Search

AIM: The current study was designed at assessing whether the sympathetic cardiovascular drive (SNS) is differently activated in chronic kidney disease (CKD) patients displaying less or more elevated resting heart rate (HR) values. It was also designed at determining at which HR cutoff value the SNS displays a greater activation. METHODS: In 95 CKD middle-age patients we evaluated muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (HPLC assay), subdividing the patients in different groups according to their resting clinic and 24-h HR. RESULTS: In CKD progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and norepinephrine. HR cutoff values indicated by large-scale clinical trials for determining cardiorenal risk, that is more than 80 bpm, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for norepinephrine. Both MSNA and norepinephrine were significantly related to clinic ( r = 0.47, P

BackgroundA small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET).MethodsSixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat.ResultsNo change in LV mass was detected at 18 months compared to baseline (95.2 g/m2(66.0–184.0) vs 99.0 g/m2(69.0–121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848–882) vs 860.0 ms (833.0–875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70–21.50) vs 14.50 mL/kg/min (11.70–18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2(72.0 (63.0–80.0) vs 69.0 (53.0–77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6–76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance.ConclusionIn treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others.Trial registration numberNCT03838237.

Objectives To elaborate an ECG-based nomogram estimating the probability to detect cardiac involvement by cardiac magnetic resonance (CMR) in Fabry Disease (FD). Methods 119 FD patients and 26 healthy controls underwent ECG and CMR. Test (n = 88, 60%) and validation cohorts (n = 57, 40%) were randomly derived. Cardiac involvement was defined as the presence of low myocardial T1 value, a CMR-surrogate of myocardial glycosphingolipid storage. ECG changes associated with low T1 value were identified in the test cohort, included in the nomogram and then tested in the validation cohort. Results Sokolow-Lyon index (AUC = 0.769), ratio between P-wave and PR-segment durations (Pwave/PRsegment) (AUC = 0.778), QRS duration (AUC = 0.703), QT (AUC = 0.769) duration were independently associated with the presence of low T1 on CMR at multivariate analysis. An ECG-based nomogram including these four parameters was accurate in identifying patients with CMR evidence of glycosphingolipid storage (c-index of the derived-nomogram = 0.90 in the test group; 0.81 in the validation group). Conclusion We propose a practical ECG-based nomogram accurately estimating the probability to detect low T1 values by CMR in FD patients. The application of this tool in clinical practice could improve early detection of FD cardiac involvement.

Objectives The search in the urinary sediment (U-sed) of fat particles with peculiar morphology is a simple and inexpensive tool for the diagnosis of Fabry disease (FD) nephropathy. In this study we investigated the morphology of a high number of such fat particles with the aim to obtain a morphological classification to be used for their identification. Methods Study of the morphology of fat particles in the U-sed of a cohort of FD patients using: bright field plus phase contrast microscopy (BF + PC), polarized light microscopy (POL), and transmission electron microscopy (TEM). Comparison of these results with those obtained for the fat particles seen in the U-sed of a control group (CG) of patients with non-FD glomerulopathies. Results FD: 18 U-sed from six patients (three samples/patient) were prospectively investigated and 506 fat particles identified. With BF + PC, these were classified in eight morphological categories (seven of which were confirmed by TEM), and with POL in 10 others. CG: eight U-sed from eight patients were investigated and 281 fat particles identified. These fell into four BF + PC morphological categories and into eight POL categories. While some categories were significantly more frequent in FD others were more frequent in the CG. Conclusions Our study demonstrates that 1. The morphology of fat particles found in the U-sed of FD patients is much wider and complex than that described so far 2. Several significant differences exist in the morphology of such fat particles between FD and CG patients.

Introduction Published data on hypertension incidence and management in Anderson–Fabry disease are scant and the contribution of elevated blood pressure to organ damage is not well recognized. Aim Therefore, we have assessed blood pressure values and their possible correlations with clinical findings in a well described cohort of Fabry patients. Methods Between January 2015 and May 2019, all adult Fabry patients (n = 24 females, n = 8 males) referred to our institute were prospectively enrolled. During the first examination patient’s genotype and clinical characteristics were recorded. Blood pressure data were obtained by standard observed office measurements followed, within 6 months, by ambulatory blood pressure monitoring and home self-recordings. Organ involvement, including kidneys, heart and brain, was monitored over time. Consequently, patients were defined as clinically stable or progressive through the Fabry Stabilization Index. Results The standard office measurements have diagnosed hypertension in three (9.37%) patients, but the ambulatory monitoring showed elevated blood pressure in six (18.75%) patients, revealing three cases of masked hypertension. All the hypertensive patients were females and, compared with normotensive subjects, they presented a lower glomerular filtration rate (p < 0.05) and a more advanced cardiac hypertrophy (p < 0.05). Four (66.7%) of them were diagnosed with a progressive form of the disease through the Fabry Stabilization Index while the majority of the normotensive group (84.6%, n = 19) was stable over time. No correlation was found between the prevalence of hypertension and the type of mutations causing Fabry disease. Conclusion Hypertension can be found in a restricted portion of clinically stable Fabry patients. In contrast, patients presenting with a progressive organ involvement, particularly renal impairment, have a major risk of developing uncontrolled blood pressure, and should be followed carefully. Moreover, the ambulatory blood pressure monitoring proved to be useful to reveal masked hypertension, which can contribute to the progressive worsening of the organ damage. Therefore, a proper diagnosis and therapy of hypertension may improve the outcome of Fabry patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40292-021-00450-0.

