Efficacy of Alkaline Phosphatase in Critically Ill Patients with COVID-19: A Multicentre Investigator-Initiated Double-Blind Randomised Placebo-Controlled Trial.

BACKGROUND: Efforts to identify therapies to treat hospitalised patients with COVID-19 are being continued. Alkaline phosphatase (AP) dephosphorylates pro-inflammatory adenosine triphosphate (ATP) into anti-inflammatory adenosine. METHODS: In a randomised controlled trial, we investigated the safety and efficacy of AP in patients with SARS-CoV-2 infection admitted to the ICU. AP or a placebo was administered for four days following admission to the ICU. The primary outcome was the duration of mechanical ventilation. Mortality in 28 days, acute kidney injury, need for reintubation, safety, and inflammatory markers relevant to the described high cytokine release associated with SARS-CoV-2 infection were the secondary outcomes. RESULTS: Between December 2020 and March 2022, 97 patients (of the intended 132) were included, of which 51 were randomised to AP. The trial was terminated prematurely based on meeting the threshold for futility. Compared to the placebo, AP did not affect the duration of mechanical ventilation (9.0 days vs. 9.3 days, p = 1.0). No safety issues were observed. After 28 days, mortality was 9 (18%) in the AP group versus 6 (13%) in the placebo group (p = 0.531). Additionally, no statistically significant differences between the AP and the placebo were observed for the other secondary outcomes. CONCLUSIONS: Alkaline phosphatase (AP) therapy in COVID-19 ICU patients showed no significant benefits in this trial.

Alkaline phosphatase treatment of acute kidney injury - an update.

Through improved insight in the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (AP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS) induced inflammation and kidney injury in animals. However, translation of these protective effects into tangible clinical benefit has proven difficult. Because the anti-inflammatory properties of AP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to AP. The reevaluation of which properties of the AP enzyme are responsible for the benefit seen in the lab, is an important step to determine where the true potential of AP as a treatment strategy for AKI in the clinic lies. In this review, we will discuss how AP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signaling, and protect barrier tissues, which together form the basis for current knowledge of the role of AP in the kidney. With this knowledge in mind and by analyzing currently available clinical evidence, we propose directions for new research that can determine whether AP as a treatment strategy for AKI has a future in the clinical field.

Real-time two-axis control of a spin qubit.

Optimal control of qubits requires the ability to adapt continuously to their ever-changing environment. We demonstrate a real-time control protocol for a two-electron singlet-triplet qubit with two fluctuating Hamiltonian parameters. Our approach leverages single-shot readout classification and dynamic waveform generation, allowing full Hamiltonian estimation to dynamically stabilize and optimize the qubit performance. Powered by a field-programmable gate array (FPGA), the quantum control electronics estimates the Overhauser field gradient between the two electrons in real time, enabling controlled Overhauser-driven spin rotations and thus bypassing the need for micromagnets or nuclear polarization protocols. It also estimates the exchange interaction between the two electrons and adjusts their detuning, resulting in extended coherence of Hadamard rotations when correcting for fluctuations of both qubit axes. Our study highlights the role of feedback in enhancing the performance and stability of quantum devices affected by quasistatic noise.

Alkaline phosphatase to treat ischaemia-reperfusion injury in living-donor kidney transplantation: APhIRI I feasibility pilot study.

AIMS: Ischemia-reperfusion injury (IRI) during kidney transplant procedures is associated with adverse outcome. Alkaline phosphatase (AP) is an enzyme that has the potential to dampen IRI. Prior to this study, it had not been tested in the setting of kidney transplantation. This study aimed to evaluate the safety and feasibility of peri-procedural AP administration in living donor kidney transplantation. METHODS: In this double blind, randomized, placebo-controlled, single-center pilot study, all eligible recipients of living donor kidneys were asked to give informed consent. AP (bRESCAP) or a placebo was administered intravenously over 24 hours after the transplantation procedure. The primary outcome-graft function at 1 year-was represented by iohexol measured glomerular filtration rate (mGFR). Serum and urine biomarkers within seven days after surgery were used as surrogate markers of kidney function and injury. RESULTS: Eleven patients were enrolled of whom five were treated with bRESCAP and six with placebo. After 1 year, mGFR was not different between groups. No specific adverse events were observed in the bRESCAP group. Urine expression of injury biomarkers CCL14, NGAL and Cystatin C was lower in the bRESCAP group at day seven. This was statistically significant. CONCLUSION: This study illustrates that bRESCAP treatment is feasible in kidney transplantation, might have a dampening effect on IRI induced renal inflammation, and raises no safety concerns. Future research will evaluate the effects of bRESCAP treatment in donation after circulatory death kidney transplantation where IRI is more pronounced.

