Conservative treatment versus elective repair of umbilical hernia in patients with liver cirrhosis and ascites: results of a randomized controlled trial (CRUCIAL trial).

PURPOSE: To establish optimal management of patients with an umbilical hernia complicated by liver cirrhosis and ascites. METHODS: Patients with an umbilical hernia and liver cirrhosis and ascites were randomly assigned to receive either elective repair or conservative treatment. The primary endpoint was overall morbidity related to the umbilical hernia or its treatment after 24 months of follow-up. Secondary endpoints included the severity of these hernia-related complications, quality of life, and cumulative hernia recurrence rate. RESULTS: Thirty-four patients were included in the study. Sixteen patients were randomly assigned to elective repair and 18 to conservative treatment. After 24 months, 8 patients (50%) assigned to elective repair compared to 14 patients (77.8%) assigned to conservative treatment had a complication related to the umbilical hernia or its repair. A recurrent hernia was reported in 16.7% of patients who underwent repair. For the secondary endpoint, quality of life through the physical (PCS) and mental component score (MCS) showed no significant differences between groups at 12 months of follow-up (mean difference PCS 11.95, 95% CI - 0.87 to 24.77; MCS 10.04, 95% CI - 2.78 to 22.86). CONCLUSION: This trial could not show a relevant difference in overall morbidity after 24 months of follow-up in favor of elective umbilical hernia repair, because of the limited number of patients included. However, elective repair of umbilical hernia in patients with liver cirrhosis and ascites appears feasible, nudging its implementation into daily practice further, particularly for patients experiencing complaints. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01421550, on 23 August 2011.

Safety and efficacy of transarterial embolization of hepatocellular adenomas.

BACKGROUND: Hepatocellular adenoma (HCA) larger than 5 cm in diameter has an increased risk of haemorrhage and malignant transformation, and is considered an indication for resection. As an alternative to resection, transarterial embolization (TAE) may play a role in prevention of complications of HCA, but its safety and efficacy are largely unknown. The aim of this study was to assess outcomes and postembolization effects of selective TAE in the management of HCA. METHODS: This retrospective, multicentre cohort study included patients aged at least 18 years, diagnosed with HCA and treated with TAE. Patient characteristics, 30-day complications, tumour size before and after TAE, symptoms before and after TAE, and need for secondary interventions were analysed. RESULTS: Overall, 59 patients with a median age of 33.5 years were included from six centres; 57 of the 59 patients were women. Median tumour size at time of TAE was 76 mm. Six of 59 patients (10 per cent) had a major complication (cyst formation or sepsis), which could be resolved with minimal therapy, but prolonged hospital stay. Thirty-four patients (58 per cent) were symptomatic at presentation. There were no significant differences in symptoms before TAE and symptoms evaluated in the short term (within 3 months) after TAE (P = 0·134). First follow-up imaging was performed a median of 5·5 months after TAE and showed a reduction in size to a median of 48 mm (P < 0·001). CONCLUSION: TAE is safe, can lead to adequate size reduction of HCA and, offers an alternative to resection in selected patients.

Effects of training physicians in electronic prescribing in the outpatient setting on clinical, learning and behavioural outcomes: a cluster randomized trial.

