Screening: Taiwan, Japan, Korea…. Chronic Kidney Disease in Children (CKiD) study- USA Italkid Project- Italy

Smith et al., KI, 2008

Chronic Kidney Disease in Children (CKiD) study Glomerular filtration rate measurement and

estimation in chronic kidney disease. Pediatr Nephrol. 2007 Nov;22(11):1839-48.

Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study. Clin J Am Soc Nephrol. 2006 Sep;1(5):1006-

Validation of creatinine assays utilizing HPLC and IDMS traceable standards in sera of children. Pediatr Nephrol. 2009 Jan;24(1):113-9.

New Equations to Estimate GFR in Children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37.

Specific Aims

Identify risk factors for the progression of CKD

Characterize the impact of CKD on neurodevelopment, cognitive abilities, and behavior

Identify the prevalence and the evolution of CV disease risk factors in children with CKD

Examine the effects of declining GFR on growth

Recruit CKD stage 2&3

Prospective cohort study 540 children

CKiD Study Organization

Urea percentiles in children with chronic renal failure. Data from the ItalKid project. Pediatr Nephrol. 2003 Mar;18(3):261-5.

Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics. 2003 Apr;111(4 Pt 1):e382-7.

The probability of ESRD by age 20 years was 68% (eGFR<75=CKD stage 2B-5)

Severe vesicoureteral reflux and chronic renal failure: a condition peculiar to male gender? J Pediatr. 2004 May;144(5):677-81.

Italkid: Started in 1990

Italkid

Proteinuria as a predictor of disease progression in children with hypodysplastic nephropathy. Data from the Ital Kid Project. Pediatr Nephrol. 2004 Feb;19(2):172-7.

Long-term outcome of VUR associated chronic renal failure in children. Data from the ItalKid Project.

The probability of ESRD by age 20 years was 56% (eGFR<75=CKD stage 2B-5) J Urol. 2004 Jul;172(1):305-10.

Italkid

Prescription of drugs blocking the renin-angiotensin system in Italian children. Pediatr Nephrol. 2007 Jan;22(1):144-8.

No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy--report from the ItalKid. Nephrol Dial Transplant. 2007 Sep;22(9):2525-

30.

Prevention of CKD in Children Primary

Reduce exposure to factors that cause renal disease Reduce antenatal exposure to infections, drugs Prevention of inheritable renal disease by genetic counseling Prevention of obesity, dyslipidemia Early detection/management of hypertension and DM

Secondary Appropriate measures at various stages of CKD

Tertiary Reduction of complications impairments or

disabilities Requiring RRT

Vijayakumar et al., Indian J Nephrol, 2007

三段五級的預防工作

針對疾病自然史，就預防醫學而言，採三段五級預防工作，以中止或遲緩疾病自然使得醫療保健措施。

促進健康 特殊保護

早期診斷與適當治療

限制殘障 復健

初段預防

次段預防

末段預防

疾病自然史與三段五級預防工作

Outlines Cr-based eGFR Questionnaire design

Which phenotype: High risk group CKD screen: which parameter(s) Global status of CKD prevention programs in children

Intervention: ACEi, ARB, OR? CVD in CKD Sub-committee OR interesting topic

林 : FGF-23, Ghrelin 邱 : Solitary kidney outcome/LN/Cystic kidney 田 : ADMA and SDMA

Final Common Pathway for Progression of Chronic Kidney Disease Brenner BM, JCI, 2002

Prevention of CKD progression by ACEI/ARB

www.eguidelines.co.uk/.../clark_angiotensin.gif

Surrogate end-point of CKD Progression: Proteinuria &Hypertension

Risk factors

Hypertension

Proteinuria

CKD progression

Risk factors

CKD

Hypertension

Proteinuria

CKD progression

End-point: Hypertension

The use of ACEI/ARB in children with diabetes and microalbuminuria or proteinuric renal disease. The Fourth Report on the Diagnosis,

Evaluation, and Treatment of High Blood Pressure in Children and Adolescents , Pediatrics, 2004

ACEI/ARB for Hypertension in Children The Fourth Report on the Diagnosis, Evaluation, and Treatment of

High Blood Pressure in Children and Adolescents , Pediatrics, 2004

Matchar DB et al. Ann Intern Med 2008; 148:16-29.

