Esther de Beus

Impact of Medication Adherence on the Effect of Renal DenervationNovelty and Significance: The SYMPATHY Trial

Randomized trials of catheter-based renal denervation (RDN) as therapy for resistant hypertension showed conflicting results in blood pressure (BP) lowering effect. Adherence to medication is modest in this patient group and may importantly drive these conflicting results. SYMPATHY is a prospective open label multicenter trial in Dutch patients with resistant hypertension. Primary outcome was change in daytime systolic ambulatory BP at 6 months. Patients were randomly assigned to RDN on top of usual care. Adherence to BP lowering drugs was assessed at baseline and follow-up, using blood samples drawn synchronously with BP measurements. Patients and physicians were unaware of the adherence assessment. Primary analyses showed a mean difference between RDN (n=95) and control (n=44) in changes in daytime systolic ambulatory BP after 6 months of 2.0 mm Hg (95% confidence interval, −6.1 to 10.2 mm Hg) in favor of control. In 80% of patients, fewer medications were detected than prescribed and adherence changed during follow-up in 31%. In those with stable adherence during follow-up, mean difference between RDN and control for daytime systolic ambulatory BP was −3.3 mm Hg (−13.7 to 7.2 mm Hg) in favor of RDN. RDN as therapy for resistant hypertension was not superior to usual care. Objective assessment of medication use shows that medication adherence is extremely poor, when patients are unaware of monitoring. Changes over time in adherence are common and affect treatment estimates considerably. Objective measurement of medication adherence during follow-up is strongly recommended in randomized trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850901.

Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation?

Percutaneous ablation of the renal nerves [renal denervation (RDN)] has recently become available for treatment of (therapy-resistant) hypertension. In this review, the potential importance of RDN for patients with chronic kidney disease (CKD) is discussed. An overview of the role of the renal nerves is given, and the role of the kidneys as both generators and recipients of sympathetic hyperactivity is described. The clinical relevance of increased sympathetic nervous system activity in CKD is reviewed, and the effects of conventional treatment on sympathetic hyperactivity are summarized. Next, we present the current knowledge on the effect of RDN in CKD from both experimental and clinical studies. Finally, we discuss how this knowledge may help us in predicting the effect of RDN in hypertensive patients and ways to monitor the effect of the procedure itself.

Prevalence of Apparent Therapy-Resistant Hypertension and Its Effect on Outcome in Patients With Chronic Kidney Disease

New options recently became available for treatment of uncontrolled blood pressure. Information on the prevalence of therapy-resistant hypertension (TRH) in patients with chronic kidney disease and its consequences is relevant to balance risks and benefits of potential new therapies. Data of 788 patients with chronic kidney disease came from a multicenter study investigating the effect on outcome of an integrated multifactorial approach delivered by nurse practitioners added to usual care versus usual care alone. Blood pressure was measured at the office and during 30 minutes using an automated oscillometric device. Apparent TRH (aTRH) was defined as a blood pressure ≥130/80 mm Hg despite treatment with ≥3 antihypertensive drugs, including a diuretic or treatment with ≥4 antihypertensive drugs. Participants were followed up for the occurrence of myocardial infarction, stroke or cardiovascular mortality (composite cardiovascular end point) and end-stage renal disease. aTRH was present in 34% (office blood pressure) and in 32% (automated measurements). During 5.3 years of follow-up, 17% of patients with aTRH reached a cardiovascular end point and 27% reached end-stage renal disease. aTRH lead to a 1.5-fold higher risk (95% confidence interval, 0.8–3.0) of a cardiovascular end point compared with controlled hypertensives in multivariable-adjusted analysis. aTRH increased end-stage renal disease risk 2.3-fold (95% confidence interval, 1.4–3.7). During 4 years of follow-up, the prevalence of aTRH did not decline in either treatment group. The prevalence of aTRH is high in patients with chronic kidney disease even after optimization of nephrologist care. The presence of TRH is related to a substantially increased risk of renal and cardiovascular outcomes.

Denosumab for treatment of immobilization-related hypercalcaemia in a patient with advanced renal failure

We describe the case of a young adult with immobilization-related hypercalcaemia and advanced renal insufficiency. Because of the uncertain safety profile of bisphosphonates in such patients, only a low dose of pamidronate was administered twice. This did not result in a sufficient decrease in the serum calcium concentration nor was the decrease sustained. We decided to administer a single dose of denosumab, a monoclonal antibody against the receptor activator of nuclear factor-κB ligand, a new antiresorptive agent registered for use in osteoporosis. This resulted in rapid and sustained decrease in the serum calcium concentration. Transient hypocalcaemia ensued with normalization after vitamin D supplementation. Furthermore, we summarize what is known about hypercalcaemia caused by immobilization.

