Prof. Dr. Berthold Hocher Institut für Ernährungswissenschaften Universität Potsdam Homepage:

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1 Prof. Dr. Berthold Hocher Institut für Ernährungswissenschaften Universität Potsdam Homepage:

2 Aufgabenvielfalt der Niere Knochenhärte Stoffwechsel- Endprodukte Kalzium- Haushalt Vitamin D Aktivierung Blutbildung Ausscheidung von Harnstoff, Kreatinin, Phosphat etc. Erythropoetin- Bildung Wasserhaushalt Kaliumhaushalt Herztätigkeit Rückgewinnung Bikarbonat Kochsalzausscheidung Regulation ph-wert Blutdruck

3 Was ist eigentlich Dialyse?

4 Maschinelle Nierenersatztherapie - Die Dialyse - Hämodialyse Peritonealdialyse

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7 Hämodialyse Blut Dialysat Optimierung der Entgiftung durch das Gegenstromprinzip!

8 Die Peritonealdialyse

9 Prinzip der Peritonealdialyse - Dreiporenmodell - transzelluläre Pore r < 0.5nm kleine Pore r = 4-6 nm große Pore r > 20 nm

10 Dacron - Cuffs PD-Kath. Symphyse Harnblase Prostata Douglas Rektum Lage des Peritonealdialysekatheters

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12 Annual mortality (%) Cardiovascular Mortality in the General Population and in Dialysis Patients 100 General population Male Female Black White Dialysis population Male Female Black White Age (years) Foley et al. Am J Kidney Dis 1998

13 Todesursachen bei Dialysepatienten

14 Deaths/100 patient-years Änderung der Ein-Jahres-Mortalität bei Dialysepatienten 35 Dialysis All ESRD Cadaveric Transplant Living Related Transplant annual report of the US Renal Data System Year of ESRD Incidence or Transplantation

15 Die Millionen-Dollar Frage in der Nephrologie Warum ist das absolute Risiko eines 30-ig jährigen Dialysepatienten an Herzkreislauferkrankungen zu sterben.. gleich dem Risiko eines 85-jährigen Nicht-Dialysepatienten? Foley et al. Am J Kidney Dis 1998

16 Ursachen der Herzkreislauferkrankungen bei Dialysepatienten ein kompliziertes Puzzle Anämie Sympathikusaktivierung Insulinresistenz LVH Rauchen Oxidativer Stress Entzündung AGEs Gefäßverkalkung Endotheliale Dysfunktion Malnutrition Fettstoffwechselstörung Unbekannte Risikofaktoren

17 Pro-inflammatorische Cytokine sind bei Patienten mit terminalem Nierenversagen erhöht. Kimmel P et al. Kidney Int 1998

18 Grunderkrankung Genetische und Immunologische Faktorenbb Gefäß- Verkalkung Volume overload heart failure Urämietoxine Inflammation bei terminalem Nierenversagen Dialyse-bedingte Faktoren (Dialysemembranen, Eisen-iv- Therapie) Nebenerkrankungen Infektionen Oxidativer Stress

19 C-reaktives Protein ist ein starker Mortalitätsprediktor bei Dialysepatienten Stenvinkel P, Wanner C. and Zoccali C., Kidney Int 2002

20 Ursachen der Herzkreislauferkrankungen bei Dialysepatienten ein kompliziertes Puzzle Anämie Sympathikusaktivierung Insulinresistenz LVH Rauchen Oxidativer Stress Entzündung AGEs Gefäßverkalkung Endotheliale Dysfunktion Malnutrition Fettstoffwechselstörung Unbekannte Risikofaktoren

21 Generation of reactive oxygen and reactive nitrogen species. From Okamura et al. with permission. Sem Dialysis; 22, No 6, 2009 pp

22 Protein thiols are a major source of antioxidant defence and participate in redox signaling. (A) Cysteine residues are perticularly susceptible to oxidative modification and can lead to inactivation of enzymes or binding sites. Glutathione and other thiols can reversibly oxidize cysteine residues regulating signal transduction and cellular metabolism. (B) Peroxiredoxin (Prx) and other thioredoxin molecules can also reverse mild oxidative modifications of proteins. From Okamura et al. with permission. Himmelfarb, Sem Dialysis; Vol 22, No 6 (November December) 2009 pp