We present the case of a 76-year-old man with late-onset Fabry disease caused by the p.N215S missense mutation, with Fabry cardiomyopathy and nephropathy. In this case, the diagnosis of Fabry disease was incidental and followed minimal change disease (MCD) onset, with nephrotic syndrome and acute kidney injury requiring renal replacement therapy. Fabry nephropathy associated with the p.N215S mutation is becoming increasingly recognized among older patients. The importance of electron microscopy is herein highlighted and histological features common to Fabry nephropathy and MCD are discussed, along with the challenges associated with the diagnosis and clinical management.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

Background Fabry disease (FD) is a rare x-linked lysosomal storage disease characterized by accumulation of glicosphingolipids in several organs, including the heart. Cardiac involvement manifests as left ventricular (LV) hypertrophy, often complicated by myocardial fibrosis. The impact of disease on functional capacity is not well defined, as well as the potential gender-related differences. Aim To evaluate the functional capacity in a cohort of FD patients with different degree of cardiac involvement. Methods Seventy-two patients were prospectively enrolled from March 2015 to December 2019. Patients underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) with cycle ergometer. In addition to standard CPET parameters, Chronotropic Index (CI) was calculated as (HR max − HR rest) / (HR max predicted − HR rest), adjusting with HR max predicted calculated as 119 + (HR rest/2) − (age/2) in case of beta-blockers treatment. Results CMR showed left ventricle (LV) hypertrophy (LV mass greater than normal reference value) in 36.1% of patients, LGE and reduced T1 values were detected in 30.6% and 59.7% of subjects respectively. Twenty-eight patients were males (39%), the median age was 40 (28–54) [median (25th–75th)] years and only 11 (15%) subjects were on beta-blockers. All subjects performed a maximal test [RQ max = 1.21 (1.14–1.26)] using a ramp protocol of 15 (15–20) Watt. The absolute peakVO2 was 18.2 (15.75–24.08) mL/min/kg, whilst the percentage of predicted peakVO2 was 67.7 (57.3–76.6)%. The chronotropic response of the overall population was characterized by reduced peak heart rate (HRmax) [80.3 (73.8–87.6)% of predicted], and diminished chronotropic index (CI) [0.67 (0.55–0.77) normal value: 0.80], but preserved heart rate reserve (HRR) [21 (12–28) bpm]. Ventilatory efficiency was preserved [VE/VCO2 = 25.70 (23.18–28.00)]. At gender analysis, men showed higher absolute peakVO2 [men vs females: 19.95 (17.20–28.28) vs 17.80 (15.50–21.28) mL/min/kg, p=0.02] but lower percentage of predicted [64.24 (52.58–70.61) vs 70.75 (59.05–78.02)%, p Conclusions This large cohort of FD patients with different degree of cardiac involvement showed a significantly impaired functional capacity, mainly characterized by relevant chronotropic incompetence (independent from the use of beta-blockers), consistent with systemic autonomic dysfunction. The degree of chronotropic incompetence was similar between the genders, but females showed higher predicted peakVO2 despite a lower peak O2 pulse. Funding Acknowledgement Type of funding sources: None.

