Show Summary Details
Page of

Kidney disease 

Kidney disease
Chapter:
Kidney disease
Author(s):

Debasish Banerjee

, Robin Ramphul

, and David Goldsmith

DOI:
10.1093/med/9780198759935.003.0020
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

date: 18 October 2019

Introduction

CV events are commoner in CKD patients, and prognosis is poor; the pathophysiology in these patients is different from that in patients without CKD and is poorly understood. There are few robust clinical guidelines in this area, due to the fact that patients with CKD are systematically excluded from many major trials and nephrologists have not been able to conduct many appropriate interventional studies (and those that have been conducted frequently do not show positive findings). The rate of CV events increases and prognosis worsens in patients with reduced kidney function, which is worst in dialysis, with partial improvement with kidney transplantation. In clinical practice, pharmacotherapy is suboptimal, and despite appropriate treatment, patient prognosis remains poor. Hence, a better understanding of CV drugs among nephrologists, cardiologists, internists, and non-nephrologists is necessary for improved and timely care of these patients.

CKD patients are classified according to the eGFR and the level of proteinuria, as shown in Fig. 6.1.1. The Modification of Diet in Renal Disease Study (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are used to determine the stages of CKD; yet most studies use the Cockcroft–Gault equation to determine safe drug dosing in CKD patients. The differences between these different derived GFR values, while often clinically trivial, can sometimes be substantial. Patients on dialysis and those post-kidney transplantation are often referred to as CKD-D and CKD-T, respectively.

Fig. 6.1.1 CKD categories by eGFR and albuminuria and associated risk (KDIGO classification). Green = low risk (if no other markers of CKD: no CKD); yellow = moderate risk; orange = high risk; red = very high risk.

Fig. 6.1.1 CKD categories by eGFR and albuminuria and associated risk (KDIGO classification). Green = low risk (if no other markers of CKD: no CKD); yellow = moderate risk; orange = high risk; red = very high risk.

Renal elimination of drugs

Many drugs are filtered and excreted unchanged through the kidney. Other drugs are metabolized prior to excretion. Drug elimination through the kidney is determined by the following factors.

  • Drug filtration across the glomerulus: drug molecules of <20kDa and that are not protein-bound are filtered freely. When partially protein-bound, only free drug molecules are filtered through the glomerulus. The elimination of small free drug molecules decreases with progressive CKD.

  • Tubular secretion of drugs: this involves two types of transporters:

    • Organic anion transporters—these can transport across a concentration gradient and hence are very effective, e.g. glucuronides, sulfates, furosemide, bendroflumethiazide, probenecid, and penicillins. The secretion of transporter-dependent drugs decreases with decreasing kidney function.

    • Organic cation transporters, e.g. for morphine, pethidine, triamterene.

  • Diffusion across the tubular membrane: this is easier for lipid-soluble drugs and depends on the concentration gradient. The tubular fluid pH is very important for excretion of polar, non-lipid-soluble drugs, such as furosemide, digoxin, gentamicin, methotrexate, atenolol, penicillins, etc. For example, ionization is pH-dependent, and hence, alkaline urine favours the loss of phenobarbital.

Altered protein binding may affect drug elimination in the kidney, as described above. Inhibition of tubular excretion by certain drugs may affect the excretion of others, e.g. probenecid and penicillin/zidovudine; verapamil, amiodarone, quinidine, and digoxin; and aspirin, NSAIDs, and methotrexate. Some drugs can alter urine flow and urine pH, thereby affecting the elimination of other drugs, e.g. diuretics and lithium; and sodium bicarbonate and phenobarbital.

Management of acute coronary syndrome (STEMI/unstable angina/NSTEMI)

ACS is common in patients with CKD and those on dialysis. The incidence of NSTEMI is higher in CKD patients, although STEMI is also common, compared to the general population.1 Prognosis of CKD patients after MI is poor, and presentation can be atypical, with less obvious chest pain and more prominent HF. Often these patients do not receive optimal care, due to a lack of knowledge about the safety and efficacy of appropriate medicines which are routinely used in non-CKD patients. This section provides guidance, based on available evidence on the management of CKD (including dialysis and kidney transplant) patients with ACS. In mild CKD and an eGFR of >60mL/min/1.73m2, there is very little difference in management. However, knowledge about drug safety and efficacy is important for CKD stages 4 and 5 (see Table 6.1.1).2,3

Table 6.1.1 Pharmacotherapy of acute coronary syndrome in predialysis CKD and dialysis patients

Recommendation for use

Dose modification

Aspirin

Should be used in all CKD patients

Not necessary

Oral P2Y12 receptor antagonist

Should be considered in mild to moderate CKD patients only

No dose reduction necessary

β‎-blockers

Should be used in all CKD patients

Carvedilol and metoprolol require no dose modification. Dose reduction necessary for atenolol

ACEIs

Should be used in all patients

Dose reduction may be necessary, but kidney function and potassium levels should be monitored

Statins

Should be used in all patients

No dose reduction necessary

Fibrinolysis

Should be considered in all patients when PPCI is not available. PPCI is the therapy of choice

No dose reduction necessary

Glycoprotein IIb/IIIa antagonist

May be considered but increases the risk of bleeding

Dose reduction necessary

UFH

Should be considered in all patients

No dose reduction necessary

Other anticoagulants

Enoxaparin may be used, but with an increased risk of bleeding

Fondaparinux and bivalirudin may be considered, as they are associated with less bleeding in CKD stages 3–4

Enoxaparin requires dose reduction

Source data from Ibanez, B., et al, ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–177 and Roffi, M., et al, Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315.

Prehospital management

Transport time from the onset of chest pain to a hospital should be kept to a minimum. There is no direct evidence to support this statement in CKD patients, but kidney failure patients suffer sudden death due arrhythmias much more commonly than non-CKD cohorts. Hence, the time to reach hospital may be even more relevant to prevent out-of-hospital deaths.

Management in the emergency department

CKD patients presenting with chest pain are high risk, and if the initial ECG is non-diagnostic, then multiple ECGs are necessary, along with estimation of blood biomarkers such as serial troponin assays. Bedside echocardiography looking for RWMAs can be useful. Baseline troponin values are often elevated in predialysis CKD and dialysis patients, and so a rising troponin is necessary to establish a diagnosis of ACS.

Aspirin

Aspirin 150–375mg should be given to chew, as there is some trial and observational study evidence that aspirin therapy is associated with lower mortality, without a significant increase in the risk for bleeding in CKD patients. Observational data show benefit in both predialysis CKD and dialysis patients.

