Smilde, Tom Derk Jan

English

Both left ventricular dysfunction, and renal dysfunction are world wide public health problems. In the western countries there is a rising incidence and prevalence of both conditions, with poor outcomes and high cost. These two conditions do often co-exist and the concomitant presence of both conditions accumulates risk for morbidity and mortality. In severe chronic heart failure (CHF), impaired renal function is often present, and is even a stronger risk marker than functional cardiac parameters, such as left ventricular ejection fraction or NYHA class.1 On the other hand, left ventricular dysfunction is likely to develop in patients with chronic renal dysfunction (CRD) and accumulates with worsening renal function.2 One of the first signs of left ventricular dysfunction in patients with CRD is left ventricular hypertrophy (LVH). Several studies have demonstrated an association between renal dysfunction and LVH and the prevalence of LVH increases with worsening of renal function.3 Finally, several prevalence and longitudinal studies have shown that the well known age associated decline in renal function is more pronounced in patients with coexisting cardiovascular risk factors and pre-existing atherosclerotic vascular disease, suggesting that this decline is not a consistent phenomenon and reflect cardiovascular co-morbidity rather than normal aging

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   University of GroningenLeft ventricular and renal dysfunctionSmilde, Tom Derk JanIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2005Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Smilde, T. D. J. (2005). Left ventricular and renal dysfunction: an exploration of the cardiorenal axis. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-10-20229I N T R O D U C T I O N  A N D  A I M  O F  T H E  T H E S I SChapter 1Introduction and Aim of the ThesisC H A P T E R  110INTRODUCTIONBoth left ventricular dysfunction, and renal dysfunction are world wide public healthproblems. In the western countries there is a rising incidence and prevalence of bothconditions, with poor outcomes and high cost. These two conditions do often co-exist andthe concomitant presence of both conditions accumulates risk for morbidity and mortality.In severe chronic heart failure (CHF), impaired renal function is often present, and is evena stronger risk marker than functional cardiac parameters, such as left ventricular ejectionfraction or NYHA class.1 On the other hand, left ventricular dysfunction is likely to developin patients with chronic renal dysfunction (CRD) and accumulates with worsening renalfunction.2 One of the first signs of left ventricular dysfunction in patients with CRD is leftventricular hypertrophy (LVH). Several studies have demonstrated an association betweenrenal dysfunction and LVH and the prevalence of LVH increases with worsening of renalfunction.3 Finally, several prevalence and longitudinal studies have shown that the wellknown age associated decline in renal function is more pronounced in patients with co-existing cardiovascular risk factors and pre-existing atherosclerotic vascular disease, suggestingthat this decline is not a consistent phenomenon and reflect cardiovascular co-morbidityrather than normal aging.4;5The cardiorenal axisThe association between cardiac and renal function described above, reflects more than amere association, and in fact implies a causal interaction, which has gained a lot of interestover the last decades. Research has shown that both cardiac dysfunction and renal dysfunctionaffect each other through similar pathways.6 This cardiorenal “cross-talk” is often referredto as the cardiorenal axis. Accordingly, hemodynamic alterations, renin-angiotensinaldosterone system (RAS) activation, sympathetic nervous system (SNS) activation,endothelial dysfunction, and inflammation are the main pathways involved and actingsynergistically in the cardiorenal axis.The systemic hemodynamic status has a central role. Changes, initially caused by eithercardiac or renal impairment can initiate a cascade of mechanisms, which ultimately canlead to secondary end organ damage e.g. CHF or CRD.In CHF inadequate cardiac output leads to arterial underfilling, which is sensed byvarious receptors. In response, vascular and neurohormonal mechanisms are activated in anattempt to provide compensatory mechanisms for the impaired cardiac output. However,these compensatory mechanisms contribute to the reduction in renal blood flow, renalsodium retention and consequently pulmonary congestion. In this process the SNS andRAS play a key role. As the condition progresses endothelial function becomes more impaired,associated with further reduction in renal perfusion.7;8 Furthermore, chronic inflammationcontributes to (renal) vascular, but also to cardiac dysfunction.9 All of these aspects areinvolved in the deterioration of renal function in CHF. However the extent of theirinvolvement, and their pathophysiological interrelationships, remain unclear. Conversely,in CRD the RAS and SNS also play a key role. The adaptation to loss of renal functioninvolves local changes in renal hemodynamics that activate the RAS. As a result of sodium11I N T R O D U C T I O N  A N D  A I M  O F  T H E  T H E S I Sretention and increased vascular resistance the blood pressure is increased, which leads toboth increased volume and pressure overload. In CRD anemia, due to erythropoietinedeficiency, can result in a volume overload. Both anemia and high blood pressure increasethe cardiac workload, leading to LVH or left ventricular dilatation, which are precursors ofCHF.10;11 