AIMS: Electronic prescribing systems may improve medication safety, but only when used appropriately. The effects of task analysis-based training on clinical, learning and behavioural outcomes were evaluated in the outpatient setting, compared with the usual educational approach. METHODS: This was a multicentre, cluster randomized trial [EDUCATional intervention for IT-mediated MEDication management (MEDUCATE trial)], with physicians as the unit of analysis. It took place in the outpatient clinics of two academic hospitals. Participants comprised specialists and residents (specialty trainees, in the UK) and their patients. Training took the form of a small-group session and an e-learning. The primary outcome was the proportion of medication discrepancies per physician, measured as discrepancies between medications registered by physicians in the electronic prescribing system and those reported by patients. Clinical consequences were estimated by the proportion of patients per physician with at least one missed drug-drug interaction with the potential for causing adverse drug events. A questionnaire assessed physicians' knowledge and skills. RESULTS: Among 124 participating physicians, primary outcome data for 115 (93%) were available. A total of 1094 patients were included. A mean of 48% of registered medications per physician were discrepant with the medications that their patients reported in both groups (P = 0.14). Due to registration omissions, a mean of 4% of patients per physician had one or more missed drug-drug interactions with the potential to cause a clinically relevant adverse drug event in the intervention group, and 7% in controls (P = 0.11). The percentages of correct answers on the knowledge and skills test were higher in the intervention group (57%) compared with controls (51%; P = 0.01). CONCLUSION: The training equipped outpatient physicians with the knowledge and skills for appropriate use of electronic prescribing systems, but had no effect on medication discrepancies.

Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

Retrospective study on timing of resection of hepatocellular adenoma.

BACKGROUND: Hepatocellular adenoma (HCA) is a benign liver tumour that may be complicated by bleeding or malignant transformation. Present guidelines advise cessation of oral contraceptives and surgical resection if the lesion is still larger than 5 cm at 6 months after diagnosis. The aim of this study was to evaluate whether this 6-month interval is sufficient to expect regression of a large HCA to 5 cm or smaller. METHODS: This retrospective cohort study included all patients with an HCA larger than 5 cm diagnosed between 1999 and 2015 with follow-up of at least 6 months. Medical records were reviewed for patient characteristics, clinical presentation, lesion characteristics, management and complications. Differences in characteristics were assessed between patients kept under surveillance and those who underwent treatment for an HCA larger than 5 cm. RESULTS: Some 194 patients were included, of whom 192 were women. Eighty-six patients were kept under surveillance and 108 underwent HCA treatment. Patients in the surveillance group had a significantly higher BMI (P = 0·029), smaller baseline HCA diameter (P < 0·001), more centrally located lesions (P < 0·001) and were more likely to have multiple lesions (P = 0·001) than those in the treatment group. There were no significant differences in sex, age at diagnosis, symptoms, complication rates and HCA subtype distribution. Time-to-event analysis in patients managed conservatively and those still undergoing treatment more than 6 months after diagnosis showed that 69 of 118 HCAs (58·5 per cent) regressed to 5 cm or smaller after a median of 104 (95 per cent c.i. 80-128) weeks. Larger HCAs took longer to regress (P < 0·001). No complications were documented during follow-up. CONCLUSION: This study suggests that a 6-month cut-off point for assessment of regression of HCA larger than 5 cm to no more than 5 cm is too early. As no complications were documented during follow-up, the cut-off point in women with typical, non-ß-catenin-activated HCA could be prolonged to 12 months, irrespective of baseline diameter.

Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area.

BACKGROUND: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs. METHODS: We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry. RESULTS: A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018). CONCLUSIONS: We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.

Time-trends in disease characteristics and comorbidities in patients with chronic hepatitis B in the period 1980-2020.