23 Biomarkers of oxidative stress Proteins 3-Nitrotyrosine 3-Chlorotyrosine Dityrosine Advanced glycated endproducts (AGEs) Carboxymethyllysine Advanced oxidation protein products Protein thiols Lipids HODE 4-Hydroxynonaneal F2-isoprostane Malondialdehyde Oxidazed LDL HOCL-modified LDL Nucleic acids DNA oxidation 8-oxodG RNA oxidation Himmelfarb, Sem Dialysis; Vol 22, No 6 (November December) 2009 pp

24 Comparison of inflammatory and oxidative stress biomarkers in patients with chronic kidney disease and healthy subjects Biomarker Helthy subjects median (range) CKD subjects median (range) p CRP (mg/l) 1,8 (0-28,6) 3,9 (0,6-28,4) 0,02 IL-6 (pg/ml) 2,1 (1,5-12,5) 6,4 (1,5-95,4) 0,001 Thiols (um) 415 ( ) 303 ( ) <0,001 Carbonyls (mmol/mg protein) 0,029 (0-0,154) 0,061 (0,020-0,134) <0,001 F2-isoprostanes (ng/ml) 0,036 (0,019-0,179) 0,046 (0,025-0,156) <0,001 Source: Oberg BP et al. with CKD, permission chronic kidney disease; CRP, C-reactive protein; IL-6, interleukin-6 Himmelfarb, Sem Dialysis; Vol 22, No 6 (November December) 2009 pp

25 McCullough PA, Li S, Jurkovitz CT, Stevens L, Collins AJ, Chen SC, Norris KC, McFarlane S, Johnson B, Shlipak MG, et al.: Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality. Am Heart J 156: , 2008 Handelman GJ, Walter MF, Adhikarla R, Gross J, Dallal GE, Levin NW, Blumberg JB: Elevated plasma F2-isoprostanes in patients on long-term hemodialysis. Kidney Int 59: , 2001

26 Does Dialysis Modality Influence the Oxidative Stress of Uremic Patients? Capusa C. et al. Kidney Blood Press Res 2012;35:

27 Ursachen der Herzkreislauferkrankungen bei Dialysepatienten ein kompliziertes Puzzle Anämie Sympathikusaktivierung Insulinresistenz LVH Rauchen Oxidativer Stress Entzündung AGEs Gefäßverkalkung Endotheliale Dysfunktion Malnutrition Fettstoffwechselstörung Unbekannte Risikofaktoren

28 1980 Furchgott, Ignarro & Murad discover Nitric-Oxide s role in CV regulation. Nobel Prize awarded in Ganz group assess intracoronary endothelial function 1992 Celermajer and Deanfield describe technique of ultrasonic assessment of Flow Mediated Dilation 1992 Vallance et al. Published in the Lancet ADMA as a biomarler of endothelial dysdunction Confidential 28

29 Dilation Growth Inhibition Anti-thrombotic Anti-inflammatory Anti-oxidant Constriction Growth Promotion Pro-thrombotic Pro-inflammatory Pro-oxidant Age Family history Smoking Hypertension Low HDL-C High LDL-C Diabetes Mellitus New Risk factors

30 Warum endotheliale Dysfunktion messen? Schachinger, et al Circulation 101: 1899

31 Asymmetrisches Dimethyl-Aarginine (ADMA) hemmt NO Synthasen enos NO ADMA

32 S-adenosylmethionine (methyl donor) -CH 3 S-adenosylhomocysteine α-ketoagt2acids (minor amount) protein synthesis PRMTs (post-translational modifications) methylated protein proteinase (turn over) ADMA DDAH DDAH (more than 90%) citrulline + amines urinary elimination Synthese und Metabolismus von Asymmetrischen Dimethyl-Aarginine (ADMA) Abkürzungen: AGT2 : Alanine-Glyoxylate Transaminase 2; DDAH : Dimethylarginine Dimethylaminohydrolase; PRMT : Protein Methyltransferase

33 ADMA ist ein kompetitiver Inhibitor aller NO-Synthasen L-Arginine Konzentrationen regulieren ebenfalls die NO-Synthase Aktivität SDMA ADMA NO-synthases Endothelzelle L-arginine NO L-citrulline O 2 - Sauerstoffradikale hemmen insbesondere die Aktivität der löslichen Guanylat-Cyklase (sgc) NO Löskiche Guanylyl-Cyclase cgmp Glatte Gefäßmuskelzelle

34 Plasma ADMA concentrations in renal patients who reached a progression end point (n = 65) and in patients who did not progress (n = 112) during follow-up. Mean plasma ADMA concentration was significantly higher (P < 0.01) in patients who doubled their serum creatinine and/or reached terminal renal failure necessitating renal replacement therapy. Data are presented as 95% confidence intervals of the mean. Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study Danilo Fliser et al. J Am Soc Nephrol 16: , 2005

