Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant Polycystic Liver and Kidney Disease.

BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. ClinicalTrials.gov, Number: NCT01616927.

Symptom relief and not cyst reduction determines treatment success in aspiration sclerotherapy of hepatic cysts.

OBJECTIVE: To assess whether quantitative assessment of symptom reduction is a better outcome parameter than cyst volume reduction for treatment success in patients treated by aspiration sclerotherapy. METHODS: We included patients with symptomatic, large (> 5 cm), hepatic cysts from a randomized controlled trial (NCT02048319). At baseline and 6 months after treatment, symptoms were assessed with the polycystic liver disease questionnaire (PLD-Q) and we measured cyst volume using ultrasonography. Patient-reported change in health was assessed on a 5-point Likert scale (much worse to much better) after 6 months. We tested whether PLD-Q scores and cyst volumes changed after aspiration sclerotherapy (responsiveness). Changes in PLD-Q scores and cyst volume were compared with change in health as a measure of treatment success (discriminative ability). As secondary analysis, we compared baseline characteristics between responders (improved) and non-responders (not improved). RESULTS: We included 32 patients. Six months after treatment, 23 patients (72%) improved. Both PLD-Q score and cyst volume significantly decreased (median 38 to 18 points, p < 0.001, and 479 to 68 mL, p < 0.001). Larger improvement in PLD-Q score was associated with a positive change in health (p = 0.001), while larger proportional reduction in cyst volume was not significantly associated with health improvement after treatment (p = 0.136). Responders had larger baseline cyst volumes compared to non-responders (median 624 mL [IQR 343-1023] vs. 322 mL [IQR 157-423] p = 0.008). CONCLUSION: Cyst diameter reduction does not reflect treatment success in aspiration sclerotherapy from patients' perspective, while symptoms measured with the PLD-Q can be used as a reliable outcome measure. KEY POINTS: • Cyst diameter reduction poorly reflects treatment success in aspiration sclerotherapy. • Symptoms measured by the polycystic liver disease questionnaire (PLD-Q) is a better outcome measure than cyst volume reduction for treatment success after aspiration sclerotherapy. • Particularly patients with larger cysts (≥ 529 mL) benefit from aspiration sclerotherapy.

Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial.

Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. Design, Setting, and Participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017. Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). Main Outcomes and Measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to -0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). Conclusions and Relevance: Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01616927.

Development and Validation of a Disease-Specific Questionnaire to Assess Patient-Reported Symptoms in Polycystic Liver Disease.

UNLABELLED: Treatment of polycystic liver disease (PLD) focuses on symptom improvement. Generic questionnaires lack sensitivity to capture PLD-related symptoms, a prerequisite to determine effectiveness of therapy. We developed and validated a disease-specific questionnaire that assesses symptoms in PLD (PLD-Q). We identified 16 PLD-related symptoms (total score 0-100 points) by literature review and interviews with patients and clinicians. The developed PLD-Q was validated in Dutch (n = 200) and United States (US; n = 203) PLD patients. We assessed the correlation of PLD-Q total score with European Organization for Research and Treatment of Cancer (EORTC) symptom scale, global health visual analogue scale (VAS) of EQ-5D, and liver volume. To test discriminative validity, we compared PLD-Q total scores of patients with different PLD severity stages (Gigot classification) and PLD-Q total scores of PLD patients with general controls and polycystic kidney disease patients without PLD. Reproducibility was tested by comparing original test scores with 2-week retest scores. In total, 167 Dutch and 124 US patients returned the questionnaire. Correlation between PLD-Q total score and EORTC symptom scale (The Netherlands [NL], r = 0.788; US, r = 0.811) and global health VAS (NL, r = -0.517; US, r = -0.593) was good. There was no correlation of PLD-Q total score with liver volume (NL, r = 0.138; P = 0.236; US, r = 0.254; P = 0.052). Gigot type III individuals scored numerically higher than type II patients (NL, 46 vs. 40; P = 0.089; US, 48 vs. 36; P = 0.055). PLD patients scored higher on the PLD-Q total score than general controls (NL, 42 vs. 17; US, 40 vs. 13 points) and polycystic kidney disease patients without PLD (22 points). Reproducibility of PLD-Q was excellent (NL, r = 0.94; US, 0.96). CONCLUSION: PLD-Q is a valid, reproducible, and sensitive disease-specific questionnaire that can be used to assess PLD-related symptoms in clinical care and future research. (Hepatology 2016;64:151-160).

