Sympathetic nervous system and NO in CKD. Francesca Mallamaci

Transcription

1 Sympathetic nervous system and NO in CKD Francesca Mallamaci

2 Go AS, New Engl J Med. 351: 1296; individuals, follow up 2.8 yea risk factors peculiar to CKD Old age Relative Risk (fully independent) REFERENCE Anemia Phosphate emerging risk factors Hypertriglycerid. High LDL Cholest. fasting hyperglycemia GFR ml/min 12 6 REFERENCE 6< CKD 3a CKD3b CKD4 CKD5 Inflammation sympathetic activity

3 Sympathetic fibers, peroneal nerve High sympathetic activity

4 Nitroprussiate, a vasorelaxant elicits a potent sympathetic activation Sympathetic activation inhibits NO Synthase Baroreceptors Norepinephrine, a vasoconstrictor elicits a potent sympathetic inhbition Endothelium-dependent vasoconstriction Sympathetic activity Bursts/min Nitroprussiate Healthy subjects Norepinephrine Sympathetic 8 activation 9 1 interferes 11 with 12 endothelial 13 function 14 by inhibiting NO syntase MAP and promoting (mmhg) vasoconstrition.

5 Sympathetic activity in pre-dialysis CKD and in stage 5D-CKD patients Sympathetic activity and Left ventricular and Mass. Interplay of Sympathetic activity with a biomarker of endothelial dysfunction, asymmetric dimethylarginine (ADMA) in LVH and CV death in pre-dialysis CKD and stage 5D CKD patients. Prognostic and therapeutic relevance of high sympathetic activity

6 Ligtenberg 1999;34:1321 Control subjects Bursts/min 6 Patients with CKD Clonidine test, 3 µg orally MBP (mmhg) measured over 3 hours CKD stages 3-4 Creatinine clearance 15-6 ml/min Healthy subjects CKD patients

7 Converse RL 1992;327:1912 Ligtenberg 1999;34:1321 Control subjects Bursts/min 6 Patients with CKD HD patients HD patients Post Nephrectomy MAP mmhg 4 12 CKD stages 3-4 Creatinine clearance 15-6 ml/min Sympathetic activity is mediated by the kidney and is reversible after nephrectomy in dialysis patients.

8 baroreceptors To have a sensible estimate of differences in sympathetic activity we should make comparisons at similar BP levels. Sympathetic activity Bursts/min Healthy subjects Patients with CKD MAP (mmhg) The increase in sympathetic activity in CKD is even more marked than it appears in face to face comparisons with healthy subjects.

9 Norepinephrine pg/ml Renalase (a renal monoaminoxidase) Ligtenberg 1999;34:1321 Control subjects Patients with CKD pmol/l Neuropeptide Y Zoccali C, Mallamaci F, unpublished Control subjects Patients with CKD

10 Sympathetic activity in pre-dialysis CKD and in stage 5D-CKD patients Sympathetic activity and Left ventricular and Mass. Interplay of Sympathetic activity with a biomarker of endothelial dysfunction, asymmetric dimethylarginine (ADMA) in LVH and in CV death in pre-dialysis CKD and stage 5D CKD patients. Prognostic and therapeutic relevance of high sympathetic activity

11 Left Ventricular Mass mg 11 Norepinephrine 6 µg kg-1 h-1, subcutaneous pump days Norepinefrine in rats increases LV mass and this finding implicates Kaddoura S. et al., Circulation. 1996;93: that Norepinefrine is crucial for cellular growth in animals.

12 concentric LVH Siddiqi L (21) 25: CKD pts MRI LV wall thickness (mm) The muscular component of LVH r= muscle Sympathetic activity (impulses /min)

13 % Prevalence of concentric LVH in dialysis patients 5 4 Independent of classical and other risk factors 3 2 1rst tertile 2 nd tertile th rd tertile Nor epinephrine Zoccali C. Mallamaci F et al., Hypertension 22; 4:41

14 Grassi G, Zoccali C et al. Clin J Am Soc Nephrol 211 Stage 2-4 CKD patients Endothelium-dependent CH 3 vasoconstriction HN ADMA (lg 1 µmol/l).2 C N CH 3 NH CH 2 CH2.1 r=.32, P=.25 NO Synthase CH 2 CH H 2 N C=O. ADMA OH The association between high sympathetic activity and ADMA MSNA (lg 1 bursts/min) could imply a causal association that develops during the evolution of renal diseases

15 Grassi G, Zoccali C et al. Clin J Am Soc Nephrol 6: , 211 Stage 2-4 CKD patients LV mass to volume ratio (g/ml) 2.2 r=.36, P=.1 r=.31, P= MSNA (lg 1 bursts/min) Statistical adjustment for MSNA ADMA (lg 1 µmol/l) Statistical adjustment for ADMA

16 Grassi G, Zoccali C et al. Submitted 211 Stage 2-4 CKD patients Trigger Mediator Mediators lost predictive power in statistical models which included the trigger Is statistical modelling supported by experimental evidence?

17 Liao Y et al., 24;11: HN HN NH N CH 3 C NH NH CH CH 2 2 CH2 CH2 LNMA OH OH L-Arginine Experimental evidence in the rat supports statistical modeling in CKD patients +55% Ao banding Sham Ao banding + 1 blockade.79 LNMA % LNMA ( another inhibitor) CH 2 blocks NO synthase and abolishes the effect of betablockade indicating CH 2 CH CH enos 2 that the sympathetic system NO and the NO system share a H C=O 2 N C=O common pathway

18 Sympathetic activity in pre-dialysis CKD and in stage 5D-CKD patients Sympathetic activity and Left ventricular and Mass. Interplay of Sympathetic activity with a biomarker of endothelial dysfunction, asymmetric dimethylarginine in LVH and in CV death in predialysis CKD and stage 5D CKD patients. Prognostic relevance of high sympathetic activity

19 LVH is a strong predictor of CV events.cross sectional data need to be substantiated by studies looking at clinical outcomes Cumulative mortality (%) CKD stages 3-4 Sympathetic activity <75th Independent risk of BP and (%) other risk factors Zoccali C, Mallamaci F et al., Cumulative CV events Zoccali C, Mallamaci 14: , F et al 23 fatal and non-fatal 22;15:1354 (redrawn) 6 CV Death (%) Nor-Epi > median value III tertile Neuropeptide Y 2 Sympathetic activity >75th years Lars Penne E., et l., J Nephrol. 29;22: II tertile Nor-Epi I tertile < median value months Time (months)

20 Sympathetic activity and ADMA are in the same pathway conducing to LVH in CKD patients

21 Summary and Conclusions When renal function declines risk factors other than classical risk factors play an increasingly important role, particularly sympathetic activity. There is consistent evidence that high sympathetic activity is implicated in LVH and in the high CV risk of CKD and ESRD patients Statistical modelling suggests that high sympathetic activity and high ADMA are in the same pathway conducive to LVH in predialysis CKD patients.

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