GEBRAUCHSINFORMATION FÜR DEN ANWENDER besitzen, sowie PDE5-Hemmer (Potenzmittel, Sildenafil), Alpha-Nehmen Sie keinen Alkohol innerhalb 24 Stunden vor oder nach PRILIGY 30 mg/60 mg Filmtabletten (Dapoxetin) dem Einnehmen von Priligy! Das Risiko von Nebenwirkungen auf Nervensystem, Herz und Kreislauf kann erhöht werden. Dapoxetin darf nicht zusammen mit Drogen eingenommen Lesen Sie
Suomen sivusto, jossa voit ostaa halvalla ja laadukas Viagra http://osta-apteekki.com/ toimitus kaikkialle maailmaan.
Erityisesti laatu viagra tästä kaupasta voi taata henkilökohtaisesti propecia Paras laatu kehotan Teitä miellyttää.
Diagnostic and Therapeutic
Utility of B-Type Natriuretic
Peptide in Patients With
Renal Insufficiency and
Decompensated Heart Failure
Peter A. McCullough, MD, MPH, FACC, FACP, FCCP FAHA,* Kuncheria Joseph, MD,† Vandana S. Mathur, MD‡ *Divisions of Cardiology, Nutrition and Preventive Medicine, William Beaumont Hospital, RoyalOak, MI, †Bon Secours Hospital, Venice, FL, ‡Department of Medicine, Department of Nephrologyand Renal Transplantation, University of California San Francisco, San Francisco, CA Chronic kidney disease (CKD) and congestive heart failure (CHF) are epidemiologicallyand pathophysiologically linked. A recent study in patients with severe CHF demonstratedthat renal plasma flow was inversely correlated with pulmonary capillary wedge pres-sure, right atrial pressure, pulmonary pressure, and right ventricular ejection fraction.
This article reviews the utility of B-type natriuretic peptide (BNP) levels in assessingcardiac function and volume status in patients with CKD and examines the safetyand efficacy of BNP therapy in patients with renal insufficiency and decompensatedheart failure. [Rev Cardiovasc Med. 2004;5(1):16-25] Key words: Congestive heart failure • Renin-angiotensin-aldosterone system •
B-type natriuretic peptide • Nesiritide • Chronic kidney disease
Only 16% of chronic kidney disease (CKD) patients who have reached end-stage renal disease (ESRD) have echocardiographically normal leftventricles,1 and 40% have clinically diagnosed congestive heart failure (CHF).2 The activation of the renin-angiotensin-aldosterone system (RAAS),sympathetic nervous system (SNS), and endothelin-1 by heart failure reduces VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
losclerosis, tubulointerstitial fibrosis, patients with glomerular filtrationrates (GFRs) of 50 mL/min to 75mL/min, 25 mL/min to 50 mL/min, Chronic CHF and CKD may aggravate the progression of each other, leading to an inexorable vicious cycle and accelerated cardiac and renal fibrosis. approximately 30%, 33%, and 49%,respectively. Chronic Kidney Disease and
Congestive Heart Failure
past 15 years.19 According to the U.S.
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 17 Utility of B-Type Natriuretic Peptide continued
presentation with acute decompen-sated CHF are typically due to renal Aldosterone
acute CHF. IV diuretics have beenshown to cause significant increases Figure 1. Central role of the renin-angiotensin-aldosterone axis in progressive cardiomyopathy and chronic kidney
disease. CHF, congestive heart failure; CKD, chronic kidney disease; LVH, left ventricular hypertrophy. within 20 minutes of administra-tion.36 Hence, while helpful in clear- ulation is reflected by studies ofpatients with advanced CHF (andmean serum creatinine (Cr) of Hence, while helpful in clearing pulmonary congestion, the early and singular use of IV loop diuretics further activates the RAAS and SNS while leading to elevations in Cr in many patients. from universal (VMAC, 69%15;OPTIME, 69%28). Renal Function as a Predictor
Natriuretic Peptides and Acute
strongest independent predictors ofmortality among U.S. patients whowere hospitalized with a primary Adverse Consequences of Chronic Systemic and
Tissue Level RAAS Activation
60-day hospital readmissions amonga Medicare cohort (N = 2176) with • Coronary atherosclerosis vasoconstriction • Prothrombotic effects/increased plasminogen RAAS, renin-angiotensin-aldosterone system Data from: Epstein M,5 Brewster UC, et al,6 and Hostetter TH, et al.23 VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
Correlation of Systemic Hemodynamic Parameters to
Renal Plasma Flow in Heart Failure Patients45
epithelial and mesangial cells insmaller quantities.7 Both peptidesagonize the guanylate cyclase-cou- Hemodynamic Parameter
r-value for Correlation With RPF
Renal plasma flow did not correlate significantly with cardiac index, systemic vascular resistance PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure; RAP, right atrialpressure; RVEF, right ventricular ejection fraction. Data from: Kos, et al.45 BNP, but not ANP.37,38 Both ANP andBNP are cleared by neutral endopep-tidase (NEP 24.11), which is found differences in physiologic response.
