Rosa L. de Jager

Sympathetic Hyperactivity in Chronic Kidney Disease: Pathophysiology and (New) Treatment Options

Abundant evidence shows that chronic kidney disease (CKD) is a disease state characterized by increased sympathetic activation. Kidney injury (ischemia) plays a central role in this pathogenesis. Sympathetic excitation is associated with an increased risk of cardiovascular morbidity and mortality. Several pharmacologic strategies are developed to decrease sympathetic activity. However, these medications have limitations. Percutaneous catheter-based renal denervation has the potential to become a new treatment option for CKD. This current report focuses on the effects of sympathetic hyperactivity in CKD, and gives an overview in experimental as well as clinical evidence for a central role of the kidneys in the pathophysiology of sympathetic hyperactivity. Moreover, the effect of pharmacologic treatment and the potential beneficial effect of renal denervation will be discussed.

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.

Chronic Kidney Pain in Autosomal Dominant Polycystic Kidney Disease: A Case Report of Successful Treatment by Catheter-Based Renal Denervation

Chronic pain is a common concern in patients with autosomal dominant polycystic kidney disease (ADPKD). We report what to our knowledge is the first catheter-based renal denervation procedure in a patient with ADPKD resulting in successful management of chronic pain. The patient was a 43-year-old woman whose chronic pain could not be controlled by pain medication or splanchnic nerve blockade. Transluminal radiofrequency renal denervation was performed as an experimental therapeutic option with an excellent result, indicating that this procedure should be considered for chronic pain management in ADPKD.

Novel treatment protocol for ameliorating refractory, chronic pain in patients with autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) patients can suffer from chronic pain that can be refractory to conventional treatment, resulting in a wish for nephrectomy. This study aimed to evaluate the effect of a multidisciplinary treatment protocol with sequential nerve blocks on pain relief in ADPKD patients with refractory chronic pain. As a first step a diagnostic, temporary celiac plexus block with local anesthetics was performed. If substantial pain relief was obtained, the assumption was that pain was relayed via the celiac plexus and major splanchnic nerves. When pain recurred, patients were then scheduled for a major splanchnic nerve block with radiofrequency ablation. In cases with no pain relief, it was assumed that pain was relayed via the aortico-renal plexus, and catheter-based renal denervation was performed. Sixty patients were referred, of which 44 were eligible. In 36 patients the diagnostic celiac plexus block resulted in substantial pain relief with a change in the median visual analogue scale (VAS) score pre-post intervention of 50/100. Of these patients, 23 received a major splanchnic nerve block because pain recurred, with a change in median VAS pre-post block of 53/100. In 8 patients without pain relief after the diagnostic block, renal denervation was performed in 5, with a borderline significant change in the median VAS pre-post intervention of 20/100. After a median follow-up of 12 months, 81.8% of the patients experienced a sustained improvement in pain intensity, indicating that our treatment protocol is effective in obtaining pain relief in ADPKD patients with refractory chronic pain.

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.

Renal denervation in a real life setting : A gradual decrease in home blood pressure

Objectives To investigate the blood pressure dynamics after renal denervation through monthly home blood pressure measurements throughout the first 12 months. Methods A cohort of 70 patients performed highly standardized monthly home blood pressure monitoring during the first year after denervation according to the European Society of Hypertension guidelines. At baseline and 12 months follow-up, office and ambulatory blood pressure as well as routine physical and laboratory assessment was performed. Results Home blood pressure decreased with a rate of 0.53 mmHg/month (95% CI 0.20 to 0.86) systolic and 0.26 mmHg/month (95% CI 0.08 to 0.44) diastolic throughout 12 months of follow-up, while the use of antihypertensive medication remained stable (+0.03 daily defined doses/month, 95% CI -0.01 to 0.08). On average, a 12 month reduction of 8.1 mmHg (95% CI 4.2 to 12.0) was achieved in home systolic blood pressure, 9.3 mmHg (95% CI -14.2 to -4.4) as measured by 24-hour ambulatory blood pressure monitoring and 15.9 mmHg (95% CI -23.8 to -7.9) on office measurements. Conclusion Blood pressure reduction after renal denervation occurs as a gradual decrease that extends to at least one-year follow-up. Home monitoring seems a suitable alternative for ambulatory blood pressure monitoring after renal denervation.

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.

Hypertensie die slecht op behandeling reageert

SamenvattingDe Jager RL, Rutten FH,Bots ML, Spiering W, Blankestijn PJ. Hypertensie die slecht op behandeling reageert. Huisarts Wet 2016;59(1):24-6. Maar liefst 65% van de patiënten met hypertensie bereikt niet de streefwaarde van een spreekkamerbloeddruk < 140/90 mmHg. Een patiënt heeft pas daadwerkelijk therapieresistente hypertensie als andere oorzaken van een slecht gereguleerde bloeddruk zijn uitgesloten, waaronder therapieontrouw, secundaire oorzaken en wittejassenhypertensie. Bij aanwijzingen voor een secundaire oorzaak, dan wel daadwerkelijk therapieresistente hypertensie, kan men de patiënt doorverwijzen naar een internist met hypertensie als aandachtsgebied. Daarnaast kan een deel van de groep patiënten met daadwerkelijk therapieresistente hypertensie baat hebben bij nieuwe, experimentele behandelingen, zoals renale denervatie of baroreflexactivatietherapie.AbstractDe Jager RL, Rutten FH,Bots ML, Spiering W, Blankestijn PJ. Treatment-resistant hypertension. Huisarts Wet 2016;59(1):24-6. At least 65% of the patients with hypertension do not achieve the target blood pressure of < 140/90 mmHg. A patient is considered to have treatment-resistant hypertension if other causes of poorly controlled blood pressure have been excluded, such as non-adherence, secondary causes, and the white coat effect. If there is evidence of a secondary cause or treatment-resistant hypertension, the patient can be referred to a hypertension specialist. In addition, some patients with treatment-resistant hypertension may benefit from new, experimental treatments, such as renal denervation or baroreflex activation therapy.