Importance of Blood Pressure Control and Antihypertensive Therapy
The main goal of BP reduction in CKD patients is to reduce the risk of CV events and to slow the decline of GFR. Most of the evidence for reducing BP comes from large randomised controlled trials in the general population. These trials showed that treatment of BP reduces CV outcomes. In CKD patients with proteinuria, it has been shown that BP reduction is associated with a slower decline of renal function.25,26 The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the management of BP in CKD acknowledges that no single BP target is optimal for all CKD patients and encourages individualisation of treatment depending on age, the severity of albuminuria and co-morbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mmHg systolic and ≤90 mmHg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 hour (i.e. those with both micro- and macroalbuminuria), a lower target of ≤130 mmHg systolic and ≤80 mmHg diastolic is suggested.26,27 In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged in all guidelines.
Blocking the renin-angiotensin-aldosterone system (RAAS), using ACE inhibitors or angiotensin receptor blockers (ARBs), is the current gold standard pharmacological treatment approach for hypertension and proteinuria in CKD. Numerous randomised controlled trials in diabetic and non-diabetic CKD patients have shown that these agents slow the decline of CKD compared with placebo or with other antihypertensive agent.28–33 The beneficial effect was confirmed in a meta-analysis.34 These agents act not only to lower BP but also through a BP-independent effect on proteinuria. The most recent analysis of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) have documented that the initial treatment-induced reduction in albuminuria is highly predictive of reduction of fatal and non-fatal renal and CV events.35 This predictive effect of the decrease in proteinuria prompted trials, which studied the effect of intensive blockade of the renin-angiotensin system (RAS). Unfortunately, the results from ONTARGET showing a lack of an additional benefit of double blockade (ramipril–telmisartan) over monotherapy (ramipril or telmisartan alone), with an increased risk of hyperkalaemia, renal failure, discourage the use of ACE inhibitors/ ARBs combination in patients at high-risk of CV events. Aliskiren, the first direct renin inhibitor to receive approval for hypertension treatment, was thought to provide additional renoprotective effects over standard treatment.36,37 The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), which included 8,606 patients with type 2 diabetes, compared the effects of aliskiren or placebo added to standard treatment of RAS blockade. This study was terminated prematurely due to higher adverse events occurring in patients receiving aliskiren in addition to the standard care, such as an increased incidence of a non-fatal stroke, renal failure, hyperkalaemia and hypotension. The use of a single drug to block the RAAS is therefore recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 hour.
In order to achieve BP targets, more than one drug is often necessary, particularly in CKD.38 Therefore, the question arising is which is the best antihypertensive drug to combine with a RAS blocker? In the Avoiding Cardiovascular Events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, a randomised controlled trial comparing fixed-dose combination of the ACE inhibitor benazepril and the dihydropyridine calcium channel blocker amlodipine with the combination of benazepril and hydrochlorothiazide in reducing CV morbidity and mortality, the progression of CKD was a prespecified endpoint. This study, which included 11,506 high-risk hypertensive patients, showed that events of CKD defined as double serum creatinine or ESRD were lower in the benazepril–amlodipine group compared with the benazepril–hydrochlorothiazide group (hazard ratio [HR] 0.52, 0.42–0.65). A possible explanation may come from the differential effect of calcium channel blockers compared with thiazides on vascular calcification.
In fact, no study has really investigated the effect of treatment on vascular calcifications and BP and the progression of renal diseases. A substudy of the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Therapy (INSIGHT) trial,39 which compared the effect of nifedipine once-daily versus co-amilozide (hydrochlorothiazide 25 mg, amiloride 2.5 mg) on mortality and morbidity in high-risk hypertensive patients, was interested in progression of coronary calcification in a subgroup of patients (n=201). While the main study failed to show any difference in mortality and morbidity between the two arms, the substudy showed a slower progression of coronary calcification in the nifedipine versus the co-amilozide group.40 This finding may be of relevance since even CKD patients with mild renal dysfunction have accelerated coronary calcifications independently of other risk factors.41 However, it is worth mentioning that the use of calcium channel blockers is associated with more peripheral oedema that might limit its use in CKD.39,42
As salt and fluid retention are largely responsible for the high BP in CKD patients, it is not surprising that diuretics still play an important role in the control of hypertension in these patients. Most guidelines recommend using loop diuretics over thiazides for the treatment of hypertension once CKD reaches stage 4 (eGFR<30 ml/min/1.73 m2). However, recent evidence from small trials suggest that thiazides may still be useful in advanced CKD.43 The combined use of blockers of the RAS, diuretics and a low sodium diet appears to be particularly useful in reducing BP and proteinuria.44
The use of beta-blockers may be particularly useful in patients with CKD and systolic heart failure. Indeed, a meta-analysis reported that compared with placebo the risk ratio of all-cause mortality (relative risk [RR] 0.72, 95 % confidence interval [CI] 0.64–0.80) and CV mortality (RR 0.66, 95 % CI 0.49–0.89) was reduced.45 Beta-blockers, however, are not the preferred first-line drugs because it has be shown that if peripheral (brachial) BP is lowered similarly by atenolol and amlodipine, central BP is decreased more intensively by amlodipine.46 This may be of importance because in the same cohort, central BP was significantly associated with a composite outcome of total CV events/procedures and the development of renal impairment.
Finally, as renal function declines, the pharmacokinetics of drugs due to impaired renal clearance may be affected. It is important to adapt the dose of antihypertensive drugs to the eGFR in order to avoid accumulation, which may result in serious side effects.
Lifestyle interventions are recommended in most hypertension or renal disease guidelines. If restriction of sodium intake makes sense from a pathophysiological point of view (reduced capacity to excrete sodium in CKD, effect on proteinuria, effect on nocturnal BP, increased effectiveness of RAS blockade), the level of sodium intake that should be targeted in CKD remains a matter of debate since recent post hoc analysis have shown that a J-curve may exist.47 This indicates that a restriction in sodium intake that is too strict may actually be deleterious. Well-designed prospective trials targeting sodium intake are needed to confirm this phenomenon. In addition to sodium intake, moderate alcohol intake, regular exercise,48 weight loss in those with a body mass index >25 kg/m2 and reduced amount of saturated fat help to reduce BP.49