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 19 Utility of B-Type Natriuretic Peptide continued
Figure 2. (A) Effect of nesiritide
(NES) on urine volumes over 6 hours.
(B) Effect of nesiritide on clinical
by blinded patients (PT) and physi- BNP Levels in Patients With
Physiologic Effects of B-Type Natriuretic Peptide
A number of studies have examined
or Clinical Effect
Known or Presumed Mechanism
Direct inhibition of aldosterone, renin, secondary to improvements in cardiac function and inhibition of endothelin-1, Enhanced potassium secretion secondary 55 to natriuretic effects balanced by aldosterone inhibition Arterial dilatation and potential reflexive VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
that BNP is not significantly (if at all) reduction in BNP with a dialysis ses-sion may prove to be an importantindicator of optimally reduced left Nesiritide was significantly better at reducing PCWP than placebo plus standard therapies and intravenous nitroglycerin plus standard therapies. Physiologic Effects of BNP
BNP has myriad physiologic and
ics, they either reduce renal filtrationfunction or activate adverse neuro- Hemodynamic Effects of Nesiritide
Hemodynamics and Heart
Nesiritide consistently and rapidly
and pulmonary artery pressures,and it increases cardiac index in a Values are means + SD. P values are for the comparison among all three groups, calculated with the * P < .001 for the pairwise comparison with placebo, by the F test. † P < .05 for the pairwise comparison with placebo, by the F test.
PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; SVR, systemic vascular resistance; CI, cardiac index; SBP, systolic blood pressure. VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 21 Utility of B-Type Natriuretic Peptide continued
even in the absence of urine output.
effects predicts that its use as a natri- conducted. It may be possible, withthe early use of nesiritide in com-bined kidney failure and CHF, to It may be possible, with the early use of nesiritide in combined kidney failure and CHF, to reduce the use of additional therapies, including pies, including inodilators. Thus,the use of additional hospital resources and risks of invasive hemo-dynamic monitoring and arrhyth- Management of Patients With
or GFR occurred (despite natriuresis).
Chronic Kidney Disease and
Natriuresis and Renal
Function Preservation in
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
days (10% vs 23%, P = .06), and the > 65, history of sustained ventriculartachycardia, ischemic etiology ofCHF, history of diabetes, outpatient FUSION data suggest that serial outpatient infusions of nesiritide given to patients with advanced heart failure who are at high risk for hospitalization potentially reduces morbidity and mortality due to heart failure. ly infusions of nesiritide in an out-patient setting in patients with VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 23 Utility of B-Type Natriuretic Peptide continued
plasma endothelin-1 levels in patients withdecompensated congestive heart failure. Am J Stevens TL, Burnett JC, Kinoshita M, et al. Afunctional role for endogenous atrial natri- uretic peptide in a canine model of early left ventricular dysfunction. J Clin Invest. 1995;95:1101-1108.
Full Prescribing Information for NATRECOR Maisel A, Cremo R, Gardetto N. The effects of nesiritide on serum levels of B-type natriuretic peptide (BNP) in patients admitted for decom-pensated congestive heart failure [abstract]. J References
Parfrey PS, Foley RN, Harnett JD, et al.
Abraham WT, Lowes BD, Ferguson DA, et al.
Outcome and risk factors for left ventricular disorders in chronic uremia. Nephrol Dial renal effects of a steady-state infusion of Transplant. 1996;11:1277-1285.
human brain natriuretic peptide in patients Sarnak MJ. Cardiovascular complications in chronic kidney disease. Am J Kidney Dis. 2003; failure. J Card Fail. 1998;4:37-44.
