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supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62

Alpha-blockers in Renal Disease :


Appraisal of Evidence
Natarajan Gopalakrishnan*, R Sakthirajan**, T Dineshkumar**

Introduction nephrectomy, in patients undergoing


dialysis or transplantation, normalises

I n patients of chronic kidney diseases


(CKD), the significance of cardiovascular
complications is well known. Progressive
the sympathetic activity. 1,2
Renal ischaemia is a very important
causative factor, as the accumulation of
decline in renal function is associated adenosine triggers central sympathetic
with increasing rates of hypertension and
o u t f l o w . I n c r e a s e i n a n g i o t e n s i n II
dyslipidemia.
is another crucial mechanism, which
Management of hypertension in CKD is may influence sy mpat het ic a c t i v i t y
a critical issue, as blood pressure is often via multiple mechanisms. Angiotensin
poorly controlled in early or advanced II may act on the vasomotor centre in
renal disease. Many factors contribute the brainstem, and may reset the blood
to the development of hypertension pressure homoeostasis to a higher level.
in CKD. Sympathetic overactivity It may also act on the sympathetic nerve
plays an important role, apart from terminals, to increase the release and
volume overload and increased renin- prevent the reuptake of norepinephrine.
angiotensin activity. This review is an Stimulation of carotid chemoreceptors is
attempt to understand the significance of also a likely mechanism, observable in
sympathetic activity in CKD and possible dialytic patients due to the underlying
ways to address the same, with a focus mild acidaemia and nocturnal
on the role of α-blockers. hypoxaemia. Reduction in nitric oxide
availability and oxidative stress also
Causes and Consequences: result in increased sympathetic activity.
Sympathetic Activity in Renal Ob esit y may influence sy mpa t h et i c
Disease activity through increased leptin and
insulin levels. In patients with CKD,
Causes of Increased Sympathetic Activity sympathetic activity induced by high
(Figure 1) s e r u m l e p t i n l e ve l s , c o n t r i b u t e s t o
The signals arising from the development of hypertension.
malfunctioning kidneys result in an Dyslipidaemia, observed commonly
increase in the sympathetic activity. in CKD, may enhance the α-1 pressor
This is evident by the fact that bilateral sensitivity or impair the functioning

 Sympathetic
Causes Consequences
Activity
e
osin
den LVH
A
Renal Ischaemia CCF
IHD
Aggravation Salt Retention
Dyslipidaemia AS  BP
Oxidative Stress R Volume Overload
O Glomerulosclerosis
Obesity N
Sleep apnoea  Atherogenesis
Smoking  Vascular Compliance
Professor and Head, ** Assistant
*

Professor, Nephrology; Madras


Endothelial Factors Hypercoagulability
Medical College, Chennai Fig. 1 : Causes and Consequences of Sympathetic Activity in Renal Disease
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62 35