Clopidogrel

Clopidogrel reduces further events in mild to moderate CKD, without a marked increased risk for bleeding, as demonstrated in further analyses of RCTs (loading dose of 300mg, maintenance dose of 75mg od) in ACS patients. Prasugrel (loading dose of 60mg and maintenance dose of 10mg od) and ticagrelor (loading dose of 180mg and maintenance dose of 90mg bd) have both been shown to be better than clopidogrel in patients with mild CKD, similar to those without CKD, without an increased risk for bleeding, although none has been tested in ESRD patients. All antiplatelet agents should be used with caution due to an increased risk for bleeding.

Morphine

Morphine can be administered for pain at 4mg IV, followed by 2–8mg every 15min (caution: the metabolites accumulate and can cause toxicity). It may also impact antiplatelet action, e.g. delaying the onset of, and decreasing exposure to, ticagrelor.

Nitrates

Nitrates may be used for pain control, provided the SBP is >90mmHg, in all CKD patients.

Oxygen

Oxygen, if indicated in the presence of hypoxaemia on pulse oximetry, can be administered in all CKD patients.

Beta-adrenergic blocking agents

These agents are proven to improve outcome post-MI. Short-acting drugs are preferred. Long-acting drugs require careful monitoring of heart rate. Carvedilol, metoprolol, and bisoprolol (10mg daily if eGFR is <20mL/min/1.73m2) are all safe to use. Atenolol tends to accumulate, due to its renal clearance, and hence a dose reduction may be necessary for safety (maximum dose of 50mg daily if the eGFR is 15–30mL/min/1.73m2; maximum dose of 25mg daily if the eGFR is <15mL/min/1.73m2). Large observational studies support the use of β‎-blockers in both predialysis and dialysis patients, with a 30-day mortality reduction of 30% and 22%, respectively.

Angiotensin-converting enzyme inhibitors

Use of ACEIs is associated with improved outcome in post-MI patients with LV dysfunction. However, they may be associated with hyperkalaemia and worsening kidney function in predialysis patients. So if judged necessary, they should be used with careful monitoring of creatinine and potassium levels. The new oral potassium binders may help with the management of hyperkalaemia in CKD patients on ACEIs if the potassium level is >5.5mEq/L. However, they have not been tested in ACS patients.

Mineralocorticoid receptor blockers

Although aldosterone blockers have been recommended for post-MI patients with LV systolic dysfunction, their use is restricted in patients with significant CKD and high potassium levels because of the risk for hyperkalaemia.4

Fibrinolysis

Data on fibrinolysis are limited to a pooled analysis of RCTs and observational cohorts. There is some evidence of an increased risk for intracranial haemorrhage in patients with severe CKD, from 0.6% in patients with normal eGFR of >90mL/min/1.73m2 to 3% in those with severe CKD (eGFR <30mL/min/1.73m2). However, large observational studies indicate no difference in in-hospital mortality with fibrinolysis in moderate CKD and higher mortality with severe dysfunction. Angiographic flow after fibrinolysis was similar in patients with severe CKD. Hence, fibrinolysis can be an option in patients with all stages of CKD when PCI is not available.

Primary percutaneous coronary intervention

There is high-grade evidence of benefits of PPCI for the management of patients with STEMI in the general population. Data from large observational studies suggest a decrease in mortality with PPCI in CKD patients with eGFR of 30–59mL/min/1.73m2. However, contrast-induced acute kidney injury (AKI) in patients undergoing PPCI is commoner in patients with significant CKD (21% risk with creatinine level of >133micromol/L versus 6% in those with creatinine levels <133micromol/L), which, in turn, is associated with an increased risk of death and dialysis. Hence, use of low-volume and iso-osmolar contrast, with adequate rehydration, is necessary, with use of normal saline and, in selected cases, N-acetylcysteine and sodium bicarbonate, particularly in patients with CKD stages 3b and 4 and stage 3a with other risk factors, including diabetes.5 However, a recent study of CKD stage 3 did not show benefits of hydration.6 The benefits of PPCI outweigh the risk associated with contrast-induced AKI, and hence, it should be offered to patients with CKD and post-kidney transplantation, with adequate hydration and a minimum possible volume of contrast.2 Patients on haemodialysis or peritoneal dialysis may be offered PPCI. However, the benefits are not clear, despite a very high mortality, up to 73% at 2 years.

Statins

Post-MI statin treatment is associated with improved 1-year mortality in patients with CKD stages 2–4 in a retrospective analysis. An RCT of simvastatin treatment in primary prevention reduced atherosclerosis events by 17% in both CKD and haemodialysis patients.7 There are several observational studies which have demonstrated improved outcomes in post-ACS patients. Thus, there is evidence for use of statins in both primary and secondary prevention of atherosclerotic artery disease.

Glycoprotein IIb/IIIa antagonist therapy

Glycoprotein IIa/IIIb therapy in CKD patients is associated with some reduction in ischaemic events, but an overall increase in bleeding events. If used, doses should be reduced for eptifibatide (50% reduction for eGFR <50mL/min/1.73m2; after ACS: 180mcg/kg bolus, followed by an infusion of 1mcg/kg/min for up to 72h) and tirofiban (25mcg/kg IV over 3min, followed by an infusion of 0.075mcg/kg/min for up to 18h post-PCI; if eGFR <30mL/min/1.73m2).

Anticoagulation

UFH remains the recommended anticoagulation agent by major guidelines for ACS, both STEMI and NSTEMI. It is mainly cleared by the reticuloendothelial system and very minimally by the kidney.

Enoxaparin in patients with moderate CKD provides an added benefit but has an increased risk for bleeding, even with a dose adjustment of 1mg/kg/day. Fondaparinux, compared to enoxaparin, was associated with better outcome in moderate CKD with unstable angina and NSTEMI (GFR <58mL/min) but has not been tested in patients with severe kidney failure, and it is excreted through the kidneys. Bivalirudin is similar in efficacy, compared to UFH, but may be expected to have less major bleeding complications in moderate CKD; it has not been tested in severe CKD (reduce the rate to <1.4mg/kg/h if eGFR is 30–60mL/min/1.73m2). Thus, the newer agents have not been tested in patients with severe CKD and are not associated with significantly improved outcome.

Management of heart failure in chronic kidney disease

Kidney disease in patients with HF is common, is associated with poor prognosis, and is often difficult to manage due to associated biochemical abnormalities.

