The clinical course of ANCA small-vessel vasculitis on chronic dialysis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis frequently affects the kidney. Here we describe the rates of infection, disease relapse, and death in patients with ANCA small-vessel vasculitis before and after end-stage renal disease (ESRD) in an inception cohort study and compare them to those of patients with preserved renal function. All patients had biopsy-proven ANCA small-vessel vasculitis. Fisher's exact tests and Wilcoxon rank sum tests were used to compare the characteristics by ESRD status. ESRD follow-up included time on dialysis with transplants censored. Over a median follow-up time of 40 months, 136 of 523 patients reached ESRD. ESRD was associated with new-onset ANCA small-vessel vasculitis in 51% of patients, progressive chronic kidney disease without active vasculitis in 43%, and renal relapse in 6% of patients. Relapse rates of ANCA small-vessel vasculitis, reported as episodes/person-year, were significantly lower on chronic dialysis (0.08 episodes) compared with the rate of the same patients before ESRD (0.20 episodes) or with patients with preserved renal function (0.16 episodes). Infections were almost twice as frequent among patients with ESRD on maintenance immunosuppressants and were an important cause of death. Given the lower risk of relapse and higher risk of infection and death, we suggest that immunosuppression be geared to patients with ESRD who present with active vasculitis

Association of Silica Exposure with Anti-Neutrophil Cytoplasmic Autoantibody Small-Vessel Vasculitis: A Population-Based, Case-Control Study

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with a category of small-vessel vasculitis (SVV) with frequent glomerulonephritis. The goal of this study was to evaluate the association of lifetime silica exposure with development of ANCA-SVV, with particular attention to exposure dosage, intensity, and time since last exposure. A southeastern United States, population-based, case-control study was conducted. Case patients had ANCA-SVV with pauci-immune crescentic glomerulonephritis. Population-based control subjects were frequency-matched to case patients by age, gender, and state. Jobs were assessed in a telephone interview. Silica exposure scores incorporated exposure duration, intensity, and probability for each job and then were categorized as none, low/medium, or high lifetime exposure. Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Silica exposure was found in 78 (60%) of 129 case patients and in 49 (45%) of 109 control subjects. There was no increased risk for disease from low/medium exposure relative to no exposure (OR 1.0; 95% CI 0.4 to 2.2) but increased risk with high exposure (OR 1.9; 95% CI 1.0 to 3.5; P = 0.05). Crop harvesting was associated with elevated risk (OR 2.5; 95% CI 1.1 to 5.4; P = 0.03). However, both agricultural and traditional occupational sources contributed to the cumulative silica exposure scores; therefore, the overall effect could not be attributed to agricultural exposures alone. There was no evidence of decreasing by duration of time since last exposure. High lifetime silica exposure was associated with ANCA-SVV. Exposure to silica from specific farming tasks related to harvesting may be of particular importance in the southeastern United States. Interval of time since last exposure did not influence development of ANCA-SVV

Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy

Primary membranous nephropathy is associated with increased risk of venous thromboembolic events, which are inversely correlated with serum albumin levels. To evaluate the potential benefit of prophylactic anticoagulation (venous thromboembolic events prevented) relative to the risk (major bleeds), we constructed a Markov decision model. The venous thromboembolic event risk according to serum albumin was obtained from an inception cohort of 898 patients with primary membranous nephropathy. Risk estimates of hemorrhage were obtained from a systematic literature review. Benefit-to-risk ratios were predicted according to bleeding risk and serum albumin. This ratio increased with worsening hypoalbuminemia from 4.5:1 for an albumin under 3 g/dl to 13.1:1 for an albumin under 2 g/dl in patients at low bleeding risk. Patients at intermediate bleeding risk with an albumin under 2 g/dl have a moderately favorable benefit-to-risk ratio (under 5:1). Patients at high bleeding risk are unlikely to benefit from prophylactic anticoagulation regardless of albuminemia. Probabilistic sensitivity analysis, to account for uncertainty in risk estimates, confirmed these trends. From these data, we constructed a tool to estimate the likelihood of benefit based on an individual’s bleeding risk profile, serum albumin level, and acceptable benefit-to-risk ratio (http://www.gntools.com). This tool provides an approach to the decision of prophylactic anticoagulation personalized to the individual’s needs and adaptable to dynamic changes in health status and risk profile

ANCA patients have T cells responsive to complementary PR-3 antigen

Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3138-169-peptide; while only a third of the patients had HI-PR3 protein responsive T cells. A significant number of T cells from patients responded to cPR3138-169 peptide and to HI-PR3 protein by proliferation and/or secretion of IFN-γ, compared to healthy controls while there was no response to scrambled peptide. Cells responsive to cPR3138-169-peptide were not detected in MPO-ANCA patients suggesting that this response is specific. The HLADRB1* 15 allele was significantly overrepresented in our patient group and is predicted to bind cPR3138-169 peptide with high affinity. Regression analysis showed a significant likelihood that anti-cPR3 antibodies and cPR3-specific T cells coexist in individuals, consistent with an immunological history of encounter with a PR3-complementary protein. We suggest that the presence of cells reacting to potential complementary protein pairs might provide an alternative mechanism for auto-immune diseases