of baroreceptor reflex. Sleep apnoea is frequently Vonend et al observed that in patients with chronic
observed in association with dialysis. The resultant renal failure (CRF) maintained on RAS inhibition,
hypoxaemia also stimulates sympathetic activity. add-on central sympatholytic moxonidine halted
CKD is associated with reduced availability of nitric the progression of renal insufficiency, relative to
oxide (NO), owing to multiple factors prompting CCB nitrendipine, with minimal influence on blood
a decrease in NOS activity, increase in levels of pressure.6 Moxonidine has also demonstrated
natural inhibitors of NO such as asymmetric dimethyl reduction in albuminuria in early kidney disease,
L-arginine (ADMA), and oxidative stress. Such a state despite no change in ambulatory blood pressure. 6 This
of reduced NO availability, enhances the hypertensive highlights the importance of sympathetic activity in
effect of sympathetic activity. Sympathetic overactivity human kidney disease.
may be genetically determined as well, with genes Apart from kidneys, increased sympathetic
like phosducin playing important roles. Some or all activity in renal disease, may significantly damage
of these mechanisms may jointly play a part, in the the cardiovascular system. Adverse cardiac outcomes
development of hypertension in patients with CKD. 1-3 include development of left ventricular hypertrophy,
In patients on dialysis, hypertension is perceived to cardiac dysfunction, arrhythmias or failure. Vascular
be largely volume dependent. However, the influence outcomes include increased arterial tone, vascular
of sympathetic overactivity cannot be understated stiffness, and atherogenesis, which may result in
in these patients. Sympathetic activity contributes complications. Alterations in haemostasis lead to
significantly to development of hypertension in renal increased coagulability. Even younger patients with
disease. renal disease may suffer from advanced coronary
Consequences artery disease. 1-4 Cardiovascular deaths account for
Sympathetic hyperactivity contributes to substantial mortality in CKD patients.
hypertension, and leads to significant damage to the
kidneys and the cardiovascular system. 1-5 In CKD, Role of α-Blockers
apart from the elevation in office BP, elevation in the In the Indian scenario, several drugs like clonidine
ambulatory BP and lack of diurnal variation in BP are and prazosin are commonly used, which are not
important clinical consequences. Ambulatory BP or represented in the international clinical guidelines of
circadian rhythm of BP are better predictors of clinical hypertension. 7 Post the observations from ALLHAT,
outcomes than office BP. Using these parameters, Cha regarding increased risk of cardiac failure with
et al demonstrated a significantly higher prevalence of doxazosin compared to chlorthalidone, the use of
masked and sustained hypertension in CKD patients. 5 α-blockers as first line antihypertensive therapy
Masked or sustained hypertension is increasingly has declined. 8 However, in combination with other
observed in proportion to the extent of kidney disease.5 antihypertensives, α-blockers have demonstrated
Addressing the increased sympathetic activity a good safety and efficacy profile as third line
assumes significant relevance, in the management of drugs. 9-11 The good lipid and glycaemic profile of
hypertension associated with renal disease. α-blockers also favour their utility in patients with
Increase in blood pressure may result in these comorbidities, which are commonly observed
glomerulosclerosis. This may be facilitated by podocyte with CKD. In the ASCOT trial, addition of doxazosin
injury mediated through adrenoceptors, independently as the third antihypertensive drug resulted in
of blood pressure. α-1 adrenoceptors are also involved improvements in BP control, without any increase
in vascular smooth muscle proliferation, resulting in in cardiac failure. 9 Similar results were observed
progression of atherosclerosis. Catecholamines can in a study by Ohta et al, which demonstrated the
also influence inflammatory activity in the tissues. beneficial effects of addition of low dose doxazosin
These adrenergic effects may contribute to kidney to RAS inhibitor and CCB combination regimens. 10
damage over a period of time, independently of blood The ZAFRA study, carried out in patients of chronic
pressure.1-3 In CKD, the availability of nitric oxide (NO) renal failure (CRF) with uncontrolled hypertension,
is reduced, which may increase the responsiveness evaluated the utility of α-blocker, as third add-on to
to sympathetic activity. In such a state, even a low RAS inhibitor and CCB. 11 Over 6 months of follow-up,
level of sympathetic activity may be detrimental to good antihypertensive effect was observed with the
kidneys, on account of increased hypertensive and addition of α-blocker to antihypertensive regimen,
inflammatory actions. 1,2 without any observations of increased cardiac failure. 11
Non-clinical and clinical studies have demonstrated These observations suggest a beneficial profile of
that inhibition of sympathetic activity slowed the α-blockers, when used as third line antihypertensive
progression of renal failure. Blockade of either of α drugs, including in patients with renal failure.
or β adrenergic receptors, has demonstrated renal Studies on α-blockers in patients with renal diseases,
protection, with additive effects on combination. have consistently demonstrated beneficial effects in
36 supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62

terms of effective BP reduction, preservation of renal various pathophysiological mechanisms lead to


