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European Journal of Heart Failure 2002 4(2):125-130; doi:10.1016/S1388-9842(01)00238-0
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© 2002 European Society of Cardiology

Influence of progressive renal dysfunction in chronic heart failure

A. Peter Maxwella, Hean Y. Ongb and D. Paul Nichollsb,*

a Regional Nephrology Unit Belfast City Hospital, Belfast, Northern Ireland, UK
b Department of Medicine, Royal Victoria Hospital Grosvenor Road, Belfast BT12 6BA, Northern Ireland, UK

* Corresponding author. Tel.: +44-28-9089-4951; fax: +44-28-9026-3168. E-mail address: dp.nicholls{at}royalhospitals.n-i.nhs.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Acute renal failure
 3. Chronic renal failure
 4. Treatment of renal...
 5. Conclusion
 References
 
Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.

Key Words: Chronic cardiac failure • Chronic renal failure

Received September 4, 2001; Revised October 24, 2001; Accepted October 29, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Acute renal failure
 3. Chronic renal failure
 4. Treatment of renal...
 5. Conclusion
 References
 
Renal failure is a frequent co-existing problem complicating chronic heart failure (CHF), and impaired renal function is associated with increased morbidity and mortality in patients with CHF [1]. Reduced glomerular filtration rate (GFR) is a strong independent predictor of mortality in patients with CHF [2]. Patients in the lowest quartile of GFR (<44 ml/min) had a relative risk of 2.85 when compared to those in the upper quartile (>76 ml/min; P<0.001) [2]. Undoubtedly, a major contribution to the reduction in GFR is a reduction in renal plasma flow. Under normal circumstances at rest, blood flow is distributed mainly to the hepatic–splanchnic (17–24%), renal (15–19%) and cerebral (10–15%) circulation [3]. During exercise, up to 70% of blood flow is diverted to working muscle, at the expense of other areas [4]. In patients with CHF, there is an increase in peripheral resistance and reduction in cardiac output, both at rest [5,6] and during exercise [7,8], and a corresponding reduction in renal plasma flow [9]. Some of these haemodynamic changes may relate to reflex activation of the renin–angiotensin–aldosterone system (RAAS) and arginine vasopressin [10,11].

Three broad categories of renal dysfunction are recognised, namely: acute renal failure; acute-on-chronic renal failure; and chronic renal failure. Careful assessment of the clinical history and physical signs coupled with interpretation of laboratory and radiological investigations will usually point the clinician to the correct diagnosis and subsequent treatment of renal impairment.


   2. Acute renal failure
Top
 Abstract
 1. Introduction
 2. Acute renal failure
3. Chronic renal failure
 4. Treatment of renal...
 5. Conclusion
 References
 
In the setting of CHF the most common type of acute renal dysfunction is pre-renal azotaemia. Reduction in renal perfusion and consequent fall in GFR leads to reflex activation of the RAAS. The resulting autoregulation of glomerular capillary pressure and avid tubular reclamation of salt and water is an appropriate renal response, which ultimately exacerbates heart failure. A high urinary specific gravity on dipstick urinalysis, low urine sodium concentration (<20 mmol/l) and high urine osmolality (>1.5xplasma osmolality) are typical laboratory findings in pre-renal azotaemia. These simple investigations reflect the intact kidney's response to high circulating aldosterone and vasopressin levels. Without improvement in the CHF an increasing proportion of nephrons will be at risk of hypoxic injury leading to progressive tubular dysfunction and eventual acute tubular necrosis (ATN).

Patients with CHF are particularly susceptible to ATN during periods of haemodynamic instability, sepsis, or following the administration of nephrotoxic drugs and radiocontrast agents. In contrast to pre-renal azotaemia, the urinary sodium concentration is higher (typically >40 mmol/l) and urinary osmolality lower (<1.5xplasma osmolality). Fortunately, ATN will usually recover if the patient's clinical state can be improved or the offending nephrotoxic drug discontinued.

An important differential diagnosis of acute renal dysfunction in patients with CHF is renal atheroembolism. This rarely occurs spontaneously but may occur following interventions such as: angiography; angioplasty; vascular surgery; use of an intra-aortic balloon pump; or thrombolysis [12,13]. Cholesterol emboli result in obstruction of smaller renal arteries leading to ischaemia, inflammation, hypertension and renal failure. It is unusual for renal function to recover to baseline levels following renal atheroembolism. Clinical clues to renal atheroembolism include: other organ dysfunction; livedo reticularis; petechial lesions; and lower limb digital ischaemia. Variable laboratory findings reported include: leucocytosis; eosinophilia; eosinophiluria; raised LDH and ESR; and hypocomplementaemia [14–16]. Diagnosis is confirmed by renal biopsy where typical biconcave clefts left by cholesterol crystals are seen in arterioles [12].