BACKGROUND & AIMS: The incidence of chronic hepatitis B (CHB) is declining due to successful implementation of vaccination programs and widespread use of antiviral therapy. We aimed to study time-trends in disease characteristics and comorbidities in newly referred CHB patients. METHODS: We collected information on hepatitis B virus (HBV) related disease characteristics (including hepatitis B e-antigen (HBeAg) status, viremia, stage of liver fibrosis and indication for treatment and/or hepatocellular carcinoma (HCC) surveillance) and presence of comorbidities in all CHB patients referred to our center from 1980 through 2020. Patient characteristics were compared according to referral date (before 2000, between 2000 and 2010 and after 2010). RESULTS: We identified 1515 eligible patients. Patients referred after 2010 were older (36 versus 34 years, p < 0.001), more often non-Caucasian (82.3% versus 55.0%, p < 0.001) and more frequently HBeAg negative (81.5% versus 49.8%, p < 0.001) when compared to patients referred before 2000. Adjusted for ethnicity, sex and age, patients referred after 2010 were less likely to have significant fibrosis (adjusted odds ratio [aOR]:0.178, p < 0.001) or indication for antiviral therapy (aOR:0.342, p < 0.001) but were more likely to be affected by the metabolic syndrome (aOR:1.985, p = 0.013), hepatic steatosis (aOR:1.727, p < 0.001) and metabolic dysfunction associated fatty liver disease (MAFLD) (aOR:1.438, p = 0.013). CONCLUSIONS: The characteristics of the CHB populations are changing. Newly referred patients are older, have less active HBV related liver disease but are more likely to be co-affected by MAFLD. These findings provide guidance for adequate allocation of resources to cope with the changing characteristics of the CHB population. FUNDING: Foundation for Liver and Gastrointestinal Research Rotterdam, the Netherlands and Gilead Sciences.

Systematic review of haemorrhage and rupture of hepatocellular adenomas.

BACKGROUND: Although benign in itself, hepatocellular adenoma (HCA) can be complicated by hormone-induced growth, and subsequent haemorrhage and rupture. The exact risk of haemorrhage and rupture is not known. This systematic review of the literature was carried out with the aim of estimating the risk of haemorrhage and rupture in HCA. METHODS: A systematic literature search of the PubMed and Embase databases was performed for all articles relevant to haemorrhage and/or rupture of HCA, published between 1969 and March 2011. RESULTS: Twenty-eight articles met the selection criteria, containing a total of 1176 patients. Haemorrhage was reported with an overall frequency of 27·2 per cent among patients, and in 15·8 per cent of all HCA lesions. Rupture and intraperitoneal bleeding were reported in 17·5 per cent of patients. Bleeding was the first symptom in 68·5 per cent of patients with a bleeding HCA. Six of 13 articles reporting the size of HCA lesions in which bleeding occurred mentioned haemorrhage in HCAs smaller than 5 cm. CONCLUSION: Haemorrhage and rupture are common in patients with HCA.

Hepatitis E infection with a benign course during vedolizumab treatment for Crohn's disease: A case report.

We present a 49 year old female patient with Crohn's disease (CD) in remission on vedolizumab therapy who experienced a symptomatic, though benign, course of acute hepatitis E. Routine blood tests showed substantial elevation of liver enzymes and polymerase chain reaction (PCR) testing confirmed hepatitis E virus (HEV) infection. Vedolizumab therapy was paused, liver enzymes improved three weeks after infection and normalized after six months. The patient recovered completely from mild symptoms. This case shows that hepatitis E is a potential cause of acute hepatitis during vedolizumab therapy, and in this case the infection has run a benign course.

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

This retrospective analysis was conducted to describe the characteristics of nucleoside-naïve hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg-positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double-blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off-treatment follow-up. Through a maximum duration of 96 weeks on-treatment and 24 weeks off-treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside-naïve HBeAg-positive patients treated with entecavir, and that HBsAg loss is associated with sustained off-treatment suppression of HBV DNA.

Diagnosis and treatment of hepatocellular adenoma in the Netherlands: similarities and differences.