Background Fabry Disease (FD) is a rare X-linked lysosomal storage disorder. Since 2016, pharmacological chaperone Migalastat has been approved for treatment of FD patients with amenable mutations to stabilize defective forms of the enzyme α-galactosidase A. A small but significant reduction in left ventricular (LV) mass after 18 months of Migalastat treatment has been previously reported by echocardiography. However, an integrated assessment of the effect of Migalastat on cardiac involvement, combining LV morphology and tissue composition by CMR with exercise capacity by cardiopulmonary test, is lacking. Purpose To determine the effects of 18 month treatment with Migalastat on LV mass, native T1 value and functional capacity in naïve patients with genetically confirmed FD cardiomyopathy. Methods Sixteen treatment naïve FD patients (4 females, mean age 46.4±16.2) with amenable mutations and signs of cardiac involvement underwent CMR with T1 mapping and cardio-pulmonary testing before and after 18 months of migalastat therapy as a part of MAIORA Study. Cardiac involvement was defined as presence of reduced native T1 values at CMR (a surrogate of myocardial glycosphingolipid storage) and/or LV hypertrophy (LVH). Nine patients (56%, 2 females, mean age 56.4±12.7 years) had LVH at baseline. Results Migalastat treatment was well tolerated in all patients, with no serious adverse event. No change in LV mass was detected at 18 months compared to baseline (95.2 (66.0–184.0) vs 103.0 (71.0–182.0) g/m2; p=0.5516). The same result was found after stratifying patients according to presence/absence of Late Gadolinium Enhancement (LGE) (LGE+ n=8, 2 females, mean age 56.2±13.1 years). There was a trend towards an increased native septal T1 value (870.0 (848–882) vs 860.0 (833.0–875.0) ms at baseline; p 0.056) with unchanged extracellular volume (ECV) (0.26 (0.23–0.028) vs 0.26 (0.22–0.29) at baseline; p 0.276) in the overall cohort. An improvement in functional capacity with a trend towards an increase in percent-predicted peak VO2 (72.0 (61.25–80.75) vs 67.0 (45.2–79.2) at baseline; p 0.056) and a significant increase in VO2 at anaerobic threshold (14.8 (12.6–20.0) vs 13.10 (6.8–18.6) ml/kg/min at baseline; p 0.004) was reported in the total population. Conclusion In treatment naïve FD patients with amenable mutations and signs of early or overt cardiac involvement, 18-month treatment with Migalastat stabilized LV mass both in patients with and without LGE and was associated with an improvement in exercise tolerance. The trend towards an increase in T1 value associated with unchanged ECV suggests partial clearance of cardiomyocyte glycoshingolipid storage. These real-world data are consistent with a beneficial impact of migalastat on the progression of cardiac involvement in FD. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amicus Therapeutics

Funding Acknowledgements Type of funding sources: None. Background Left ventricular (LV) diastolic dysfunction (DD) is a hallmark of hypertrophic cardiomyopathy (HCM) and its phenocopies, such as Fabry disease (FD). Together with left atrial (LA) size, LA function is emerging as a sensitive marker of the adaptive changes to backward transmission of LV cardiac filling pressure, thus implementing DD assessment. Additionally, both HCM and FD are characterized by a primitive atrial myopathy, but LA morpho-functional changes in HCM and FD have never been directly compared. More recently, LA strain by Cardiovascular Magnetic Resonance Feature Tracking (CMR-FT) has been demonstrated to be a feasible and reproducible tool to explore LA function. Purpose To compare LA morpho-functional changes in HCM and FD and to explore their correlation with tissue alterations. Methods 15 HCM and 15 sex-, age- and LV mass index-matched FD patients underwent CMR (Magnetom Aera 1.5T, Siemens) and Doppler Echocardiography for LV diastolic function assessment (E/e’ and DD grading from 0 to 3). LA phasic function was evaluated by CMR-FT strain (Qstrain Medis). The software output included passive (εe, conduit function), active (εa, booster pump function) and total strain (εs, reservoir function), along with LA volumes and ejection fraction (EF). Late gadolinium enhancement (LGE) was quantified as a percentage of LV mass using the standard deviations (SDs) method (≥ 5 SDs). Interstitial fibrosis was assessed by extracellular volume (ECV) quantification in remote myocardium. All patients were in sinus rhythm. Results In the HCM group, the proportion of patients with DD grade 2-3 was only slightly higher than in FD (p 0.26). Accordingly, no significant difference was found in E/e’ value (p 0.78). Compared to FD, HCM patients showed more severe LA morpho-functional changes, including larger LA end-systolic volume (ESV) (113 ± 35 vs 84 ± 23 ml), lower LA EF (37 ± 7 vs 44 ± 9 %) and a greater reduction of εs (-20 ± 5 vs -25 ± 6 %) and εa (-10 ± 4 vs -15 ± 4 %) (all p < 0.05). LV size and function and the burden of fibrosis (LGE quantification and ECV) were comparable between the two groups. Interestingly, in HCM population, unlike in FD, LA morpho-functional measurements significantly correlated with tissue characterization parameters (LA ESV with LGE, r 0.56, p 0.03; εs and εa with ECV, r -0.51, p 0.05 and r -0.59, p 0.02, respectively). Conclusions LA morpho-functional alterations are much more severe in HCM compared to FD with similar degree of LV hypertrophy. A more severe atrial myopathy or different mechanisms of atrial damage in the two cardiomyopathies may explain these findings. LA CMR-FT analysis may represent a sensitive tool to discriminate between HCM and FD, although larger studies are needed to confirm this finding and the possible correlation with the occurrence of atrial arrhythmias and thromboembolic risk.