CKD, present normally in around one-third of chronic HF patients, and worsening renal function in patients during admissions for acute HF, which occurs in one-tenth of patients, are both associated with high mortality.

HFpEF in patients with CKD is probably as common as HFrEF but is difficult to diagnose, as fluid overload due to CKD has the same symptoms and signs as does congestion due to HF. HF in patients on dialysis is associated with very high mortality, and even a diagnosis of ‘fluid overload’ (which is often clinically conflated with HF) is equally serious.

Patients with CKD stages 1–3 have often been included in clinical trials of HF by chance, but those with CKD stages 4–5 and dialysis patients have been routinely excluded.8 Thus, there is some evidence to support the use of most guideline-recommended life-prolonging therapy in CKD stages 1–3, but such evidence in CKD stages 4–5 and in dialysis and post-kidney transplantation patients is worryingly lacking.

Management of HF involves symptom control and use of drugs to improve survival. Management of chronic HF patients with CKD requires careful use of ACEIs/ARBs, β‎-blockers, and mineralocorticoid inhibitors to improve prognosis, while monitoring serum creatinine and potassium levels. Management of acute decompensated HF may require large doses of diuretics and cautious use of ACEIs/ARBs or MRAs, again with regular monitoring of serum creatinine levels and electrolytes (see Table 6.1.2).

Table 6.1.2 Pharmacotherapy in patients with CKD and heart failure

Agents

CKD stages 1, 2, and 3

CKD stages 4 and 5

ACEIs

Should be used in all patients with HFrEF, with monitoring of creatinine and potassium levels

May be used in HFrEF patients, with monitoring of creatinine and potassium levels. Dose modification may be necessary

β‎-blockers

Should be used in all HFrEF patients

May be used in HFrEF patients

Mineralocorticoid receptor antagonists

Should be used in HFrEF, with careful monitoring of potassium levels

May be used in HFrEF patients, with caution and monitoring of potassium levels

ARBs

Should be used in all HFrEF patients with caution

May be used in HFrEF patients, with monitoring of creatinine and potassium levels

Ivabradine

May be used in HFrEF patients in sinus rhythm and already on ACEIs and β‎-blockers

Unknown effects

Hydralazine and isosorbide dinitrate

Should be considered in HFrEF patients intolerant to ACEIs/ARBs

May be considered in HFrEF patients intolerant to ACEIs/ARBs

Source data from Ponikowski P, et al, Authors/Task Force Members, Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.

ACE inhibitors in patients with heart failure and chronic kidney disease

Subgroup analysis of several RCTs of ACEIs in HF patients with CKD have shown benefits, with a reduction in mortality and hospitalizations with enalapril and lisinopril in CKD patients with an eGFR of <60mL/min/1.73m2 and <45mL/min/1.73m2, respectively. Angiotensin receptor blockers can be used in patients intolerant of ACEI.

Use of ACEIs and ARBs together is associated with adverse outcomes, such as hyperkalaemia and AKI, even in non-CKD patients, and hence, dual blockade in CKD patients is not recommended.

Beta-blockers in patients with heart failure and chronic kidney disease

Data from trials with metoprolol and carvedilol have suggested improvement in all-cause mortality in CKD patients with an eGFR of <60mL/min/1.73m2. Carvedilol has been shown to be beneficial in a small RCT of dialysis patients.9 β‎-blockers should be used in all HFrEF patients. Evidence suggests nebivolol may be useful in elderly HFpEF and HFmEF patients.8

Mineralocorticoid receptor antagonists in heart failure and chronic kidney disease

These agents are proven to be beneficial in patients with HFrEF who remain symptomatic after adequate treatment with ACEIs and β‎-blockers, and after an MI. Close to half of the patients in a large RCT of spironolactone and one-third of those in a trial of eplerenone had an eGFR of <60mL/min/1.73m2 at baseline and benefited from therapy. Hence, these drugs should be used in CKD patients with HFrEF.

Hyperkalaemia is common in patients with HF and CKD, particularly in those on ACEIs and MRAs. Potassium levels of >5.5mmol/L may be present in one-third of patients with CKD stages 4 and 5, which may require careful management to maximize the use of ACEIs and MRAs, including use of loop diuretics, correction of metabolic acidosis, advice on low-potassium diet, and, in the future, on use of novel potassium binders.

Ivabradine

Trials of ivabradine included patients with an eGFR of <60mL/min/1.73m2. However, no trial has included patients with CKD stages 4 and 5. Benefits may exist in CKD stage 3, but further evidence is needed.

Diuretic therapy

Diuretics are key in treating and preventing fluid overload in patients with HF and CKD. Patients with chronic HF and CKD stages 1–3 may benefit from thiazide diuretics. However, patients with CKD stages 4–5 may need loop diuretics, as thiazide diuretics are less effective with an eGFR of <30mL/min/1.73m2. Use of loop diuretics can be challenging, due to changes in creatinine and electrolytes, although helpful in tempering RAAS-induced hyperkalaemia. In acute decompensated HF, both continuous and bolus IV loop diuretics are equally effective in achieving symptom control. Adequate diuretic therapy combining different agents remains the mainstay in relieving congestion in acute decompensated HF, even compared to ultrafiltration. A combination of a loop diuretic and a potassium-sparing diuretic may help prevent hypokalaemia, although this is unusual in advanced CKD. Hyponatraemia is common with diuretics particularly thiazides, which is managed by diuretic dose reduction, fluid restriction, and in future may be with vasopressin receptor antagonists. In HF patients on dialysis, who may have very low urine output, fluid removal during dialysis is often associated with symptomatic intradialytic hypotension and may require daily isolated ultrafiltration.

Neprilysin and angiotensin receptor blocker

The role of the sacubitril/valsartan combination is established in non-CKD patients but is yet to become widely used. An RCT showing benefit in HF patients excluded patients with an eGFR of 30mL/min/1.73m2 or less and further excluded patients with rising creatinine levels of >2.5mg/dL during the run-in phase. It may be used in stable CKD stages 1–3; in CKD 4 up to eGFR 20ml/min/1.73m2.

Management of arrhythmias in chronic kidney disease

Supraventricular tachyarrhythmias are usually associated with narrow QRS complexes. They can be sustained or paroxysmal, originating from the atria, the AVN, or AV accessory pathways. AF is the commonest of such arrhythmias, and its management is discussed separately in Kidney disease Management of atrial fibrillation in chronic kidney disease, pp. [link][link]. Acute management of paroxysmal supraventricular arrhythmias requires the use of IV adenosine or verapamil/diltiazem. An initial episode of atrial flutter requires cardioversion, but recurrent episodes may require sotalol, dofetilide, disopyramide, amiodarone, or catheter ablation, unless the patient is haemodynamically unstable, needing urgent cardioversion (see Table 6.1.3).

