The European Journal of Heart Failure 4 (2002) 125–130

Review
Influence of progressive renal dysfunction in chronic heart failure
A. Peter Maxwella, Hean Y. Ongb, 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

Received 4 September 2001; received in revised form 24 October 2001; accepted 29 October 2001

Abstract

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. 䊚 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.

Keywords: Chronic cardiac failure; Chronic renal failure

1. Introduction relate to reflex activation of the renin–angiotensin–

aldosterone system (RAAS) and arginine vasopressin
Renal failure is a frequent co-existing problem com- w10,11x.
plicating chronic heart failure (CHF), and impaired renal Three broad categories of renal dysfunction are recog-
function is associated with increased morbidity and nised, namely: acute renal failure; acute-on-chronic renal
mortality in patients with CHF w1x. Reduced glomerular failure; and chronic renal failure. Careful assessment of
filtration rate (GFR) is a strong independent predictor the clinical history and physical signs coupled with
of mortality in patients with CHF w2x. Patients in the interpretation of laboratory and radiological investiga-
lowest quartile of GFR (-44 mlymin) had a relative tions will usually point the clinician to the correct
risk of 2.85 when compared to those in the upper diagnosis and subsequent treatment of renal impairment.
quartile ()76 mlymin; P-0.001) w2x. Undoubtedly, a
major contribution to the reduction in GFR is a reduction 2. Acute renal failure
in renal plasma flow. Under normal circumstances at
rest, blood flow is distributed mainly to the hepatic– In the setting of CHF the most common type of acute
splanchnic (17–24%), renal (15–19%) and cerebral renal dysfunction is pre-renal azotaemia. Reduction in
(10–15%) circulation w3x. During exercise, up to 70% renal perfusion and consequent fall in GFR leads to
of blood flow is diverted to working muscle, at the reflex activation of the RAAS. The resulting autoregu-
expense of other areas w4x. In patients with CHF, there lation of glomerular capillary pressure and avid tubular
is an increase in peripheral resistance and reduction in reclamation of salt and water is an appropriate renal
cardiac output, both at rest w5,6x and during exercise response, which ultimately exacerbates heart failure. A
w7,8x, and a corresponding reduction in renal plasma high urinary specific gravity on dipstick urinalysis, low
flow w9x. Some of these haemodynamic changes may urine sodium concentration (-20 mmolyl) and high
urine osmolality ()1.5=plasma osmolality) are typical
*Corresponding author. Tel.: q44-28-9089-4951; fax: q44-28-
9026-3168. laboratory findings in pre-renal azotaemia. These simple
E-mail address: [email protected] investigations reflect the intact kidney’s response to high
(D.P. Nicholls). circulating aldosterone and vasopressin levels. Without

1388-9842/02/$ - see front matter 䊚 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.
PII: S 1 3 8 8 - 9 8 4 2 Ž 0 1 . 0 0 2 3 8 - 0
126 A.P. Maxwell et al. / The European Journal of Heart Failure 4 (2002) 125–130