Treatment of idiopathic membranous glomerulopathy

Idiopathic Membranous Glomerulopathy and its treatment have always been an enigma and a challenge for practicing nephrologists. Continuing efforts to explore this disease reveal potential pathways that might be involved in its pathogenesis and consequently its therapy. We describe two series of patients who received two different kinds of pharmacological agents relying on data reported in the literature. As we seek to investigate the possibility to exploit these agents in patients with MG, the primary goal in both cases was to evaluate their safety and tolerability profile. Subsequently, we assessed efficacy, if any, and the associated characteristics. i. Inhibition of Tumor Necrosis Factor Alpha (TNF-α) in idiopathic MGΝ Aim: To evaluate the safety, tolerability and potential efficacy of the TNF-α inhibitor, Etarnecept (ET), in patients with idiopathic Membranous Glomerulopathy. Patients-Methods: Patients with biopsy proven MGΝ, nephrotic range proteinuria and clearance of creatinine 50 ml/min or more were included in the study. Exclusion criteria were; treatment with steroids or cyclosporine during the previous 3 months, or cytotoxic agents within six months prior to entry. Etanercept was administered subcutaneously twice per week at a dose of 25 mg for 3 months. Plasma levels of TNF-α, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL- 10), soluble intercellular adhesion molecule type 1 (sICAM-1), E-selectin, and the soluble form of tumor necrosis factor receptor-55 (sTNFR-55) were measured at the entry and at months 3, 6, and 9 post therapy start. Results: Twelve patients entered the study (4 females/8 males, mean time from diagnosis 8.3 months). The therapy was well tolerated; no infections or other adverse events were recorded by the end of follow up. Two patients exhibited complete -70- remission of proteinuria for at least four years. No significant change was found in the levels of TNF-α, IL-1, IL-6 IL-8 and IL-10 during the study. Similarly the levels of Eselectin and sICAM-1 were not significantly altered by therapy. Although we found no change in sTNFR-55 at 3 and 6 months, the levels of sTNFR-55 were found significantly decreased 9 months after therapy (mean difference from baseline: 334 ± 527pg/ml, p=0.028) ii. Depletion of B lymphocytes in idiopathic MGΝ Aim: To assess the potential therapeutic benefit of temporary depletion of B lymphocytes Rituximab in patients with idiopathic Membranous Glomerulopathy and describe any associated alterations in the subsets of lymphocytes. Patients-Methods: Patients were entered in the study if they had biopsy proven MG and no clinical or laboratory evidence of secondary causes of the disease. They should also have glomerular filtration rate above 30 ml/min/1.73m2, and minimum 24 hour proteinuria >3 g/day. Patients who had been treated with cyclosporine or cytotoxic agents the year prior to entry were excluded. Depletion of B cells was achieved with Rituximab, which was administered intravenously, in a dose of 375 mg/m2, once weekly, for 4 consecutive weeks. Partial remission was defined as a > 50% decrease in proteinuria and absolute proteinuria 50% decrease in proteinuria and an absolute protein excretion50 ml/min. Τα κριτήρια αποκλεισμού περιελάμβαναν: θεραπεία με στεροειδή ή κυκλοσπορίνη το προηγούμενο 3μηνο, ή κυτταροτοξικά φάρμακα το 6μηνο πριν την ένταξη στη μελέτη. Το Etanercept χορηγούνταν υποδορίως 2 φορές την εβδομάδα, σε δόση 25 mg για 3 μήνες. Τα επίπεδα των: TNF-α, Ιντερλευκίνη-1 (IL-1), Ιντερλευκίνη-6 (IL-6), Ιντερλευκίνη-10 (IL-10), διαλυτό ενδοκυττάριο μόριο προσκόλλησης τύπου-1 (sICAM-1), E-selectin, και η διαλυτή μορφή του υποδοχέα- 55 του TNF-α, (s-TNFR-55), μετρούνταν στο πλάσμα κατά την είσοδο στη μελέτη και ακολούθως στους μήνες 3, 6, και 9 μετά την έναρξη της θεραπείας. Αποτελέσματα: Δώδεκα ασθενείς εισήχθησαν στη μελέτη (4 γυναίκες/8 άνδρες) σε μέσο χρόνο από τη διάγνωση 8.3 μήνες. Η θεραπεία με το ΕΤ έγινε καλά ανεκτή. Δεν παρατηρήθηκαν λοιμώξεις ή άλλες ανεπιθύμητες ενέργειες στη διάρκεια της θεραπείας και της μετέπειτα παρακολούθησης. Δύο ασθενείς πέτυχαν πλήρη ύφεση της πρωτεϊνουρίας, η οποία διατηρήθηκε για τουλάχιστον 4 χρόνια. Δεν παρατηρήθηκε στατιστικά σημαντική μεταβολή στα επίπεδα των TNF-α, IL-1, IL-6 IL- 8 και IL-10 κατά τη διάρκεια της μελέτης. Παρομοίως, τα επίπεδα των E-selectin και sICAM-1 δεν μεταβλήθηκαν σημαντικά μετά την θεραπεία. Παρότι τα επίπεδα του -66- υποδοχέα sTNFR-55 δεν παρουσίασαν μεταβολή 3 και 6 μήνες μετά τη θεραπεία, μια στατιστικά σημαντική μεταβολή παρατηρήθηκε 9 μήνες μετά την θεραπεία (μέση διαφορά από την τιμή εκκίνησης: 334 ± 527pg/ml, p=0.028) Συμπέρασμα: Βραχύχρονη χορήγηση ET σε μια μικρή σειρά ασθενών με ιδιοπαθή ΜΣ φάνηκε να είναι ασφαλής και καλά ανεκτή. Το σύστημα του TNF-α ανεστάλη, όπως διαπιστώθηκε από την μείωση των επιπέδων του υποδοχέα του sTNFR-55, αλλά δεν συνοδεύτηκε από θεραπευτικό όφελος Β. Εξάλειψη των Β Λεμφοκυττάρων στην ιδιοπαθή ΜΣ Σκοπός: Να αξιολογηθεί η δραστικότητα του μονοκλωνικού αντισώματος Rituximab, στη θεραπεία της ιδιοπαθούς ΜΣ, καθώς και να μελετηθούν οι ενδεχόμενες μεταβολές των λεμφοκυττάρων που ακολουθούν. Ασθενείς-Μέθοδοι: Οι ασθενείς με ιστολογικά επιβεβαιωμένη ΜΣ θεωρούνταν υποψήφιοι για ένταξη στη μελέτη εάν είχαν ελάχιστη πρωτεϊνουρία 3 g/24ωρο, υπολογιζόμενη CrCl >30 ml/min/1.73m2 και ηλικία >18 έτη. Ασθενείς με ενεργό ή μη θεραπευμένη οξεία ή χρόνια λοίμωξη, ή με ιστορικό πρόσφατης θεραπείας με κυτταροτοξικά φάρμακα (χλωραμβουκίλη, κυκλοφωσφαμίδη) αποκλείσθηκαν

An uncommon cause of acutely altered mental status in a renal transplant recipient

Introduction. Neurological complications are quite frequent in patients after solid organ transplantation presenting with focal or generalized neurologic symptoms as well as altered mental status. Posterior reversible encephalopathy syndrome is a rare cliniconeuroradiological entity characterized by headache, altered mental status, cortical blindness, seizures, and other focal neurological signs and a diagnostic magnetic resonance imaging. Case report. We present a case of a 57-year-old woman with one episode of seizures and sudden onset of altered mental status (time and person perception) accompanied with headache at the thirtieth postoperative day after renal transplantation. Conclusion. Posterior reversible encephalopathy syndrome, although an uncommon post-renal transplantation complication, should be considered in these patients, as several factors surrounding the setting of transplantation have been implicated in its development. Thus, physicians should be aware of this condition in order to establish the diagnosis and offer appropriate treatment

The paradigm shift from polycythemia to anemia in COPD: the critical role of the renin-angiotensin system inhibitors

Introduction Although polycythemia has been considered a common adverse event in COPD, anemia is reported more often and has gained more importance than polycythemia over the last thirty years. Areas covered Factors considered to be associated with the development of anemia in COPD have included: Aging and kidney dysfunction with erythropoietin deficiency and bone marrow suppression due to uremic toxins; heart failure (HF), often encountered in COPD and accompanied by anemia in one-third of the cases; Low-grade chronic inflammation, directly suppressing bone marrow and diminishing iron absorption and utilization via increased hepcidin levels; long-term oxygen therapy (LTOT), ameliorating chronic hypoxia, and most important, RAS inhibitors, which are widely used for the comorbidities associated with COPD (hypertension, HF, CKD, diabetes) and have previously been shown to lower hematocrit values or cause anemia in various clinical conditions. Expert opinion Introduction of LTOT in COPD and especially the established use of RAS inhibitors form the basis for the shift from polycythemia to anemia in COPD. Interestingly, when the SGLT2 inhibitors are introduced for cardiorenal protection in COPD, one could anticipate correction of anemia or even reemergence of polycythemia, since this new class of drugs can augment erythropoietin secretion and increase hematocrit values