Colucci WS, Elkayam U, Horton DP, et al.
Dzau VJ. Renin-angiotensin system and renal Intravenous nesiritide, a natriuretic peptide, circulation in clinical congestive heart failure.
in the treatment of decompensated congestive Kidney Int Suppl. 1987;20:S203-S209.
heart failure. Nesiritide Study Group. N Engl J Kramer BK, Schweda F, Riegger GA. Diuretic treatment and diuretic resistance in heart fail- ure. Am J Med. 1999;106:90-96.
Investigators. Intravenous nesiritide vs nitro- Epstein M. Aldosterone as a mediator of pro- glycerin for treatment of decompensated con- gressive renal disease: pathogenetic and clini- gestive heart failure: a randomized controlled cal implications. Am J Kidney Dis. 2001; trial. JAMA. 2002;287:1531-1540.
effects of nesiritide, as well as its safe- Silver M, Horton D, Ghali J, Elkayam U. Effect Brewster UC, Setaro JF, Perazella MA. The of nesiritide versus dobutamine on short-term renin-angiotensin-aldosterone system: car- outcomes in the treatment of patients with diorenal effects and implications for renal and acutely decompensated heart failure. J Am Coll cardiovascular disease states. Am J Med Sci. expression and synthesis of natriuretic pep- nesiritide in observation patients. Presented at tides by cultured human glomerular cells. J the 52nd Annual Scientific Session of the Hypertension. 1999;17:575-583.
American College of Cardiology; March 30- Chen HH, Burnett JC. The natriuretic peptides in heart failure: diagnostic and therapeutic Protter AA, Wallace AM, Ferraris VA, Weishaar potentials. Proc Assoc Am Physicians. 1999; RE. Relaxant effect of human brain natriuretic peptide on human artery and vein tissue. Am J Aronson D, Burger AJ. Intravenous nesiritide (human B-type natriuretic peptide) reduces McCullough P, Philbin E, Spertus J, et al.
• B-type natriuretic peptide (BNP), produced by the cardiac ventricles and, to a small degree, by the renal glomerular
epithelial and mesangial cells, is a counter-regulatory hormone that physiologically opposes and suppresses the RAASendothelin-1 and the SNS.
• Baseline renal function and renal functional changes are important predictors of outcome in acute heart failure. • Independent of age, left ventricular ejection fraction, diabetes, and discharge Cr level, even small deteriorations in renal function (Cr elevations of 0.2 mg/dL) during hospitalization for acute CHF, are predictors of increased mortality.
• As a therapy, BNP is the only available compound that creates improvements in both renal and cardiac function when • The ability of nesiritide to suppress sodium retentive and renal vasoconstrictive neurohormonal systems while exerting natriuretic effects predicts that its use as a natriuretic should not be hindered by worsening renal function,as occurs with conventional diuretics.
• In patients with acute worsening of renal function in the setting of acute CHF, nesiritide would be expected to improve renal function by inhibiting renal vasoconstrictive hormones that are mediating the renal functional decline.
• FUSION demonstrated that weekly infusions of nesiritide in an outpatient setting in patients with advanced CHF were • There may be a role for long-term intermittent treatment with nesiritide in high-risk patients with advanced VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
Confirmation of a heart failure epidemic: find- Goy MF, Oliver PM, Purdy KE, et al. Evidence for care results in favorable reduction in systolic a novel natriuretic peptide receptor that prefers blood pressure and heart rate compared to stan- Congestive Heart failure (REACH) study. J Am brain natriuretic peptide over atrial natriuretic dard care alone. J Card Fail. 2003;9:S61. peptide. Biochem J. 2001;358:379-387.
Mathur V, Butler J, Emerman C, Young J. Efficacy McCullough P. Cardiorenal risk: an important Brunner-La Rocca HP, Woods RL, Kaye DM, et al.
of B-Type Natriuretic Peptide (BNP) in Patients clinical intersection. Rev Cardiovasc Med. Divergent effects of ANP and BNP in acute heart with Renal Insufficiency and Acute Heart Failure: failure: evidence for a putative BNP-selective Results from the VMAC Trial. J Am Soc Nephrol. Levin A, Thompson CR, Ethier J, et al. Left ven- receptor? J Hypertens. 2002;20:1195-1201.