improvement in the CHF an increasing proportion of linked to development of left ventricular hypertrophy
nephrons will be at risk of hypoxic injury leading to (LVH), left ventricular dilatation, myocardial fibrosis
progressive tubular dysfunction and eventual acute tubu- and calcification of both blood vessels and cardiac
lar necrosis (ATN). valves w22–26x. In addition, the metabolic milieu asso-
Patients with CHF are particularly susceptible to ATN ciated with uraemia leads to increased oxidative stress,
during periods of haemodynamic instability, sepsis, or oxidised low density lipoprotein and hyperhomocystei-
following the administration of nephrotoxic drugs and naemia, which are risk factors for atherosclerosis in the
radiocontrast agents. In contrast to pre-renal azotaemia, general population. Accumulation of advanced glyco-
the urinary sodium concentration is higher (typically ) sylation end-products (AGEs) and asymmetric dimethyl
40 mmolyl) and urinary osmolality lower (-1.5=plas- arginine (ADMA), an endogenous inhibitor of nitric
ma osmolality). Fortunately, ATN will usually recover oxide synthase, are putative risk factors for endothelial
if the patient’s clinical state can be improved or the dysfunction in renal failure patients.
offending nephrotoxic drug discontinued.
An important differential diagnosis of acute renal 3.1. Blood pressure and renal function
dysfunction in patients with CHF is renal atheroembol-
ism. This rarely occurs spontaneously but may occur An underlying chronic renal disease is the most
following interventions such as: angiography; angioplas- commonly identified cause of secondary hypertension
ty; vascular surgery; use of an intra-aortic balloon pump; and there is a direct correlation between elevated blood
or thrombolysis w12,13x. Cholesterol emboli result in pressures and risk of developing CRF w27x. Perhaps
obstruction of smaller renal arteries leading to ischaemia, surprisingly there has been controversy regarding the
inflammation, hypertension and renal failure. It is unu- relationship between hypertension and outcome in dial-
sual for renal function to recover to baseline levels ysis patients w28–30x. This is likely to reflect the impact
following renal atheroembolism. Clinical clues to renal of long-standing hypertension in patients with CRF that
atheroembolism include: other organ dysfunction; livedo results in concurrent cardiac failure with consequent
reticularis; petechial lesions; and lower limb digital reduction in blood pressure. In prospective studies,
ischaemia. Variable laboratory findings reported include: however, there is a definite association between raised
leucocytosis; eosinophilia; eosinophiluria; raised LDH mean blood pressure and progressive LVH, de novo
and ESR; and hypocomplementaemia w14–16x. Diag- cardiac failure and cardiovascular death w21,31x.
nosis is confirmed by renal biopsy where typical bicon-
cave clefts left by cholesterol crystals are seen in 3.2. Anaemia and cardiac function
arterioles w12x.
In chronic renal disease, anaemia secondary to relative
3. Chronic renal failure erythropoietin deficiency is also an important determi-
nant of LVH w32x. A compensatory hyperdynamic cir-
Chronic renal failure (CRF) and CHF in an individual culation develops in patients with reduced oxygen
patient poses many management problems. The most transport capacity due to renal anaemia. Distinct left
common causes of CRF are diabetes, hypertension, ventricular geometry patterns are recognised — concen-
glomerulonephritis and polycystic kidney disease. Car- tric LVH is associated with the pressure overload effect
diovascular disease is the leading cause of morbidity of hypertension, and eccentric LVH is linked to the
and mortality in patients requiring renal replacement volume overload related to anaemia w33x. The impor-
therapy, accounting for all most 50% of deaths w17,18x. tance of anaemia-induced LVH is underlined by the
Standard risk factors for cardiovascular disease such as finding that the eccentric pattern of LVH is twice as
hypertension, diabetes, smoking, dyslipidaemia and pre- frequent as the concentric pattern in patients with CRF.
existing atherosclerotic vascular disease are also risk In addition, anaemia is found in a considerable number
factors for progressive renal dysfunction w18,19x. In of patients with CHF w34x. The proportion increases in
addition to these ‘traditional’ risk factors, renal failure proportion with the severity of the disease and with the
itself may accelerate development of cardiovascular decline in renal function, from almost 20% of those in
disease and worsen prognosis in heart failure. Myocar- NYHA symptom grade II to almost 80% of those in
dial dysfunction is common in individuals with progres- NYHA grade IV.
sive renal dysfunction, with up to 80% of patients The poor prognosis associated with LVH in patients
having an abnormal echocardiogram prior to initiation with renal failure may be improved by optimal control
of dialysis, and over 30% of patients have evidence of of blood pressure and the correction of anaemia with
congestive heart failure at onset of dialysis w20,21x. recombinant erythropoietin (EPO) w35x. Partial or com-
CRF is associated with hypertension, anaemia, vol- plete regression of LVH with EPO treatment has been
ume overload, hyperparathyroidism and abnormal cal- reported presumably by improving myocardial oxygen
cium–phosphate metabolism. These factors have been supply and allowing a reduction in cardiac output and
 A.P. Maxwell et al. / The European Journal of Heart Failure 4 (2002) 125–130 127