Early Eculizumab Withdrawal in Patients With Atypical Hemolytic Uremic Syndrome in Native Kidneys Is Safe and Cost-Effective: Results of the CUREiHUS Study.

Introduction: The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy. Methods: All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted. Results: A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight. Conclusion: It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.

Functional constipation in patients with hemorrhoids: a systematic review and meta-analysis.

Hemorrhoids are common anorectal pathology, with high recurrence rates after surgical treatment. It is hypothesized that high straining forces during paradoxical contractions and inadequate relaxation are causally related to hemorrhoids. This review aimed to assess the coprevalence of functional constipation and dyssynergic defecation in a population with hemorrhoids. Moreover, the effects of rubber band ligation (RBL) were analyzed. Sources included Pubmed, Embase and CENTRAL . Randomized trials, cohort and case-control studies that investigated the prevalence of constipation in patients with hemorrhoids or the prevalence of hemorrhoids in patients with constipation compared to healthy subjects were included. Manometric studies were also eligible. Quality assessment was performed by using the Newcastle Ottawa Quality Assessment Scale. The primary outcome was the prevalence of functional constipation or dyssynergic defecation in patients with hemorrhoids. Nineteen studies were included. Prevalence of constipation was significantly higher in patients with hemorrhoids compared to controls [OR (odds ratio), 2.09; 95% CI (confidence interval), 1.27-3.44]. No significant difference in the prevalence of hemorrhoids between patients with constipation compared to controls was found (OR, 2.37; 95% CI, 0.67-8.44). Anal pressures in patients with hemorrhoids were significantly higher compared to healthy controls in all manometric studies. After RBL, these pressures remained significantly higher in patients with hemorrhoids ( P = 0.001). Functional constipation, dyssynergic defecation and higher basal anal pressures are more prevalent in patients with hemorrhoids compared to controls. Improvement of therapy for functional constipation, especially dyssynergic defecation patterns, might lead to better long-term outcomes and reduce recurrence.

Oncological and functional outcomes of transanal total mesorectal excision in a teaching hospital in the Netherlands.

PURPOSE: Transanal total mesorectal excision (TaTME) was developed to overcome surgical difficulties experienced in distal pelvic dissection. Concerns have been raised about potential worse postoperative functional outcomes after TaTME. Also, the oncological safety was questioned. This study aimed to describe the functional, surgical, oncological outcomes and quality of life (QoL) after TaTME. METHODS: All consecutive TaTME cases for rectal cancer without disseminated disease between December 2016 and April 2019 were included. The Wexner incontinence score, low anterior resection syndrome (LARS) score, fecal incontinence-related QoL, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-core questionnaire and 29-item module (EORTC QLQ-C30/CR29) were collected. Kaplan-Meier analysis was used to calculate local recurrence-free survival. RESULTS: Thirty patients were eligible for analysis of which 23 received questionnaires. Response rate was 74%. After a median follow-up of respectively 20.0 and 23.0 months for functional and oncological outcomes, the median (interquartile range) of Wexner incontinence and LARS scores were 9.0 (7.0-12.0) and 33.1 (25.0-39.0). Major LARS was present in 73.3%. Fecal incontinence, general and colorectal-specific QoL subdomains that are associated with poor bowel function scored in line with previously reported data. The 2-year actuarial cumulative local recurrence rate was 3.7% (95% confidence interval, 2.4%-5.0%). CONCLUSION: TaTME may lead to significant functional impairments. Patients should receive preoperative counseling on this topic and be fully aware of the potential consequences of their treatment. Oncological data were in line with other short- to moderate-term data and did not show alarming results.

Trajectories of health-related quality of life and psychological distress in patients with colorectal cancer: A population-based study.

BACKGROUND: The aim of this nationwide cohort study was to examine the course of symptoms and trajectories of health-related quality of life (HR-QoL) and psychological distress during follow-up and to identify vulnerable patients. METHODS: Patients with pathological stage I-III colorectal cancer (CRC) between 2013 and 2018 were included. Baseline characteristics were collected from the Netherlands Cancer Registry, and patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30/CR29, Hospital Anxiety and Depression Scale and low anterior resection syndrome (LARS) questionnaires at the baseline and subsequently at 3, 6, 12, 18 and 24 months. Latent class growth and multinomial logistic regression analyses were performed to outline 24-month trajectories in HR-QoL and distress and to identify predictive factors. RESULTS: A total of 1535 patients with colon cancer or rectal cancer were included. Trajectory analysis of HR-QoL identified three patient classes: high HR-QoL (62.7%), improving HR-QoL (29.0%) and low HR-QoL (8.3%). The following patient groups were identified with having low distress (64.0%), moderate distress (26.9%) and high distress (9.1%). Around 13% of the total cohort had either persistent low HR-QoL or high psychological distress throughout follow-up. Patients belonging to this vulnerable group were significantly more likely to be female, to be younger aged, to have lower education, to have disease stage II-III or to have major LARS. CONCLUSIONS: Although most patients treated for stage I-III CRC fared well, a small but significant proportion of around 13% did not recover during follow-up and reported low HR-QoL and/or high psychological distress levels throughout. This study's findings should be taken into account when organising and selecting patients for tailored follow-up.