Background The current study evaluates the application of histology and in situ proteomics (MALDI-MSI) in Fabry nephropathy (FN), showing investigative and classification role for this coupled approach. Methods A retrospective series of 14 formalin fixed paraffin embedded (FFPE) renal biopsies with diagnosis of FN and 1 biopsy from a patient bearing a galactosidase-alpha (GLA) genetic variant of unknown significance (GVUS, c.376A>G) have been classified for clinical characteristics. Groups were compared for histological differences (following the ISGFN scoring system). Moreover, renal biopsies from these cases have been analyzed with MALDI-MSI as previously described to find proteomic signatures among different mutations and phenotypes. Results Comparison of clinical features revealed lower mean 24 h proteinuria in females (225 mg/24 h) than in males (1477.5 mg/24 h, p = 0.006). As for clinical characteristics, females significantly differed from males only for lower arterial sclerosis, with a mean value of 0.82 vs. 1.05 (p = 0.001). Proteomic analysis demonstrated specific signatures in different subgroups of FN patients. Moreover, MALDI correctly classified cases with undetermined mutation or GVUS. Conclusions The present study demonstrated the feasible application of MALDI-MSI in the analysis of FN FFPE renal biopsies, allowing the detection of putative signatures for phenotypic distinction and demonstrating genetic classification capabilities.

Background and Aims Renal involvement in ANCA-associated vasculitis (AAV) impacts significantly on patients’ prognosis. The role of different induction regimens on remission rates and long-term renal outcomes according to renal histological characteristics has not been explored yet. Method AAV patients with biopsy-proven renal involvement were collected retrospectively from eleven centers and stratified according to the induction regimen employed: Rituximab (RTX), Cyclophosphamide (CYC) or both (RTX-CYC). Kidney biopsies were classified according to the Berden and Brix classifications. Renal remission rate was assessed 6 months after the induction regimen and defined as a renal Birmingham Vasculitis Activity Score (BVAS) of 0. Among patients who achieved remission at 6 months, renal relapse was defined as a renal-BVAS>0 associated with an increase in immunosuppressive treatment. ESRD was defined as an eGFR Results 323 patients were identified and followed-up for a median time of 36 months (IQR 18-72). The cohort included 38% patients with GPA and 62% with MPA, 53% patients were MPO-ANCA and 41% PR3-ANCA positive. The median baseline eGFR in the overall cohort was 19 ml/min/1,73m2 (IQR 12- 34). 58% of patients were treated with CYC, 24% with RTX-CYC and 18% with RTX. According to the Berden classification, 24% biopsies were classified as Focal, 31% as Crescentic, 33% as Mixed and 12% as Sclerotic. The Brix score was assessable in 270/323 (84%) patients: 17%, 52% and 31% were respectively in the Low, Medium and High-risk class. The overall renal remission at 6 months was 90%; according to the Berden classification, 94% patients achieved remission in the Focal, 88% in the Crescentic, 91% in the Mixed and 86% in the Sclerotic class. According to the Brix risk score, 88% patients achieved remission in the High risk, 91% in the Medium and 96% in the Low-risk class. According to induction regimen employed, 91%, 90% and 90% patients achieved remission in the RTX, CYC and RTX plus CYC group respectively. In a logistic regression model adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria at onset, the induction regimen employed was not predictive of renal remission at 6 months, neither in Berden Focal plus Crescentic and Mixed plus Sclerotic classes, nor in Brix High and Low plus Medium risk classes. Of the 185 patients with at least 6 months of follow-up available after remission, 25% experienced a renal relapse. In a Cox regression model adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria at onset, the induction regimen or histological score were not predictive of renal relapse. In the unadjusted survival analysis with the Kaplan-Maier curve, patients in the Crescentic group treated with RTX had a shorter ESRD-free survival compared to the CYC group (p=0.033) and the RTX-CYC group (p=0.044); figure 1: This was confirmed also with a Cox regression analysis adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria when comparing the RTX group with the CYC one (HR 8.30 [95% CI 1.64 to 42.01], p=0.011); figure 2: While the eGFR changes over time in the Focal plus Crescentic and Mixed plus Sclerotic classes showed a similar trend between treatment groups, in the Crescentic class the median eGFR values in the RTX group tended to be lower compared to the CYC and the RTX-CYC ones; figure 3: The rate of severe infections in the RTX, CYC and RTX-CYC group was respectively 6.3, 8.5 and 8.8 per 100 patient-years during the first 12 months. Conclusion in a retrospective multicenter survey, response rates and relapse risk after different induction regimens in AAV patients with renal involvement were comparable in the overall cohort and in the different histopathological subgroups. Although in a small subset of patients, the ESRD-free survival in the Crescentic class was shorter in the RTX group compared to the CYC one.