The effect of disease severity markers on quality of life in autosomal dominant polycystic kidney disease: a systematic review, meta-analysis and meta-regression.

BACKGROUND: Little is known about determinants of quality of life (QoL) in autosomal dominant polycystic kidney disease (ADPKD). Recent studies suggest that QoL in ADPKD is determined by more factors than mere renal function. We investigated the effect of ADPKD on QoL and evaluated how Qol is affected by disease severity markers renal function, kidney volume and liver volume. METHODS: We performed a systematic review, meta-analysis and meta-regression analyses of cohort studies and randomized controlled trials investigating patient-reported QoL in adult patients with ADPKD not yet on dialysis. EMBASE, MEDLINE, and Web of Science were searched to August 2015 without language restrictions. Two investigators independently reviewed title, abstracts and full text of potentially relevant citations to determine eligibility. We compared pooled QoL summary scores of ADPKD patients using a random-effects meta-analytic model. These scores were compared with mean and age-corrected reference scores of the general population. In a meta-regression analysis, we investigated the univariate effect of renal function, kidney volume and liver volume on QoL. RESULTS: We included nine studies in meta-analysis including 1623 patients who completed the SF-36 questionnaire. Pooled physical (PCS) and mental component scores (MCS) of the SF-36 of individuals with ADPKD were lower than those of the reference population (45.7 vs. 50.0 and 47.8 vs. 50.0 points, both P < 0.001). QoL of ADPKD patients remained lower after comparison with age-corrected reference values (age 35-44 year; PCS 52.2, MCS 49.9 points, both P < 0.05). Larger liver volume negatively impacted PCS (P < 0.001) and MCS (P = 0.001), whereas there was no association with renal function (PCS P = 0.1, MCS P = 0.9) and kidney volume (PCS P = 0.5, MCS P = 0. 5). Total liver and kidney volume had no impact on PCS (P = 0.1), but did have impact on MCS (P = 0.02). CONCLUSIONS: QoL reported by non-dialysis patients with ADPKD is impaired compared to the general population. Large liver volume was the most important factor that diminishes QoL. PROSPERO International Registry number CRD42015026428.

Ursodeoxycholic acid in advanced polycystic liver disease: A phase 2 multicenter randomized controlled trial.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) inhibits proliferation of polycystic human cholangiocytes in vitro and hepatic cystogenesis in a rat model of polycystic liver disease (PLD) in vivo. Our aim was to test whether UDCA may beneficially affect liver volume in patients with advanced PLD. METHODS: We conducted an international, multicenter, randomized controlled trial in symptomatic PLD patients from three tertiary referral centers. Patients with PLD and total liver volume (TLV) ⩾2500ml were randomly assigned to UDCA treatment (15-20mg/kg/day) for 24weeks, or to no treatment. Primary endpoint was proportional change in TLV. Secondary endpoints were change in symptoms and health-related quality of life. We performed a post-hoc analysis of the effect of UDCA on liver cyst volume (LCV). RESULTS: We included 34 patients and were able to assess primary endpoint in 32 patients, 16 with autosomal dominant polycystic kidney disease (ADPKD) and 16 with autosomal dominant polycystic liver disease (ADPLD). Proportional TLV increased by 4.6±7.7% (mean TLV increased from 6697ml to 6954ml) after 24weeks of UDCA treatment compared to 3.1±3.8% (mean TLV increased from 5512ml to 5724ml) in the control group (p=0.493). LCV was not different after 24weeks between controls and UDCA treated patients (p=0.848). However, UDCA inhibited LCV growth in ADPKD patients compared to ADPKD controls (p=0.049). CONCLUSIONS: UDCA administration for 24weeks did not reduce TLV in advanced PLD, but UDCA reduced LCV growth in ADPKD patients. Future studies might explore whether ADPKD and ADPLD patients respond differently to UDCA treatment. LAY SUMMARY: Current therapies for polycystic liver disease are invasive and have high recurrence risks. Our trial showed that the drug, ursodeoxycholic acid, was not able to reduce liver volume in patients with polycystic liver disease. However, a subgroup analysis in patients that have kidney cysts as well showed that liver cyst volume growth was reduced in patients who received ursodeoxycholic acid in comparison to patients who received no treatment. Trial registration number https://www.clinicaltrials.gov/: NCT02021110. EudraCT Number https://www.clinicaltrialsregister.eu/: 2013-003207-19.