Furthermore, loss of renal function is associated with the presence of endothelialdysfunction, higher levels of inflammatory markers and changing lipoprotein structure, allprecursors of atherosclerosis.The susceptibility to develop LVH might also be influenced by genetic factors. Severalpolymorphisms, especially of the RAS, have been related to the development of LVH.12;13RAS-polymorphisms have been shown to modulate RAS -activity or –responsiveness inseveral experimental and human settings.14;15 However, it has been argued that the biologicaleffects of a single polymorphism are not sufficient to cause LVH, but can make a differencein the presence of other pathophysiological risk factors for LVH.16 Renal dysfunction issuch a risk factor, but whether renal dysfunction influences the impact of geneticpolymorphisms and LVH is unknown.Detection of renal dysfunctionEarly recognition of renal dysfunction is important. Renal damage is characterised by reducedglomerular filtration rate (GFR) and an increase in urinary albumin excretion (UAE).The GFR refers to the ability of the kidney to clear the blood plasma of certain substancesand can be measured using exogenous tracers, like inulin or iothalamate. However thesemeasurements are expensive and time consuming and not routinely available in most cases.Alternatives are to measure 24h creatinine clearance or to estimate GFR by using severalformulas.17;18 The formulas are easy to obtain and are frequently used as marker for renalfunction in large-scale CHF trials.1;19 However, these formulas are prone to bias, and havenever been validated in CHF patients.Increased UAE is thought to precede manifest renal dysfunction.20;21 The pathogenicmechanisms leading to the development of increased urinary albumin levels are still notcompletely known. Blood pressure load and increased systemic vascular permeability, possiblydue to early endothelial damage, seem to play a major role. Atherogenic processes,inflammation, RAS activity, increased oxidative stress and SNS activation are suggested todamage the endothelial layer and enhance the (renal) vascular permeability. Elevated UAE,especially microalbuminuria (30-300mg), is an important risk marker for cardiovascularand renal disorders in various conditions, such as diabetes and hypertension22;23, but also inthe general population.24 In CHF increased levels of UAE are frequently observed.25 Mostof the mechanisms, which damage the endothelium, are activated in CHF, but their preciseparticipation and or interactions remains to be elucidated.This thesisThe current thesis focuses on several aspects of the cardiorenal axis. The starting-point isprovided by the concomitant presence of left ventricular dysfunction and renal dysfunction.We review the clinical importance of renal failure, and evaluate to what extent several para-meters of the cardiorenal axis contribute to the CRD in CHF. We will also study theC H A P T E R  112interrelationship between different parameters of renal function and genes in an environ-ment of left ventricular dysfunction. Finally, we will study measurement methodologiesand mutual pathogenic mechanisms that can link left ventricular dysfunction to renaldysfunction.In part I prognostic and clinical importance of renal function impairment in CHF will bediscussed. In moderate to severe CHF, as discussed earlier, estimated glomerular filtrationrate (eGFR) is an important predictor of cardiovascular death. Whether this holds true formild CHF as well remains to be elucidated. Therefore, in chapter 2 we will evaluate thepredictive value of eGFR for cardiovascular mortality in patients with early mild CHF.The observed relation between impaired eGFR and cardiovascular mortality might beexplained by renal dysfunction being a marker of generalised atherosclerosis. On the otherhand, this relation might also be explained by an impaired renal perfusion when leftventricular dysfunction is present. This suggests that the predictive value of eGFR forcardiovascular mortality might be different between ischemic (atherosclerosis present) andnon-ischemic (atherosclerosis not present) heart failure patients. Therefore, in chapter 3and 4, the prognostic value of eGFR is compared between patients with ischemic and non-ischemic CHF. First, we will address this issue in mild CHF patients. Second, we willaddress this in severe CHF patients, and moreover, we evaluated the relation ofneurohormones and renal function in both populations. In chapter 5 the influence of renal(dys)function on the pharmacokinetics of a selective Na+/H+-exchange inhibitor in patientswith CHF will be evaluated.In severe CRD LVH is frequently present, as mentioned earlier. Whether mild renaldysfunction is related to LVH is unknown. Therefore, in chapter 6 the presence of mildrenal dysfunction will be related to electrocardiographically determined LVH.This studywill be performed in the subjects participating in the Prevention of REnal and VascularENd-stage Disease (PREVEND) study. The PREVEND study is designed to prospectivelyinvestigate the natural course of albuminuria and its relation to renal and cardiovasculardisease in a large cohort drawn from the general population. Another factor related to the susceptibility to develop LVH is genetic predisposition,for instance by genetic variability in the RAS. In chapter 7 we investigated whether renalfunction modulates the relation of RAS-polymorphisms with LVH.In part II, methodological issues regarding assessment of renal dysfunction in patientswith CHF will be addressed and pathways within the cardiorenal axis will be explored.Most studies use creatinine based formulas to estimate renal function, but these formulashave never been validated in CHF. Therefore, in chapter 8 several frequently used creatinine-based formulas are validated by comparing them to the true GFR in patients with CHF. Inchapter 9 the relationships between renal blood flow, GFR, parameters of endothelialfunction, systemic RAS and inflammation are determined in patients with CHF.Furthermore, we will focus on the amount of UAE in these patients and the course of UAEin relation to renal function.13I N T R O D U C T I O N  A N D  A I M  O F  T H E  T H E S I SReference List1. Hillege HL, Girbes AR, de Kam PJ, Boomsma F, de Zeeuw D, Charlesworth A, Hampton JR, vanVeldhuisen DJ. Renal function, neurohormonal activation, and survival in patients with chronic heartfailure. Circulation. 