   3. Chronic renal failure
Top
 Abstract
 1. Introduction
 2. Acute renal failure
 3. Chronic renal failure
4. Treatment of renal...
 5. Conclusion
 References
 
Chronic renal failure (CRF) and CHF in an individual patient poses many management problems. The most common causes of CRF are diabetes, hypertension, glomerulonephritis and polycystic kidney disease. Cardiovascular disease is the leading cause of morbidity and mortality in patients requiring renal replacement therapy, accounting for all most 50% of deaths [17,18]. Standard risk factors for cardiovascular disease such as hypertension, diabetes, smoking, dyslipidaemia and pre-existing atherosclerotic vascular disease are also risk factors for progressive renal dysfunction [18,19]. In addition to these ‘traditional’ risk factors, renal failure itself may accelerate development of cardiovascular disease and worsen prognosis in heart failure. Myocardial dysfunction is common in individuals with progressive renal dysfunction, with up to 80% of patients having an abnormal echocardiogram prior to initiation of dialysis, and over 30% of patients have evidence of congestive heart failure at onset of dialysis [20,21].

CRF is associated with hypertension, anaemia, volume overload, hyperparathyroidism and abnormal calcium–phosphate metabolism. These factors have been linked to development of left ventricular hypertrophy (LVH), left ventricular dilatation, myocardial fibrosis and calcification of both blood vessels and cardiac valves [22–26]. In addition, the metabolic milieu associated with uraemia leads to increased oxidative stress, oxidised low density lipoprotein and hyperhomocysteinaemia, which are risk factors for atherosclerosis in the general population. Accumulation of advanced glycosylation end-products (AGEs) and asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are putative risk factors for endothelial dysfunction in renal failure patients.

3.1. Blood pressure and renal function
An underlying chronic renal disease is the most commonly identified cause of secondary hypertension and there is a direct correlation between elevated blood pressures and risk of developing CRF [27]. Perhaps surprisingly there has been controversy regarding the relationship between hypertension and outcome in dialysis patients [28–30]. This is likely to reflect the impact of long-standing hypertension in patients with CRF that results in concurrent cardiac failure with consequent reduction in blood pressure. In prospective studies, however, there is a definite association between raised mean blood pressure and progressive LVH, de novo cardiac failure and cardiovascular death [21,31].

3.2. Anaemia and cardiac function
In chronic renal disease, anaemia secondary to relative erythropoietin deficiency is also an important determinant of LVH [32]. A compensatory hyperdynamic circulation develops in patients with reduced oxygen transport capacity due to renal anaemia. Distinct left ventricular geometry patterns are recognised — concentric LVH is associated with the pressure overload effect of hypertension, and eccentric LVH is linked to the volume overload related to anaemia [33]. The importance of anaemia-induced LVH is underlined by the finding that the eccentric pattern of LVH is twice as frequent as the concentric pattern in patients with CRF. In addition, anaemia is found in a considerable number of patients with CHF [34]. The proportion increases in proportion with the severity of the disease and with the decline in renal function, from almost 20% of those in NYHA symptom grade II to almost 80% of those in NYHA grade IV.

The poor prognosis associated with LVH in patients with renal failure may be improved by optimal control of blood pressure and the correction of anaemia with recombinant erythropoietin (EPO) [35]. Partial or complete regression of LVH with EPO treatment has been reported presumably by improving myocardial oxygen supply and allowing a reduction in cardiac output and workload. The main side effect of EPO treatment is a rise in blood pressure which, unless vigorously treated, will increase cardiac afterload and counterbalance the benefit of anaemia correction. Correction of anaemia also corrects the uraemic platelet dysfunction and increases blood viscosity.

