childhood ckd prevention program in taiwan: what are we going to do?
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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 - PowerPoint PPT PresentationTRANSCRIPT
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?