Catheter-based renal denervation as a novel treatment for loin pain haematuria syndrome

Renal denervation using a catheter delivering radiofrequency energy to the renal artery vessel wall has recently emerged as a promising new treatment for difficult-to-treat hypertension. The beneficial effect of this intervention, attributable to sympathetic nerves interruption, has been coherently demonstrated in both an observational study [1, 2] and a controlled trial [3, 4]. Of note, according to the available follow-up studies, the hypotensive effect of renal denervation has been shown to last for up to 2–3 years. The European Society of Hypertension has published a position paper with recommendations for the application of this new technique including the eligibility criteria and issues that need to be addressed in further trials [5]. Several other conditions associated with sympathetic overactivity as diverse as heart failure, atrial fibrillation, insulin resistance [6], sleep apnoea [7] and polycystic ovary syndrome [8] have been described as being responsive to renal denervation and/or are being subjected to further study. Renal denervation has become a hot topic as illustrated by the large number of ongoing and planned trials of the technique [9]. In this issue, Gambaro et al. describe the use of catheterbased renal denervation for yet another indication, namely pain control in loin pain haematuria syndrome (LPHS). LPHS is a rare condition of uncertain aetiology and definition. Over 100 papers on LPHS have been cited in PubMed (accessed on 18 March 2013) so far, but many nephrologists agree that the actual number of cases is probably far larger. First described in 1967, LPHS is still a poorly understood condition consisting of recurrent flank pain often accompanied by nonvisible or visible haematuria. Women are more often affected (about three-fourths of cases described so far) than men and patients are typically young at onset. The pain is often unilateral, but recurrences on the contralateral side after invasive treatment are the rule rather than the exception. Pain exacerbations may be accompanied by low-grade fever and sometimes urinary symptoms mimicking urinary tract infection [10]. Episodes of (particularly) visible or non-visible haematuria very often accompany exacerbation of loin/flank pain. The duration of such episodes is variable but in some cases symptoms persist for months and cause serious disability. Pain may be severe and associated with nausea and vomiting, mimicking renal colic. Often, opioid analgesics are eventually prescribed in the most severe cases. Kidney function remains normal and development of hypertension is not associated with the syndrome. Although spontaneous disappearance of symptoms can occur after years, many patients remain symptomatic long-term [11]. A diagnosis of LPHS can only be made after a thorough evaluation for, and exclusion of other causes of loin pain and/or haematuria. Interestingly, many patients report a history of nephrolithiasis [12]. A kidney biopsy shows no glomerular abnormalities, but intratubular erythrocytes are seen more often than in healthy controls (7.2 versus 1.6%), suggesting a glomerular origin of haematuria [12]. Disparate structural abnormalities of the glomerular basement membrane, from excessive thickening to excessive thinning, may be the explanation [12]. Several other hypotheses for the cause of LPHS have been proposed including microvascular abnormalities, abnormal platelet function, intra-tubular microcrystal formation and complement activation [10, 13]. The complexity of this disorder is underscored by the fact that many patients meet the criteria for somatoform disorder on the basis of other physical complaints preceding the onset of LPHS [14].

Presence of albuminuria predicts left ventricular mass in patients with chronic systemic arterial hypertension

Increased left ventricular mass (LVM) is known to predict cardiovascular morbidity and mortality. LVM is high in patients with advanced kidney disease. Our aim was to study the relationship between renal parameters and LVM in hypertensive subjects at high risk of cardiovascular disease.

The effect of renal denervation added to standard pharmacologic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: Rationale and design of the SYMPATHY trial

The first studies on renal denervation (RDN) suggest that this treatment is feasible, effective, and safe in the short term. Presently available data are promising, but important uncertainties exist; therefore, SYMPATHY has been initiated. SYMPATHY is a multicenter, randomized, controlled trial in patients randomized to RDN in addition to usual care (intervention group) or to continued usual care (control group). Randomization will take place in a ratio of 2 to 1. At least 300 participants will be included to answer the primary objective. Sample size may be extended to a maximum of 570 to address key secondary objectives. The primary objective is to assess whether RDN added to usual care compared with usual care alone reduces blood pressure (BP) (ambulatory daytime systolic BP) in subjects with an average daytime systolic BP ≥135, despite use of ≥3 BP-lowering agents, 6 months after RDN. Key secondary objectives are evaluated at 6 months and at regular intervals during continued follow-up and include the effect of RDN on the use of BP-lowering agents, in different subgroups (across strata of estimated glomerular filtration rate and of baseline BP), on office BP, quality of life, and cost-effectiveness.