The optimal haemoglobin (or haematocrit) to be targeted in patients with progressive renal dysfunction is not yet established. One large randomised study of anaemia treatment in high risk haemodialysis patients (i.e. those with CHF or coronary artery disease) was stopped after interim analysis revealed an increased number of deaths and myocardial infarctions in the group with the higher target haematocrit [36]. However, studies in patients with CHF have shown the benefit of maintaining the haemoglobin at approximately 12.5 g/dl using EPO and iron [37] — LVEF increased in the active treatment group, and the days in hospital decreased. A prospective randomised multi-centre study (CREATE) is now in progress to address the effects of optimal correction of haemoglobin on LVH and cardiovascular outcome in pre-dialysis patients.

3.3. Metabolic changes
As noted above, in CHF there is reflex activation of the RAAS in order to preserve central volume [38,39]. The effect of this is to produce electrolyte abnormalities that are often quite marked [40], and compounded by diuretic use (see below). Circulating plasma levels of the natriuretic peptides ANP and BNP are increased in response to the volume expansion [41]. In severe CHF there is also cachexia due to increased resting energy expenditure [42] and cytokine activation [43]. There is, therefore, a resetting of many homeostatic mechanisms even without any deterioration in renal function.

CRF is also associated with abnormal calcium and phosphate metabolism that may have a subtle but profound impact on cardiovascular morbidity. There is a direct link between hyperphosphataemia and mortality in patients with CRF [22]. Secondary hyperparathyroidism and elevated calcium and phosphate levels have been linked with accelerated calcification of coronary arteries and cardiac valves [24,25]. Myocardial and vascular endothelial cells express parathyroid hormone receptors, and it is postulated that hyperparathyroidism contributes to myocardial dysfunction by uncoupling oxidative phosphorylation, reducing cellular ATP concentrations and impairing calcium extrusion, leading to calcium overload in cardiomyocytes. In addition, animal models have demonstrated that elevated parathyroid hormone levels are associated with intra-myocardial fibrosis. Clinical studies however have been less consistent in linking hyperparathyroidism with cardiovascular outcome. Nevertheless, vigorous management of hyperphosphataemia, preferably with non-calcium containing phosphate binders, should reduce the accelerated cardiac and arterial calcification (target <1.7 mmol/l).


   4. Treatment of renal and cardiac dysfunction
Top
 Abstract
 1. Introduction
 2. Acute renal failure
 3. Chronic renal failure
 4. Treatment of renal...
5. Conclusion
 References
 
Improving the outcome of CHF in patients with chronic renal dysfunction can be achieved by focusing on treatable factors. Hypertension is a major contributor to morbidity in both conditions, and it has been shown that excellent control of blood pressure (target <140/90 mmHg) can retard the progression of diabetic and non-diabetic renal diseases [44–47]. The drug of choice would be an ACE inhibitor, because of their additional beneficial effects on LVH and on outcomes in CHF [48–50]. However, several clinical problems may arise with the use of such drugs. ACE inhibition may initially cause an acute fall in GFR with an accompanying rise in serum creatinine. A decrease in efferent arteriolar resistance will usually lead to a fall in glomerular capillary pressure and a decline in GFR. Autoregulation of glomerular blood flow can be further compromised by concurrent prostaglandin inhibition with non-steroidal anti-inflammatory drugs (NSAIDs) [51]. The combined prescription of an ACE inhibitor and an NSAID should therefore be avoided in patients with CHF.

The initial dose of an ACE inhibitor may cause a marked fall in blood pressure, which is not desirable in a patient with impaired renal perfusion, although this effect is much less with ‘third generation’ drugs such as perindopril. The best plan therefore is to omit diuretic therapy that day so as to avoid central volume depletion, and to give the first dose of ACE inhibitor at night. In addition, many patients with CHF due to ischaemic heart disease have concurrent renovascular disease such as renal artery stenosis and, on occasion, acute renal failure may be precipitated. Finally, potassium balance needs to be closely monitored. Levels may already be raised due to renal dysfunction or other medication, such as spironolactone [52], and the addition of an ACE inhibitor may cause a sudden rise of potassium that can be potentially fatal.

Overall though, a moderate degree of renal dysfunction is an indication for ACE inhibition, so as to increase renal plasma flow. Their use in advanced CRF requires more caution, mainly because of potassium balance.

4.1. Use of diuretics
As renal function deteriorates, so does the response to diuretics. This may lead to problems with fluid retention and produce related symptoms such as oedema, ascites and (most seriously) pulmonary oedema. It is possible to increase the dose of loop diuretic — 500-mg tablets of frusemide are available — and these very high doses are sometimes used as a therapeutic challenge in oliguric states. As might be expected, there is a real risk of producing a critical reduction in renal plasma flow and consequent ATN, as well as disturbing potassium balance, or precipitating acute urinary retention in elderly men.