Table 6.1.3 Antiarrythmia agents, route of elimination, half-life, and dose adjustments in CKD

Drug

Elimination

Half-life (h)

Renal dose adjustment

Atenolol

Renal

6–9

eGFR 15–35mL/min/1.73m2: max 50mg od

eGFR <15mL/min/1.73m2: max 25mg od

Acebutolol

Renal/hepatic

6–7

eGFR 25–50mL/min/1.73m2: half dose

eGFR <25mL/min/1.73m2: quarter dose

Metoprolol

Hepatic

3–8

None

Nadolol

Renal

10–24

eGFR <50mL/min/1.73m2: increase dose interval

Sotalol

Renal

12

eGFR 30–60mL/min/1.73m2: half dose

eGFR 10–30mL/min/1.73m2: quarter dose

eGFR <10mL/min/1.73m2: avoid

Verapamil

Hepatic/renal

4.5–12

None

Diltiazem

Hepatic

3–4.5

Lower starting dose

Flecainide

Hepatic 75%/renal

7–22

eGFR <35mL/min/1.73m2: reduce dose, max 100mg od

Mexiletine

Hepatic

10–14

Disopyramide

Renal 50%/hepatic

4–10

Reduce dose

Quinidine

Hepatic 75%/renal

6–8

Caution

Propafenone

Hepatic

2–8

None

Dofetilide

Renal

10

Avoid

Amiodarone

Hepatic

40–55

None

Dronedarone

Hepatic

13–19

eGFR <30mL/min/1.73m2: avoid

Digoxin

Renal

38–48

Reduce dose, monitor plasma level

Ventricular arrhythmias are associated with wide QRS. They originate from the ventricular myocardium or the His–Purkinje system and include premature ventricular beats, sustained and non-sustained ventricular arrhythmias, and VF. They are common in all CKD patients and particularly those on dialysis, and they are the most frequent cause of death. Several drug classes are recommended in ventricular arrhythmias, including β‎-blockers, CCBs (diltiazem, verapamil), sodium channel-blocking agents (mexiletine, disopyramide, flecainide, propafenone), potassium channel-blocking agents (sotalol, dofetilide), and amiodarone. Despite the fact that ICDs are the most effective agents in the prevention of SCD due to ventricular arrhythmias, and bearing in mind that there is a 6.5% rate of SCD in patients on haemodialysis, most patients on haemodialysis are not eligible for ICD therapy, according to current guidelines. A retrospective analysis of ICD use in dialysis patients has failed to demonstrate benefits and has shown high rates of associated infections. A prospective trial using a wearable defibrillator is ongoing.

Management of atrial fibrillation in chronic kidney disease

AF is a common arrhythmia in patients with CKD, with a prevalence estimated to be 20% in the non-dialysis-dependent CKD population and between 13% and 27% in the chronic dialysis-dependent CKD population. There is an elevated risk of thromboembolism, particularly stroke, and bleeding, when compared to the general population without CKD. The most effective way to reduce the risk of thromboembolism in the general population is through anticoagulation, but the higher bleeding risk, especially in those on dialysis, complicates management, often resulting in underuse of anticoagulation in this high-risk group. The large trials supporting the use of anticoagulation to reduce the risk of stroke in non-valvular AF (NVAF) have largely excluded patients with moderate to severe renal impairment (eGFR <30mL/min/1.73m2), and data in the CKD and dialysis populations are limited to observational studies only and often have conflicting messages (see Table 6.1.4). Thus, it is unclear whether anticoagulation is safe and effective at reducing the risk of stroke in the CKD population. Catheter ablation for AF in CKD patients is relatively safe in expert hands but is less effective than non-CKD patients.

Table 6.1.4 Anticoagulation for atrial fibrillation in CKD

Recommendation for use

Dose modification

Aspirin

No evidence of benefit

Not necessary

Warfarin

Should be considered for prevention of stroke and systemic thromboembolism in CKD stages 1–5. May reduce stroke risk in CKD, but not in dialysis, patients. Bleeding risk appears to be elevated in dialysis patients

No dose reduction necessary, but more frequent monitoring of INR/prothrombin time may be required to maintain within target range

Apixaban

Should be considered for prevention of stroke and systemic thromboembolism in CKD stages 1–3. May be considered for use in CKD stages 4–5 and dialysis

5mg bd if eGFR >30mL/min/1.73m2 (or 2.5mg bd if age >80 or weight <60kg). Reduce to 2.5mg bd if eGFR <30mL/min/1.73m2 and use with caution, particularly in CKD stage 5 on dialysis (FDA approval only)

Dabigatran

Should be considered for prevention of stroke and systemic thromboembolism in CKD stages 1–3. May be considered for use in CKD stage 4

110–150mg bd if eGFR ≥30mL/min/1.73m2 (avoid if eGFR <30)

Edoxaban

Should be considered for prevention of stroke and systemic thromboembolism in CKD stages 1–3. May be considered in CKD stage 4

60mg od if eGFR ≥50mL/min/1.73m2. Reduce to 30mg od if eGFR 15–49mL/min/1.73m2. Use with caution if eGFR <30mL/min/1.73m2. Contraindicated if eGFR <15mL/min/1.73m2

Rivaroxaban

Should be considered for prevention of stroke and systemic thromboembolism in CKD stages 1–3. May be considered in CKD stage 4

20mg od if eGFR ≥50mL/min/1.73m2; 15mg od if eGFR 15–49mL/min/1.73m2. Use with caution if eGFR <30mL/min/1.73m2. Avoid if eGFR <15mL/min/1.73m2

Source data from Kirchhof P, et al, 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–2962.

Stroke and systemic thromboembolism prevention

Aspirin

There is no evidence to suggest aspirin is effective at reducing the risk of stroke in patients with AF and CKD or those on dialysis, although there is an increased risk of bleeding. Therefore, in patients at an increased risk of stroke, aspirin monotherapy should not be used in the place of anticoagulation.

Aspirin and warfarin

Combination therapy with aspirin and warfarin did not reduce the risk of stroke in one study, but the risk of significant bleeding was increased. Therefore, this combination should be avoided.