workload. The main side effect of EPO treatment is a phosphate binders, should reduce the accelerated cardiac
rise in blood pressure which, unless vigorously treated, and arterial calcification (target -1.7 mmolyl).
will increase cardiac afterload and counterbalance the
benefit of anaemia correction. Correction of anaemia 4. Treatment of renal and cardiac dysfunction
also corrects the uraemic platelet dysfunction and
increases blood viscosity. Improving the outcome of CHF in patients with
The optimal haemoglobin (or haematocrit) to be chronic renal dysfunction can be achieved by focusing
targeted in patients with progressive renal dysfunction on treatable factors. Hypertension is a major contributor
is not yet established. One large randomised study of to morbidity in both conditions, and it has been shown
anaemia treatment in high risk haemodialysis patients that excellent control of blood pressure (target -140y
(i.e. those with CHF or coronary artery disease) was 90 mmHg) can retard the progression of diabetic and
stopped after interim analysis revealed an increased non-diabetic renal diseases w44–47x. The drug of choice
number of deaths and myocardial infarctions in the would be an ACE inhibitor, because of their additional
group with the higher target haematocrit w36x. However, beneficial effects on LVH and on outcomes in CHF
studies in patients with CHF have shown the benefit of w48–50x. However, several clinical problems may arise
maintaining the haemoglobin at approximately 12.5 gy with the use of such drugs. ACE inhibition may initially
dl using EPO and iron w37x — LVEF increased in the cause an acute fall in GFR with an accompanying rise
active treatment group, and the days in hospital in serum creatinine. A decrease in efferent arteriolar
decreased. A prospective randomised multi-centre study resistance will usually lead to a fall in glomerular
(CREATE) is now in progress to address the effects of capillary pressure and a decline in GFR. Autoregulation
optimal correction of haemoglobin on LVH and cardio- of glomerular blood flow can be further compromised
vascular outcome in pre-dialysis patients. by concurrent prostaglandin inhibition with non-steroidal
anti-inflammatory drugs (NSAIDs) w51x. The combined
3.3. Metabolic changes prescription of an ACE inhibitor and an NSAID should
therefore be avoided in patients with CHF.
As noted above, in CHF there is reflex activation of The initial dose of an ACE inhibitor may cause a
the RAAS in order to preserve central volume w38,39x. marked fall in blood pressure, which is not desirable in
The effect of this is to produce electrolyte abnormalities a patient with impaired renal perfusion, although this
that are often quite marked w40x, and compounded by effect is much less with ‘third generation’ drugs such as
diuretic use (see below). Circulating plasma levels of perindopril. The best plan therefore is to omit diuretic
the natriuretic peptides ANP and BNP are increased in therapy that day so as to avoid central volume depletion,
response to the volume expansion w41x. In severe CHF and to give the first dose of ACE inhibitor at night. In
there is also cachexia due to increased resting energy addition, many patients with CHF due to ischaemic
expenditure w42x and cytokine activation w43x. There is, heart disease have concurrent renovascular disease such
therefore, a resetting of many homeostatic mechanisms as renal artery stenosis and, on occasion, acute renal
even without any deterioration in renal function. failure may be precipitated. Finally, potassium balance
CRF is also associated with abnormal calcium and needs to be closely monitored. Levels may already be
phosphate metabolism that may have a subtle but pro- raised due to renal dysfunction or other medication,
found impact on cardiovascular morbidity. There is a such as spironolactone w52x, and the addition of an ACE
direct link between hyperphosphataemia and mortality inhibitor may cause a sudden rise of potassium that can
in patients with CRF w22x. Secondary hyperparathyroid- be potentially fatal.
ism and elevated calcium and phosphate levels have Overall though, a moderate degree of renal dysfunc-
been linked with accelerated calcification of coronary tion is an indication for ACE inhibition, so as to increase
arteries and cardiac valves w24,25x. Myocardial and renal plasma flow. Their use in advanced CRF requires
vascular endothelial cells express parathyroid hormone more caution, mainly because of potassium balance.
receptors, and it is postulated that hyperparathyroidism
contributes to myocardial dysfunction by uncoupling 4.1. Use of diuretics
oxidative phosphorylation, reducing cellular ATP con-
centrations and impairing calcium extrusion, leading to As renal function deteriorates, so does the response
calcium overload in cardiomyocytes. In addition, animal to diuretics. This may lead to problems with fluid
models have demonstrated that elevated parathyroid retention and produce related symptoms such as oedema,
hormone levels are associated with intra-myocardial ascites and (most seriously) pulmonary oedema. It is
fibrosis. Clinical studies however have been less consis- possible to increase the dose of loop diuretic — 500-
tent in linking hyperparathyroidism with cardiovascular mg tablets of frusemide are available — and these very
outcome. Nevertheless, vigorous management of hyper- high doses are sometimes used as a therapeutic challenge
phosphataemia, preferably with non-calcium containing in oliguric states. As might be expected, there is a real
128 A.P. Maxwell et al. / The European Journal of Heart Failure 4 (2002) 125–130

risk of producing a critical reduction in renal plasma 5. Conclusion

flow and consequent ATN, as well as disturbing potas-
sium balance, or precipitating acute urinary retention in Advanced CHF is a multi-system disease, characteri-
elderly men. sed by neuroendocrine activation and fluid retention.
Alternative strategies for the treatment of resistant Renal dysfunction is frequently associated with CHF.
fluid retention include the use of i.v. diuretic instead, or Renal failure may be due to reduced renal plasma flow
using the equivalent dose of another loop diuretic (e.g. and abnormal autoregulation of glomerular blood flow.
1 mg bumetanide for 40 mg frusemide). The effect of Structural changes such as progressive nephrosclerosis
i.v. diuretics may be potentiated by the concurrent may also contribute to declining GFR in CHF. Therefore,
administration of aminophylline or dobutamine. Oral there must be constant and close monitoring of renal
metolazone in small doses (e.g. 2.5 mg twice weekly) function in all patients with CHF, and in particular of
may help but major electrolyte disturbances are frequent- potassium balance, in view of the complex interaction
ly produced, and so close supervision is essential. Fluid of underlying disease process and medication.
restriction (to -1200 ml daily) and sodium restriction
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