Outcome of atypical haemolytic uraemic syndrome relapse after eculizumab withdrawal.

BACKGROUND: The introduction of eculizumab has significantly improved the outcome of patients with atypical haemolytic uraemic syndrome (aHUS). Because of the risk of relapse after discontinuation, eculizumab was proposed as life-long therapy. However, data on the outcome of relapse are limited. In the Netherlands, patients with aHUS are treated with a restrictive eculizumab regime and are included in a national observational study (CUREiHUS, Dutch Trial Register NTR5988/NL5833). METHODS: For this interim safety analysis, we evaluated the outcome of all adult patients with a suspected relapse, defined as the need to intensify eculizumab after tapering or withdrawal of therapy. RESULTS: We describe 11 patients who received renewed eculizumab therapy because of suspected relapse. In three patients with aHUS in native kidneys, estimated glomerular filtration rate (eGFR) returned to baseline value and remained stable without overt proteinuria after follow-up. Six out of eight transplanted patients responded to eculizumab therapy with improvement in eGFR. After a median follow-up of 24.6 months, a reduction of eGFR ≥25% was observed in three of these transplanted patients, which was attributed to the aHUS relapse in only one patient. CONCLUSIONS: This interim analysis suggests that re-treatment with eculizumab after relapse is safe and feasible. We will continue to use our restrictive treatment strategy.

Poor response at restaging MRI and high incomplete resection rates of locally advanced mucinous rectal cancer after chemoradiation therapy.

AIM: Mucinous carcinoma is a histological subtype of rectal cancer and has been associated with a poor response to neoadjuvant chemoradiotherapy (CRT). The primary aim of this study was to analyse the response on MRI of mucinous locally advanced rectal cancer (LARC) after CRT compared to regular adenocarcinoma. METHOD: Patients with LARC (defined as cT4 and/or cN2), who underwent CRT followed by restaging MRI and surgery in two tertiary referral hospitals were retrospectively included in the study. Pre- and post-treatment MRI was reviewed by an experienced abdominal radiologist. RESULTS: A total of 102 patients, of whom 29 were diagnosed with mucinous carcinoma, were included for analysis. At restaging MRI, adenocarcinoma patients demonstrated significantly less clinical involvement of the mesorectal fascia (37% vs. 62%, P = 0.003) while this was not demonstrated in mucinous carcinoma patients (86% vs. 97%, P = 0.16). Significant downstaging after CRT in adenocarcinoma patients (P = 0.01) was seen while, in mucinous carcinoma patients, no downstaging after CRT (P = 0.89) was seen. Pathology revealed significantly higher rates of an involved circumferential resection margin in mucinous carcinoma versus adenocarcinoma patients (27.6% vs. 1.4%; P < 0.001). After multivariate regression analysis, mucinous carcinoma remained an independent prognostic factor for local recurrence (hazard ratio 3.6; 95% CI 1.1-12.4), although no differences in overall or disease-free survival were observed. CONCLUSION: Mucinous rectal carcinoma is associated with a poor clinical response at restaging MRI after CRT, leading to relatively higher rates of involved circumferential resection margins at pathology. In this cohort, mucinous carcinoma seems to be a prognostic factor for increased risk of local recurrence, without an effect on overall survival.

Engineering long spin coherence times of spin-orbit qubits in silicon.

Electron-spin qubits have long coherence times suitable for quantum technologies. Spin-orbit coupling promises to greatly improve spin qubit scalability and functionality, allowing qubit coupling via photons, phonons or mutual capacitances, and enabling the realization of engineered hybrid and topological quantum systems. However, despite much recent interest, results to date have yielded short coherence times (from 0.1 to 1 µs). Here we demonstrate ultra-long coherence times of 10 ms for holes where spin-orbit coupling yields quantized total angular momentum. We focus on holes bound to boron acceptors in bulk silicon 28, whose wavefunction symmetry can be controlled through crystal strain, allowing direct control over the longitudinal electric dipole that causes decoherence. The results rival the best electron-spin qubits and are 104 to 105 longer than previous spin-orbit qubits. These results open a pathway to develop new artificial quantum systems and to improve the functionality and scalability of spin-based quantum technologies.