Evaluating health-related quality of life in patients with polycystic liver disease and determining the impact of symptoms and liver volume.

BACKGROUND & AIMS: Polycystic liver disease (PLD) follows a progressive course ultimately leading to severe hepatomegaly and mechanical complaints in a subset of patients. It is still unknown to what extent this compromises health-related quality of life (HRQL). Our aim was to determine HRQL in PLD patients and investigate its association with concurrent abdominal symptoms and liver volume. METHODS: Pooled data of 92 severe PLD patients from two randomized clinical trials were used for our cross-sectional analysis. HRQL was assessed using the generic short-form health survey (SF-36) resulting in eight scale scores and the summarizing physical (PCS) and mental component score (MCS). Subsequently, these were compared with the general population. Abdominal symptoms were measured with a standardized, 7-point scale questionnaire in 54 patients. We dichotomized symptoms for absence or presence and compared them with the component scores. Finally, a possible correlation between liver volume and HRQL was explored. RESULTS: Demographics showed severe polycystic livers (mean 4906 ± 2315 ml). PCS was significantly lower compared with the general population (P < 0.001), in contrast with a similar MCS (P = 0.82). PLD patients had statistically significant (P < 0.05) diminished physical functioning, role physical, general health, vitality and social functioning scores. Upper- and lower abdominal pain and dyspnoea were significantly associated with a reduced PCS (P < 0.01). No correlation was found between liver volume and HRQL. CONCLUSION: Polycystic liver disease patients had significantly lower HRQL in the physical dimension compared with the general population. Abdominal pain and dyspnoea had a significant impact on this physical dimension of HRQL.

Improving Care for Recently Diagnosed Inflammatory Bowel Disease Patients: Lessons Learned From a Patient-Centred, Mixed-Method Study.

BACKGROUND AND AIMS: Newly diagnosed inflammatory bowel disease [IBD] patients need to deal with the physical and emotional impact of the disease. We aimed to evaluate care for recently diagnosed IBD patients from the patient perspective and assess themes for improvement. METHODS: A mixed-method study with adult IBD patients 4-15 months after diagnosis was performed. First, relevant themes were identified through semi-structured interviews until data saturation. Next, a questionnaire assessing satisfaction with care [SATI-Q] was developed and validated with 15 items divided into two domains: medical care and information and psychosocial care. Higher scores indicate higher patient satisfaction [0-100]. RESULTS: We interviewed 20 patients. Next, 84/107 patients completed the SATI-Q: 51% female, aged 37 years (interquartile range [IQR 25-58]), 36% Crohn's disease, disease duration 9 months [IQR 6-12] and 74% in clinical remission. The median SATI-Q score was 82 [IQR 72-92]. Patients were more satisfied with medical care than with information and psychosocial care (score 92 [IQR 81-98] vs 74 [IQR 60-90], p < 0.001). Patients were least satisfied with the attention given to IBD-related emotions and information on IBD medication, diet and future perspectives [77, 76, 57 and 54% of patients satisfied]. Patients [81%] preferred spoken information. Only 26-27% preferred brochures and websites. CONCLUSIONS: In this study, the SATI-Q questionnaire was developed and validated to assess patient satisfaction with care in early IBD. Our findings suggest that psychosocial care and information on IBD medication, diet influence and future perspectives for recently diagnosed IBD patients require improvement.

