Recognizing the need to integrate palliative care into nephrology, an “action-research” model was launched in April 2023. A multidisciplinary pilot group (6 nephrologists, 7 nurses), led by a psychologist, was established and operated through seven focus groups to explore perceived challenges, training needs, and potential strategies for integrating palliative care into clinical practice. The model employed was an “action-research” one, model characterised by a cyclical process of inquiry, action, and reflection, where data is collected, analysed, and used to inform and to promote empowering collaboration to needed change. The discussions were transcribed and analysed manually (“paper and pencil”). Based on the main themes/topics that emerged, a questionnaire was administered to all nephrologist and nurses of the unit. The questionnaire included four Likert scale questions (1 = not at all, 5 = very much), one multiple-choice question, and one open-ended question, aiming to identify perceived barriers and resources for implementing palliative care. The answers of the open-ended question were analysed using the T-Lab software. The findings informed the creation of a teaching initiative for all the unit staff. Additionally, the number of patients referred to palliative care pathways before and after the initiative was started was recorded to quantify its impact. The content analysis of the seven focus groups revealed the need to challenge stereotypes about palliative care and to develop tools for timely activation of palliative care pathways. Key findings included characteristics of palliative care patients (psychological suffering [6/10 participants] and physical suffering [4/10 participants]); highly relational tasks (10/10 participants) for nurse-physician roles in order to support patients and families in a flexible decision-making process. These insights informed the development of a questionnaire distributed to all the unit staff. A total of 114 out of 205 staff members (55%) participated, comprising 77 nurses (68%) and 37 doctors (32%). The findings showed that 66% of respondents considered palliative care “very important”, but 38% felt it was only “fairly” achievable. 62% agreed that palliative care is a “shared treatment pathway”. 31% believed patients were “minimally involved” in decision-making, while 90% felt family members were “quite” or “very involved”. Thematic analysis identified four key clusters (Fig. 1). Those were classified as “Need for a culture in palliative care” (38% of variance), highlighted primarily by doctors, who cited lack of experience and resources as major barriers. “Patient centered care” (35% of variance), emphasized by nurses. “Necessary approaches” (17% of variance). “Dignified death” (11% of variance). Following the questionnaire, the pilot group organized for all the unit staff a teaching day on the clinical, psychological and ethical challenges of palliative care, involving palliative care specialists and ethicists. As a measure of the overall initiative impact, patient referrals to palliative care before and after the initiative were compared: in the 390 days before the integration process, 30 patients were referred (26 in the acute settings); in the 390 days following the start of the initiative, 73 patients were referred (61 in the acute settings). The overall initiative significantly increased awareness of palliative care as an integral treatment option. For the Nephrology Unit, palliative care is viewed as a valuable resource for supporting patients and families at the end of life. However, limitations remain, particularly in terms of experience and resources. From this perspective, a close integration between palliative care specialists and nephrologists is required in order to activate processes for simultaneous care and reduce the number of referrals in the acute setting.

Using immunobinding and enzymatic assays we determined in rat muscle extracts the proportion of tyrosinatable tubulin, that is, tubulin that participates in the tyrosination/detyrosination cycle. We found that in muscle, in contrast with nervous tissue, practically all tubulin molecules are tyrosinatable. In the case of rat brain the non-tyrosinatable tubulin pool accounts for about 50% of the tubulin. In addition, isolectrofocusing of 14C-tyrosinated tubulin from brain and muscle extracts revealed a different composition in tyrosinatable tubulin isotypes. One of the isotypes, which in muscle accounts for 86% of the 14C-tyrosinated tubulin species, was detyrosinated by the action of tubulin carboxypeptidase faster than the rest of the 14C-tyrosinated tubulin isotypes taken in whole. In the case of brain extract, that isotype accounts for only 16% of the labeled tubulin.