Warfarin

There are no RCTs investigating the effect of warfarin on stroke risk reduction in the CKD population with AF. Observational data have been conflicting, with some studies reporting a reduced incidence of stroke, while others reported no significant difference and even an increased risk of stroke.10 Similarly, the risk of significant bleeding with warfarin was increased. In a meta-analysis consisting of 11 studies, in a total of >48,500 patients including >11,600 warfarin users, warfarin was associated with a significant reduction in the risk of stroke and no effect on major bleeding in the CKD population. Contrary to this, however, warfarin had no effect on the risk of stroke but significantly increased the risk of bleeding in the dialysis population. Hence, warfarin may reduce the risk of ischaemic stroke in the CKD population without a significant increase in the risk of haemorrhage, but in the dialysis population, warfarin may not reduce the risk of ischaemic stroke but increase the risk of occurrence of major bleeding. Warfarin is given at variable doses, adjusted to a target INR of 2.5. Close monitoring of the INR to ensure it remains within the specified range of 2–3 may help to reduce the risk of stroke, while minimizing the risk of significant haemorrhage. However, recent data suggest that the time within the therapeutic range in CKD and dialysis patients is significantly lower than in non-CKD cohorts, despite best efforts.

Direct oral anticoagulants

Unlike warfarin, DOACs have predictable pharmacokinetics and do not require frequent monitoring and have fewer diet and drug interactions.11 They all undergo renal excretion, albeit to varying degrees, and therefore, the risk of bleeding increases with the severity of renal impairment. As a result, dose modification is recommended.

Apixaban

Apixaban is an oral, irreversible direct factor Xa inhibitor, given at 5mg bd or 2.5mg bd if any two of the following three conditions are present: age ≥80 years, body weight ≥60kg, or serum creatinine ≥133micromol/L. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial demonstrated that apixaban, when compared to warfarin, was associated with a reduced risk of stroke, thromboembolism, major bleeding, and all-cause mortality in patients with moderate CKD (eGFR <50mL/min/1.73m2). However, patients with moderate to severe renal dysfunction (i.e. eGFR <25mL/min/1.73m2) were excluded from the study. There have been no studies investigating the efficacy and safety of apixaban in patients with severe renal dysfunction (eGFR <25mL/min/1.73m2). Although the US FDA has approved apixaban for use in severe renal impairment, including in patients on dialysis, this recommendation was based on pharmacokinetic data obtained from two open-label, parallel-group, single-dose studies, which included seven patients with an eGFR of <30mL/min/1.73m2 and not on dialysis and eight patients with ESRD on haemodialysis.12 Until further more robust evidence is obtained, apixaban should be used with considerable caution in patients with moderate to severe renal impairment (eGFR <25mL/min/1.73m2) and particularly in dialysis patients. Any such patient offered apixaban should be informed of the data limitations, and alternative anticoagulation such as warfarin considered.

Dabigatran

Dabigatran is an oral, reversible direct thrombin inhibitor. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial showed that, at a dose of 150mg bd, dabigatran, when compared to warfarin, resulted in lower rates of stroke and systemic thromboembolism and no significant difference in the rate of major bleeding across the range of renal function groups. A lower dose of dabigatran 110mg bd resulted in few major bleeds, when compared to warfarin, but similar stroke risk reduction across the renal function groups. Patients with an eGFR of <30mL/min/1.73m2 were excluded from the RE-LY study. However, using pharmacokinetic modelling, the US FDA has approved dabigatran at a reduced dose of 75mg bd for NVAF in patients with an eGFR of 15–30mL/min/1.73m2. There are very few data to support the use of dabigatran in this severe renal impairment population, and until more robust studies have investigated the efficacy and safety of dabigatran in this patient population, it should be used with extreme caution, with consideration given to alternative anticoagulants such as warfarin, and patients should be clearly informed of the data limitations. Dabigatran is contraindicated in patients on dialysis and with an eGFR <15mL/min/1.73m2.

Edoxaban

Edoxaban is an oral, reversible direct factor Xa inhibitor, given at 60mg od for patients with an eGFR of >50mL/min/1.73m2 and 30mg od for those with an eGFR of 15–50mL/min/1.73m2. The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial was a large multicentre RCT comparing two dose regimens of edoxaban with warfarin (60mg and 30mg od) and included patients with an eGFR of up to 30mL/min/1.73m2. When compared to warfarin, both doses of edoxaban were similar in terms of efficacy in preventing stroke and systemic embolism and were associated with significantly lower rates of bleeding and death from CV causes. Pharmacokinetic data were used to support edoxaban at a reduced dose of 30mg od for severe renal impairment (eGFR 15–30mL/min/1.73m2), and it should be used with caution in the absence of robust clinical studies in this subgroup. Consideration should be given to alternative anticoagulants, such as warfarin, in this scenario, and patients should be clearly informed of the data limitations. Edoxaban is contraindicated in patients on dialysis and with an eGFR of <15mL/min/1.73m2.

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial was a large multicentre RCT comparing rivaroxaban to warfarin. The trial demonstrated a trend, albeit not statistically significant, towards a lower risk of stroke, systemic embolism, and fatal bleeding in the moderate renal impairment subgroup (eGFR 30–49mL/min/1.73m2), compared to warfarin. The recommended dose is 20mg od for eGFR of >50mL/min/1.73m2 and 15mg od for eGFR of 15–49mL/min/1.73m2, although there is little clinical evidence to support the use of rivaroxaban in patients with an eGFR of <30mL/min/1.73m2, and it should be used with caution in this patient population. There are no clinical data for eGFR of <15mL/min/1.73m2, and therefore, rivaroxaban is not recommended in this population.

Rhythm control in atrial fibrillation

Pharmacological cardioversion therapies

Flecainide

Flecainide is a sodium channel blocker with antiarrhythmic class 1c properties. It has been shown to prevent paroxysmal AF, compared to placebo, in the general population, and in selected patients, it has been shown to be feasible and safe when it is self-administered out-of-hospital (pill-in-pocket approach). Thirty-five per cent is excreted unchanged in the urine. A dose reduction is recommended in renal impairment (eGFR <35mL/min/1.73m2).

Propafenone

Propafenone is a sodium channel blocker and a class Ic antiarrhythmic agent. It is used in the treatment of paroxysmal AF and cardioversion of AF to sinus rhythm. In selected patients, it has been shown to be feasible and safe when it is self-administered out-of-hospital (pill-in-pocket approach). It undergoes extensive first-pass metabolism in the liver, producing metabolites with antiarrhythmic activity similar to propafenone. Less than 1% of propafenone and 38% of its metabolites are excreted unchanged in the urine. It should be used with caution and initiated under hospital conditions, with ECG and BP monitoring.