tricular mass index increase in early renal dis- Kishimoto I, Hamra FK, Garbers DL. Apparent B- Butler J, Emerman C, Mathur V. Nephrol Dial ease: impact of decline in hemoglobin. Am J type natriuretic peptide selectivity in the kidney due to differential processing. Can J Physiol Seta K, Hayashi T, Sugawara A, et al. Atrial natri- Silverberg DS, Wexler D, Blum B, Iaina A.
uretic peptide as a preload depressor in acute Anemia in chronic kidney disease and conges- Chen H, Boerrigter G, Catalliotti A, et al. The renal failure secondary to congestive heart fail- tive heart failure. Blood Purif. 2003;21:124-130. Cardiac Peptide BNP and the Renally Derived ure. Ren Fail. 1998;20:717-723.
Peptide Urodilatin Are Superior to ANP in Mathur V, Joseph K. Use of nesiritide (B-type chronic kidney and cardiac disease. J Am Soc natriuretic peptide) as a bridge to urgent "mid- Experimental CHF. In: J Card Fail, Heart Failure dle-of-the-night" hemodialysis. J Am Soc Nephrol. The SOLVD Investigators. Effect of enalapril on Society of America, Boca Raton, FL, 2002.
survival in patients with reduced left ventricular Chinkers M. Regulation of the atrial natriuretic Rudy DW, Voelker JR, Greene PK, Esparza FA, ejection fractions and congestive heart failure. N peptide receptor guanylyl cyclase. Proc Soc Exp Brater DC. Loop diuretics for chronic renal insuf- Engl J Med. 1991;325:293-302.
ficiency: a continuous infusion is more effica- Agodoa LY, Appel L, Bakris GL, et al. Effect of Stevens TL, Rasmussen TE, Wei CM, et al. Renal cious than bolus therapy. Ann Intern Med. ramipril vs amlodipine on renal outcomes in role of the endogenous natriuretic peptide sys- hypertensive nephrosclerosis: a randomized tem in acute congestive heart failure. J Card Fail. Yoshimura M, Yasue H, Morita E, et al.
controlled trial. JAMA. 2001;285:2719-2728.
Hemodynamic, renal, and hormonal responses Brenner BM, Cooper ME, de Zeeuw D, et al.
Cermak R, Kleta R, Forssmann WG, Schlatter E.
to brain natriuretic peptide infusion in patients Natriuretic peptides increase a K+ conductance Effects of losartan on renal and cardiovascular with congestive heart failure. Circulation. in rat mesangial cells. Pflugers Arch. outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
Zellner C, Protter AA, Ko E, et al. Coronary Pitt B, Zannad F, Remme WJ, et al. The effect of Hemodynamic and renal excretory effects of vasodilator effects of BNP: mechanisms of action spironolactone on morbidity and mortality in human brain natriuretic peptide infusion in in coronary conductance and resistance arteries.
patients with severe heart failure. Randomized patients with congestive heart failure. A double- Am J Physiol. 1999;276:H1049-H1057.
Aldactone Evaluation Study Investigators. N Engl blind, placebo-controlled, randomized crossover Kos T, Pacher R, Wimmer A, et al. Relationship trial. Circulation. 1996;94:3184-3189.
between kidney function, hemodynamic vari- Cuffe MS, Califf RM, Adams KF, et al. Short-term Jensen KT, Eiskjaer H, Carstens J, Pedersen EB.
ables and circulating big endothelin levels in intravenous milrinone for acute exacerbation of Renal effects of brain natriuretic peptide in patients with severe refractory heart failure.
chronic heart failure: a randomized controlled patients with congestive heart failure. Clin Sci Wien Klin Wochenschr. 1998;110:89-95.
trial. JAMA. 2002;287:1541-1547.
Beltowski J, Wojcicka G. Regulation of renal Fonarow G, Adams K, Abraham W. Risk stratifi- Mathur V. Use of Nesiritide (NES) for Treatment tubular sodium transport by cardiac natriuretic cation for in-hospital mortality in heart failure peptides: two decades of research. Med Sci Monit. using classification and regression tree (CART) Decompensated Congestive Heart Failure (CHF).
methodology: Analysis of 33,046 patients in the Am Soc Nephrol. 2002 Annual Meeting Online Mistry SK, Chatterjee PK, Weerackody RP, et al.
ADHERE Registry. J Cardiac Fail. In press, 2003.