35 Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes Adjusted rate of changes in egfr (ml min -1 1,73 m -2 year -1 ) Below the median (N=99) Above the median (N=100) Ko Hanai et al. Nephrol Dial Transplant (2009) 24:

36 Effects of DDAH overexpression on BP and renal function in rats that underwent five-sixths subtotal nephrectomy (Nx). Four weeks after the Nx, the rats were treated with Adv-DDAH, Adv-LZ, or hydralazine (Hyz). Then, systolic BP (SBP; A), mean BP (B), and creatinine clearance (Ccr; C) were measured at the indicated days after treatment. Data are means ± SEM. *P < 0.05 versus Adv-LZ; # P < 0.05 versus Hyz-treated rats. Dimethylarginine Dimethylaminohydrolase Prevents Progression of Renal Dysfunction by Inhibiting Loss of Peritubular Capillaries and Tubulointerstitial Fibrosis in a Rat Model of Chronic Kidney Disease Yuriko Matsumoto et al. J Am Soc Nephrol 18: , 2007

37 Ursachen der Herzkreislauferkrankungen bei Dialysepatienten ein kompliziertes Puzzle Anämie Sympathikusaktivierung Insulinresistenz LVH Rauchen Oxidativer Stress Entzündung AGEs Gefäßverkalkung Endotheliale Dysfunktion Malnutrition Fettstoffwechselstörung Unbekannte Risikofaktoren

38 VASKULÄRE MEDIAL VERKALKUNG (Mönckeberg s Media Sklerose, ElastoKalcinosis) Atherosclerotic Plaques Medial Calcification Webpath Price et al. ATVB 2000

39 Vascular Calcification Is Associated with Vascular Disease: Intima Media Adventitia Atherosclerosis Renal Failure Diabetes Mönckeberg s (Media sclerosis) Renal Failure Diabetes Diabetes Heart valves Atherosclerosis

40 Transformation von Gefäßmuskelzellen zu Knochen- Bildenden-Zellen PTH/Pi/Ca Uremic Toxins Contractile SMC SM-MHC SM22alpha SM-alpha actin Desmin Osteochondrogenic cell Cbfa1 OPN Osteocalcin Alk Phos Type III sodium-dependent phosphate co-transporters (Pit-1, Pit-2) Blockage of these transporters leads to phosphate induced SMC mineralization Pit-1 can be induced by BMP-2

41 Calcification Score Age (years) Goodman WG et al. N Engl J Med.2000

42 Mortalitäts-Wahrscheinlichkeit in Abhängigkeit der Verkalkung Calcification Score Duration of Follow-Up (Month) Blacher A, et al. Hypertension, 2001

43 Das Mortalitätsrisiko nimmt zu mit steigender Phosphat-Konzentration im Blut Serum Phosphorus Quintile(mmol/L) *P=0.03 **P< (N=6407) Block GA, et al. Am J Kidney Dis. 1998

44 Percentage of Patients Gefäßklappenverkalkung in Dialysepatienten und nierengesunden Kontrollpatienten 1 60% 50% 40% 30% 45% 52% Dialysis Normal 20% 10% 0% 10% Mitral Annulus 4% Aortic Annulus 1. Ribeiro S, et al. Nephrol Dial Transplant. 1998;13:

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46 Mechanismen der Gefäßverkalkung

47 Normal Vessels Don t Mineralize Active Inducers Active Inhibitors

48 Mineral Precipitation Ca 2+ PO 4 2- Cell Differentiation osteoblast-like cell matrix vesicles CaPO 4 mineral precipitation Active inhibitor Ca 2+ PO 4 2- osteoid (matrix) CaPO 4 mineral precipitation hydroxyapatite

49 Westenfeld et al. Trends Cardiovasc Med 2007 Fetuin, 2 Hermann-Schmid Glycoprotein (AHSG) Made in the liver Inhibitor of spontaneous hydroxyapatite (HA) formation from supersaturated calcium- and phosphate containing solutions Fetuin null mice have decreased serum HA inhibitory activity and increased soft tissue calcification (Jahnen-Dechent 1997, Schafer 2003) Normal mouse after phosphate challenge Fetuin-deficient mouse after phosphate challenge

50 Potential Origins of Osteoblast-like Cells in the Artery Wall Pericytes Mesenchymal stem cells Multipotent cells from the adventitia Resident cells in the media or intima Trans-differentiated SMC (Synthetic vs contractile phenotype)

