Michael Venning

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.

Ambulatory blood pressure monitoring in renal dialysis and transplant patients

Blood pressure (BP) elevation and left ventricular hypertrophy are important factors in the high cardiovascular mortality rate in patients on the renal replacement program. Ambulatory BP monitoring is widely regarded as superior to random BP monitoring in predicting end-organ damage from elevated BP. One hundred seventeen patients (60 on hemodialysis [35 with long sessions and 25 with short sessions], 29 on continuous ambulatory peritoneal dialysis, and 28 transplant recipients) underwent ambulatory BP monitoring, with target organ assessment by electrocardiography. Mean 24-hour BP for the patients with the long hemodialysis sessions (LHD) was 115.5/66.6 mm Hg, without the regular use of antihypertensive drugs. The parathormone (PTH) level was the major determinant of BP on ambulatory BP monitoring analysis, with interdialytic weight gain and age each having weaker associations. The BPs of the other three patient cohorts were much higher (short hemodialysis session [SHD], 143.2/82.1 mm Hg; continuous ambulatory peritoneal dialysis, 137.1/76.8 mm Hg; transplant recipients, 135.9/79.2 mm Hg). Overall, two thirds of the patients had reduced diurnal BP variability. Electrocardiogram voltage criteria for left ventricular hypertrophy were exceeded in approximately one third to one half of the patients. Our findings show that good control of BP is possible without recourse to antihypertensive drugs in the context of dialysis with slow ultrafiltration.

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.

Limitations of Kinetic Models as Predictors of Nutritional and Dialysis Adequacy in Continuous Ambulatory Peritoneal Dialysis Patients

Nutrition has been shown to predict clinical outcome in continuous ambulatory peritoneal dialysis (CAPD) patients. However, despite the positive relationship between KT/V (urea) and the normalised protein catabolic rate, the ability of urea kinetic modelling to predict clinical outcome or nutrition remains inconclusive. We have evaluated the relationship between nutrition and achieved dialysis in a cross-sectional study of 147 stable CAPD patients on dialysis for a mean period of 22 months. Protein-energy malnutrition was present in 22-32% of the study population. 39 and 41% of the population failed to achieve suggested adequacy targets of 50 liters/week for total creatinine clearance and a weekly KT/V (urea) of 1.7, respectively. Severely malnourished patients had significantly greater normalised clearance and adequacy values than well-nourished patients. Intrinsic actual peritoneal clearance bore no relation to patient size. The subsequent normalisation of this value by a component of patient mass results in a mathematical bias against well-nourished or obese patients. This may explain the failure of such adequacy values to reflect outcome and argues against accepting such values as measures of dialysis well-being.

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.

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.

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.

Successful renal transplant during the first trimester of pregnancy.

We wish to report a successful outcome of pregnancy diagnosed with 24 h of renal transplantation at 6-week gestation. The patient was a 27-year-old woman, with end-stage renal failure secondary to reflux nephropathy, who received a 110-mismatched cadaveric renal transplant. Both the recipient and the donor were cytomegalovirus (CMV)-negative and the left kidney was transplanted into the right iliac fossa with a standard anastomosis, following a total ischaemia time of 29 h and 30 min. The kidney started functioning immediately and she was given basiliximab (Simulect, Novartis, Camberley, UK) induction therapy and methylprednisolone 1 g i.p. Twelve hours following transplant, her urinary output fell slightly and an ultrasound was performed to assess the graft. This revealed that the kidney was well perfused and unexpectedly also revealed the presence of a viable intrauterine pregnancy of approximately 6-week gestation. Despite extensive counselling regarding the risks of pregnancy in this situation, the patient was delighted and keen to continue with the pregnancy. A paucity of information regarding the use of Simulect in pregnancy prompted a decision to withhold the second dose and a duel immunosupression regime of azathioprine and tacrolimus was commenced. In view of her previous history of thrombosis, she was also treated with low-molecularweight heparin. The patient made a rapid post-operative recovery and was discharged 7 days following the transplantation. At the time of discharge, her serum creatinine was 60 lmol/l. The patient remained well throughout the first and second trimesters, with stable renal function (serum creatinine range 60–81 lmol/l in the second trimester) and no episodes of acute rejection. Her blood pressure remained consistently normal and she never required antihypertensive treatment. Repeated detailed ultrasound examination showed normal fetal anatomy and growth. During the third trimester her serum creatinine climbed slowly and at 36 weeks suddenly increased to 141 lmol/l. Her tacrolimus levels were within the normal range and her blood pressure was normal. Labour was therefore electively induced and a healthy live born-male infant weighing 2.25 kg (25th Individualized Birth Centile [1]) was delivered normally. Following delivery, her serum creatinine slowly decreased and 6 weeks post-natally was 109 lmol/l. The patient had first presented with renal failure at 16week gestation in her first pregnancy 2 years earlier. One twin died in utero at 17-week gestation and she subsequently underwent medical termination at 18-week gestation. Following this, two unsuccessful attempts were made at fistula formation in her left arm, but on both occasions the vessels thrombosed. She therefore commenced continuous ambulatory peritoneal dialysis (CAPD) and at the time of admission for transplantation she had a serum creatinine of 486 lmol/l and a glomerular filtration rate (GFR) of 10 ml/min/l. Her periods had been infrequent whilst on dialysis and she had been amenorrhoic for 5 months prior to transplantation. Whilst pregnancy following renal transplant is well documented, spontaneous pregnancy in women with endstage renal failure undergoing dialysis is rare. Estimates of the frequency of conception in dialysis patients range from 0.3% to 0.5% per year [2,3]. Impaired ovulation and amenorrhea, which may be related to uremia or to co-morbidities of chronic renal failure, are common [4]. However, there is a widespread impression that conception among dialysis patients is becoming more frequent because of advances in dialysis techniques. The management of pregnant patients undergoing dialysis remains difficult [5–7]. Advances in care and surveillance have led to improved pregnancy outcomes in such patients in recent years. Nevertheless, fetal mortality in pregnant women on dialysis is still extremely high. Frequent perinatal complications include miscarriage, preterm delivery, perinatal and infant death, or other adverse sequelae [8,9]. This is in marked contrast to pregnancy outcomes in women who have undergone transplantation. The US Renal Data System shows that since 1991 only 16–37% of pregnancies in dialysis patients have resulted in live births compared with up to 63% of pregnancies among women with a transplant. Indeed recent reports suggest that after the first trimester, the majority (94%) of pregnancies to allograft recipients are successful. However, concerns remain regarding the possible adverse interaction between