BACKGROUND: The diagnosis of hepatocellular adenoma (HA) has a great impact on the lives of young women and may pose clinical dilemmas to the clinician since there are no standardized protocols to follow. We aimed to establish expert opinions on diagnosis and treatment of HA by collecting data from a nationwide questionnaire in the Netherlands. METHODS: A questionnaire was sent to 20 Dutch hospitals known to offer hepatologic and surgical experience on liver tumours. RESULTS: 17 hospitals (85%) responded to the questionnaire. Annually, a median of 52 patients presented with a solid liver tumour. In 15 (88%) hospitals, hepatic adenomas were diagnosed with contrast-enhanced, multiphase spiral CT or MRI. In 2 (12%) hospitals, histology was required as part of a management protocol. Surveillance after withdrawal of oral contraceptives was the initial policy in all clinics. MRI, CT or ultrasound was used for follow-up. Criteria for surgical resection were a tumour size >5 cm and abdominal complaints. In 5 (29%) hospitals, patients were dismissed from follow-up after surgery. In complex cases (e.g. large, multiple or centrally localized lesions, a wish for pregnancy), the treatment policy was highly variable. Pregnancy was not discouraged in 15 hospitals, but in 11 (65%) of these, strictly defined conditions were noted: frequent follow-up, peripheral tumour localization that makes surgery easier if necessary, stable tumour size, and a good informed consent. CONCLUSION: The management of HAs in the Netherlands is rather uniform, except in complex cases in which multiple factors may influence policy.

Fendrix® compared to Engerix® in HIV-infected patients nonresponding to initial- and re-vaccination schedule.

BACKGROUND: In HIV-infected patients, the immunogenicity of hepatitis B vaccines is impaired. In this randomised controlled study (RCT), we investigated the effect of Fendrix® versus double-dose Engerix® vaccination in previously non-responsive HIV-infected subjects. METHODS: Patients included those who were HIV-infected and non-responders to a primary (single-dose hepatitis B (HBV) vaccination) and a subsequent double-dose HBV revaccination schedule. Subjects were randomised 1:1 to receive Fendrix® (t = 0, 4, 8, 24 weeks) or double-dose Engerix® (t = 0, 4, 24 weeks) vaccinations. Primary efficacy, defined as anti-HBs response ≥ 10 IU/l, was evaluated at week 28 in both study arms. RESULTS: A subset of 48 patients non-responsive to HBV vaccination was selected, from a cohort of patients at our institution, who underwent HBV vaccination unsuccessfully either in a previous RCT or through standard care. The anti-HBs ≥ 10 IU/l response rate at week 28 in the Fendrix® arm and the Engerix® arm were 85.7% and 65.0%, respectively (p = 0.09). There was no significant difference between the two used vaccine types in the anti-HBs levels reached. In our institution, the overall response rate after initial standard-dose vaccination schedule and double-dose revaccination in our cohort was 75%. In this study, combining the effects of Fendrix and Engerix resulted in a 75% response rate in the 25% remaining non-responders on initial and double-dose revaccination series. This yielded an absolute 19% increase and an overall response to HBV vaccination in HIV-infected patients of around 94% in our cohort. CONCLUSION: These results together, suggest that continuing HBV vaccination in non-responders to a first course of single-dose vaccine and a double-dose revaccination scheme is worth the effort. No superiority of one of the investigated hepatitis B vaccines was shown in this cohort but an appropriate number of patients needed to achieve reliable answers was not achieved.

Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

Entecavir is a potent inhibitor of hepatitis B virus (HBV) polymerase. The efficacy and safety of entecavir in nucleoside-naïve patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B was established in a large, international, double-dummy study (ETV-022) where patients were randomized to entecavir 0.5 mg/day (n = 354) or lamivudine 100 mg/day (n = 355) once daily. ETV-022 had a 52-week blinded treatment phase, followed by an extended blinded treatment phase for up to 44 additional weeks (96 weeks total). Treatment was discontinued for patients achieving a protocol-defined response as determined by patient management criteria that intended to test the possibility of finite therapy, which has not previously been studied for entecavir or other anti-HBV agents in a large trial. Early results from this study have been previously presented/published separately. This paper compiles the results of up to 2 years of treatment for protocol-defined responders, virologic responders and nonresponders. For responders who discontinued therapy (per protocol), 24-week off-treatment evaluation is presented to provide a more 'complete picture' of what clinicians can expect when treating nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. For patients who discontinued therapy because of nonresponse (nonresponders) and subsequently entered the rollover study ETV-901, follow-up results, including resistance profile, are provided.

