Niek F. Casteleijn

Rationale and design of the DIPAK 1 study: A randomized controlled clinical trial assessing the efficacy of lanreotide to halt disease progression in autosomal dominant polycystic kidney disease

BACKGROUND There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. STUDY DESIGN The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. SETTING & PARTICIPANTS We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years. INTERVENTION Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. OUTCOMES Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. MEASUREMENTS Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. RESULTS Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided α = 0.05, and 20% protocol violators and/or dropouts. LIMITATIONS The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. CONCLUSIONS The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD.

A stepwise approach for effective management of chronic pain in autosomal-dominant polycystic kidney disease

Chronic pain, defined as pain existing for >4-6 weeks, affects >60% of patients with autosomal-dominant polycystic disease (ADPKD). It can have various causes, indirectly or directly related to the increase in kidney and liver volume in these patients. Chronic pain in ADPKD patients is often severe, impacting physical activity and social relationships, and frequently difficult to manage. This review provides an overview of pathophysiological mechanisms that can lead to pain and discusses the sensory innervation of the kidneys and the upper abdominal organs, including the liver. In addition, the results of a systematic literature search of ADPKD-specific treatment options are presented. Based on pathophysiological knowledge and evidence derived from the literature an argumentative stepwise approach for effective management of chronic pain in ADPKD is proposed.

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.

Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease: Secondary Analysis From a Randomized Controlled Trial

Background Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3:4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain. Study Design Secondary analysis from a randomized controlled trial. Setting & Participants Patients with ADPKD with preserved kidney function. Intervention Tolvaptan or placebo. Outcomes Kidney pain events defined by objective medical interventions. Measurements Kidney pain events were recorded and independently adjudicated. Incidence of a first kidney pain event was assessed overall and categorized into 5 subgroups according to severity. Results Of 1,445 participating patients (48.4% women; mean age, 39 ± 7 [SD] years; mean estimated glomerular filtration rate, 81 ± 22 mL/min/1.73 m2; median total kidney volume, 1,692 [IQR, 750–7,555] mL), 50.9% reported a history of kidney pain at baseline. History of urinary tract infections, kidney stones, or hematuria (all P < 0.001) and female sex (P < 0.001) were significantly associated with history of kidney pain. Tolvaptan use resulted in a significantly lower incidence of kidney pain events when compared to placebo: 10.1% versus 16.8% (P < 0.001), with a risk reduction of 36% (HR, 0.64; 95% CI, 0.48–0.86). The reduction in pain event incidence by tolvaptan was found in all groups irrespective of pain severity and was independent of predisposing factors (P for interaction > 0.05). The effect of tolvaptan was explained at least in part by a decrease in incidence of urinary tract infections, kidney stones, and hematuria when compared to placebo. Limitations Trial has specific inclusion criteria for total kidney volume and kidney function. Conclusions Tolvaptan decreased the incidence of kidney pain events independent of patient characteristics predisposing for kidney pain and possibly in part due to reductions in ADPKD-related complications.

The Effect of Renal Function and Hemodialysis Treatment on Plasma Vasopressin and Copeptin Levels

Introduction Copeptin is increasingly used in epidemiological studies as a substitute for vasopressin. The effect of renal function per se on copeptin and vasopressin concentrations as well as their ratio have, however, not been well described. Methods Copeptin and vasopressin levels were measured in 127 patients with various stages of chronic kidney disease, including 42 hemodialysis patients and 16 healthy participants in this observational study. Linear (segmental) regression analyses were performed to assess the association between renal function and copeptin, vasopressin and the C/V ratio. In addition, clearance of copeptin and vasopressin by hemodialysis was calculated. Results Both copeptin and vasopressin levels were higher when renal function was lower, and both showed associations with plasma osmolality. The C/V ratio was stable across renal function in subjects with an eGFR >28 ml/min per 1.73 m2. In contrast, the C/V ratio increased with worsening renal function in patients with eGFR ≤28 ml/min per 1.73 m2. During hemodialysis, the initial decrease in vasopressin levels was greater compared with copeptin and, consequently, the C/V ratio increased. This was, at least in part, explained by a greater dialytic clearance of vasopressin compared with copeptin. Discussion Our data indicate that copeptin is a reliable substitute for vasopressin in subjects with an eGFR >28 ml/min per 1.73 m2, whereas at an eGFR ≤28 ml/min per 1.73 m2, that is, CKD stages 4 and 5, a correction for renal function is required in epidemiological studies that use copeptin as a marker for vasopressin. Intradialytic copeptin levels do not adequately reflect vasopressin levels because vasopressin clearance by hemodialysis is higher than that of copeptin.

Management of renal cyst infection in patients with autosomal dominant polycystic kidney disease: a systematic review

Background. Renal cyst infection is one of the complications faced by patients with autosomal dominant polycystic kidney disease (ADPKD). Cyst infection is often difficult to treat and potentially leads to sepsis and death. No evidence-based treatment strategy exists. We therefore performed a systematic review to develop an effective approach for the management of renal cyst infection in ADPKD patients based on the literature. Methods. A systematic search was performed in PubMed (January 1948–February 2014), EMBASE (January 1974–February 2014) and the Cochrane Library (until February 2014) according to the PRISMA guidelines. Results. We identified 60 manuscripts that included 85 ADPKD patients with renal cyst infection (aged 52 ± 12 years, 45% male, 27% on dialysis, 13% history of renal transplantation and 6% diabetes mellitus). Included patients received a total of 160 treatments of which 92 were antimicrobial, 29 percutaneous and 39 surgical. Initial management often consisted of antimicrobials (79%), and quinolone-based regimens were favoured (34%). Overall, 61% of patients failed initial treatment, but treatment failure has decreased over time (before the year 2000: 75%; during and after the year 2000: 51%, P = 0.03). Post-renal obstruction, urolithiasis, atypical or resistant pathogens, short duration of antimicrobial treatment and renal function impairment were documented in patients failing treatment. Conclusions. First-line treatment of renal cyst infection in ADPKD consists of antimicrobials and is associated with a high rate of failure, but treatment success has increased over recent years. A large-scale unbiased registry is needed to define the optimal strategy for renal cyst infection 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.

