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Eberhard Ritz Heidelberg (Germany)

Cardiovascular problems on hemodialysis – current deficits and potential improvements. Eberhard Ritz Heidelberg (Germany). Epidemiological facts Underlying cardiac disease coronary heart disease cardiomyopathy New therapeutic targets - salt and salt mediated hormones

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Eberhard Ritz Heidelberg (Germany)

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  1. Cardiovascular problems on hemodialysis – current deficits and potential improvements Eberhard Ritz Heidelberg (Germany)

  2. Epidemiological facts Underlying cardiac disease • coronary heart disease • cardiomyopathy New therapeutic targets - salt and salt mediated hormones - sympathetic activity Neglected cardiovascular risks - depression - sleep apnea • disrupted biorhythm Attractive areas for future investigation - micro-RNA – arrhythmia/cardiac fibrosis • salt and marinobufagenin • sympathetic overactivity and beta blockers • oxydative stress

  3. Only observational evidence, but … Ultrafiltration rate andtreatment time – impact on mortality (DOPPS study) ultrafiltration rate treatment time odds ratio intradialytic hypotension 1.3 (p=0.045) Saran, Kidn.Internat.(2006) 69:1222

  4. Diureticuse (DOPPS study) rel.risk diureticvsnodiuretic all cause mortality 0.93 p=0.12 cardiac mortality 0.86 p<0.03 interdialytic weight gain > 5.7% 0.51 p<0.0001 hypotensive episodes 0.55 p<0.006 Bragg-Gresham, Am.J.Kidn.Dis.(2007) 49:426

  5. In the case of dialysis patients, a low normal level of ECV is maintained by the powerful tool of ultrafiltration, which if properly used along with moderate dietary sodium restriction and maintenance of natriuresis by diuretics, are the only proven method of controlling blood pressure in the hemodialysis population. Scribner, Trans. Am. Soc. Artif. Intern. Organs (1960) 6:114

  6. Epidemiological facts Underlying cardiac disease • coronary heart disease vs. • cardiomyopathy New therapeutic targets - salt and salt mediated hormones - sympathetic activity Neglected cardiovascular risks - depression - sleep apnea - disrupted biorhythm Attractive areas for future investigation - micro-RNA – arhythmia/cardiac fibrosis - salt and marinobufagenin - sympathetic overactivity and beta blockers - oxydative stress

  7. Causes of death in dialysis patients USRDS 4D study coronary heart disease 9 % 6 % other cardiac causes 35 % 33 % (sudden death 26%; heart failure 6%; other cardiac 3%) stroke 6 % 10 % non-cardiovascular 50 % 51% Wanner, New Engl J Med (2005) 353:238

  8. Higher mortality in CKD patients with diastolic (EF>45%) vs systolic heart failure(Digitalis Investigation Group Trial) systolicmalfunction diastolicmalfunction Ahmed, Am.J.Cardiol.(2007) 99: 393

  9. Myocardial changes in patients with renal failure normal morphology morphology of the myocardium of a patient with chronic renal failure

  10. Consequences of cardiac fibrosis on heart function • reduced LV compliance • arrhythmia fibrous tissue encircling cardiomyocytes has high electrical resistance local delay of the spreading front of action potential favours “reentry” type atrial and ventricular arrhythmias

  11. Cardiac fibrosis – most powerful predictor of survival in HD patients (endomyocardial biopsies) dilated cardiomyopathy idiopathic < 30% fibrosis area hemodialysis > 30% Aoki, Kidn.Internat.(2005) 67:333

  12. Cardiovascular risk in chronic kidney disease vascular disease cardiomyopathy • atherosclerosis (plaques) • arteriosclerosis (arterial stiffening) • inappropriate (LV) hypertrophy • interstitial fibrosis • microvessel disease (wall thickening of postcoronary arteries, capillary deficit) systolic dysfunction, diastolic dysfunction,electrical instability

  13. Epidemiological facts Underlying cardiac disease Novel pathogenetic pathways and therapeutic targets - salt and salt mediated hormones - (phosphate - vitamin D) - sympathetic activity Neglected cardiovascular risks - depression - sleep apnea - disrupted biorhythm Attractive areas for future investigation - micro-RNA – arhythmia/cardiac fibrosis - salt and marinobufagenin - sympathetic overactivity and beta blockers - oxydative stress

  14. Adverse effects of high salt • not only high blood pressure and hypervolemia, but also • blood pressure independent target organ damage (cardiovascular damage, progression of CKD) Frohlich, Hypertension (2007) 50:161 Matavelli, Journal of Physiology (Heart Circulation Physiol.) (2007) 292:h814 Sanders, Hypertension (2004)143:142