51 Lernen von Mausmodellen der Gefäßverkalkung

52 MUTATION Genes Associated with Ectopic Calcification in Mice PHENOTYPE Matrix Gla Protein Fetuin Osteopontin Fibrillin Osteoprotegerin FGF23 PC-1/Enpp1/NPP1 (nucleotide pyrophosphatase) Ank (pyrophosphate transporter) ß-glucosidase (klotho) Carbonic Anhydrase II Smad6 Desmin Arterial, valve and cartilage calcification Decreased serum HA inhibitory activity Increased calcification of implanted bioprosthetic valves Vascular calcification, aortic stenosis Osteoporosis, vascular calcification Hyperphosphatemia, vascular calcification Vascular and articular cartilage calcification Articular cartilage calcification, soft tissue calcification Vascular calcification, rapid aging Calcification of small arteries Valve calcification Neonatal cardiomyopahty with calcificationariall

53 Percentage of Patients 25% 20% 15% 10% 5% Patients Above Normal CMAS (1990) mean = 2.00 DMMS (1993) mean = % Serum Phosphorus (mmol/l) Block GA, et al. Am J Kidney Dis. 1998;31:

54 Major Players of Vascular Calcification LOSS OF INHIBITION Pyrophosphate MGP OPN Fetuin/alpha2-HS glycoprotein Others DISTURBED Ca/Pi BALANCE Hyperphosphatemia Hypercalcemia Ca x Pi VASCULAR CALCIFICATION INDUCING FACTORS Pi Lipids Inflammatory cytokines Others INDUCTION OF BONE FORMATION Vascular bone and cartilage-like cells CIRCULATING NUCLEATIONAL COMPLEXES Matrix Vesicles Bisphosphonates OPG Apoptotic bodies Bone metabolism CELL DEATH Adapted from Speer & Giachelli, Cardiovasc Path 2004

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56 Ursachen der Herzkreislauferkrankungen bei Dialysepatienten ein kompliziertes Puzzle Anämie Sympathikusaktivierung Insulinresistenz LVH Rauchen Oxidativer Stress Entzündung AGEs Gefäßverkalkung Endotheliale Dysfunktion Malnutrition Fettstoffwechselstörung Unbekannte Risikofaktoren

57 Survival 1,0 Total cholesterol,9,8 > 176 mg/dl,7,6,5 P<0.001 < 176 mg/dl,4, Time (days) Hocher et al., JASN 2003

58 Survival 1,0 HDL cholesterol,9,8 < 38 mg/dl > 38 mg/dl,7,6,5 P<0.01,4, Time (days) Hocher et al., JASN 2003

59 Determination of cardiovascular endpoints in NIDDM Dialysis patients 4D-Study a randomized controlled trial with atorvastatin in dialyzed diabetic patients for biomarker resaerch PI: Prof. Dr. Christoph Wanner

60 Change from baseline (%) Change from baseline in lipid parameters (4 weeks) Placebo Atorvastatin TC LDL-C TG HDL-C Intent-to-treat population Week 4 median data

61 LDL cholesterol (mg/dl) LDL Cholesterol Lowering by Atorvastatin Placebo Atorvastatin Time of visit (years)

62 Cumulative 30 Incidense % Primary Outcome : cardiac death, nonfatal MI & stroke (fatal and non-fatal) Relative Risk Reduction 8 % (95 % CI: , P=0.37) Placebo Atorvastatin years Years from Randomization Median follow-up time of 4 years

63 GFR Cardiovascular risk reduction 100 Renoprotection 50 Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.

64 Ursachen der Herzkreislauferkrankungen bei Dialysepatienten ein kompliziertes Puzzle Anämie Sympathikusaktivierung Insulinresistenz LVH Rauchen Oxidativer Stress Entzündung AGEs Gefäßverkalkung Endotheliale Dysfunktion Malnutrition Fettstoffwechselstörung Unbekannte Risikofaktoren

65 Survival 1,0 Albumin,9 >3.665 g/dl,8,7,6,5 P< < g/dl,4, Time (days) Hocher et al., JASN 2003

66 上醫醫未病之病 中醫醫慾病之病 下醫醫已病之病 Der hervorragende Arzt erkennt die Erkrankung bevor sie ausbricht. Der normale Arzt erkennt und handelt Frühsymptome der Erkrankung Ein schlechter Arzt erkennt und startet die Behandlung, wenn der Patient manifest erkrankt ist Huang Di Nei Jing: Das erste Medizinlehrbuch in China, 770 BC

67 Danke für Ihre Aufmerksamkeit!