Symptom relief and quality of life after combined partial hepatectomy and cyst fenestration in highly symptomatic polycystic liver disease.

BACKGROUND: Polycystic liver disease can cause severe symptomatic hepatomegaly. Combined partial hepatectomy and cyst fenestration can be performed to reduce liver volume and symptom burden. We aimed to assess change in symptom relief and quality of life 6 months after partial hepatectomy and cyst fenestration in polycystic liver disease patients. METHOD: We established a prospective cohort between 2014 and 2018 at a referral center in the United States. Patients who underwent partial hepatectomy and cyst fenestration for volume-related symptoms were included. Primary outcome was change in polycystic liver disease-related symptoms, measured with Polycystic Liver Disease Questionnaire. Secondary outcomes were change in liver volume (computed tomography/ magnetic resonance imaging) and change in quality of life, measured with the 12-Item Short Form Survey and the EuroQoL Visual Analogue Scale. Questionnaire scores range from 0 to 100 and were assessed before and 6 months after partial hepatectomy and cyst fenestration. Surgical complications were scored according to Clavien-Dindo (grade 1 to 5). RESULTS: We included 18 patients (mean age 52 years, 82% female). Partial hepatectomy and cyst fenestration reduced median liver volume (4,917 to 2,120 mL). Symptoms, measured with Polycystic Liver Disease Questionnaire, decreased (76.9 to 34.8 points; P < .001) 6 months after surgery; 15/16 symptoms declined after treatment, with the most impact seen on early satiety and dyspnea. Quality of life also improved after surgery: median physical and mental component scales of the 12-Item Short Form Survey and EuroQoL Visual Analog Scale increased (24.9 to 45.7, P = .004; 40.5 to 55.4, P = .02; and 40.0 to 72.5, P = .003). Major complications (grade 4) occurred in 2 patients. There was no procedure-related mortality. CONCLUSION: Partial hepatectomy and cyst fenestration substantially improves symptom burden and quality of life in highly symptomatic polycystic liver disease patients.

Impact of liver volume on polycystic liver disease-related symptoms and quality of life.

BACKGROUND: Symptoms in polycystic liver disease (PLD) are thought to be caused by compression of organs and structures by the enlarged liver. AIM: The aim of this article is to assess the impact of liver volume on symptoms and quality of life (QoL) in PLD. METHODS: We included PLD patients from two prospective studies that used the PLD-questionnaire (PLD-Q) for symptom assessment. QoL was assessed through SF-36, summarized in a physical (PCS) and mental (MCS) component score. Liver volume was correlated with PLD-Q total scores. Patients were classified based on height-corrected liver volume in mild (<1600 ml), moderate (1600-3200 ml), and severe (>3200 ml) disease. PLD-Q and QoL (PCS and MCS) scores were compared across disease stages. RESULTS: We included 82 of 131 patients from the original studies (disease stages; mild n = 26, moderate n = 33, and severe n = 23). Patients with larger liver volume reported higher symptom burden (r = 0.516, p < 0.001). Symptom scores increased with disease progression, except for abdominal pain (p = 0.088). PCS decreased with advancing disease (p < 0.001), in contrast to MCS (p = 0.055). Moderate (p = 0.007) and severe (p < 0.001) PLD patients had lower PCS scores than the general population. CONCLUSION: PLD with larger liver volume is more likely to be symptomatic and is associated with lower QoL.