Background and Aims To date, the literature shows that HCV eradication with DAA leads to remission from HCV-related cryoglobulinemic syndrome (CS). The goal of our study is to evaluate the effect of DAA treatment on cryoglobulinemic kidney disease. Method Since 2015, 58 patients (pts) have been treated in our Centre; among them we have selected 12 pts with active kidney disease at the time of treatment. Clinical manifestations, renal function and immunological tests were monitored during follow-up (range 6-48 months). Results General characteristics of the population are shown in Table 1. At the time of treatment 6 pts had nephritic syndrome (sdr), 1 had nephrotic sdr and 5 pts had mixed nephritic-nephrotic sdr. It should be noted that 8/12 pts had been treated with Rituximab (RTX) in the 6 months preceding the DAA; despite that they had active disease at baseline. Ten out of 12 pts went into complete remission after HCV-eradication, 1 went into partial remission. One pt, never treated, did not respond clinically to HCV eradication and therefore underwent RTX therapy. Other 2 pt with a recent diagnosis of cryoglobulinemic syndrome came to our attention with a clinical picture of nephritic sdr: they’d never been treated with immunosuppressive therapy and get remission only whit HCV eradication. One pt, although complete CS remission, started hemodialysis for ESRD secondary to ADPKD. During follow-up 3 pts underwent CS relapse: 2 pts, one with lymphoma, were retreated with RTX after 12 and 48 months respectively; 1 pt, with type I cryoglobulinemia and clinical manifestation of vasculitis, died of acute disease reactivation in Cameroon after 9 months from the end of DAA. By evaluating the overall population there is a rapid and prolonged clinical response to DAA therapy, in particular a complete resolution of skin ulcers (Tab 2). Cryocrit decreases and C3 and C4 increase early and persistently after treatment; vice versa the rheumatoid factor does not undergo significant variations. Proteinuria is reduced at the end of the treatment (EOT) and shows a decreasing trend also afterwards; urinary sediment is drastically reduced at EOT and further decreases during follow-up up to the presence of only isolated urinary anomalies in almost all patients (Tab 3). Conclusion The eradication of HCV, and therefore the removal of the immunological stimulus underlying the cryogloblinemic syndrome, appears to be crucial in the control of cryoglobulinemic glomerulonephritis, also after failure of RTX treatment. However, relapses at variable interval from DAA therapy do not allow us to lose these patients to follow-up even after several years from disease remission.

Abstract Background and Aims Lupus Nephritis (LN) is the organ manifestation with the most severe prognosis in Systemic Lupus Erythematosus (SLE). Treatment options are limited due to partial efficacy, intolerance or side effects; moreover 10% of patients reach ESRD despite treatments. Rituximab (RTX) in LN is recommended as second line drug for induction of the remission after failure of Cyclophosphimide or Mycophenolate Mofetil. We have shown a role for RTX as maintenance therapy (RMT) in SLE however the effects of such approach on LN are still unclear. Aim of this study was a sub-analyses of a cohort of SLE patients treated with RTX focusing on the ones with active LN at the moment of the first RTX administration. Methods Patients with active LN at the time of the first RTX administration within a cohort of 147 patients with SLE were identified. Patients with SLE and a flare of LN were classified as treated with a “Single RTX course” (any RTX regimen administered within a single month) (SRC) or with RMT. Patients receiving at least three SRCs with the aim of relapse prevention and within 4 to 8 months between consecutive treatments, were classified as receiving RMT. LN activity was determined according to creatinine, proteinuria and haematuria; complete response (CR) was defined as a decrease of proteinuria to <0.5 g/day, normal creatinine and negative urinary sediment; partial response (PR) was defined as ≥50% improvement in creatinine and proteinuria, treatment failure (TF) was any other condition. A renal flare (RF) was defined as an increase of creatinine and/or proteinuria >30% or the detection of an active urinary sediment due, according to the treating physician, to active disease. Results 33 patients were identified; a renal biopsy had been performed in 76% with prevalence of class IV lupus nephritis in 16/33 (48%). Six months after RTX the rate of CR, PR and TF was respectively 36%, 27% and 36%; proteinuria and the prednisolone dose reduced significantly compared to baseline (respectively from a median of 2200 mg/day (IQR 499-5400) to 850 mg/day (IQR 400-1700) (p=0.005)) and from 25 mg (IQR 11-25) to 10 mg (IQR 6.125-15) (p<0.0001)). At univariate analyses the only factor associate to the risk of TF was a high number of immunosuppressive drugs employed before RTX (p=0.0077). Of the 33 patients, 11 received RMT with a median duration of 18 months (IQR 12,6-23,4) and a median RTX dose of 5 g (IQR 4-6). During the RMT 3 patients experienced a renal flare. The median follow-up after the last RTX administration within the SRC and the RMT groups was respectively 15 months (IQR 13,5-18,4) and 16 months (IQR 3,5-23). Comparing the RF free-survival of the two subgroups after the last RTX infusion, there was a trend towards a longer relapse free survival after the RMT (p=0.057) (figure, left panel). Of interest, the renal relapse free-survival of the 11 patients treated with RMT after the last RTX infusion was significantly longer compared to the one of the same group after the first RTX (p=0.0271) (figure, right panel). The incidence of SAEs per 100 patient years was 0.31 in the SRC group and 0.74 in the RMT group. Conclusion RTX is confirmed as an effective option for patients with LN. A RMT may have a role in improving LN disease control compared to a single RTX administration.