Alternative strategies for the treatment of resistant fluid retention include the use of i.v. diuretic instead, or using the equivalent dose of another loop diuretic (e.g. 1 mg bumetanide for 40 mg frusemide). The effect of i.v. diuretics may be potentiated by the concurrent administration of aminophylline or dobutamine. Oral metolazone in small doses (e.g. 2.5 mg twice weekly) may help but major electrolyte disturbances are frequently produced, and so close supervision is essential. Fluid restriction (to <1200 ml daily) and sodium restriction (to <50 mmol daily) may also be helpful, but has to be carefully monitored if renal function is impaired. In general terms, most patients with CHF prefer to be slightly ‘wet’ (i.e. jugular venous pulsation just visible, trace of ankle oedema) rather than ‘bone dry’, which produces thirst, lethargy and hypotension, and adds greatly to the misery of the condition. Finally, if fluid retention persists, then consultation with a nephrologist may be appropriate, to consider the option of using dialysis or ultrafiltration therapy.

The effect of diuretics on overall mortality remains to be formally tested, although it is unlikely that such a trial could be conducted in any patients with evidence of fluid overload. However, their role in the treatment of asymptomatic left ventricular dysfunction has been questioned. The independent effect of spironolactone, probably by virtue of its action as an RAAS antagonist, has been noted above [52]. Trials with conivaptan, an arginine vasopressin antagonist, are also currently underway [53].

4.2. Other treatments
Several other treatments have been shown to be of benefit in patients with CHF, either by reducing overall mortality, or by improving clinical endpoints such as exercise capacity or hospital admission rate. Digoxin is of undoubted benefit to patients in atrial fibrillation, and in patients with sinus rhythm, hospitalisations are reduced [54]. Excretion is dependent on renal function, and increased plasma levels cause anorexia, nausea, xanthopsia and cardiac arrhythmias. Close monitoring of plasma levels is, therefore, required if renal function is impaired. β-adrenoceptor antagonists such as bisoprolol, metoprolol and carvedilol reduce mortality as well [55–57], and are less likely to cause problems in the presence of renal dysfunction, but close supervision is still recommended. The role of EPO treatment and of phosphate binders is discussed above. In addition, in CRF, further studies are required to assess if folate and vitamin B6 and B12 supplementation improve cardiovascular outcome.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Acute renal failure
 3. Chronic renal failure
 4. Treatment of renal...
 5. Conclusion
References
 
Advanced CHF is a multi-system disease, characterised by neuroendocrine activation and fluid retention. Renal dysfunction is frequently associated with CHF. Renal failure may be due to reduced renal plasma flow and abnormal autoregulation of glomerular blood flow. Structural changes such as progressive nephrosclerosis may also contribute to declining GFR in CHF. Therefore, there must be constant and close monitoring of renal function in all patients with CHF, and in particular of potassium balance, in view of the complex interaction of underlying disease process and medication.


   References
Top
 Abstract
 1. Introduction
 2. Acute renal failure
 3. Chronic renal failure
 4. Treatment of renal...
 5. Conclusion
 References
 

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Effects of Multiple Oral Doses of an A1 Adenosine Antagonist, BG9928, in Patients With Heart Failure: Results of a Placebo-Controlled, Dose-Escalation Study
J. Am. Coll. Cardiol., August 14, 2007; 50(7): 600 - 606.
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 Eur J Heart FailHome page
T. Juhlin, S. Bjorkman, and P. Hoglund
Cyclooxygenase inhibition causes marked impairment of renal function in elderly subjects treated with diuretics and ACE-inhibitors
Eur J Heart Fail, October 1, 2005; 7(6): 1049 - 1056.
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 Eur Heart JHome page
Endorsed by the European Society of Intensive Care, Authors/Task Force Members, M. S. Nieminen, M. Bohm, M. R. Cowie, H. Drexler, G. S. Filippatos, G. Jondeau, Y. Hasin, J. Lopez-Sendon, et al.
Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The Task Force on Acute Heart Failure of the European Society of Cardiology
Eur. Heart J., February 2, 2005; 26(4): 384 - 416.
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 J Am Coll CardiolHome page
M. R. Mehra, P. A. Uber, and G. S. Francis
Heart failure therapy at a crossroad: are there limits to the neurohormonal model?
J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1606 - 1610.
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