Implementation of a Postoperative Screening and Treatment Guidance for the Low Anterior Resection Syndrome: Preliminary Results.

BACKGROUND: Even years after a low anterior resection, many patients experience persisting bowel complaints. This is referred to as low anterior resection syndrome and has a severe adverse effect on quality of life. Its diverse nature makes it difficult to find a gold-standard therapy for this syndrome. However, most importantly, postoperative guidance appears to be suboptimal. OBJECTIVE: The purpose of this study was to describe and evaluate the implementation of a multimodel guidance with structured screening and treatment options. DESIGN: A retrospective, comparative, cross-sectional study was conducted. Data of patients treated before protocol implementation were compared with a cohort after implementation. SETTINGS: This was a single-center study. PATIENTS: Patients seen after low anterior resection or sigmoid resection between 2010 and 2017 for colorectal malignancy were included. INTERVENTION: This included implementation of a postoperative guidance protocol. MAIN OUTCOME MEASURES: Bowel dysfunction was assessed by the low anterior resection score, whereas the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (C30 and CR29) assessed general and colorectal-specific quality of life. RESULTS: A total of 243 patients were included; 195 were guided before and 48 after protocol implementation. Patients who underwent low anterior resection after protocol implementation showed significantly lower median low anterior resection scores (31 vs 18; p = 0.02) and less major low anterior resection syndrome (51.9% vs 26.3%; p = 0.045). Patients who underwent sigmoid resection did not present with similar changes. Multiple quality-of-life domains showed clinically significant positive changes since our postoperative protocol was implemented. LIMITATIONS: Patient characteristics are not comparable between groups, which makes it difficult to draw firm conclusions. CONCLUSIONS: We recommend that others reconsider their current postoperative management for patients with rectal cancer and suggest a change to a comparable noninvasive, patient-driven postoperative guidance to enhance patient coping mechanisms and self-management and therefore improve their quality of life. See Video Abstract at http://links.lww.com/DCR/A970. IMPLEMENTACIÓN DE UNA GUÍA POSTOPERATORIA DE DETECCIÓN Y TRATAMIENTO PARA EL SÍNDROME DE RESECCIÓN ANTERIOR BAJA: RESULTADOS PRELIMINARES: Incluso años después de una resección anterior baja, muchos pacientes experimentan quejas intestinales persistentes. Esto se conoce como síndrome de resección anterior baja y tiene un efecto adverso grave en la calidad de vida. Su naturaleza diversa hace que sea difícil encontrar una terapia patrón de oro para este síndrome. Pero lo más importante, la guía postoperatoria parece ser subóptima. OBJETIVO: Describir y evaluar la implementación de una guía de múltiples modelos con opciones estructuradas de selección y tratamiento. DISENO: Se realizó un estudio retrospectivo de corte transversal comparativo. Los datos de los pacientes tratados antes de la implementación del protocolo se compararon con una cohorte después de la implementación. MARCO: Centro de estudio único. PACIENTES: Pacientes después de resección anterior baja o resección sigmoidea entre 2010-2017 por neoplasia colorectal. INTERVENCIÓN:: La implementación de un protocolo de guía postoperatoria. PRINCIPALES MEDIDAS DE RESULTADO: La disfunción intestinal se evaluó mediante la puntuación de resección anterior baja, mientras que la Organización Europea para la Investigación y Tratamiento de Cuestionarios de Calidad de Vida del Cáncer (C30 y CR29) evaluó la calidad de vida general y específicamente colorectal. RESULTADOS: Se incluyeron 243 pacientes, 195 fueron guiados antes y 48 después de la implementación del protocolo. Los pacientes que se sometieron a una resección anterior baja después de la implementación del protocolo mostraron puntuaciones de resección anterior bajas medias significativamente más bajas (31 frente a 18; p = 0,02) y menos puntuaciones de síndrome de resección anterior baja (51,9% frente a 26,3%; p = 0,045). Los pacientes sometidos a resección sigmoidea no presentaron cambios similares. Los múltiples dominios de calidad de vida mostraron cambios positivos clínicamente significativos desde que se implementó nuestro protocolo postoperatorio. LIMITACIONES: Las características de los pacientes no son comparables entre los grupos, lo que dificulta sacar conclusiones firmes. CONCLUSIÓNES:: Recomendamos a otros que reconsideren su manejo postoperatorio actual para pacientes con cáncer de recto y sugerimos un cambio a una guía postoperatoria impulsada por el paciente no invasiva comparable para mejorar los mecanismos de afrontamiento y el autocontrol de los pacientes y, por lo tanto, mejorar su calidad de vida. Vea el Video del Resumen en http://links.lww.com/DCR/A970.