function and haemodynamics, and metabolic benefits. hypertension. 19 Volume overload represents a very
In a study on patients with CRF, doxazosin therapy common problem in dialysis, which may also result
resulted in effective BP control, along with increase in in refractory hypertension. A resultant imbalance in
glomerular filtration and decrease in plasma BUN and RAS activity and ECF volume is frequently observed,
creatinine levels. 12 Reduction in BP was significantly leading to an increase in plasma renin activity.
correlated to reduction in proteinuria, over 6 months Increased sympathetic activity is an important feature,
of doxazosin therapy. Metabolic benefits were also resulting from the fluctuating fluid volumes during
evident with doxazosin therapy, in terms of reduction dialysis, apart from the several other causative factors
in triglyceride levels and increase in HDL cholesterol associated with kidney disease. Apart from volume,
levels. 12 A study by Yildiz et al evaluated the effects renin and sympathetic activity, other causative
of doxazosin on insulin resistance, in patients with associations for hypertension in dialysis include
CRF. Over 12 weeks of follow-up, insulin resistance erythropoietin replacement therapy, secondary
(assessed by HOMA and fasting insulin levels) hyperparathyroidism, nocturnal hypoxaemia and
significantly decreased with doxazosin therapy. 13 imbalance in endothelial vasoactive substances. 19
Another study by Erley et al evaluated the effects Management of hypertension may pose significant
of various drugs (administered for 12 weeks) on clinical challenges for the dialysis patients.
renal function, in hypertensive patients with non- Appropriate correction of volume overload is the
insulin dependent diabetes. 14 Doxazosin therapy most essential consideration, towards addressing
was associated with a significant improvement in the development of resistant hypertension.
creatinine clearance, which was more pronounced Pharmacotherapeutic approach during dialysis
as compared to captopril therapy. Also, doxazosin involves special considerations, as the kinetics of
therapy resulted in the reduction of proteinuria by many drugs may be influenced by physiological
34%, an effect consistently observed in each diabetic changes. 20-21 α1 blockers are largely bound to plasma
patient studied. 14 proteins, and are relatively stable during dialysis.
Chronic therapy with prazosin has demonstrated In a study by Vanholder et al, the protein binding
a fall in renovascular resistance, with the afferent capacity of prazosin fell by approximately ± 2% in
arteriole being the site of action, in principle. 15-17 This dialysis. 21 However, as prazosin is highly bound to
observation implies consistent renal vasodilatation plasma proteins (> 95%), even a modest increase in
during chronic prazosin therapy, which facilitates free drug concentration may have clinically relevant
preservation of renal function and renal blood flow, effects. Hence, careful titration of the dose may be
despite significant reduction of renal perfusion necessary and lower doses of up to 3 to 8 mg / day
pressure. Prazosin has also demonstrated a marked may be effective. 21-23 Good efficacy of prazosin has
decline in plasma renin activity, due to the complex been observed in all types of hypertensive patients
interplay between RAS and adrenergic systems on dialysis, either as monotherapy or in combination,
within the kidney. 15-17 α1 adrenergic blockade may with minimal side effects. 16,22,23 In patients with
complement β adrenergic blockade in balancing the intradialytic hypotension, use of α blockers should
renal haemodynamic alterations, as is discussed in be avoided. 20
subsequent sections. Hypertension in Renal Transplantation
α1 blockade is also associated with improvement Cardiovascular risk is significantly associated
in endothelial functioning. A study evaluated the with renal transplantation, and accounts for a huge
effect of doxazosin, carvedilol and atenolol, on mortality rate in these patients. Hypertension is
endothelial fibrinolytic activity and lipoprotein widely observed post transplantation, and poses
metabolism, in hypertensive patients with ischaemic risk for renal allograft dysfunction, as well as for
heart disease.18 Doxazosin therapy was associated with cardiovascular complications. 19 For each 10 mmHg
an improvement in endothelial fibrinolytic activity rise in systolic BP, the risk for allograft loss is
(before or after anoxia), and beneficial modifications in increased by 12% to 15%. 19 BP control is of prime
lipoprotein ratio. Carvedilol administration improved relevance in transplant recipients. Hypertension
endothelial fibrinolytic activity only after anoxia, may develop in transplant recipients due to multiple
and did not modify lipoprotein ratio. Atenolol did reasons. Apart from the causative factors observed
not improve fibrinolytic activity, and unfavourably in renal disease, dysfunction of the graft, or the use
modified lipoprotein ratio. 18 of immunosuppressant medications may contribute
Hypertension in Dialysis to high BP. 19 Pre-glomerular vasoconstriction may
Hypertension is very commonly observed in be an essential factor in hypertension, rather than
ESRD patients, which results in cardiovascular glomerular hypoperfusion. 24
morbidity and mortality. In patients on dialysis, In the pharmacological considerations
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62 37

