Treating Patients With ANCA-Associated Vasculitis and Very Severe Renal Injury With an Intensified B Cell Depletion Therapy: Comparison With a Control Cohort Receiving a Conventional Therapy.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Management of acute kidney injury in frail patients with biopsy-proven cast nephropathy: a combined approach with chemotherapy plus Supra-hemodiafiltration with post-adsorption endogenous reinfusion.

BACKGROUND: Patients with multiple myeloma often have kidney involvement with acute kidney injury which is frequently due to cast nephropathy. Hemodiafiltration with endogenous reinfusion (HFR) allows removal from the circulation of significant amounts of free light chains (FLCs) responsible for tubular damage. METHODS: Between 2014 and 2018, 13 patients affected by multiple myeloma (64% λ chain and 36% k), including 10 cases with biopsy-proven cast nephropathy, were treated with this technique. Each patient had high free light chains levels at diagnosis: median 8586 mg/l for λ and 4200 mg/l for k, and stage III acute kidney injury (median serum creatinine 7.5 mg/dl). We initially performed daily HFR-Supra sessions and then modulated them based on renal response (mean 10 sessions/patient). At the same time, the patients also received various chemotherapy regimens, depending on their hematological criteria. RESULTS: Forty-six percent of patients showed at least partial renal function recovery within the third month, thus allowing dialysis discontinuation; 38% remained on dialysis. Two patients died. The mean reduction rate of free light chains at the end of the HFR-Supra cycle was 85% (k) and 40% (λ), respectively. Serum albumin remained stable during the whole treatment. DISCUSSION: In our experience, the synergistic effect of chemotherapy and HFR-Supra led to a recovery of renal function in 6 out of 13 patients presenting with severe dialysis-requiring acute kidney injury. HFR-Supra allowed stable albumin levels, with high free light chains removal rate, at a relatively low costs.

Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors.

INTRODUCTION: Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). OBJECTIVES: The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset. MATERIALS AND METHODS: A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed. RESULTS: One-hundred and six patients were included (median age at onset of 55 years [IQR 42-67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13-77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4-9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51-13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality. CONCLUSIONS: Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.

IgG4-related kidney disease: the effects of a Rituximab-based immunosuppressive therapy.

IgG4-related disease (IgG4-RD) is a recently recognized disorder, characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells and storiform fibrosis. Treatment is usually based on steroids, however, relapses and long-term adverse effects are frequent. We prospectively studied 5 consecutive patients with histologically-proven IgG4-RD and renal involvement, treated with an extended Rituximab protocol combined with steroids. Two doses of intravenous cyclophosphamide were added in 4 patients. Five patients with IgG-RD were investigated: three had tubulointerstitial nephritis (TIN), while two had retroperitoneal fibrosis (RPF). In the patients with TIN, renal biospy was repeated after 1 year. In the patients with TIN, estimated glomerular filtration rate (eGFR) at 12 months increased from 9 to 24 ml/min per 1.73 m2; IgG/IgG4 decreased from 3,236/665 to 706/51 mg/dl; C3/C4 increased from 49/6 to 99/27 mg/dl; CD20+ B-cells decreased from 8.7% to 0.5%; Regulatory T-cells decreased from 7.2% to 2.5%. These functional and immunologic changes persisted at 24 months and in two patients at 36 months. A repeat renal biopsy in the patients with TIN showed a dramatic decrease in interstitial plasma cell infiltrate with normalization of IgG4/IgG positive plasma cells. The patients with RPF showed a huge regression of retroperitoneal tissue. In this sample of patients with aggressive IgG4-RD and renal involvement, treatment aimed at depleting B cells and decreasing antibody and cytokine production was associated with a substantial, persistent increase in eGFR, and a definite improvement in immunologic, radiologic and histological parameters.

Comparison of different cyclosporine immunoassays to monitor C0 and C2 blood levels from kidney transplant recipients: not simply overestimation.