Evidence for atrial natriuretic factor induced Krumholz HM, Chen YT, Wang Y, et al.
Tann S. B-Natriuretic Peptide improves hemody- natriuretic peptide receptor subtype switching in Predictors of readmission among elderly sur- namics and renal function in heart transplant rat proximal tubular cells during culture. Exp vivors of admission with heart failure. Am Heart patients immediately after surgery. International Heart Lung Transplant Meeting. Vienna, Austria, Cataliotti A, Malatino LS, Jougasaki M, et al.
Gottlieb SS, Abraham W, Butler J, et al. The prog- Circulating natriuretic peptide concentrations in nostic importance of different definitions of Suganami T, Mukoyama M, Sugawara A, et al.
patients with end-stage renal disease: role of worsening renal function in congestive heart brain natriuretic peptide as a biomarker for ven- Overexpression of brain natriuretic peptide in failure. J Card Fail. 2002;8:136-141.
tricular remodeling. Mayo Clinic Proceedings. Smith GL, Vaccarino V, Kosiborod M, et al.
injury. J Am Soc Nephrol. 2001;12:2652-2663.
Worsening renal function: what is a clinically Ishizaka Y, Yamamoto Y, Fukunaga T, et al.
Kasahara M, Mukoyama M, Sugawara A, et al.
meaningful change in creatinine during hospi- Plasma concentration of human brain natriuret- Ameliorated glomerular injury in mice overex- talization with heart failure? J Card Fail. 2003; ic peptide in patients on hemodialysis. Am J pressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol. 2000;11:1691-1701.
Krumholz HM, Chen YT, Vaccarino V, et al.
Ishikura F, Ando Y, Park YD, et al. Changes of 68. Yancy CW, Saltzberg M, Berkowitz RL, et al.
Correlates and impact on outcomes of worsen- plasma atrial and brain natriuretic peptide levels Management of patients with congestive heart ing renal function in patients > or =65 years of during hemodialysis. Ren Fail. 1996;18:261-270.
failure after hospitalization: Results from the age with heart failure. Am J Cardiol. 2000; Akiba T, Tachibana K, Togashi K, et al. Plasma human brain natriuretic peptide in chronic renal (FUSION) trial. J Card Fail. 2003;5(supple- Dzau VJ. Renal and circulatory mechanisms in failure. Clin Nephrol. 1995;44(suppl 1):S61-64.
congestive heart failure. Kidney Int. 1987; McCullough PA, Duc P, Omland T, et al. B-type 69. Burger AJ, Elkayam U, Neibaur MT, et al.
natriuretic peptide and renal function in the Comparison of the occurrence of ventricular diagnosis of heart failure: an analysis from the arrhythmias in patients with acutely decompen- Cataliotti A, Burnett JC. Angiotensin II AT1 Breathing Not Properly Multinational Study. Am sated congestive heart failure receiving dobuta- receptor antagonism prevents detrimental renal J Kidney Dis. 2003;41:571-579.
mine versus nesiritide therapy. Am J Cardiol. actions of acute diuretic therapy in human heart Lee SW, Song JH, Kim GA, et al. Plasma brain failure. Am J Physiol Renal Physiol. 2003; natriuretic peptide concentration on assessment Roden R. Inotropic Effect of Human B-Type of hydration status in hemodialysis patient. Am Natriuretic Peptide in the Failing Human Heart.
Francis GS, Siegel RM, Goldsmith SR, et al. Acute J Kidney Dis. 2003;41:1257-1266.
McCullough P, Sandberg K. B-type natriuretic Michaels AD, Klein A, Madden JA, Chatterjee K.
furosemide in patients with chronic congestive peptide and renal disease. Heart Fail Rev. In press, Effects of intravenous nesiritide on human coro- heart failure. Activation of the neurohumoral nary vasomotor regulation and myocardial oxy- axis. Ann Intern Med. 1985;103:1-6.
Emerman C, et al. Nesiritide added to standard gen uptake. Circulation. 2003;107:2697-2701.
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 25
Unlicensed use of Misoprostol for stillbirth delivery leading to catastrophic brain injury Claimant aged 28 suffered catastrophic brain injury caused by unlicensed use of Misoprostol The NHS Litigation Authority defended the claim until three weeks before the case was due to come to court The Claimant became pregnant in 2004 and was booked for delivery at the West Cumberland