  15. Marinobufagenin cardiotonic steroid inhibitor of Na+ K+ ATP’ase - concentration correlated to cardiomyopathy in subtotally nephrectomised rats • cardiomyopathy reproduced by administration of marinobufagenin • cardiomyopathy prevented by neutralizing antibodies to marinobufagenin - deserves investigation in dialsysis patients Kennedy, Hypertension (2006) 47:488 Federova, American Journal Physiology (Renal Physiology) (2009) e-pub

  16. Correlationbetweenouabain (OLF) andleft ventricularabnormalities in dialysispatients Stella, J.Intern.Med.(2008) 263:274 Antagonist: Rostafuroxin ?

  17. Therapeutic targets and potential future approaches # reduction of salt intake (recommended by Scribner, but sadly forgotten today) Ritz, Blood Purification (2006) 24:63 # lowering of serum Na concentration (physicochemical activity) by adjusting dialysate Na concentration ? even minor increases of sodium concentration in serum or cerebrospinal fluid stimulate pressor-mechanisms and increases the release of cardiotonic steroids Huang, Hypertension (2007) 49:1315

  18. Newlydiagnosed essential hypertension : diastolicbloodpressureand plasmasodium in different quartilesofouabain Manunta, J.Hypertens.(2007) 26:914

  19. Plasma sodium concentration stiffens human vascular endothelium in vitro –in the presence of aldosterone,abrogated by eplerenone Oberleithner, Proc.Natl.Acad Sci USA (2007) 104:16281

  20. In presence of activated mineralocorticoid receptor NO production by endothelial cells loweredby sodium Wildling, Pflügers Arch. (2008)e-pub Sept 3rd

  21. Therapeutic targets and potential future approaches # reduction of salt intake Ritz, Blood Purification (2006) 24:63 # lowering of serum Na concentration by adjusting dialysate Na concentration ? Huang, Hypertension (2007) 49:1315 # ouabain antagonistRostafuroxin Ferrari, American Journal of Physiology (Regul. Integr. Comp. Physiol.) (2006) 290:r529 # aldosterone antagonist Spironolactone Bomback, Nat.Clin.Pract.Nephrol.(2009) 5:74

  22. Lowering of blood pressure by 50 mg Spironolactone in anurichemodialysis patients – no change in S-K+ Blood pressure : Spironolactone 142→131 mmHg Placebo 146→142 mmHg Gross, Am.J.Kidn.Dis (2005) 46:94

  23. Quartiles of plasma aldosterone concentrations within the normal range – progressively higher hazard ratio for CV death in 3153 coronary patients LURIC study Tomatschik, submitted

  24. Nature Clin.Practice Nephrol. (2009) 5: 74

  25. Sympathetic overactivity(well investigated, few practical consequences)documented in earliest stage of CKD Klein, J.Am.Soc.Nephrol. (2001) 12:2427pronounced in endstage kidney diseaseConverse, New Engl.J.Med. (1992) 327:1912caused by increased afferent signals emanating from the kidneyYe, Kidney International (1997) 51:722

  26. in dialysis patients: beta blockers 22.9% in USA, 29.5% worldwide (DOPPS I and II) Kidney International (2006) 70: 1905 like the prophet in the desert

  27. Phagocytic cells produce catecholamines amplifying inflammatory reactions Flierl, Nature (2007) 449:721 PLoS ONE (2009) 4:e4414 benefit beyond blood pressure and antiarrhythmic activity?

  28. LPS stimulates production of noradrenaline by macrophages and neutrophils Flierl, Nature (2007) 449:721

  29. Renalase –normally detected in blood or urine but absent if renal function is lost Li, Circulation (2008) 117:1277

  30. Epidemiological facts Underlying cardiac disease New therapeutic targets - salt and salt mediated hormones - phosphate - vitamin D - sympathetic activity Neglected cardiovascular risks - depression - sleep apnea - disrupted biorhythm Attractive areas for future investigation - micro-RNA – arhythmia/cardiac fibrosis - salt and marinobufagenin - sympathetic overactivity and beta blockers - oxydative stress

  31. Science’s greatest advances occur on the frontiers, at the interface between ignorance and knowledge, where the most profound questions are posed Science (2005) 309: 76

  32. Depression and adverse outcomes on HD(DOPPS study) prevalence of depression ~ 20 % adjusted rel.risk death hospitalisation physician diagnosed 1.23 1.11 patient diagnosed !! 1.48 1.15 (“so down in the dumps”) Lopes, Kidn.Intern. (2002) 62:199