Rate of cough as a side effect of ACE inhibitor and ARB therapy

Research settingACE inhibitor (%)

ARB (%)

Randomized controlled trials 9.9 3.2

Cohort-based studies 1.7 0.6

ARB=angiotensin receptor blocker

Kunz R et al. Ann Intern Med 2008; 148:30-48.

Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals

Randomized therapy Over 1-4 mo Over 5-12 mo

ARBs vs placebo 0.57 (0.47–0.68) 0.66 (0.63–0.69)

ARBs vs ACE-I 0.99 (0.92–1.05) 1.08 (0.96–1.22)

ARBs vs CCBs 0.69 (0.62–0.77) 0.62 (0.55–0.70)

ARB+ACE-I vs ARBs 0.76 (0.68–0.85) 0.75 (0.61–0.92)

ARB+ACE-I vs ACE-I 0.78 (0.72–0.84) 0.82 (0.67–1.01)

ACE-I=angiotensin-converting-enzyme inhibitorARB=angiotensin-receptor blockerCCB=calcium-channel blocker*Ratio of means=ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE-I) relative to the control group (placebo or single-drug comparator), with 95% CI

Complete blockade of RAAS: Experiences from adult CKD (1) Anti-proteinuria

ACEI = ARB ACEI+ARB > monotherapy Kunz et al., AIN, 2008

Aldosterone blocker + ACEI +/- ARB> monotherapy

Renin inhibitor + ARB > ARB Parving et al., NEJM, 2008

Triple therapy >Dual Tylicky et al., AJKD, 2008

Anti-hypertension Dual > mono Doulton et al., Hypertension, 2005

Complete blockade of RAAS: Experiences from adult CKD (2)

CKD progression ACEI OR ARB

Casas et al., Lancet, 2005

ACEI+ARB> mono COOPERATE, Lancet,

2003 MRA+ACEI OR

ARB>mono ? Renin inhibitor +ACEI

OR ARB>mono ? ALTITUDE, NDT, 2009

Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study

*primary composite end point of a doubling of the serum Cr, ESRD, or death

Benazepril 10 mg/d to 20, 30, and 40 mg/d.

Losartan 50 to 100, 150, and 200 mg/d

Hou FF, JASN, 2007

Safety of Combination therapy The combination of ACE-inhibitor and ARB therapy

in patients with chronic proteinuric renal disease is safe, without clinically meaningful changes in serum potassium levels or glomerular filtration rates. Mcakinnon et al., AJKD, 2006

ONTARGET, NEJM, 2008 Dual therapy (ACEI+ARB) increased risk of hypotensive

symptoms, syncope, and renal dysfunction. Adding MRBs to ACEI and/or ARB therapy yields

significant decreases in proteinuria without adverse effects of hyperkalemia and impaired renal function Bomback et al., AJKD, 2008