OBJECTIVE:Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion.METHODS:The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews.RESULTS:Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals.

Background: The powerful drugs with direct antiviral action (DAA) against hepatitis C virus (HCV) has made it possible to eliminate the trigger factor of Mixed Cryoglobulin Syndrome (MCS) and to extend the treatment to patients who could not tolerate IFN-based antiviral regimens. However, the persistence of cryoglobulin production and MCS-related symptoms despite SVR achievement is frequently reported. Objectives: The aim of this study was to assess the persistency rate of MCS-related clinical and laboratory indexes after successful treatment with DAA. Methods: CRESO (CRyoglobulinaemia Eradication Study Observational) is a multicentre observational study promoted by the Italian Society of Infectious and Tropical Diseases (SIMIT) and the Italian Group for the Study of Cryoglobulinaemias (GISC), aimed to assess the impact of DAA therapy on MCS symptoms and cryoglobulin production. Patients could be enrolled if they presented, during the 12 months before the enrolment, a cryocrit ≥0.5% and, at least, one episode of palpable purpura or, alternatively, arthralgia and fatigue with at least one symptom among peripheral neuropathy, Raynaud’s phenomenon, lower limb ulcers or nephropathy, and a C4 level ≤8 mg/dL. Results: The present analysis was based on clinical and laboratory data of 94 patients (75.5% female with a median age of 67.5 years) that have been followed up for a median time of 24 weeks (IQR 12-24) after SVR12 achievement. At baseline the cryocrit was frankly positive in 85 (90.43%), detectable (>0.5%) in 4 and negative in 4 cases; patients with type II cryoglobulins and C4levels ≤8 mg/dL were prevalent, respectively with 81.5% and 75.9%. Low eGFR values (≤45 mL/min/1.73m2) were present in 12 cases (12.8%), 10 patients (10.6%) had a history of B-cell non-Hodgkin’s lymphoma (NHL), and 1 of hepatocellular carcinoma, while liver cirrhosis was diagnosed in 22 cases (23.4%) and glomerulonephritis in 17 cases (18.1%). Patients were treated for 12 (72 cases) or 24 (21 cases) weeks with a total of ten different IFN-free DAA regimens. SVR12 was achieved in all 94 cases. Both prevalence and median cryocrit values decreased significantly after DAA treatment (p<0.0001), however, at the time of the last observation 56.4% of patients were still positive for MCs. The prevalence of purpura and fatigue significantly decreased (p<0.0001) as well sicca syndrome prevalence (p<0.015), while arthralgia and lower limb ulcers decrease did not reach statistical significance. In multivariate analysis, eGFR≤45 mL/min/1.73m2 was an independent predictor of persistence of cryoglobulin production (AOR 7.7, CI 95% 1.6-37.2; p<0.011). Conclusion: CRESO study data confirm the persistence of cryoglobulin production and MCS symptoms in some patients, despite the eradication of HCV. This finding rises questions about the possible further evolution of the disease over time regardless the persistence of its original trigger. Disclosure of Interests: None declared

OBJECTIVE:To assess the prevalence and risk factors for endothelial dysfunction detected by peripheral artery tonometry in systemic lupus erythematosus patients with early disease without cardiovascular disease and risk factors. METHODS:All the consecutive adult lupus patients, with a disease duration <5 years, seen in our hospital from December 2014 to March 2016 were considered. We excluded patients with any history of cardiovascular disease or risk factors possibly affecting peripheral artery tonometry. Enrolled patients were matched for sex, age, body mass index, and blood pressure with healthy controls with the same exclusion criteria. Patients and controls received a transthoracic Doppler echocardiogram and an evaluation of endothelial function by peripheral artery tonometry. RESULTS:Twenty patients (100% female) with a median disease duration of 14 months (range 1-58 months), a mean ± SD age of 42 ± 15 years, and a mean ± SD age at diagnosis of 40 ± 16 years were enrolled and matched with 20 controls. Peripheral artery tonometry showed a significantly higher prevalence of endothelial dysfunction (P = 0.003) and vascular stiffness (P = 0.02), while echocardiography detected a significantly higher prevalence of left ventricular concentric remodeling (P = 0.003), grade I diastolic dysfunction (P = 0.047), and subclinical increase of filling pressures (P = 0.039) in lupus patients compared to controls. Among lupus patients, no features were associated with endothelial dysfunction. CONCLUSION:A high rate of endothelial dysfunction and vascular stiffness occurs in early lupus patients without cardiovascular risk factors and disease. Larger studies are needed to confirm our results and to look for patients' characteristics possibly associated with these abnormalities.