Background In patients with end stage renal disease and atrial fibrillation (AF), undergoing chronic dialysis, direct oral agents are contraindicated and warfarin does not fully prevent embolic events while increasing the bleeding risk. The high hemorrhagic risk represents the main problem in this population. Aim of the study was to estimate the safety and efficacy for thromboembolic prevention of left atrial appendage (LAA) occlusion in a cohort of dialysis patients with AF and high hemorrhagic risk. Methods Ninety-two dialysis patients with AF who underwent LAA occlusion were recruited. For comparative purposes, two cohorts of dialysis patients with AF, one taking warfarin (oral anticoagulant therapy, OAT cohort, n = 114) and the other not taking any OAT (no-therapy cohort, n = 148) were included in the study. Primary endpoints were (1) incidence of peri-procedural complications, (2) incidence of 2-year thromboembolic and hemorrhagic events, (3) mortality at 2 years. In order to evaluate the effect of the LAA occlusion on the endpoints with respect to the OAT and No-therapy cohorts, a multivariable Cox regression model was applied adjusted for possible confounding factors. Results The device was successfully implanted in 100% of cases. Two major peri-procedural complications were reported. No thromboembolic events occurred at 2-year follow-up. The adjusted multivariable Cox regression model showed no difference in bleeding risk in the OAT compared to the LAA occlusion cohort in the first 3 months of follow-up [HR 1.65 (95% CI 0.43–6.33)], when most of patients were taking two antiplatelet drugs. In the following 21 months the bleeding incidence became higher in OAT patients [HR 6.48 (95% CI 1.32–31.72)]. Overall mortality was greater in both the OAT [HR 2.76 (95% CI 1.31–5.86)] and No-Therapy [HR 3.09 (95% CI 1.59–5.98)] cohorts compared to LAA occlusion patients. Conclusions The study could open the way to a non-pharmacological option for thromboembolic protection in dialysis patients with AF and high bleeding risk.

Objectives Fabry disease (FD) is an X-linked lysosomal storage disorder, resulting from a deficiency of the enzyme α-galactosidase A, responsible for breaking down glycolipids such as globotriaosylceramide and its deacylated derivative, globotriaosylsphingosine (LysoGb3). Here, we compare the levels of LysoGb3 in dried blood spots (DBS) and plasma in patients with classic and late-onset phenotypes. Methods LysoGb3 measurements were performed in 104 FD patients, 39 males and 65 females. Venous blood was collected. A portion was spotted onto filter paper and another portion separated to obtain plasma. The LysoGb3 concentrations in DBS and plasma were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Agreement between different matrices was assessed using linear regression and Bland Altman analysis. Results The method on DBS was validated by evaluating its precision, accuracy, matrix effect, recovery, and stability. The analytical performances were verified by comparison of a total of 104 paired DBS and plasma samples from as many FD patients (representing 46 GLA variants). There was a strong correlation between plasma and the corresponding DBS LysoGb3 concentrations, with few exceptions. Discrepancies were observed in anemic patients with typically low hematocrit levels compared to the normal range. Conclusions The method proved to be efficient for the rapid analysis of LysoGb3. DBS provides a convenient, sensitive, and reproducible method for measuring LysoGb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with FD.

Background and objectives Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. Design, setting, participants, & measurements In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25–10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. Results At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: −16.3 g/m2; 95% confidence interval, −29.4 to −3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. Conclusions Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. Clinical Trial registry name and registration number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008–003529–17.

Nephropathy represents a major complication of Fabry Disease and its accurate characterization is of paramount importance in predicting the disease progression and assessing the therapeutic responses. The diagnostic process still relies on performing renal biopsy, nevertheless many efforts have been made to discover early reliable biomarkers allowing us to avoid invasive procedures. In this field, proteomics offers a sensitive and fast method leading to an accurate detection of specific pathological proteins and the discovery of diagnostic and prognostic biomarkers that reflect disease progression and facilitate the evaluation of therapeutic responses. Here, we report a review of selected literature focusing on the investigation of several proteomic techniques highlighting their advantages, limitations and future perspectives in their application in the routine study of Fabry Nephropathy.

Background Cardiac Magnetic Resonance (CMR) allows to detect progressive stages of cardiac involvement in Fabry Disease (FD). A systematic description of electrocardiographic (ECG) alterations occurring in FD is currently missing. Purpose To explore ECG changes in progressive stages of FD cardiomyopathy. Methods 71 FD patients and 17 healthy controls underwent CMR with T1 mapping and 12-lead ECG. ECG analysis included the duration of the P-wave and the interval between the end of P-wave and the beginning of QRS (PendQ). FD patients in the test cohort were divided into 3 groups with increasing severity of cardiac involvement: A) normal T1, no LVH; B) low T1, no LVH; C) low T1, LVH. Results An increase of Pwave/PendQ ratio was observed in Group A compared to Controls (1.08 vs. 0.75, p Conclusion FD is characterized by progressive ECG changes. The identification of ECG parameters able to predict a lowering of myocardial T1 values on CMR may promote early detection of cardiac involvement, helping to target the therapeutic approach. Progressive ECG and CMR changes in FD Funding Acknowledgement Type of funding source: Other. Main funding source(s): This study was partially supported by Ricerca Corrente funding from the Italian Ministry of Health to IRCCS Policlinico San Donato.