BACKGROUND: Immunoassays used for the measurement of cyclosporine (CsA) usually show cross-reactivity for CsA metabolites, usually resulting in unacceptable bias. METHODS: To assess the performance of different immunoassays, CsA concentrations were analyzed in 132 samples using ACMIA, EMIT-VIVA, CEDIA-PLUS, and HPLC. Samples were collected from kidney transplant patients monitored with the traditional blood CsA trough level (C0, n=73) and the new sampling at 2-h post CsA dosing (C2, n=59). RESULTS: Overall, the correlations between HPLC and other methods were good (r values ranging from 0.85 to 0.97). The use of C2 concentrations to monitor CsA exposure were associated with an overall better performance of all the immunoassays as compared with C0 values. However, none of the immunoassays agreed with the guidelines proposed in the Lake Louis Consensus Conference. Of note, the CEDIA-PLUS was the only that provided a linear relationship with HPLC for both sampling times. A false positive case associated with ACMIA was also documented in blood samples from a patient withdrawn from CsA for 1 month. CONCLUSION: These data suggest that the performance of some of the most used immunoassays is not satisfactory, eventually leading to incorrect therapeutic decision guided by erroneous CsA monitoring.

High-performance liquid chromatography with ultraviolet detection for therapeutic drug monitoring of everolimus.

We developed and validated a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining everolimus concentrations in human whole blood. Sample preparation involved a solid-phase extraction after protein precipitation. The separation of everolimus from internal standard (IS) and endogenous components was achieved using an isocratic elution on an octyl column. The method showed a linear relationship between peak height ratios and blood concentrations in the range of 1-200 ng/mL (r(2)=0.9997). The observed intra- and inter-day assay imprecision had a coefficient of variation (CV)=12.8%, and inaccuracy was 11.4%. The method was found to be precise, accurate, and sensible making it useful for routine therapeutic monitoring of everolimus.

Therapeutic drug monitoring of sirolimus: effect of concomitant immunosuppressive therapy and optimization of drug dosing.

Sirolimus (SRL) is a new immunosuppressant which shares a common metabolic pathway with several other immunosuppressive agents. This leads to potential pharmacokinetic interactions that might affect SRL blood levels with relevant clinical consequences. As a validated laboratory, 2658 SRL trough samples (corresponding to 495 kidney transplant recipients treated with different immunosuppressive regimens) from more than 40 Italian Transplant Units were analyzed. We found that dose-normalized SRL trough levels were significantly higher in patients treated with cyclosporine (CsA) and SRL (4.15 +/- 2.23 ng/mL/mg SRL), compared with patients treated with mycophenolate mofetil (MMF) and SRL (3.26 +/- 1.86 ng/mL/mg SRL; p < 0.01) or with MMF, steroids and SRL (2.52 +/- 1.73 ng/mL/mg SRL; p < 0.01). Mean intra- and interpatient variabilities were 19% and 47%, respectively. Both parameters are significantly affected by the time postsurgery, with the first week post transplantation being associated with the greatest variability. As additional analysis, a simple dose-adjustment formula has been proposed as a useful tool to guide SRL dose changes. The proposed equation has been able to predict SRL concentration after a dose change in 73% of the tested samples. These findings suggest that different immunosuppressants significantly interfere with SRL bioavailability. Strategies aimed at reducing variability in SRL exposure may have a positive clinical impact.

Clinical and psychosocial outcome of patients affected by panic disorder with or without agoraphobia: results from a naturalistic follow-up study.

OBJECTIVE: A clinical and psychosocial follow-up study of a cohort of 85 patients affected by panic disorder (PD) with or without agoraphobia was performed an average of 40 months after initial observation and following a mean duration of illness of 8 years. METHODS: Eighty-five out of 130 patients affected by PDs with or without agoraphobia according to DSM-III R criteria, examined between 1990 and 1995 at an outpatient clinic were re-examined in 1997/1998 using the same standardized clinical evaluation performed on admission. Patients also underwent a structured diagnostic interview (Mini International Neuropsychiatric Interview, MINI) and psychosocial evaluation (Scale of Sheehan's Disability Scale, DISS, Baker and Intagliata's Satisfaction with Life Domains Scale, SLDS). RESULTS: At follow-up, the percentage of patients who had either improved or were in remission was considerably higher among those initially diagnosed as PD with respect to those diagnosed as panic disorder with agoraphobia (PDA): Thirty-eight percent of PD and 20.6% of PDA patients were in clinical remission. Mild panic symptoms and phobic avoidance were found in the majority of patients who were still symptomatic (respectively 71% and 57%). Approximately 60% of patients reported a significant difficulty in performing daily activities and 40% expressed dissatisfaction in at least 50% of life domains considered. Seventy-two percent of subjects examined were still undergoing pharmacological treatment at the time of follow-up. CONCLUSIONS: The findings of the study are suggestive of a chronic illness with a significant impact on everyday quality of life of patients.