Megan Griffith

Prospective study of TNFα blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic Vasculitis

UNLABELLED Tumor necrosis factor alpha (TNFalpha) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNFalpha blockade is a potential therapy for these disorders. METHODS An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] > or = 10; n = 16); study II examined persistent disease (BVAS > or = 4; n = 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. RESULTS Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] = 10.5 to 14.0) at entry to 0.3 (CI = 0.2 to 0.9) at wk 14 (P < 0.001). C-reactive protein (mg/L) decreased from 29.4 (CI = 16.8 to 42.0) at entry to 7.0 (CI = 3.3 to 10.9) by wk 14 (P = 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI = 15.0 to 32.5) at entry to 8.8 (CI = 5.9 to 11.7) at wk 14 (P = 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. CONCLUSION TNFalpha blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.

Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids

Objectives Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN. Methods We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)<50 mg/mmol or partial remission (PR) if PCR>50 mg/mmol but non-nephrotic and >50% reduction. Results A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4–200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11–58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19–58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20–112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required >2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode. Conclusions The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN.

Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids

BACKGROUND Lupus nephritis is a life-threatening complication of SLE. Treatment regimes include steroids and cyclophosphamide, both associated with significant morbidity. Newer regimes include mycophenolate mofetil (MMF). We report our outcomes in a prospectively monitored cohort of patients receiving our new standard treatment protocol, comprising rituximab induction therapy and MMF maintenance in patients already taking maintenance immunosuppression for SLE who developed lupus nephritis. We then attempted steroid reduction/withdrawal. METHODS Patients with class III/IV/V lupus nephritis were included. All patients were on steroids prior to the development of lupus nephritis. Eighteen patients have reached at least 1 year follow-up. These patients received rituximab induction therapy and MMF maintenance therapy. Steroid reduction/withdrawal was guided by clinical response. RESULTS Fourteen of 18 (78%) patients achieved complete or partial remission with a sustained response of 12/18 (67%) at 1 year, with 2 patients having a relapse of proteinuria. Four patients did not respond. There was a significant decrease in proteinuria from a mean protein:creatinine ratio (PCR) of 325 mg/mmol at presentation to 132 mg/mmol at 1 year (P = 0.004). Serum albumin significantly increased from a mean of 29 g/L at presentation to 34 g/L at 1 year (P = 0.001). The complication rate was low with no severe infections. Following treatment with rituximab, 6 patients stopped prednisolone, 6 patients reduced their maintenance dose and 6 patients remained on the same dose (maximum 10 mg). CONCLUSION This data demonstrates the efficacy of a rituximab and MMF based regime in the treatment of lupus nephritis, allowing a reduction or total withdrawal of corticosteroids.

Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCA-associated vasculitis

BACKGROUND Rituximab (RTX) has been shown to be effective as an induction agent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), but studies have been limited by short-term follow-up. We decided to investigate the long-term efficacy and safety of an RTX-based cyclophosphamide (CYP)-sparing regimen (CycLowVas) for renal AAV. METHODS Consecutive patients with renal AAV presenting de novo or with a major relapse, except those with serum creatinine >500 μmol/L, previous treatment with RTX and pulmonary haemorrhage or cerebral vasculitis, were treated with two pulses of RTX 2 weeks apart and six fortnightly doses of CYP, as well as a reducing protocol of daily oral steroids. Maintenance was with low-dose steroids and azathioprine. RESULTS Twenty-three patients were treated. Median follow-up was 39 months, with 17 patients reaching >2 years of follow-up. All patients achieved clinical remission within 6 weeks. Three major and two minor relapses occurred in five patients at a median of 30 months, which were treated by re-dosing with RTX for major relapses and steroid increase alone for minor relapses. Adverse events included one severe drug reaction, four non-serious and one serious infective episodes in the first 3 months, one skin malignancy at 21 months and one death at 19 months not related to treatment or disease. CONCLUSIONS A RTX-based low-dose CYP regimen is effective at inducing long-term disease-free remission and may be the platform on which to develop a steroid-minimizing regimen to further decrease adverse events in the future.

Determinants of mycophenolic acid levels after renal transplantation.

There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.

Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors

BACKGROUND Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA-associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli.

The magnitude and time course of changes in mycophenolic acid 12-hour predose levels during antibiotic therapy in mycophenolate mofetil-based renal transplantation.

There is increasing evidence that monitoring predose plasma levels of mycophenolic acid (MPA) is of benefit in renal transplant recipients treated with mycophenolate mofetil (MMF). Concomitant treatment with oral antibiotics leads to a 10% to 30% reduction in MPA area under the curve (AUC)0-12, probably by reducing enterohepatic recirculation (EHR). Because of the timing of EHR (6 to 12 hours postdose), the magnitude of predose MPA level reduction may be disproportionately larger than that of AUC0-12. However, changes in predose MPA levels and the time course over which these changes occur and resolve during antibiotic treatment have not been studied. The purpose of this study was to define the extent and time course of MPA predose level reduction during antibiotic therapy. A total of 64 MMF-treated renal transplant recipients (with tacrolimus cotherapy) were prospectively studied. Clinically indicated cotherapy with either oral ciprofloxacin or amoxicillin with clavulanic acid resulted in a reduction in 12 hour predose MPA level to 46% of baseline within 3 days of antibiotic commencement. No demographic or biochemical variables were associated with the magnitude of MPA level reduction. No further fall in MPA level was seen by day 7, but MPA levels recovered spontaneously to 79% of baseline after 14 days of antibiotics. Levels normalized within 3 days of antibiotic cessation. No changes in daily MMF dose (normalized for body weight) were made during antibiotic treatment. This data should help the clinician to recognize the extent of MPA predose level reduction during antibiotic therapy, and to avoid inappropriate MMF dose escalation and potential risk of toxicity.