Awareness and management of low anterior resection syndrome: A Dutch national survey among colorectal surgeons and specialized nurses.

INTRODUCTION: Substantial progress has been made in the treatment of rectal cancer in the past two decades. Low anterior resection is a cornerstone in current treatment, combined with neo-adjuvant (chemo-) radiation in selected cases. However, side effects such as increased frequency, urgency and incontinence are seen in a majority of patients postoperatively. These symptoms, referred to as low anterior resection syndrome (LARS), have a severe impact on quality of life. Management of LARS is complex, and surgeons seem to underestimate and misinterpret the impact of symptoms associated with LARS. AIM AND METHODS: We investigated the awareness and management of LARS in The Netherlands, conducting a national survey in which colorectal surgeons and colorectal care nurses were asked for their views on this complex syndrome. RESULTS: 242 health-care professionals participated in the survey. Most participants estimate the prevalence of major LARS is 20-40% after low anterior resection (LAR); a severe underestimation of actual prevalence - around 70%. Only 10% of surgeons use LARS screening tools in the preoperative period, and fewer than half of surgeons use LARS scores before or after a LAR. Although most surgeons inform their patients preoperatively about the changes in bowel function that they may experience after rectal cancer treatment, a majority of these surgeons indicate more information and patient counselling would improve the quality of life of their patients. DISCUSSION: Impact and prevalence of LARS is underestimated by their physicians. Uniform clinical guidelines should be developed to guide physicians in adequate management of patients with LARS.

Readout and control of the spin-orbit states of two coupled acceptor atoms in a silicon transistor.

Coupling spin qubits to electric fields is attractive to simplify qubit manipulation and couple qubits over long distances. Electron spins in silicon offer long lifetimes, but their weak spin-orbit interaction makes electrical coupling challenging. Hole spins bound to acceptor dopants, spin-orbit-coupled J = 3/2 systems similar to Si vacancies in SiC and single Co dopants, are an electrically active spin system in silicon. However, J = 3/2 systems are much less studied than S = 1/2 electrons, and spin readout has not yet been demonstrated for acceptors in silicon. Here, we study acceptor hole spin dynamics by dispersive readout of single-hole tunneling between two coupled acceptors in a nanowire transistor. We identify m J = ±1/2 and m J = ±3/2 levels, and we use a magnetic field to overcome the initial heavy-light hole splitting and to tune the J = 3/2 energy spectrum. We find regimes of spin-like (+3/2 to -3/2) and charge-like (±1/2 to ±3/2) relaxations, separated by a regime of enhanced relaxation induced by mixing of light and heavy holes. The demonstrated control over the energy level ordering and hybridization are new tools in the J = 3/2 system that are crucial to optimize single-atom spin lifetime and electrical coupling.

Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy.

BACKGROUND: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling. METHODS: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis. RESULTS: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%). CONCLUSIONS: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.

Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies.

OBJECTIVES: Several chronic inflammatory diseases are associated with cardiovascular disease, but the risk in ANCA-associated vasculitis is poorly quantified. The aim of the present study was to review the evidence for an increased cardiovascular risk, including ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease, in patients with ANCA-associated vasculitis. METHODS: A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses. The databases PubMed, Embase.com and the Cochrane Library (Wiley) were searched for original observational studies comparing vasculitis patients with at least one control group. Summary estimates were derived with a random-effects model and reported as relative risks. RESULTS: One thousand three hundred and seventy-five studies were identified. Seven studies were included, comprising almost 14 000 ANCA-associated vasculitis patients vs general population controls in six studies and chronic kidney disease patients in one study. ANCA-associated vasculitis carried a relative risk of 1.65 (95% CI: 1.23, 2.22) for all cardiovascular events, 1.60 (95% CI: 1.39, 1.84) for ischaemic heart disease and 1.20 (95% CI: 0.98, 1.48) for cerebrovascular accidents. We did not find studies that addressed the risk for peripheral arterial disease separately. No heterogeneity was seen in the estimates. CONCLUSION: This meta-analysis of observational studies supports an increase in cardiovascular risk in patients with ANCA-associated vasculitis of ∼65%, similar to that found in other chronic inflammatory diseases. Hence, there is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis.