IgA vasculitis nephritis-outcomes in adult-onset disease.

OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.

Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: a Health Economic Model.

Background: Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems. Methods: We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. Results: At 1-year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of £95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of -£5251.03 but with a reduced quality of life (incremental QALY of -0.512) giving an ICER of £10 246.09. Conclusions: Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Long-term outcomes of persistent disease and relapse in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS: We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS: One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS: Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice.

Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody-associated small vessel vasculitis.

Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies.

Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.

Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention.

Digestive properties of the venom of the Australian Coastal Taipan, Oxyuranus scutellatus (Peters, 1867).

The digestive properties of Australian elapid snake venoms have not been studied to any great extent. To address this, the in vitro digestive properties of Oxyuranus scutellatus (Australian Coastal Taipan) venom were investigated in a simulation of the in vivo conditions using the parameters reported for the stomach of snakes and representative prey for this species. The amount of soluble protein released was measured over time using a bicinchoninic acid (BCA) assay. Dismembered mouse hindlegs were injected intramuscularly with 0.1 ml O. scutellatus venom (concentration 10 mg/ml) and maintained in a micro-anaerobic, acidic environment (pH approximately 1.2-1.7) at 25 degrees C. The bathing liquid was sampled every 24 h for 7 days, and assayed for soluble protein. Statistical analysis revealed that O. scutellatus venom increased the rate at which proteins were released when compared to a negative control suggesting the potential importance of envenomation in the digestion of whole prey.

Rituximab in combination with corticosteroids for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis: a NICE single technology appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of rituximab (Roche Products) to submit evidence of the clinical and cost effectiveness of rituximab in combination with corticosteroids for treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology, based upon the manufacturer's submission to NICE. The evidence was derived mainly from a double-blind, phase III, placebo-controlled trial of rituximab in patients with new or relapsed 'severe' AAV, which compared a rituximab treatment regimen with an oral cyclophosphamide treatment regimen. Intravenous cyclophosphamide is also commonly used but was not included in the pivotal trial. The evidence showed that rituximab is noninferior to oral cyclophosphamide in terms of induction of remission in adults with AAV and de novo disease, and is superior to oral cyclophosphamide in terms of remission in adults who have relapsed once on cyclophosphamide. The ERG concluded that the results of the manufacturer's economic evaluation could not be considered robust, because of errors and because the full range of relevant treatment sequences were not modelled. The ERG amended the manufacturer's model and demonstrated that rituximab was likely to represent a cost-effective addition to the treatment sequence if given after cyclophosphamide treatment.

Urinary protein selectivity in nephrotic syndrome and pregnancy: resurrection of a biomarker when renal biopsy is contraindicated.

Significant proteinuria in pregnancy can indicate the presence of serious conditions requiring investigation and treatment. The nephrotic syndrome in pregnancy presents a multitude of difficulties and is a relative contraindication of renal biopsy, particularly in the third trimester. We present a case of nephrotic syndrome of unknown cause presenting at 33 weeks of pregnancy. With renal biopsy contraindicated, we used the urine protein selectivity test, a largely discarded test predicting steroid-responsive nephrotic syndrome, to help inform the decision to give steroids. This led to a successful clinical outcome including the avoidance of neonatal ICU care for baby.

Outpatient management of Gitelman's syndrome in pregnancy.

Gitelman's syndrome is a congenital renal tubular defect which affects the apical membrane of the distal convoluted tubule of the renal system. The syndrome is characterised by hypokalaemia, hypomagnesaemia, metabolic alkalosis and hypocalcuria. There are only a few cases describing the impact of Gitelman's syndrome on pregnancy and the foetus. Although most pregnancies have favourable outcomes, fetal demise has been reported in the third trimester. We report the successful outcome of pregnancy in a patient with Gitelman's syndrome who continued on amiloride in pregnancy to optimise potassium and magnesium levels and review the literature for pregnancy outcomes of this condition.

The effects of selected Australian snake venoms on tumour-associated microvascular endothelial cells (TAMECs) in vitro.

The effects of various viperid and elapid venoms on the cellular biology of tumour-associated microvascular endothelial cells (TAMECs) were determined in the current study using cells isolated from a rat mammary adenocarcinoma. Previous studies to determine the effects of snake venoms on endothelial cells in vitro have in the main been performed on either human umbilical vein endothelial cells (HUVECs), bovine aortic endothelial cells (BAECs) or endothelial cell lines. These cell populations are accessible and easy to maintain in culture, however, it is well established that endothelial cells display vast heterogeneity depending upon the local microenvironment of the tissue from which they are isolated. Vascular targeting agents have been isolated from a variety of snake venoms, particularly from snakes of the Viperidae family, but it is yet to be established to what extent the venoms from Australian elapids possess similar vascular targeting properties. The present study used endothelial cells (ECs) isolated from the microvasculature of a rat mammary adenocarcinoma to determine the effects of a panel of snake venoms, including viperid venoms with known apoptotic activity and elapid venoms (both exotic and indigenous to Australia), on endothelial morphology and viability, paying specific attention to apoptotic responses. Three of the five Australian snake venoms investigated in this study elicited significant apoptotic responses in ECs which were in many ways similar to responses elicited by the selected viperid venoms. This suggests that these Australian elapids may possess vascular targeting components similar to those found within viperid venoms.

Idiopathic or iatrogenic membranous glomerulonephritis? A case of spironolactone-induced membranous glomerulonephritis.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults in the UK. In most cases, the aetiology remains unknown, although recent data suggested a clear mechanism of pathogenesis. In approximately a quarter of cases, however, a presumed cause is found, such as systemic lupus nephritis, malignancy, hepatitis B and various drugs. Here, we present a patient who developed MN soon after commencing spironolactone and whose condition persisted for the duration of exposure to the drug only to resolve with cessation of the drug. No cases of spironolactone-induced MN have been reported in the literature previously.

Proteolytic activity of Elapid and Viperid Snake venoms and its implication to digestion.

Testing whether venoms may aid in digestion of the prey, eleven snake venoms were compared for the presence of proteases and endopeptidases that function in alkaline pH conditions. In vitro experiments examined the relative protease and endopeptidase activity of the venoms, which involved combining bovine muscle and snake venom in a buffered solution, encased within dialysis tubing. This mixture was then incubated at room temperature (∼20°C) for 24hr, with constant shaking. Bicinchoninic acid (BCA) assay and ninhydrin assay were used to determine peptide and amino acid concentrations. Histological and immunohistochemical investigations using N. kaouthia venom confirmed in vitro findings. Results show that B. arietans venom generated the highest amount of protein/peptides and amino acids in the dialysates, while O. scutellatus, N. ater niger and P. textilis venom did not show any significant protein degradation under alkaline conditions. Histological examination revealed varying degrees of muscle cell damage for each of the venom investigated, and the immunohistochemical study on N. kaouthia venom showed that the venom penetrated the muscle tissue to a significant degree. In vitro assays and histological results indicate that particular venoms may possess the ability to enhance digestion of bovine muscle tissue.