ACEi/ARB efficacy on the anti-proteinuria in childhood CKD

HUS

VUR

SRNS

Alport

Cysti-nosis

IDDM

IgAN

Proteinuric KD

Captopril Y Y

Enalapril Y Y Y Y Y

Benazepril

Y

Fosinopril Y

Lisinopril Y

Ramipril Y

Losartan Y

Irbesartan Y Y

Candesartan

Y

REFERENCES1: Van Dyck M, Proesmans W. Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome. Pediatr Nephrol. 2004 Jun;19(6):688-90. 2: Lama G, Salsano ME, Pedulla' M, Grassia C, Ruocco G. Angiotensin converting enzyme inhibitors and reflux nephropathy: 2-year follow-up. Pediatr Nephrol. 1997 Dec;11(6):714-8.3: Prasher PK, Varma PP, Baliga KV. Efficacy of enalapril in the treatment of steroid resistant idiopathic nephrotic syndrome. J Assoc Physicians India. 1999 Feb;47(2):180-2.4: Proesmans W, Van Dyck M. Enalapril in children with Alport syndrome.Pediatr Nephrol. 2004 Mar;19(3):271-5.5: Levtchenko E, Blom H, Wilmer M, van den Heuvel L, Monnens L. ACE inhibitorenalapril diminishes albuminuria in patients with cystinosis. Clin Nephrol. 2003 Dec;60(6):386-9.6: Yüksel H, Darcan S, Kabasakal C, Cura A, Mir S, Mavi E. Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes. Pediatr Nephrol. 1998 Oct;12(8):648-50.7: Coppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, Stone R, Kirschstein M, Linné T. IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol. 2007 Jun;18(6):1880-8.8: Hodson EM, Habashy D, Craig JC. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003594.9: Nakanishi K, Iijima K, Ishikura K, Hataya H, Awazu M, Sako M, Honda M, Yoshikawa N; for the Japanese Pediatric IgA Nephropathy Treatment Study Group. Efficacy and safety of lisinopril for mild childhood IgA nephropathy: a pilot study. Pediatr Nephrol. 2009 Apr;24(4):845-849.10: Seeman T, Dusek J, Vondrák K, Flögelová H, Geier P, Janda J. Ramipril in the treatment of hypertension and proteinuria in children with chronic kidney diseases.Am J Hypertens. 2004 May;17(5 Pt 1):415-20.11: Wühl E, Mehls O, Schaefer F; ESCAPE Trial Group. Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure.Kidney Int. 2004 Aug;66(2):768-76.12: Ellis D, Moritz ML, Vats A, Janosky JE. Antihypertensive and renoprotective efficacy and safety of losartan. A long-term study in children with renal disorders.Am J Hypertens. 2004 Oct;17(10):928-35.13: Ellis D, Vats A, Moritz ML, Reitz S, Grosso MJ, Janosky JE. Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria. J Pediatr. 2003 Jul;143(1):89-97. 14: Pozzi C, Del Vecchio L, Casartelli D, Pozzoni P, Andrulli S, Amore A, Peruzzi L, Coppo R, Locatelli F; Adulto e Bambino Study Group; Immunopatologia Renale Study Group of the Italian Society of Nephrology. ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study.J Nephrol. 2006 Jul-Aug;19(4):508-14. 15. Franscini LM, Von Vigier RO, Pfister R, Casaulta-Aebischer C, Fossali E,Bianchetti MG. Effectiveness and safety of the angiotensin II antagonist irbesartan in children with chronic kidney diseases.Am J Hypertens. 2002 Dec;15(12):1057-63.16: Simonetti GD, von Vigier RO, Konrad M, Rizzi M, Fossali E, Bianchetti MG.Candesartan cilexetil in children with hypertension or proteinuria: preliminary data. Pediatr Nephrol. 2006 Oct;21(10):1480-2.

Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria Mean creatinine clearance remained

unchanged during the time of follow-up.

Losartan

√

J Pediatr, 2003

ESCAPE Trial Group. Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure

The incidence of rapid rises in serum creatinine and progression to end-stage CRF during treatment did not differ from the pretreatment observation period.

Ramipril

KI, 2004

ESCAPE Trial

Thirty-three pediatric nephrology units in 13 European countries collaborated in a prospective, investigator initiated clinical trial to study the Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in PEdiatric Patients (ESCAPE trial).

ESCAPE Trial Group

Ultradian but not circadian blood pressure rhythms correlate with renal dysfunction in children with chronic renal failure. J Am Soc Nephrol. 2005 Mar;16(3):746-54.

Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. Kidney Int. 2004 Aug;66(2):768-76.

Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure. Pediatr Res. 2004 Mar;55(3):492-7

ESCAPE Trial Group

Urinary ET-1, TGF- beta1 and VEGF165 in paediatric chronic kidney diseases: results of the ESCAPE trial. Nephrol Dial Transplant. 2007 Dec;22(12):3487-

94. Reduced systolic myocardial function in

children with chronic renal insufficiency. J Am Soc Nephrol. 2007 Feb;18(2):593-8.

Left ventricular geometry in children with mild to moderate chronic renal insufficiency. J Am Soc Nephrol. 2006 Jan;17(1):218-26.

IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria

Primary end point of 30% Reduction of baseline CCr

Benazepril

JASN, 2007

No clear evidence of ACEi efficacy on the progression of CKD in children with hypodysplastic nephropathyItalKid, NDT, 2007

ACEI/ARB Combined therapy in Childhood CKD: limited evidence Tanaka et al., (2004) Combined therapy of enalapril and

losartan attenuates histologic progression in immunoglobulin A nephropathy. Pediatr Int 46:576–579

Yang et al., (2005) Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy. Clin Nephrol 64:35–40

Lubrano et al., (2006) Renal and cardiovascular effects of angiotensin-converting enzyme inhibitor plus angiotensin II receptor antagonist therapy in children with proteinuria. Pediatrics 118:e833–e838

Litwin et al., (2006) Add-on therapy with angiotensin II receptor 1 blocker in children with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors. Pediatr Nephrol 21:1716–1722

Renoprotection: one or many therapies?Hebert et al., KI, 2001

ACEI/ARB: which one we have Captopirl Enalapril Fosinopril (Monopril)

Cadesartan Irbesartan Losartan Telmisartan Valsartan

Decision ?

End point Dual or single ACEI or ARB Which ACEI (OR ARB) Dose and duration Which phenotype of CKD

Proteinuria vs. non-proteinuria CAKUT vs. GN

Outlines Cr-based eGFR Questionnaire design

Which phenotype: High risk group CKD screen: which parameter(s) Global status of CKD prevention programs in children

Intervention: ACEi, ARB, OR? CVD in CKD Sub-committee OR interesting topic

林 : FGF-23, Ghrelin 邱 : Solitary kidney outcome/LN/Cystic kidney 田 : ADMA and SDMA

Can we escape from CV event? ABPM FMD

CKiD Echo, ABPM, Carotid IMT, Lipid profile,

Clinical BP

Prevalence of complications in children with CKD CKD Stage I 57% II 29% III 10.4% IV+V 4.1%

Proteinuria

Wang et al., KI, 2006

ABPM: Oscar2

~NT $150,000

Impaired flow-mediated vasodilation, carotid artery intima-media thickening, and elevated endothelial plasma markers in obese children

Variable Obese (n = 32) Controls (n = 20) Pa

FMD, % 5.81 ± 3.42 9.29 ± 1.87 <.001

IMT segments, mm

    Common carotid artery mean 0.49 ± 0.08 0.39 ± 0.05 <.001

    Common carotid artery max 0.54 ± 0.08 0.43 ± 0.06 <.001

    Carotid bifurcation mean 0.53 ± 0.09 0.43 ± 0.07 <.001

    Carotid bifurcation max 0.59 ± 0.10 0.49 ± 0.08 .001

vWF:Ag, % 120 ± 40.3 110 ± 62.0 .491

E-selectin, ng/mL 41.1 ± 17.2 31.3 ± 9.89 .014

Thrombomodulin, ng/mL 35.7 ± 9.85 29.9 ± 7.14 .029

Meyer et al, Pediatrics 2006;

117:1560-7.

Diagnostic Tests for endothelial dysfunction

Invasive assessment Coronary angiography with Doppler flow

measurement, along with infusions of endothelium-dependent vasodilators (Ach).