Background and Aims Anderson-Fabry disease (AFD) is a rare X-linked sphingolipid disorder caused by deficient activity of the enzyme α-galactosidase A leading to a progressive lysosomal accumulation of globotriaosylceramide and a consequent organ failure. Data on blood pressure (BP) values in AFD patients are scanty, however those available have revealed a significant prevalence of high blood pressure, especially in case of moderate to severe kidney impairment, becoming more prevalent with the progression of the renal disease. High blood pressure and hypertension major risk factors prevalence were analysed among a single Fabry cohort. Method Between January 2015 and May 2019, 32 AFD patients, 24 (75%) female and 8 (25%) male, referred to the Fabry Disease Unit, Nephrology Division of San Gerardo Hospital (Monza, Italy), were enrolled. All patients were Caucasian with an average age of 50±12.2 years old. Data regarding hypertension were obtained by 24h ambulatory blood pressure monitoring (ABPM), home self-monitoring, and repeated ambulatory measurements (Table 1). Patients were defined hypertensive according to 2018 ESC/ESH Guidelines. The severity and the stability of AFD were assessed in each patient with the Fabry Stabilization Index (FASTEX). Major risk factors for hypertension were also evaluated (Table 2). Results The 24h ABPM revealed uncontrolled high blood pressure in 6 (18.7%) patients with consensual home and office BP alterations. All patients were female with an average age of 58±9.9 years old. They had mostly a sedentary life-style, half of them had a diagnosis of dyslipidaemia and one was obese (BMI > 30). In the normotensive group, half of the patients were sedentary, less than a half of them was affected by dyslipidaemia and the average BMI was between the normal ranges. Other known risk factors for hypertension were scanty represented between the two groups. No one had history of transient ischemic attack or stroke. In the normotensive group the majority of patients had a normal or near-normal renal function, while in the hypertensive group one-third showed mild proteinuria and renal impairment with a moderate reduction in glomerular filtration rate. The FASTEX index showed that 84.6% of the normotensive group were stable, while 66.6% of the hypertensive group were not. In 9 (34.6%) patients of the normotensive group ACE-inhibitors/angiotensin-receptor blockers were previously introduced for the treatment of proteinuria in normal blood pressure values, while 2 (33.3%) patients of the hypertensive group received antihypertensive drugs. Conclusion In this observational study, the majority of AFD patients were normotensive. The prevalence of hypertensive patients was lower than 20%. Overall patients had a low prevalence of well-known risk factors associated with the development of hypertension. The link between AFD disease and the development of hypertension has not been fully studied yet. Hypertension in AFD patients might be due to Fabry associated vascular or renal disease or because of an associated essential hypertension. Arterial blood pressure seems to be relatively well controlled among AFD patients presenting with a low prevalence of risk factors for hypertension and a mild and stable organ involvement. In contrast, unstable patients with a high prevalence of well-known hypertension risk factors, particularly renal impairment, should be followed carefully, because they have a major risk of developing uncontrolled blood pressure. Further prospective studies with a larger sample size are needed to better investigate the pathophysiology of hypertension in AFD patients.

Background and Aims Whole-slide imaging (WSI) and virtual microscopy are useful tools implemented in the routine pathology workflow in the last 10 years, allowing second-opinion on definitive or frozen-section diagnosis (telepathology) and demonstrating a substantial role in multidisciplinary (MDT) meetings and education (Griffin et al, Histopathology. 2017;70(1):134-145). The FDA approval of the clinical employment of this technology led to the progressive digitalization of routine pathological practice. In this setting, a recent work explored the usefulness of this technology applied to renal biopsies, stressing the possibility to create integrate networks to share cases for diagnostic and research purposes (Barisoni et al, Clin Kidney J. 2017;10(2):176–187). Here is discussed the 5-years experience of an Italian Renal Pathology service in which telepathology is a definitive standard of care. Method Renal biopsies were collected in the Anatomic Pathology Department of San Gerardo Hospital, Monza, Italy from 14 different Italian Nephrology centers (9 from the North, 1 from the Center and 4 from the South of Italy) from January 2015 to December 2019. After the routing processing of the tissue, biopsies were scanned with Aperio CS2 device for light microscopy and Aperio ScanScope FL for immunofluorescence (Leica Biosystem, Illinois, USA, Figure 1A). Digital slides were then imported in the Spectrum platform along with the final report and additional pictures (eg. electron micrographs and special stains) such as shown in Figure 1B. Results In 5 years, 704 renal biopsies (interval 110-160) were scanned and analysed with a turnaround time of around 2-3 working days. The most frequent diagnosis was represented by MN (16%, 115 cases, interval 18-28) followed by IgA nephropathy (12%, 84 cases, interval 12-21), FSGS (9%, 66 cases, interval 8-18), MCD (8%, 54 cases, interval 7-13), paucimmune crescentic GN (7%, 48 cases, interval 6-13), diabetic nephropathy (6%, 45 cases, interval 6-12), lupus nephritis (5%, 37 cases, interval 5-11), arterionephrosclerosis (5%, 35 cases, interval 5-13), amyloidosis (5%, 32 cases, interval 3-7) and tubulointerstitial nephritis (4%, 28 cases, interval 4-6). Only 4% of cases (28, interval 4-10) were suboptimal for the diagnosis and the remaining 19% (132 cases, interval 20-36) were characterized by rarer diseases, as detailed in Figure 1C. Conclusion In renal pathology the assessment of biopsies with different techniques (light and electron microscopy and immunofluorescence) is mandatory and can represent an obstacle in the routine employment of digital pathology. In the present experience we demonstrated the feasibility and sustainability of the digital switch in renal pathology routine, thanks to appropriate devices and platform. This led to store cases for teaching and MDT meetings, allowing to maintain the same short turnaround time for the diagnosis. Moreover, the employment of WSI technique can allow to couple the proteomic features of renal tissue with the classic morphological aspects of the diseased parenchyma (L’Imperio et al Proteomics Clin Appl. 2016 Apr;10(4):371-83). This approach, along with the possibility of a multicentric enrollment of patients, led to the publication of 6 scientific papers in highly impacted journals, further confirming the positive role of digital pathology in this field.