Lack of awareness of skin cancer among immunocompromised patients with antineutrophil cytoplasmic antibody‐associated vasculitis: a questionnaire survey

nosis and a lack of proper medical assessment. Secondly, the NTCR has been complete since only 1979, and our database goes only to 2007. To the best of our knowledge, our report is not just the only study reflecting large case numbers in Asia, but it is also the first report that discusses the incidence trends of EMPD in different sexes, by using the nationwide database in Taiwan. In summary, EMPD is a rare cutaneous malignancy that can be ignored by patients and misdiagnosed as eczema by physicians. This nationwide population-based study in Taiwan yielded the largest number of EMPD cases in Asia, with a significant male predisposition.

SAT0458 Vasculitis care in the UK: How do patients perceive the care provided and what should the future hold?

Background Primary Systemic Vasculitis (PSV) is a group of life-threatening auto-immune multi-system disorders. The British Society for Rheumatology recommends that these patients are referred to a consultant with a special interest with vasculitis as they require rapid diagnosis and initiation of therapy, alongside careful, comprehensive surveillance. One of the major challenges for planning vasculitis services is that due to the multi- system nature of these disorders, these patients utilise a wide range of health care services. Objectives With pressure on the National Health Service to reform patient care in a cost effective way, we set out to evaluate, on a national level how care is currently being provided for patients with Vasculitis. We wished to ascertain which disciplines patients presented to, and following diagnosis, are managed by. We aimed to evaluate for differences in care across the various specialties by means of reviewing disease monitoring and the prescription of prophylactic medication. Finally we investigated the patient’s perception and utilisation of primary care. Methods With the assistance of the patient support group, Vasculitis UK, we designed and distributed a comprehensive questionnaire to all 700 UK members. This questionnaire covered aspects of care from the onset of symptoms to their current treatment and monitoring. Results Response rate was 347 (49.6%). Of these 306 responses were analysed from patients with Primary Systemic Vasculitis. 241 (79%) had Granulomatosis with Polyangiitis, 41 (13%) Churg Strauss Syndrome, 15 (5%) Microscopic Polyangiitis and 9 (3%) other “Systemic vasculitis/ANCA Associated Vasculitis”. Patients were seen most commonly in ENT (42%) and rheumatology (25%) clinics prior to diagnosis. Post- diagnosis the majority of patients (76%) were under the care of rheumatology and/or nephrology. Of the 294 (96%) patients who received steroids, only 52% and 60% reported co- prescription of calcium and Vitamin D respectively. 229 patients (75%) received cyclophosphamide, with only 60 (25%) reporting co-trimoxazole prescription. There was no significant difference in these practices observed between nephrology and rheumatology. However, patients were significantly more likely to have blood pressure and urinalysis monitored regularly if under nephrology (p=0.01). Despite the majority of patients feeling that their GP had a significant role in managing their health (64%), only 44% and 38% had blood test and blood pressure monitoring respectively in primary care. Conclusions Vasculitis services in the UK are likely to remain in secondary care due to the complex nature of these diseases. However there is room for improvement in the monitoring and surveillance of this patient group. Despite patient confidence in their GP, primary care appears to be a resource currently underutilised by this group. Future service planning should include better collaboration to harness primary care skills in patient monitoring and primary prevention of disease and treatment related morbidity. This should translate to an improved “package of care” being provided for this complex population. Disclosure of Interest H. Arya: None Declared, N. Brown Grant/Research support from: Roche, M. Venning Grant/Research support from: Roche, I. Bruce Consultant for: Roche, GlaxoSmithKline, Human Genome Sciences, Astra Zeneca and UCB Pharma, Speakers Bureau: Roche, GlaxoSmithKline, Human Genome Sciences, Astra Zeneca and UCB Pharma