  33. Depression and mortality DOPPS How often have you felt : “So down in the dump“ “Downhearted and blue“ Lopes, Kidn.Intern. (2002) 62:199

  34. Depressive syndromes –predict later appearance of cardiovascular disease risk higher by factor 1.7 – 4.5 (e.g. NHANES and INTERHEART studies) depression independent factor predicting higher cardiovascular mortality Ferketich, Arch Int Med (2000) 160:1261 Pratt Circulation (1996) 94:3123 Yusuf, Lancet (2004) 364:953 Frasure-Smith, Circulation (1995) 91:999 Glassman Am J Psychiatr (1998) 155:4

  35. Melancholie Albrecht Dürer 1471-1528

  36. In patients with cardiovascular disease 16 – 23 % major depression requiring intervention (DSM-III-R or DSM IV) Musselman, Arch Gen Psychiatr (1998) 55:580

  37. Depression and cardiovascular risklinked to: • autonomic imbalance • hypercorticism • insulin resistance • microinflammation • … Everson-Rose, Diabetes Care (2004) 27:2856

  38. Etanercept in psoriasis improved clinical outcomes and less depression (Double-blind placebo controlled randomized phase III trial) Türing, Lancet (2006) 307:29 Depression provoked by interferon-α therapy in patients with malignancy successfully treated with the antidepressant paroxetine Musselman, New Engl.J.Med. (2001) 344:961

  39. Less depression – the explanation ? for the positive effect of : # spirituality Finkelstein, Nephrol.Dial.Transpl.(2007) 22:2432 # and support provided by care givers Tong, Nephrol.Dial.Transplant. (2008) 23:3060 ► on quality of life of patients on renal replacement therapy?

  40. Sleep quality score correlated to mortality (DOPPS study) Elder, Nephrol.Dial.Transplant.(2008) 23:998

  41. Sleep apnea in HD patients in symptomatic HD patients(restless sleep, morning headaches, daytime sleepiness, personality changes) → frequency 73 % estimated overall prevalence in HD patients → 21 - 47% prevalence in general population → 2 - 4% Kimmel,Am.J.Med.(1989)86:308 Pressman, Kidn.Intern.(1993) 43:1134 Young, New Engl.J.med.(1993) 328:1230

  42. Sleep-apnea –reduced survival Yaggi, New Engl J Med (2005) 353:2034

  43. Survival advantage with treatment ? multicenter open label randomized controlled trial 144 smokers oxygen vs support ventilation adj.hazard ratio 0.63 (0.4-0.99) p=0.045 McEvoy, Thorax, e-pub Feb12th

  44. Nocturnal episodes of arterial oxygen desaturationpredict cumulative CV events and survival in HD patients cumulative survival average nocturnal oxygen saturation SaO2 month Zoccali,J.Am.Soc.Nephrol.(2002)13:729

  45. Daily nighttime dialysis –impact on neurological and cardiovascular functions • Chan C.T.,Harvey P.J.,Picton P.,Pierratos A.,Miller J.A.,Floras J.S. Short-term blood pressure, noradrenergic and vascular effects of nocturnal home hemodialysis Hypertension (2003) 42:925 • Chan C.T.,Hanly P., Gabor J., Picton P., Pierratos A., Floras J.S. Impact of nocturnal hemodialysis on variablity of heart rate and duration of hypoxemia during sleep Kidney Int. (2004) 65:661 • Chan C.T.,Jain V., Picton P., Pierratos A., Floras J.S. Nocturnal hemodialysis increases arterial baroreflex sensitivity and compliance and normalizes blood pressure of hypertensive patients with endstage renal disease Kidney Int. (2005) 68: 338 sleep apnea a novel index of dialysis adequacy? in the 4D study 70% of sudden death during nighttime !

  46. Improvement of sleep-apnea with daily hemodialysis at nighttime (NHD) Hanly, New Engl..J.Med.(2001) 344:102

  47. New Engl.J.Med.(2005)353:2070

  48. Frequeny of sleeping disorders in dialysis patients Insomnia obstructive sleep apnea restless legs Epwoth sleepiness scale nightmares sleepwalking behaviour disorder Narcolepsy Merlino,Nephrol.Dial.Transpl.(2006) 21:184

  49. In hamsters disruption of a regulatory protein entraining circadian rhythmcompared to controlscauses- cardiomyopathy-renal disease Masson trichrome Sirius red Martino, Am.J.Physiol.(2008) 294:R1675

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