Uncertainties in BP management in dialysis patients.

Hypertension in dialysis patients is extremely common. In this article, we review the current evidence for blood pressure (BP) goals in hemodialysis patients, and consider the effectiveness of interventions by which BP may be lowered, including manipulation of dietary and dialysate sodium; optimization of extracellular water; prolongation of dialysis time; and antihypertensive medication. Although two meta-analyses suggest lowering BP using antihypertensive drugs might be beneficial in reducing cardiovascular events and mortality, there are insufficient rigorously designed trials in hypertensive hemodialysis populations to determine preferred antihypertensive drug classes. We suggest aiming for predialysis systolic BP between 130 and 159 mm Hg, while at the same time acknowledge the significant limitations of the data upon which it is based. We conclude by summarizing current knowledge as regards management of hypertension in the peritoneal dialysis population and make recommendations for future research in this field.

Renal artery sympathetic denervation: observations from the UK experience.

BACKGROUND: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response-particularly in those prescribed aldosterone antagonists at the time of RDN. METHODS: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. RESULTS: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p > 0.2). CONCLUSION: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response.

Combination renin-angiotensin system blockade with the renin inhibitor aliskiren in hypertension.

Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone, although this additive effect may be abolished with maximal monotherapy dosing. The recent ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria and disease progression more than monotherapy, but the ONTARGET study showed an increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2 mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but, considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are needed before the use of aliskiren can be recommended in combination with other RAS inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated.

Autosomal dominant polycystic kidney disease: role of the renin-angiotensin system in raised blood pressure in progression of renal and cardiovascular disease.

Raised blood pressure (BP) is extremely common in individuals with autosomal dominant polycystic kidney disease (ADPKD) and is almost invariably raised once they develop renal failure. The underlying mechanisms for the rise in BP in individuals with ADPKD are unclear. The progressive number and enlargement of renal cysts, causing structural damage to the kidneys and, thereby, affecting tubular function as well as causing distortion of the glomeruli and renal ischaemia, is likely to be of primary importance. There is some evidence from animal models that there may be over-activity of the intra-renal renin-angiotensin system (RAS) that could account for the rise in BP. Studies in man have shown conflicting results, but a recent more carefully controlled study using both measurements of activity and pharmacological blockade of the RAS clearly demonstrated no evidence of over-activity of the circulating RAS in ADPKD compared to matched individuals with essential hypertension. A more likely explanation for the rise in BP that occurs in ADPKD is retention of sodium and water due to tubular damage. Disappointingly, in spite of good evidence that RAS blocking drugs slow the progression of other renal, particularly glomerular, diseases, there is little evidence to suggest this is true for patients with ADPKD. Nevertheless, there is no doubt that lowering BP in ADPKD is just as important, if not more important, as in essential hypertension to prevent cardiovascular disease and strokes, with a recommended BP target of < 120/80 mmHg.

The effect of sodium and angiotensin-converting enzyme inhibition on the classic circulating renin-angiotensin system in autosomal-dominant polycystic kidney disease patients.

BACKGROUND: It has been suggested that inappropriate stimulation of the renin-angiotensin system (RAS) is responsible for the increase in blood pressure that occurs in autosomal-dominant polycystic kidney disease (ADPKD) before the development of renal failure. However, the interpretation of previous studies in ADPKD patients is confounded by inadequate matching with control populations for blood pressure and renal function, or failure to control the sodium intake of participants. METHODS: A double-blind, placebo-controlled study of two different sodium intakes (350 and 50 mmol/day for 5 days) in a group of 11 hypertensive ADPKD patients and eight matched control subjects with essential hypertension. In addition, blood pressure and hormonal responses were measured after the administration of the angiotensin-converting enzyme inhibitor enalapril for 3 days. RESULTS: Blood pressure and hormonal responses of the RAS after a reduction in sodium intake and after the administration of enalapril were identical in ADPKD patients and controls. CONCLUSIONS: Activation of the classic circulating RAS is no greater in hypertensive ADPKD patients than in individuals with essential hypertension.

Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension.

Some evidence suggests that long-term angiotensin-converting enzyme (ACE) inhibition may become less effective, thereby increasing angiotensin II levels, which could be inhibited by the addition of an angiotensin receptor blocker. We conducted a meta-analysis of randomized trials with searches of MEDLINE, EMBASE, and Cochrane databases. Overall, the combination of an ACE inhibitor and an angiotensin receptor blocker reduced ambulatory blood pressure by 4.7/3.0 mm Hg (95% confidence interval [CI], 2.9 to 6.5/1.6 to 4.3) compared with ACE inhibitor monotherapy and 3.8/2.9 mm Hg (2.4 to 5.3/0.4 to 5.4) compared with angiotensin receptor blocker monotherapy. Clinic blood pressure was reduced by 3.8/2.7 mm Hg (0.9 to 6.7/0.8 to 4.6) and 3.7/2.3 mm Hg (0.4 to 6.9/0.2 to 4.4) compared with ACE inhibitor and angiotensin receptor blocker, respectively. However, the majority of these studies used submaximal doses or once-daily dosing of shorter-acting ACE inhibitors and, when a larger dose of shorter-acting ACE inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the angiotensin receptor blocker on blood pressure. Proteinuria was reduced by the combination compared with ACE inhibitor and angiotensin receptor blocker monotherapy, an effect that was independent of blood pressure in several studies, suggesting that the combination could have benefits in proteinuric nephropathies. None of the studies was of sufficient size and duration to determine whether there may be safety concerns. In conclusion, although there is a small additive effect on blood pressure with an ACE inhibitor-angiotensin receptor blocker combination, the routine use of this combination in uncomplicated hypertension is not recommended until more carefully controlled studies are performed.

Blood pressure in haemodialysis patients: the importance of the relationship between the renin-angiotensin-aldosterone system, salt intake and extracellular volume.

This review outlines the major mechanisms for control of blood pressure (BP) in individuals with renal failure on haemodialysis. Dietary salt stimulates thirst and, thereby, greater fluid intake with excessive fluid gain between dialysis sessions and chronic expansion of extracellular volume. At the same time, this volume expansion often fails to suppress the renin-angiotensin system (RAS) appropriately and this inevitably leads to high BP in the majority of individuals on haemodialysis. A greater understanding of the mechanisms involved leads to more rational treatment and better BP control. This can be achieved by careful measurement of BP before and after dialysis, allowing time for the equilibration of extracellular fluid shifts that occur after dialysis, combined with measurements of plasma renin activity. It is relatively easy to then decide how the high BP should be treated: either by removal of excess volume by gradual ultrafiltration combined with restriction of salt intake to help prevent thirst and excessive fluid gain between dialyses, or by inhibition of the RAS, or by a combination of both. In those individuals who are unable to adequately reduce their dietary salt intake and still continue to gain large amounts of weight between dialysis, and are resistant to reducing their pre-dialysis weight, calcium antagonists may help to lower BP, either alone or in combination with RAS blockade. However, the BP often remains resistant to treatment unless they can be persuaded to reduce their salt intake.