for these patients, important considerations cardiac failure or dilated cardiomyopathy, the use of β
include renoprotection, favourable renovascular blockers has demonstrated reduction in cardiovascular
haemodynamics, minimisation of metabolic risk. 31-33 In CKD patients without pre-existing cardiac
complications, and efficacy in patients receiving comorbidities, the extrapolation of these cardiac
calcineurin inhibitors. α-blockers reduce peripheral benefits of β blockers is not proven. 30-32
resistance, preserve and may improve renal Various β-blockers differ in their receptor blocking,
haemodynamics, and preserve renal function. 19,24-27 pharmacologic and adjunctive properties, and have
Their use is associated with favourable metabolic variable effects on renal haemodynamics. The older
profile and minimal risk of hyperkalaemia. α-blockers nonselective agents, the cardioselective agents,
have also demonstrated good efficacy in patients and newer agents with vasodilating properties,
receiving cyclosporine. These characteristics make demonstrate markedly differing clinical profiles. Their
α-blockers preferable agents in renal transplant respective combinations with α blockers may have
recipients. 24-27 differing implications for clinical use.
A study compared the profiles of doxazosin and Nonselective β-blockers reduce the GFR and renal
enalapril monotherapies in a cross-over design, in blood flow, excepting the agents with vasodilatory
transplant recipients receiving cyclosporine. A similar effects. Labetolol has demonstrated conflicting
BP control was observed in both the groups, but evidence on renal haemodynamic alterations. 30
doxazosin was associated with better profile in terms Nonselective β-blockers like propranolol may cause
of renal function, potassium level, or haemoglobin. 27 a reflex increase in sympathetic activity, owing
Prazosin therapy has demonstrated good efficacy and to reduction in cardiac output and blockade of β2
tolerability profile, along with preservation of renal mediated vasodilatation. This results in unopposed
function. 26 Patients may respond to relatively smaller α1 activity, and unfavourable renal haemodynamics.
doses of these drugs, and initiation of therapy with Chronic administration of these agents could
lower doses, with gradual titration, should be the potentially exacerbate renal dysfunction. 30 A study
preferred approach. compared the effects of prazosin and propranolol, on
A long term study over 3 years, evaluated the renal perfusion changes in essential hypertension. 34
antihypertensive profile of doxazosin, enalapril and Following 1 month of therapy, prazosin, but not
verapamil in renal transplant recipients. 24 In long term, propranolol, was associated with preservation of
8 patients in each of the verapamil or enalapril groups, glomerular filtration rate, renal plasma flow, and
compared to only 4 patients in doxazosin group, lost renal blood flow. Addition of α1 blockade may thus
the graft due to chronic transplant nephropathy. Initial effectively counter the reflex vasoconstriction, and
tolerance to verapamil was poor, whereas enalapril may increase blood flow to skeletal muscle, thereby
use was associated with long term hyperkalaemia benefitting the glycaemic profile. 34 Nonselective
and coughing. Doxazosin was very well tolerated, β-blockers may also cause hyperkalaemia in ESRD
and relative hypotension was observed in only 2 patients, and in patients taking mineralocorticoid
patients. 24 First dose hypotension may be a concern, antagonists. α1 blockade may be protective against
particularly with the older standard formulations of this adverse effect, and may also facilitate sodium
α-blockers. This can be minimised with the use of slow excretion. 30
and sustained release formulations. Cardioselective β1-blockers may preserve renal
Combining α and β Blockers haemodynamics, and have been used successfully in
Combination of α and β blockers is a rational CKD patients. However, like the nonselective agents,
approach, for more effective and complete control of cardioselective agents may also result in insulin
the increased sympathetic activity. Apart from the resistance and worsening lipid profile, including
synergistic mechanisms of these two drug classes, increased triglyceride and decreased HDL cholesterol
additional safety advantages may be expected, levels. Addition of α1-blocker can effectively negate
particularly with regards to β-blocker use. α-blockers these adverse metabolic effects of β-blockers, by
are associated with good antihypertensive efficacy, improving insulin sensitivity, lowering triglyceride
metabolic benefits, favourable renal haemodynamics and increasing HDL cholesterol levels. Hence,
and reduction in risk of hyperkalaemia. While combination of α1 and β1 blockade may benefit
β-blockers offer less than adequate efficacy in diabetes as well as atherosclerotic vascular disease. 30
lowering BP and in vascular protection, most of The newer β blockers with vasodilating properties
these agents are associated with poor metabolic may be particularly recommended for patients
profile, hyperkalaemia or unfavourable renal with pre-existing cardiac comorbidities, including
haemodynamics. 28-30 In absence of cardiac disease, β coronary artery disease and heart failure. A study
blockers are not the preferred antihypertensive agents. evaluated the efficacy of carvedilol in patients
However, in chronic kidney disease associated with undergoing haemodialysis, and with coexistent
38 supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62

dilated cardiomyopathy. 32 In this study, the use of drugs in antihypertensive regimens. Combination of
carvedilol was associated with significant reduction α and β blockers may also be a rational approach in
in morbidity and mortality over 2 years, suggesting renal disease.
its possible benefits in dialysis patients with chronic
heart failure. 32 A meta-analysis suggested possible Acknowledgements and Disclosures
benefits of carvedilol in heart failure, in patients with
Dr Jignesh K Ved supported the development of
early, but not advanced CKD. 33 However, in terms
manuscript content. The information expressed in the
of antihypertensive efficacy, vascular protection
publication explicitly reflects the author’s opinion on
and metabolic advantages, evidence of superiority
the topic.
relative to α blockers is lacking. A study compared
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