Noninvasive Flow-mediated dilatation (FMD) of brachial

artery Reactive hyperemia Acetylcholine Nitroglycerine

Corretti et al, J Am Coll Cardiol. 2002

Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial ArteryA Report of the International Brachial Artery Reactivity Task Force

7 to 12 MHz linear array transducers

FMD

ALOKA:Prosoundα7+eTRACKING Mode

~NT $3,000,000

Biomarkers of ED

Von Willebrand factor Tissue plasminogen activator Plasminogen activator inhibitor Thrombomodulin Monocyte chemoattractant protein-1 (MCP-1) E-selectin Vascular cell adhesion molecule-1 (VCAM-1) ADMA CRP Uric acid Circulating endothelial progenitor cells ….

Tain YL, 2008

Zakrzewicz and Eickelberg BMC Pulmonary Medicine 2009 9:5  

Why is ADMA at all interesting?

ADMA is a risk factor for cardiovascular disease and endothelial dysfunction. Kidney is the major organ for metabolism of ADMA and synthesis of L-arginine.

Boger RH, 2004

Baylis C (2006) Arginine, arginine analogs and nitric oxide production in chronic kidney diseaseNat Clin Pract Neprol 2: 209–220 doi:10.1038/ncpneph0143

Figure 6 Kaplan–Meier plot of cardiovascular event rate in patients with end-stage renal disease

ADMA vs. kidney diseases

ADMA and lipid peroxidation products in early autosomal dominant polycystic kidney disease. Wilcox et al., Am J Kidney Dis. 2008

Raised plasma levels of ADMA are associated with cardiovascular events, disease activity, and organ damage in patients with SLE Bultink et al., Ann Rheum Dis. 2005

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. AJP Renal Physiol, 2008

ADMA and Progression of CKD

MMKD Study Group, JASN, 2005

Methylarginines in children with early stage of CKD

CKD II/III Sibling controls

eGFR 60.3±5,1* 153.2±24

N 28 10

SBP load 0.47±0.3* 0.1±0.1

DBP load 0.3±0.2* 0.1±0.1

ADMA 1.1±0.3* 0.8±0.2

SDMA 2.1±1.1* 0.7±0.2

L-arginine/ADMA

62.4±27.7* 86.8±30.6

Brooks et al., PN, 2008

*p<0.05 vs. controls

Example

For ADMA & SDMA Plasma (heparin) 200μl Blood sampling at M0, M12, and M24

Correlation: ADMA vs. ABPM ADMA vs. FMD SDMA vs. eGFR ….

Other markers of CKD progression? MMKD study group

ADMA Urinary exosome database

DDAH1 DDAH2

Mild-to-moderate-kidney-disease (MMKD) study group Since1997 Eight nephrology departments in

Germany (Göttingen, Greifswald, Heidelberg, Homburg/Saar, and Munich), Austria (Feldkirch, Innsbruck), and South Tyrol (Bozen)

Caucasian patients ages 19 to 65 yr Exclusion criteria: sCr >6 mg/dl

Risk Factors of CKD Progression: MMKD Study Group NGAL, urine and serum; CJASN, 2009

Pro-A-type natriuretic peptide/pro-adrenomedullin; KI, 2009

Fibroblast growth factor 23 (FGF23); JASN, 2007

Adiponectin; KI, 2007

ADMA; JASN, 2005

Apolipoprotein A-IV; JASN, 2002

Uric Acid?; Exp Gerontol, 2008; Lipoprotein?; JASN,

2000; Homocysteine? ; Atherosclerosis, 2001

Current Database Size: 1160 proteins

Purposes

(1)Intervention ： which, when, and why？ (2)CV measurement (3)Efficiency of ACEI/ARB in CKD

progression (4)Cerebral accident in ESRD children:

marker (5) Primary prevention:

1. Identify high risk group 2. how to maintain GFR

(6) Early detection: how and why? (7) Steering committee?