Objective: To evaluate the efficacy and safety in the long term of a retreatment regimen with Rituximab (RTX) alone administered at clinical relapse in cryoglobulinemic vasculitis (CV).Methods: Thirty patients with severe HCV-related CV, previously enrolled in the multicentre Italian trial on RTX in the treatment of CV, were retrospectively evaluated after the end of the trial. All of them were managed with RTX alone at clinical relapse, if any. Disease activity at the last available follow up was defined as complete remission (absence of active disease), partial remission (response > 50% of at least one manifestation among glomerulonephritis, peripheral neuropathy or skin ulcers) or active disease.Results: The mean follow up after the first RTX cycle was 72.6 (20.4) months. After the end of the trial, 21/30 (70%) patients showed an active follow up [81.7 (10.9) months)], 3/30 (10%) lost follow up and 6/30 (20%) died. 12/21 (57.1%) patients were in complete disease remission, 5/21 (23.8%) showed a partial response and 4/21 (19%) had an active disease.17/30 (56.7%) patients needed retreatment for relapse with a mean time to retreatment of 22.3 (12.1) months. Treatment survival of this regimen was 7.6 (0.3) years. Recurrent non-severe infections occurred in 3/30, with chronic hypogammaglobulinemia in 2/3 patients.Conclusions: A long-term regimen of retreatment with RTX alone given at clinical relapse seems to be effective and safe in CV, with a low rate of infections and severe hypogammaglobulinemia. (C) 2015 Elsevier Ltd. All rights reserved.

Cholesterol crystal embolism, sometimes separately designated atheroembolism, is an increasing and still underdiagnosed cause of renal dysfunction antemortem in elderly patients. Renal cholesterol crystal embolization, also known as atheroembolic renal disease, is caused by showers of cholesterol crystals from an atherosclerotic aorta that occlude small renal arteries. Although cholesterol crystal embolization can occur spontaneously, it is increasingly recognized as an iatrogenic complication from an invasive vascular procedure, such as manipulation of the aorta during angiography or vascular surgery, and after anticoagulant and fibrinolytic therapy. Cholesterol crystal embolism may give rise to different degrees of renal impairment. Some patients show only a moderate loss of renal function; in others, severe renal failure requiring dialysis ensues. An acute scenario with abrupt and sudden onset of renal failure may be observed. More frequently, a progressive loss of renal function occurs over weeks. A third clinical form of renal atheroemboli has been described, presenting as chronic, stable, and asymptomatic renal insufficiency. The renal outcome may be variable; some patients deteriorate or remain on dialysis, some improve, and some remain with chronic renal impairment. In addition to the kidneys, atheroembolization may involve the skin, gastrointestinal system, and central nervous system. Renal atheroembolic disease is a difficult and controversial diagnosis for the protean extrarenal manifestations of the disease. In the past, the diagnosis was often made postmortem. However, in the last decade, awareness of atheroembolic renal disease has improved, enabling us to make a correct premortem diagnosis in a number of patients. Correct diagnosis requires the clinician to be alert to the possibility. The typical patient is a white man aged older than 60 years with a baseline history of hypertension, smoking, and arterial disease. The presence of a classic triad characterized by a precipitating event, acute or subacute renal failure, and peripheral cholesterol crystal embolization strongly suggests the diagnosis. The confirmatory diagnosis can be made by means of biopsy of the target organs, including kidneys, skin, and the gastrointestinal system. Thus, Cinderella and her shoe now can be well matched during life. Patients with renal atheroemboli have a dismal outlook. A specific treatment is lacking. However, it is an important diagnosis to make because it may save the patient from inappropriate treatment. Finally, recent data suggest that an aggressive therapeutic approach with patient-tailored supportive measures may be associated with a favorable clinical outcome.