Amiodarone

Amiodarone is a class III antiarrhythmic agent but has other mechanisms of action, exhibiting class I, II, and IV activity also. It is used in the treatment of acute symptomatic AF for both rate control and cardioversion to sinus rhythm; paroxysmal and persistent AF to maintain sinus rhythm; and permanent AF for rate control when other interventions have failed or are not tolerated. Amiodarone has been shown to increase the success rate of electrical cardioversion if given up to 4 weeks beforehand, but because of the potential for side effects, this is not routinely recommended. It may be appropriate in cases where electrical cardioversion is unlikely to be successful or if a previous attempt has failed. Amiodarone is metabolized in the liver and excreted through hepatic and biliary routes, with almost no elimination via the kidneys. No dose adjustment is needed in mild renal impairment, but it is best avoided in severe renal failure. Thyroid dysfunction and pulmonary toxicity remain concerns with long-term use.

Sotalol

Sotalol is a non-selective β‎1-adrenergic receptor antagonist that has class II and III antiarrhythmic activity. It is indicated in the treatment of paroxysmal and persistent AF to maintain sinus rhythm and has been shown to increase the success rate of electrical cardioversion if given up to 4 weeks beforehand, but because of the potential for side effects, this is not routinely recommended. It may be appropriate in cases where electrical cardioversion is unlikely to be successful or if a previous attempt has failed. Sotalol is not metabolized, and 70% is excreted unchanged via the kidneys. Doses should be reduced by 50% in moderate renal impairment (CrCl 30–60mL/min/1.73m2) and by 75% in severe renal impairment (CrCl 10–30mL/min/1.73m2). Sotalol should be used with caution in renal impairment, hypokalaemia, and hypomagnesaemia and in the elderly because of its proarrhythmic effects.

Dronedarone

Dronedarone is an antiarrhythmic drug, similar to amiodarone in structure and which exhibits class I, II, III, and IV antiarrhythmic activity. There is less risk for thyroid dysfunction and lung toxicity, compared to amiodarone. It is used in non-permanent AF to maintain sinus rhythm and to control the ventricular rate. Serum creatinine levels are increased as a result of partial inhibition of the tubular organic cationic transporter system, rather than causing renal dysfunction. It undergoes extensive first-pass metabolism and, along with its metabolites, is excreted predominantly in faeces (84%), with 6% undergoing renal excretion mainly as active and inactive metabolites. No pharmacokinetic difference was observed in patients with mild to severe renal impairment, and no dose adjustment needs to be made for renal impairment. It is contraindicated in moderate to severe HF (NYHA classes III and IV), as it has been shown to be associated with increased mortality in these patient populations.

Ibutilide

Ibutilide is an IV antiarrhythmic agent used for cardioversion of resistant AF to sinus rhythm. It is well tolerated in renal impairment, but caution should be exercised in hypokalaemic and hypomagnesaemic states, as it may increase the risk for arrhythmias (TdP). It is unavailable in Europe.

Dofetilide

Dofetilide is renally excreted and needs dose adjustment in renal impairment, as there is an increased risk for ventricular arrhythmias. However, it is not available in Europe and Australia.

Management of hypertension in chronic kidney disease

Hypertension (see Table 6.1.5) is both a cause and a consequence of CKD. High BP levels are associated with a higher CV risk in CKD patients. However, the relationship of BP with CV events is often not clear in dialysis patients where low BP levels are also associated with poor outcomes and may represent severe cardiomyopathy. Management of high BP in patients with CKD is aimed at reducing CV events and the progression of renal impairment, and the strategy employed is determined by the presence of coexisting comorbidities, especially diabetes and other CV diseases, albuminuria, age, risk of progression of CKD, the presence of retinopathy in diabetics, and tolerance to treatment.

Table 6.1.5 Pharmacotherapy of hypertension in CKD

Recommendation for use

Dose modification

ACEIs

May be used in all CKD patients, particularly those with albuminuria, diabetes, HF, MI, stroke, and high CV risk

No dose reduction is necessary, but the starting dose may need to be modified and kidney function and potassium levels should be monitored

Aldosterone antagonists

May be used in resistant hypertension and oedema

No dose reduction necessary, but kidney function and potassium levels should be monitored. Avoid in severe renal impairment

Direct renin inhibitors (aliskiren)

May be considered in mild to moderate CKD, in addition to conventional therapy

Avoid if eGFR <30mL/min/1.73m2. Contraindicated in diabetics or if eGFR <60mL/min/1.73m2 when used in combination with ACEI or ARB

Thiazides and thiazide-like diuretics

May be used in all CKD patients, although they are less effective in when eGFR falls below 30–50mL/min/1.73m2

No dose reduction necessary

Loop diuretics

May be used in all CKD patients, although they are less effective in severe renal impairment

No dose reduction necessary (higher doses required, as GFR declines)

Potassium-sparing diuretics

May be used in mild renal impairment

Avoid in moderate to severe renal impairment

β‎-blockers

May be used in all CKD patients

Carvedilol and metoprolol require no dose modification. Dose reduction necessary in severe renal impairment for atenolol

Dose reduction necessary for bisoprolol if eGFR <20mL/min/1.73m2 (max 10mg daily)

Calcium channel antagonists

May be used in all CKD patients

No dose reduction necessary, except for nicardipine and nimodipine. Start diltiazem at lower dose

Centrally acting α‎-agonists

May be considered in all patients with resistant hypertension

No dose reduction necessary for methyldopa and clonidine. Maximum single dose of 0.2mg and maximum daily dose of 0.4mg if eGFR 30–60mL/min/1.73m2, and avoid moxonidine if eGFR <30mL/min/1.73m2

α‎-blockers

May be considered in all CKD patients

No dose reduction necessary

Direct vasodilators

May be considered in patients with resistant hypertension

Dose reduction recommended if eGFR <30mL/min/1.73m2 for hydralazine. Use minoxidil with caution in severe renal impairment

The pathophysiology of high BP in dialysis patients is complex, involving several issues unique to dialysis patients. This includes chronic fluid retention, advanced vascular disease, autonomic dysfunction, and fluctuations in BP with ultrafiltration and dialysis treatment, among others. The backbone of management focuses on achieving a normal extracellular fluid volume using ultrafiltration on dialysis and salt and fluid dietary restriction. This is rarely achieved consistently, and often pharmacological therapy for hypertension is required nonetheless. There is no compelling evidence to recommend one class of antihypertensive agent over another, and, as such, any established use of these drugs in the general population or CKD patients should be applied to dialysis patients until better evidence emerges. There is no evidence for a definition, or a target therapeutic threshold, for any particular BP level in dialysis patients.