2000;102:203-210.2. Cheung AK, Sarnak MJ, Yan G, Berkoben M, Heyka R, Kaufman A, Lewis J, Rocco M, Toto R, WindusD, Ornt D, Levey AS. Cardiac diseases in maintenance hemodialysis patients: results of the HEMOStudy. Kidney Int. 2004;65:2380-2389.3. Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ventricular hypertrophy in the predialysispopulation: identifying opportunities for intervention. Am J Kidney Dis. 1996;27:347-354.4. Krop JS, Coresh J, Chambless LE, Shahar E, Watson RL, Szklo M, Brancati FL. A community-basedstudy of explanatory factors for the excess risk for early renal function decline in blacks vs whites withdiabetes: the Atherosclerosis Risk in Communities study. Arch Intern Med. 1999;159:1777-1783.5. Manttari M, Tiula E, Alikoski T, Manninen V. Effects of hypertension and dyslipidemia on the decline inrenal function. Hypertension. 1995;26:670-675.6. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: ‘Guytonrevisited’. Eur Heart J. 2005;26:11-17.7. Abassi ZA, Gurbanov K, Mulroney SE, Potlog C, Opgenorth TJ, Hoffman A, Haramati A, Winaver J.Impaired nitric oxide-mediated renal vasodilation in rats with experimental heart failure: role of angiotensinII. Circulation. 1997;96:3655-3664.8. Elkayam U, Cohen G, Gogia H, Mehra A, Johnson JV, Chandraratna PA. Renal vasodilatory effect ofendothelial stimulation in patients with chronic congestive heart failure. J Am Coll Cardiol. 1996;28:176-182.9. Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactiveprotein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation.2000;102:1000-1006.10. Sarnak MJ. Cardiovascular complications in chronic kidney disease. Am J Kidney Dis. 2003;41:11-17.11. Pokharel S, Sharma UC, Pinto YM. Left ventricular hypertrophy: virtuous intentions, malign consequences.Int J Biochem Cell Biol. 2003;35:802-806.12. Ohishi M, Rakugi H, Ogihara T. Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med. 1994;331:1097-1098.13. Kuznetsova T, Staessen JA, Wang JG, Gasowski J, Nikitin Y, Ryabikov A, Fagard R. Antihypertensivetreatment modulates the association between the D/I ACE gene polymorphism and left ventricularhypertrophy: a meta-analysis. J Hum Hypertens. 2000;14:447-454.14. Buikema H, Pinto YM, Rooks G, Grandjean JG, Schunkert H, van Gilst WH. The deletion polymorphismof the angiotensin-converting enzyme gene is related to phenotypic differences in human arteries. EurHeart J. 1996;17:787-794.15. van Geel PP, Pinto YM, Voors AA, Buikema H, Oosterga M, Crijns HJ, van Gilst WH. Angiotensin IItype 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II inhuman arteries. Hypertension. 2000;35:717-721.16. Schunkert H. Controversial association of left ventricular hypertrophy and the ACE I/D polymorphism-is the mist clearing up? Nephrol Dial Transplant. 1998;13:1109-1112.17. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.18. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerularfiltration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal DiseaseStudy Group. Ann Intern Med. 1999;130:461-470.19. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, NordlanderR, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation betweenrenal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285-1295.C H A P T E R  11420. Mogensen CE. Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives tomicroalbuminuria? Diabetes. 1990;39:761-767.21. Pinto-Sietsma SJ, Janssen WM, Hillege HL, Navis G, de Zeeuw D, de Jong PE. Urinary albumin excretionis associated with renal functional abnormalities in a nondiabetic population. J Am Soc Nephrol.2000;11:1882-1888.22. Mattock MB, Morrish NJ, Viberti G, Keen H, Fitzgerald AP, Jackson G. Prospective study ofmicroalbuminuria as predictor of mortality in NIDDM. Diabetes. 1992;41:736-741.23. Ljungman S, Wikstrand J, Hartford M, Berglund G. Urinary albumin excretion—a predictor of risk ofcardiovascular disease. A prospective 10-year follow-up of middle-aged nondiabetic normal and hypertensivemen. Am J Hypertens. 1996;9:770-778.24. Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, van Gilst WH, de Zeeuw D, deJong PE. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and anindependent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med.2001;249:519-526.25. Eiskjaer H, Bagger JP, Mogensen CE, Schmitz A, Pedersen EB. Enhanced urinary excretion of albumin incongestive heart failure: effect of ACE-inhibition. Scand J Clin Lab Invest. 1992;52:193-199.15P R O G N O S I S  O F  R E N A L  F U N C T I O N  I N  M I L D  H E A R T  F A I L U R EPart IPrognostic and Clinical Importance of Renal Dysfunctionand Left Ventricular DysfunctionC H A P T E R  216

Left ventricular and renal dysfunction:an exploration of the cardiorenal axis

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Left ventricular and renal dysfunction:an exploration of the cardiorenal axis

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