Aims Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. Methods and results Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P Conclusion Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.

Membranous nephropathy represents the most frequent cause of nephrotic syndrome in the adult, leading to end-stage renal disease in one third of all the patients. In the last years, the discovery of circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 containing 7A domain (THSD7A), shed light on the pathogenesis of idiopathic forms, being responsible for 70% and 3% of all the cases, respectively. These identifications allowed the development of serological and histologic tests to detect autoantibodies and relative targets for diagnostic and prognostic purposes. Rising evidences suggest that serum titer correlates with disease activity and response to therapy. For these reasons, for patients with nephrotic syndrome, a serum-based approach has been proposed, reserving renal biopsy only in cases with doubtful/negative serology. However, the recent introduction of useful criteria for the interpretation of PLA2R/THSD7A immunohistochemistry could lead to high values of sensitivity and specificity for the in situ detection of target antigens. The present multicentric study on a series of membranous nephropathy cases with available serum/histologic correlation will show the importance of the crosstalk among the different techniques, recovering the possible role of electron microscopy in challenging situations.

Anderson-Fabry disease (AFD) cardiomyopathy is characterized by glycosphingolipid (Gb3) storage in all cellular components, with consequent left ventricular hypertrophy (LVH). Gb3 accumulation also involves atrial myocytes ([1][1]), ultimately leading to left atrial (LA) enlargement and reduced

Microscopic polyangiitis (MPA) is a pauci-immune necrotizing small vessel vasculitis in which necrotizing crescentic glomerulonephritis (GN) is very common and pulmonary capillaritis often occurs. It belongs to the group of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and can be differentiated from granulomatosis with polyangiitis (GPA) for the absence of granulomatous inflammation. It is a rare disease and affects patients usually >50 years old with no clear gender prevalence. Renal involvement, characterized clinically by rapidly progressive GN and histologically by pauci-immune necrotizing crescentic GN, is present in more than 90% of patients. Other features include, with decreasing frequency, constitutional symptoms, pulmonary involvement with diffuse alveolar hemorrhage or interstitial lung disease, peripheral neuropathy, skin vasculitis, gastrointestinal and heart disease. Anti-neutrophil cytoplasmic antibodies, usually P-ANCA/MPO-ANCA, are detected in up to 80–90% of patients with active MPA. Untreated MPA has an unfavorable course and is associated with increased mortality and end-stage renal disease (ESRD). Factors independently related to death are the presence and severity of renal involvement, cardiac symptoms, gastrointestinal involvement, and age over 65 years. Corticosteroids and cyclophosphamide or rituximab (with the addition of plasma-exchange in the most severe cases) are the cornerstone of induction treatment of ANCA-associated renal vasculitis, followed by azathioprine (or methotrexate, mycophenolate, rituximab) for maintenance. Despite significant improvement in patient outcomes over the past decades, MPA still results in ESRD and death in a significant percentage of patients.