Catheter-based renal denervation as therapy for chronic severe kidney-related pain

Background Loin pain haematuria syndrome (LPHS) and autosomal dominant polycystic kidney disease (ADPKD) are the most important non-urological conditions to cause chronic severe kidney-related pain. Multidisciplinary programmes and surgical methods have shown inconsistent results with respect to pain reduction. Percutaneous catheter-based renal denervation (RDN) could be a less invasive treatment option for these patients. Methods Our aim was to explore the change in perceived pain and use of analgesic medication from baseline to 3, 6 and 12 months after RDN. Patients with LPHS or ADPKD, who experienced kidney-related pain ≥3 months with a visual analogue scale (VAS) score ≥ 50/100 could be included. Percutaneous RDN was performed with a single-electrode radiofrequency ablation catheter. Results RDN was performed in 11 patients (6 with LPHS and 5 with ADPKD). Perceived pain declined in the whole group by 23 mm (P = 0.012 for the total group). In patients with LPHS and ADPKD, the median daily defined dosage of analgesic medication decreased from 1.6 [interquartile range (IQR) 0.7-2.3] and 1.4 (IQR 0.0-7.4) at baseline to 0.3 (IQR 0.0-1.9; P = 0.138) and 0.0 (IQR 0.0-0.8; P = 0.285) at 12 months, respectively. Mean estimated glomerular filtration rate decreased in the whole group by 5.4 mL/min/1.73 m2 at 6 months compared with baseline (P = 0.163). Conclusions These results suggest that percutaneous catheter-based RDN reduces pain complaints and the use of analgesic medication in patients with LPHS or ADPKD. The present results can serve as the rationale for a larger, preferably randomized (sham) controlled study.

Salt intake and blood pressure response to percutaneous renal denervation in resistant hypertension.

The effect of lowering sympathetic nerve activity by renal denervation (RDN) is highly variable. With the exception of office systolic blood pressure (BP), predictors of the BP‐lowering effect have not been identified. Because dietary sodium intake influences sympathetic drive, and, conversely, sympathetic activity influences salt sensitivity in hypertension, we investigated 24‐hour urinary sodium excretion in participants of the SYMPATHY trial. SYMPATHY investigated RDN in patients with resistant hypertension. Both 24‐hour ambulatory and office BP measurements were end points. No relationship was found for baseline sodium excretion and change in BP 6 months after RDN in multivariable‐adjusted regression analysis. Change in the salt intake–measured BP relationships at 6 months vs baseline was used as a measure for salt sensitivity. BP was 8 mm Hg lower with similar salt intake after RDN, suggesting a decrease in salt sensitivity. However, the change was similar in the control group, and thus not attributable to RDN.

Apparent resistant hypertension and the risk of vascular events and mortality in patients with manifest vascular disease

Objective: Patients with apparent resistant hypertension (aRH) are at increased risk for developing cardiovascular disease. It is unknown if this condition is related to increased cardiovascular risk in patients with clinically manifest vascular disease. Methods: In 6191 hypertensive patients with clinically manifest vascular disease, we evaluated the risk of subsequent vascular events and mortality between patients with controlled hypertension, uncontrolled hypertension, controlled aRH, and uncontrolled aRH. Controlled aRH was defined as office blood pressure less than 140/90 mmHg while using at least four antihypertensive drugs. Uncontrolled aRH was defined as office blood pressure at least 140/90 mmHg while using three antihypertensive drugs including a diuretic, or at least four antihypertensive drugs. Outcomes of interest were myocardial infarction, stroke, cardiovascular mortality, the composite outcome of cardiovascular events, and all-cause mortality. Results: In total 2564 patients (41%) had controlled hypertension, 3063 patients (49%) had uncontrolled hypertension, 123 patients (2%) had controlled aRH, and 411 patients (7%) had uncontrolled aRH. During 7.1 years of follow-up patients with controlled aRH were at a higher risk of cardiovascular mortality [hazard ratios 1.86; 95% confidence interval (CI) 1.10–3.15], and all-cause mortality (hazard ratios 1.64; 95% CI 1.07–2.52) compared with patients with controlled hypertension. Patients with uncontrolled aRH were at a higher risk of cardiovascular mortality (hazard ratios 1.36; 95% CI 1.01–1.83), and higher risk of all-cause mortality (hazard ratios 1.27; 95% CI 1.01–1.60) compared with patients with controlled hypertension. Conclusion: In hypertensive patients with clinically manifest vascular disease, presence of controlled and uncontrolled aRH is related to an increased risk of cardiovascular mortality and all-cause mortality.