On-treatment monitoring of adefovir therapy in chronic hepatitis B: virologic response can be assessed at 24 weeks.

Patients with chronic hepatitis B (CHB) who will and those who will not respond to adefovir (ADV) monotherapy need to be identified at an early stage in order to adjust treatment and prevent future development of antiviral resistance. In a single-centre cohort study, we investigated 76 CHB patients [50% hepatitis B e antigen (HBeAg)-positive] treated with long-term ADV monotherapy. During a median follow-up of 122 (24-185) weeks, 42 (55%) patients achieved virologic response (VR), defined as HBV-DNA levels <10(3) copies/mL, and 10 patients (13%) developed genotypic ADV resistance. Independent baseline predictors of VR were HBeAg negativity [hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.24-7.19; P = 0.02], high alanine aminotransferase (ALT) levels (HR 1.11; 95% CI 1.05-1.18; P = 0.001), and low HBV-DNA levels (HR 0.56; 95% CI 0.41-0.75; P < 0.001). HBV-DNA at week 24 demonstrated a higher predictive value for VR than HBV-DNA at week 48. Important predictors of genotypic resistance were presence of cirrhosis (HR 6.54; 95% CI 1.39-30.9; P = 0.018), and not achieving VR during treatment (HR 6.60; 95% CI 1.35-32.4; P = 0.008). Patients without VR at week 24 already demonstrated a trend towards the emergence of ADV resistance (P = 0.07). HBV-DNA at week 24 was a better on-treatment predictor of VR than HBV-DNA at week 48, and ADV-resistant mutations developed more frequently in patients without VR at week 24. Therefore, our study suggests that virologic response to ADV therapy can be assessed at 24 weeks, instead of the generally recommended 48 weeks.

Hepatitis B virus infected health care workers in The Netherlands, 2000-2008.

In response to the confirmed transmission of hepatitis B virus (HBV) from a surgeon to several patients in the Netherlands, a 'Committee for Prevention of Iatrogenic Hepatitis B' was established in 2000. During the years 2000-2008, the committee reviewed 99 cases of HBV-infected health care workers. Fifty of them were found to perform exposure prone procedures (EPPs). Because of high levels of HBV DNA (>100,000 copies/ml), a ban on performing EPPs was applied in 11/50 cases; 25/50 low-viremic health care workers were allowed to continue EPPs while their HBV load was being monitored; and 14/50 cases had stopped working or changed profession. In five restricted workers who started oral antiviral treatment, HBV replication was persistently suppressed, enabling the ban on EPPs to be lifted. Throughout the European Union different levels of HBV viremia have been chosen, above which health care workers are not allowed to perform EPPs. It remains unknown how this affects the safety of patients. Application in the Netherlands of a European or a British guideline would have, respectively, doubled or tripled the number of restricted health care workers.

Fulminant Liver Failure due to Hepatitis B Reactivation During Treatment With Tocilizumab.

Tocilizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor that is frequently used for the treatment of refractory rheumatoid arthritis. Since patients with hepatitis B virus (HBV) infection were excluded from pivotal trials, the risk of HBV reactivation with this novel drug class remains uncertain. We present the first case of tocilizumab-associated HBV reactivation resulting in fulminant hepatic failure and a need for liver transplant. Our findings underscore the need for prophylactic antiviral therapy in patients being treated with novel immunosuppressive agents.

Components of the renin-angiotensin-aldosterone system in plasma and ascites in hepatic cirrhosis.

BACKGROUND: Decompensated liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid. METHODS: In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites. RESULTS: Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = -0.73, P < 0.001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0.001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 +/- 11%) was slightly lower than the albumin level (23 +/- 8%), whereas the aldosterone level (43 +/- 18%) was considerably higher (P < 0.0001). For renin and prorenin these percentages were much lower (P < 0.0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in-vitro degradation rates of renin in plasma and ascitic fluid were identical. CONCLUSION: In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites-to-plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.