Riding the waves : evidence for a beneficial effect of increased water intake in autosomal dominant polycystic kidney disease patients?

Autosomal dominant polycystic kidney disease (ADPKD) can lead to end-stage kidney disease and accounts for ∼10% of people receiving renal replacement therapy. Until recently, no treatment had been proven to effectively postpone kidney failure. Interestingly, experimental studies that have been published over the past decades have suggested a detrimental role for the antidiuretic hormone arginine vasopressin (AVP) in ADPKD. V2 receptor activation by AVP was discovered to result in an increase of 30,50-cyclic adenosine monophosphate (cAMP) [1]. In turn, cAMP stimulates cell proliferation and fluid secretion, leading to cyst formation and cyst growth [2–4]. ADPKD patients appeared to have high serum levels of AVP, and AVP levels were, in cross-sectional studies, associated with disease severity [5] and, in longitudinal studies, with disease progression [6, 7]. These observations formed the rationale to study interventions that block this cAMP-mediated pathway using V2 receptor antagonists. In various animal models for cystic kidney disease, these interventions were successful to reduce cyst growth [8–10]. Subsequently, the selective AVP V2 receptor antagonist tolvaptan was tested for its efficacy in ADPKD patients in the TEMPO 3:4 trial. For the first time, a medical treatment proved to be beneficial with respect to kidney outcomes. In 1445 ADPKD patients, relatively early in the disease, treatment with tolvaptan slowed the rate of growth in total kidney volume by ∼50% and the rate of estimated glomerular filtration rate (eGFR) loss by ∼30% compared with placebo. In 2013, however, the US Food and Drug Administration (FDA) decided against approval of tolvaptan for the indication of slowing disease progression in ADPKD (http:// www.fda.gov/downloads/advisorycommittees/committeesmeeting materials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ ucm373520.pdf). This decision was based, amongst others, upon questions relating to the effectiveness of the drug and to tolvaptan’s risk of drug-induced liver injury. This decision felt surprising for some, because the effect on eGFR loss with tolvaptan is comparable with that of, for instance, angiotensin-II receptor blockers that are registered for diabetic nephropathy [11], a disease for which other treatments are available, whereas for ADPKD there is no renoprotective alternative. In addition, all liver function abnormalities that occurred in the TEMPO 3:4 trial were reversible after drug withdrawal. The FDA, however, extrapolated from these data that 1 per 3.000 treated ADPKD patients may develop hepatic failure for which a liver transplant would be needed (http://www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/Cardiovascular andRenalDrugsAdvisoryCommittee/UCM364582.pdf ). This should be weighed against the need for liver transplantation due to the cystic disease which occurs in a number of ADPKD patients anyway [12, 13]. Notwithstanding these considerations, the FDA decided not to register tolvaptan for the indication ADPKD, but to ask for additional evidence. The decision of the European Medicines Agency is expected late in 2014. With tolvaptan at present not being available for clinical care, other options that lower AVP activity should be considered. An alternative might be to lower AVP concentration by increasing water intake [14]. In a rat model for polycystic kidney disease, a 3.5-fold increased water intake reduced urinary osmolality, renal expression of the AVP V2 receptor and reduced kidney weight compared with normal water intake [15] (Figure 1). Given the theoretical background and the promising animal data, Higashihara et al. investigated the effects of increased water intake on disease progression in ADPKD, a clinically important and very timely topic. In their study, published in this issue of NDT, 34 ADPKD patients with a relatively preserved kidney function were divided based upon their preference into a high and a free water intake group.

Urinary renin-angiotensin markers in polycystic kidney disease

In autosomal dominant polycystic kidney disease (ADPKD), activation of the renin-angiotensin aldosterone system (RAAS) may contribute to hypertension and disease progression. Although previous studies have focused on circulating RAAS components, preliminary evidence suggests that APDKD may increase urinary RAAS components. Therefore, our aim was to analyze circulating and urinary RAAS components in ADPKD. We cross-sectionally compared 60 patients with ADPKD with 57 patients with non-ADPKD chronic kidney disease (CKD). The two groups were matched by sex, estimated glomerular filtration rate (eGFR), blood pressure, and RAAS inhibitor use. Despite similar plasma levels of angiotensinogen and renin, urinary angiotensinogen and renin excretion were five- to sixfold higher in ADPKD (P < 0.001). These differences persisted when adjusting for group differences and were present regardless of RAAS inhibitor use. In multivariable analyses, ADPKD, albuminuria, and the respective plasma concentrations were independent predictors for urinary angiotensinogen and renin excretion. In ADPKD, both plasma and urinary renin correlated negatively with eGFR. Total kidney volume correlated with plasma renin and albuminuria but not with urinary renin or angiotensinogen excretions. Albuminuria correlated positively with urinary angiotensinogen and renin excretions in ADPKD and CKD. In three ADPKD patients who underwent nephrectomy, the concentrations of albumin and angiotensinogen were highest in plasma, followed by cyst fluid and urine; urinary renin concentrations were higher than cyst fluid. In conclusion, this study shows that, despite similar circulating RAAS component levels, higher urinary excretions of angiotensinogen and renin are a unique feature of ADPKD. Future studies should address the underlying mechanism and whether this may contribute to hypertension or disease progression in ADPKD.

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.