Lifestyle modification

Lifestyle modification is a simple and inexpensive method to lower BP and should be considered in every patient with hypertension. In addition, it may offer benefits other than improving BP control, e.g. reducing weight and lowering cholesterol with diet modification.

Lifestyle modification recommendations, as suggested by Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on the management of hypertension in patients with CKD, are as follows:

  • Maintaining a healthy weight (BMI 20–25).

  • Lowering salt intake to 2g (90mmol) of sodium or 5g of sodium chloride per day.

  • Undertaking regular exercise, as tolerated, aiming for at least 30min five times a week.

  • Limiting alcohol intake to no more than two standard drinks for men and one standard drink for women per day.

Pharmacotherapy to lower blood pressure

With the exception of ACEIs and ARBs, which can help to lower albuminuria, there is no strong evidence to support the preferential use of any particular antihypertensive agent in patients with CKD. The choice of antihypertensive therapy tends to be tailored to the individual, taking into consideration issues such as the presence of albuminuria, comorbidities, compliance, adverse effects, and drug interactions, among others. Often, patients will require two or three agents to achieve a desired BP target.

Renin–angiotensin–aldosterone system blockers

This class of antihypertensive agents typically includes ACEIs, ARBs, aldosterone antagonists, and direct renin inhibitors (DRIs).

ACEIs and ARBs are indicated as first-line therapy in CKD patients with albuminuria, as they have a favourable impact on renal and CV outcomes. They are also recommended for use in hypertensive, diabetic patients with albuminuria. An initial acute decline in the GFR, thought to be due to a haemodynamic effect, may be seen, the magnitude of which is inversely proportional to the long-term rate of change in GFR. An acute fall in the GFR of up to 30% (or a rise in creatinine levels of 30%) is often accepted as the physiological effect of ACEI or ARB initiation, whereas larger declines in the GFR may occur as a result of volume depletion, clinically significant renal artery stenosis, or co-administration with other medications that affect GFR such as NSAIDs.13 This acute decline in the GFR is typically reversible upon cessation of therapy.

ACEIs and ARBs should be initiated and used with caution in patients with intravascular volume depletion, renal artery stenosis, sepsis, and concurrent use of NSAIDs and diuretics, as they may lead to rapid and large declines in the GFR, producing AKI, and rarely requiring emergency dialysis, with attendant clinical risk. Patients already on ACEI or ARB therapy should have their therapy withheld or stopped in these cases. Likewise, patients who develop intercurrent illness that may result in dehydration, such as diarrhoea, vomiting, and fever, who are already on ACEIs or ARBs should have their treatment withheld until the acute illness has resolved (but few patients and doctors appear to know and use this important information).

In the general population, ACEIs and ARBs have been recommended for use in patients with diabetes and hypertension, HF, MI, stroke, and high CV risk, and they may be considered for use in these patients with CKD.

Monitoring for hyperkalaemia is an important safety intervention in patients starting on, or continuing with, RAAS-blocking agents, particularly in patients with moderate to severe CKD or when used in combination with potassium-sparing diuretics, NSAIDs, COX-2 inhibitors. ACEIs and ARBs used in combination increase the risk for hyperkalaemia, hypotension, and decline in kidney function, and their combined use is no longer recommended.

Aldosterone antagonists, such as spironolactone and eplerenone, are recommended for use in non-CKD patients with HF. It is unclear whether they have the same prognostic benefit in patients with CKD. The risk of side effects, such as hyperkalaemia, is elevated, particularly in patients with advanced CKD. They have proven anti-albuminuric effects when used in combination with ACEIs or ARBs, although not in patients with an eGFR of <70mL/min/1.73m2. In CKD patients, they are often used in the treatment of resistant hypertension and/or oedema and may be considered for use in CKD patients with HF or as an additional therapy to ACEIs and ARBs to reduce albuminuria. However, the risk of side effects, such as hyperkalaemia, particularly in patients with moderate to severe CKD, are elevated. Concomitant use of other diuretics may help to mitigate the risk of hyperkalaemia but does not negate it. Aldosterone antagonists should be used with caution and closely monitored.

The DRI aliskiren has been approved for the treatment of hypertension. Limited data are available in patients with CKD, although one RCT investigating the combination of aliskiren and losartan was encouraging, suggesting significant reductions in albuminuria in patients with CKD, with no difference in the rates of adverse events. However, the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) trial, a larger RCT investigating aliskiren in addition to conventional treatment, was terminated early due to increased risks of adverse events (renal impairment, hypotension, and hyperkalaemia). It is therefore contraindicated in combination with an ACEI or ARB in patients with diabetes or in patients with an eGFR of <60mL/min/1.73m2. In all other patients, the combination of a DRI and an ACEI or ARB is not recommended.

Thiazides and thiazide-like diuretics

These diuretics exert their effect by promoting the excretion of salt and water but may also have a vasodilatory effect. Their diuretic effect diminishes, as the eGFR falls below 30mL/min/1.73m2, although their antihypertensive effect may be preserved. For this reason, loop diuretics are often preferred in patients with CKD stages 4 and 5. Thiazide and thiazide-like diuretics have been extensively studied and are thought to be similar in effect, clinical outcomes, and cost. Although they are renally excreted, no dose adjustment is required in patients with CKD. They potentiate the effect of other antihypertensive agents, particularly ACEIs and ARBs, and help to prevent hyperkalaemia. Their side effects, particularly hyperglycaemia, hyperuricaemia, and altered plasma lipid concentrations, should be considered in patients at risk of metabolic syndrome.

Loop diuretics

Loop diuretics, such as furosemide, are commonly used in the management of hypertension with oedema, particularly in patients with advanced CKD. They are effective in the short term but may not be as effective as thiazides in the long term. Concomitant use of a loop diuretic and a thiazide may potentiate the diuretic and antihypertensive effects. They may help to reduce the risk of hyperkalaemia by promoting the excretion of potassium. Larger doses are required to achieve the desired effect, as the GFR falls. They are often discontinued once haemodialysis is started, as their efficacy is debatable and ultrafiltration is far more effective in dealing with inappropriate volume expansion. In peritoneal dialysis, where continued preservation of residual renal function for as long as possible is desirable, they are often continued until the urine output becomes negligible.