Aims: To estimate the safety and the efficacy of the off label left atrial appendage (LAA) occlusion in chronic dialysis patients with atrial fibrillation (AF). In this preliminary paper, we report the design of the study and the data on peri-procedural complications. Methods: This is a prospective cohort study. Primary endpoints are i) incidence of peri-procedural complications, ii) cumulative incidence of two-year thromboembolic events iii) cumulative incidence of two-year bleedings iiii) mortality at two years. Adverse events and death within 30 days of the procedure were recorded. Results: Fifty patients who underwent LAA occlusion between May 2014 and September 2017 were recruited. Both the mean age of the sample study and the dialysis duration were high [71.8 (9.6) years and 59.4 (78.2) months, respectively]. Most patients (84%) were hypertensive and 62% suffered a previous major bleeding. About half of them presented cardiovascular diseases. CHA2DS2VASCs and HASBLED scores were 4.0 (1.5) and 4.4 (0.9), respectively. Most patients (88%) showed atrial dilatation and 44% left ventricular hypertrophy; 32% had left ventricular ejection fraction

ObjectivesTo evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time.Patients and methodsWe studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970–1985, P2 1986–2001 and P3 2002–2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test.ResultsA progressive increase in patient age at the time of LN diagnosis (pConclusionsClinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival.

Anti-glomerular basement membrane (GBM) antibody disease is a rare pathological condition that mainly involves renal and/or pulmonary parenchyma. It is characterized by the presence of circulating anti-GBM antibodies accompanied by a linear deposition of immunoglobulins (Ig) detected through immunofluorescence (IF) technique and typical signs and symptoms of organ dysfunction, such as rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage (PH). However, recently atypical forms of anti-GBM disease have been described and the presence of overlapping diseases contributed to make its diagnosis challenging. In this review will be discussed the entire spectrum of renal anti-GBM related conditions, focusing the attention on the differences in terms of pathogenesis, diagnosis and therapy of these disparate entities.

The original article can be found online.

Renal involvement is a frequent and severe complication of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). It is generally characterized by a pauci-immune necrotizing and crescentic glomerulonephritis with a very rapid decline of renal function (rapidly progressive glomerulonephritis). Even though there are no qualitative differences in glomerular lesions in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), chronic damage is usually higher in MPA (and/or P-ANCA-positive patients) than in GPA (and/or CANCA-positive patients). If untreated, necrotizing and crescentic glomerulonephritis has an unfavorable course leading in a few weeks or months to end-stage renal disease (ESRD). Serum creatinine at diagnosis, sclerotic lesions, and the number of normal glomeruli at kidney biopsy are the best predictors of renal outcome. Corticosteroids and cyclophosphamide or rituximab (with the addition of plasma exchange in the most severe cases) are the cornerstone of induction treatment of ANCA-associated renal vasculitis, followed by azathioprine (or methotrexate, mycophenolate, rituximab) for maintenance. Despite significant improvement in patient outcomes over the past decades, AAV still results in ESRD in a quarter of patients over 5 years. Relapse rates are significantly lower in patients on chronic dialysis. Patient survival on regular replacement treatment (RRT) does not differ between AAV and matched nondiabetic patients, while it is lower than that of glomerulonephritis. Patients with AAV who undergo kidney transplantation have a mortality not different from the matched control group of primary glomerulonephritides, and favorable transplant survival is similar to that of the matched control groups.

Background: A variable percentage of lupus nephritis (LN) patients (pts) achieve response after the start of induction therapy. The impact of response on long-term renal outcome of LN is still unclear. Objectives: To establish the response rate at one year after starting induction therapy and its impact on long-term development of chronic kidney disease (CKD) in LN. Methods: 381 biopsy proven LN pts (86% females, mean age 31.3±12.1years), (18 pts:class II; 88 pts:class III; 199 pts:class IV; 76 pts:class V ISN/RPS) with estimated glomerular filtration rate (eGFR) 89.8±40.4 and proteinuria 4.3±3.9g/24h entered this study. As induction therapy, pts received methylprednisolone pulses (72%), oral prednisone (28%), cyclophosphamide (55%), mycophenolate mofetil (24%), azathioprine (5,5%), other immunosuppressants (15.5%). During a follow-up of 13.5 years after LN diagnosis, 53 pts (13.9%) developed CKD and 22 (5.8%) died. Definitions: Complete response (CR) at one year: eGFR>60ml/min and proteinuria 60ml/min, 50% reduction of proteinuria to sub-nephrotic range, no response (NoR): all the other cases. Survival curves were drawn using the Kaplan-Meier estimate and compared using the log-rank test. Cox regression model was used to test variables at univariate and at multivariate analysis. Results: One year after the start of therapy, 220 pts (58%) achieved CR, 100 pts (26%) PR and 61 pts NoR. CKD developed in 11 out of 220 CR pts (5%), 18 out of 100 PR pts and 24 out of 61 NoR (39%). CKD free survival at 5, 10, 15 and 20 years were 99.5%, 96.5% 95.2% and 92.5 in CR pts, 99%, 90%, 87,6% and 83% in PR pts, and 81%, 65%, 54% and 44% in NoR pts (p Conclusion: The achievement of CR or PR at one year is associated with preservation of renal function in the long-term. For this reason, any effort should be made to achieve response. Patients with impaired renal function, with high chronicity index at renal biopsy and arterial hypertension should be more tightly monitored as they have the highest risk of NoR. Disclosure of Interests: : None declared