Retrospective Analysis of a Novel Regimen for the Prevention of Venous Thromboembolism in Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Venous thromboembolism (VTE) occurs in 7%-40% of nephrotic patients. The risk of VTE depends on the severity and underlying cause of nephrotic syndrome. This study investigated the use of low-dose prophylactic anticoagulation to prevent VTE in patients with nephrotic syndrome caused by primary glomerulonephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since 2006, all patients presenting with nephrotic syndrome to Imperial College Kidney and Transplant Centre have been considered for treatment with a novel anticoagulation prophylaxis regimen. All cases of nephrotic syndrome secondary to primary membranous nephropathy, minimal-change disease, and FSGS over a 5-year period were retrospectively reviewed. Patients with serum albumin<2.0 g/dl received prophylactic-dose low-molecular-weight heparin or low-dose warfarin; patients with albumin levels of 2.0-3.0 g/dl received aspirin, 75 mg once daily. All thrombotic events and bleeding complications were recorded. RESULTS A total of 143 patients received the prophylactic anticoagulation regimen. Median follow-up was 154 weeks (range, 30-298 weeks). The cohort had features associated with a high risk of developing VTE; 40% of the cohort had an underlying diagnosis of membranous nephropathy, and the initial median serum albumin was 1.5 g/dl (range, 0.5-2.9 g/dl). No VTE occurred in patients established on prophylaxis for at least 1 week. VTE was diagnosed in 2 of 143 patients (1.39%) within the first week after presentation and starting prophylaxis. In both cases, it is unclear whether the thrombus had developed before or after the start of prophylaxis. One of 143 (0.69%) patients receiving prophylaxis was admitted urgently with gastrointestinal hemorrhage. Two of 143 patients (1.40%) had elective blood transfusions and procedures to manage occult gastrointestinal bleeding. No other bleeding events occurred in patients receiving prophylaxis. CONCLUSIONS This regimen of prophylactic antiplatelet or anticoagulant therapy appears effective in preventing VTE in nephrotic syndrome, with relatively few hemorrhagic complications.

Classification, Pathogenesis, and Treatment of Systemic Vasculitis

Patients with systemic vasculitis (SV), especially Wegeners granulomatosis and microscopic polyangiitis, regularly present with renal involvement. Although considered a rare disease, either the incidence of SV is increasing or it is being increasingly recognized. Accurate classification systems are required to allow comparison of data from different groups investigating and treating these patients. Systemic vasculitis is known to be an autoimmune disease, but the mechanisms of pathogenesis have not been established, despite many studies on this topic in recent years. Most of this work has been done in vitro, although development of animal models is underway. Patient and renal survival have improved with aggressive immunosuppressive treatment, but morbidity is high and controversies remain in establishing the most effective regimens with minimum adverse effects. In this review we discuss the classification of SV, review the current knowledge of pathogenic mechanisms, and consider the relative merits of different treatment protocols.

Ten-year patient survival on maintenance haemodialysis: association with treatment time and dialysis dose.

BACKGROUND Analyses of national registry-based datasets have demonstrated the association of longer haemodialysis treatment times with lowered mortality risk. METHODS We performed a prospective cohort study of 451 incident haemodialysis patients and examined the effect of targeting higher dialysis dose with extended treatment time, on 10-year patient outcomes. RESULTS Mean treatment time (TT) was 233 ± 22.8 minutes (median 235, range 180-296). Overall patient survival was 95% at 1 year, 75% at 3 years, 56% at 5 years and 25% at 10 years. Increasing TT was associated with incremental 10-year patient survival (TT >/=241 minutes 39.7%, TT 226-240 minutes 19.6% and TT </=225 minutes 14.7%; p<0.001). Single pool Kt/V and TT were strong independent predictors of patient survival in Cox multivariate analysis (p<0.0001). At 10 years, each 0.1-unit increase in spKt/V and 20-minute increase in TT were associated with a 20% and 32% decrease in the relative risk of death, respectively. Survival benefits of higher dialysis dose and longer TT were cumulative, with highest survival exhibited by patients achieving both Kt/V >1.6 and TT >/=241 minutes, and lowest survival exhibited by patients receiving Kt/V <1.2 and TT </=225 minutes. CONCLUSION Extended treatment times are associated with higher patient survival irrespective of dialysis dose. Further study of extended treatment time and effect on patient outcomes is needed.