Potassium-sparing diuretics

Examples of these include amiloride and spironolactone. They are usually avoided in CKD, especially in severe renal impairment, due to their potential to cause hyperkalaemia and because they are not as effective in reducing oedema as thiazides or loop diuretics. In salt-wasting nephropathy, amiloride helps to reduce the risk for hyponatraemia. Aldosterone antagonists have been discussed previously.

Beta-blockers

β‎-blockers are a large class of CV drugs that are effective in the treatment of hypertension. In addition to their antihypertensive effect, β‎-blockers are recommended for use in HF, AF, and CAD in the general population. In CKD patients, β‎-blockers reduce mortality in patients with HF. Since the pharmacology of each β‎-blocker varies, the choice of the most appropriate one will depend on the risk of accumulation, as this may lead to concentration-dependent side effects such as bradycardic arrhythmias. Renally excreted β‎-blockers, such as atenolol, are more likely to accumulate, and therefore, dose adjustments need to be made in severe renal impairment. Metoprolol, carvedilol, and propranolol undergo hepatic metabolism and are less likely to accumulate in renal impairment (although manufacturers of propranolol advise caution in renal impairment). Bisoprolol undergoes both renal excretion and hepatic metabolism and may accumulate in severe renal impairment. Using β‎-blockers in combination with other bradycardia-inducing drugs, such as non-dihydropyridine CCBs, is not recommended, as this increases the risk of bradycardic arrhythmias. Lipid-soluble β‎-blockers may cross the blood–brain barrier and, if used with other centrally acting agents, may result in drowsiness and confusion.

Calcium channel antagonists

Calcium channel antagonists are valuable agents in the treatment of hypertension in patients with CKD and, with the exception of nicardipine and nimodipine, do not need dose adjustment in renal impairment. Two major subclasses exist: dihydropyridines (DCAs) such as amlodipine and nifedipine, and non-dihydropyridines (NDCAs) such as diltiazem and verapamil. DCAs are more selective for vascular smooth muscle, leading to vasodilatation, a side effect of which can be fluid retention. NDCAs act directly on the myocardium, including the sinoatrial and atrioventricular nodes, resulting in a reduction in myocardial contractility and heart rate.

DCAs tend to exert their effect predominantly on the afferent arteriole at the glomerulus, resulting in an increase in albuminuria, whereas NDCAs typically do not exhibit this effect.

NDCAs and β‎-blockers, used together, should be avoided, particularly in advanced CKD, as this combination may lead to bradycardia, complete heart block, or asystole. NDCAs can increase CNI (ciclosporin and tacrolimus) and mTOR (sirolimus, everolimus) concentrations. Thus, some physicians have used them to increase these immunosuppressant blood concentrations (in order to reduce cost).

Centrally acting alpha-adrenergic agonists

Centrally acting α‎-adrenergic agonists (CAAAAs) inhibit sympathetic activity within the brain and are a valuable adjunct to hypertensive therapy in patients with CKD and resistant hypertension. They reduce heart rate and promote vasodilatation. As a result, fluid retention and oedema are common side effects, and therefore, they are often used in combination with a diuretic. Other side effects include sedation, hypotension, GI symptoms, and dry mouth. Clonidine can suppress sinoatrial node and AVN function, leading to significant bradycardia, particularly in patients with CKD or sinoatrial node dysfunction. Rebound hypertension may also occur if clonidine at high doses is suddenly discontinued. No dose reductions are required for clonidine and methyldopa in renal impairment, although they should be started at small doses and increased gradually. Moxonidine is extensively renally cleared, and therefore, a dose reduction is recommended in patients with moderate renal impairment (eGFR 30–60mL/min/1.73m2) and should be avoided if the eGFR is <30mL/min/1.73m2. In addition, moxonidine should be avoided in patients with HF.

These drugs have the advantage of not interacting with other antihypertensive drugs or immunosuppressants, although caution is advised when using drugs with similar side effects [such as central nervous system (CNS) depression].

Alpha-blockers

α‎-blockers, such as doxazosin and prazosin, exert their effect by causing peripheral vasodilatation. They are often used in patients with CKD as adjuncts to antihypertensive therapy after ACEIs, ARBs, β‎-blockers, and calcium channel antagonists have been considered. α‎-blockers are often considered in men with benign prostatic hypertrophy, as they reduce the symptoms associated with this. α‎-blockers are metabolized by the liver; hence, no dose reduction is required in patients with CKD. A common side effect is hypotension, and therefore, they are often started at low doses and gradually increased.

Direct vasodilators

Hydralazine and minoxidil cause vascular smooth muscle relaxation, and therefore vasodilatation. They are potent antihypertensive agents used as an adjunct to existing therapy in cases of resistant hypertension. They can cause significant fluid retention (including pericardial effusion) and tachycardia, and for this reason, they should be used in combination with a β‎-blocker and loop diuretic. Minoxidil has the additional unwanted side effect of hypertrichosis, while hydralazine can cause an SLE-like syndrome. A dose reduction is necessary for hydralazine if the eGFR is <30mL/min/1.73m2, and minoxidil should be used with caution in severe renal impairment.

References

1 Szummer K, Lundman P, Jacobson SH, et al.; SWEDEHEART. Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register. J Intern Med 2010;268:40–9.Find this resource:

2 Ibanez B, James S, Agewall S, et al.; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77.Find this resource:

3 Roffi M, Patrono C, Collet JP, et al.; ESC Scientific Document Group. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315.Find this resource:

4 Rossignol P, Cleland JG, Bhandari S, et al. Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. Circulation 2012;125:271–9.Find this resource:

5 Weisbord SD, Gallagher M, Jneid H, et al.; PRESERVE Trial Group. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med 2018;378:603–14.Find this resource:

6 Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 2017;389:1312–22.Find this resource:

7 Baigent C, Landray MJ, Reith C, et al.; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181–92.Find this resource:

8 Ponikowski P, Voors AA, Anker SD, et al.; Authors/Task Force Members, Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.Find this resource:

9 Cice G, Ferrara L, D’Andrea A, et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol 2003;41:1438–44.Find this resource:

10 Kumar S, de Lusignan S, McGovern A, et al. Ischaemic stroke, haemorrhage, and mortality in older patients with chronic kidney disease newly started on anticoagulation for atrial fibrillation: a population based study from UK primary care. BMJ 2018;360:k342.Find this resource:

11 Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962.Find this resource:

12 Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol 2016;56:628–36.Find this resource:

13 Holtkamp FA, de Zeeuw D, Thomas MC, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011;80:282–7.Find this resource: