Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 μg/ml at month-3) is a risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients' characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission.
Summary Background In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir‐based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. Aim To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. Methods In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease–Epidemiology Collaboration ( CKD ‐ EPI ) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre‐treatment, on‐treatment and post‐treatment periods were 9 months, 3‐9 months and 4.5 months. Interactions between eGFR slopes and the pre‐treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On‐treatment eGFR slopes were separated in tertiles. Pre‐ and post‐treatment eGFR slopes were compared globally and according to tertiles. Results The post‐treatment eGFR slope was significantly better than pre‐treatment eGFR slope (+0.18 ( IQR −0.76 to +1.32) vs −0.11 ( IQR −1.01 to +0.73) mL /min/1.73 m 2 /month, P = 0.03) independently of the pre‐treatment eGFR ( P = 0.99), ribavirin administration ( P = 0.26), mycophenolate mofetil administration ( P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child‐Pugh B and C vs lower stages, P = 0.38). Tertiles of on‐treatment eGFR slopes were −1.71 ( IQR −2.54 to −1.48), −0.78 ( IQR −1.03 to −0.36) and +0.75 ( IQR +0.28 to +1.47) mL /min/1.73 m 2 /month. Pre‐ and post‐treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). Conclusion The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir‐based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.
INTRODUCTION: Phospholipase A2 receptor (PLA2R1) is a major autoantigen in idiopathic membranous nephropathy (MN).Anti-PLA2R1 antibody titers rise during clinical activity and decrease before remission.However, the pathogenic role of anti-PLA2R1 antibodies is not yet proven.MN is characterized by prevailing IgG4 with low amounts of IgG1 and IgG4 is considered unable to activate the classical pathway.This suggests that the alternative or lectin pathways might be involved in complement activation.Bally et al. described the first case of MN patient with complete MBL deficiency, intense staining of alternative pathway activation in kidney biopsy and low staining of classical pathway activation.This case suggests that MN can develop with complement activated mainly by the alternative pathway.Our aim is to study in vitro the pathogenic role of anti-PLA2R1 antibodies and to determine the contribution of the alternative pathway.METHODS: Forty-eight patients with PLA2R1-related MN from a prospective cohort SOURIS were included.Anti-PLA2R1 titer, epitope profile and anti-PLA2R1 IgG subclass were characterized by ELISA for each patient.After the incubation of HEK293 cells overexpressing PLA2R1 with patient or healthy donor sera in the presence or absence of rabbit complement and complement inhibitors, cell cytotoxicity was evaluated by immunofluorescence.RESULTS: Epitope spreading (defined by immunization over the immunodominant CysR domain) at baseline was associated with less and delayed remission (p<0.001).The presence of different IgG subclasses in addition to IgG4 was associated with poor prognosis (p=0.03).Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells expressing PLA2R1 was 262%, which increased to 246 6% after the addition of rabbit complement (p<0.001).The presence of anti-PLA2R1 IgG1, IgG2 and IgG3 antibodies, in addition to anti-PLA2R1 IgG4 antibodies, was associated with increased cell cytotoxicity (p=0.04) while epitope spreading and anti-PLA2R1 titer were not associated with cell cytotoxicity (p>0.999 and p=0.82 respectively).GVB EDTA which inhibits all complement activation pathways inhibited cell cytotoxicity whereas GVB Mg-EGTA which only inhibits classical and lectins pathway showed a persistent cytotoxicity reliable to alternative pathway activity.CONCLUSIONS: Anti-PLA2R1 antibodies induce in vitro cell cytotoxicity mediated by complement activation.Cytotoxicity increases with the number of IgG subclasses.Alternative pathway plays also a role in cell cytotoxicity mediated by complement.These findings suggest that complement inhibitors could potentially benefit to MN patients.
Deposition of perirenal adipose tissue has been associated with adverse renal and cardiovascular events. We compared various methods to measure perirenal adipose tissue using computerized tomography (CT)-scan and performed correlations with anthropometric measures associated with renal and cardiovascular events. Voluntary overweight and obese subjects undergoing a CT-scan for diagnostic purposes were included in the study. Perirenal adipose tissue volume, adipose tissue area of the renal sinus and perirenal fat thickness were manually measured bilaterally. The intra- and inter-observer coefficient correlations and the correlation between the diverse measures of renal adipose tissue, subcutaneous (SC-)fat and anthropometrics measures were analyzed using Pearson's correlation tests. The forty included patients (24 men, 16 women) had a mean age of 57.6 ± 18.1 years and a mean body mass index of 28.9 ± 2.9 kg/m2. Despite comparable waist circumference, women had a greater SC-fat thickness compared to men, and therefore a smaller amount of visceral fat, as well as smaller perirenal fat volumes. Perirenal fat thickness was better correlated with perirenal fat volume than adipose area of the renal sinus (p <0.02). The adipose area of the renal sinus did not correlate with any anthropometric measures. In women, perirenal fat volume and thickness showed a negative correlation with SC-fat thickness and no correlation with waist circumference. In men, perirenal fat volume and thickness showed a positive correlation with waist circumference and no correlation with subcutaneous fat thickness. In conclusion, perirenal fat thickness measured with CT-scan at the level of the renal veins is a simple and reliable estimate of perirenal fat volume, that correlated negatively with SC-fat in women and positively with waist circumference in men. The adipose area of the renal sinus did not correlate with any anthropometric measure.
Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure.
Background: Membranous Nephropathy (MN) is a rare autoimmune disease related to PLA2R1 antibodies in 70% of cases. One third of patients enter in spontaneous remission. PLA2R1 epitopes in MN have been characterized in four different domains of PLA2R1 and a mechanism of epitope spreading from the immunodominant CysR domain to CTLD1 and/or CTLD7 and/or CTLD8 domains has been associated with poor prognosis. Epitope spreading could predict spontaneous remission (45% in non-spreader patients vs. 0.05% in spreader patients). The comparison of different regimens of rituximab dosing showed that: (i) early remission rate depends on rituximab dosing, (ii) low dose could be enough for patients with anti-PLA2R1 activity restricted to CysR, (iii) high dose may be required for spreader patients. This study aims to evaluate the efficacy of personalized treatment in PLA2R1-related MN depending on the epitope spreading status, in comparison to the established GEMRITUX protocol. Methods: A multicenter, randomized, controlled, prospective clinical trial will be conducted in 22 French hospitals. Sixty-four consecutive patients with PLA2R1-related MN will be randomly assigned to either the control group following the GEMRITUX protocol (symptomatic treatment for 6 months, if the nephrotic syndrome (NS) persists at month-6, two 375 mg/m2 rituximab infusions at 1 week interval) or the personalized treatment group (patients with no epitope spreading at month-0 will be treated with symptomatic treatment for 6 months, if NS persists at month-6, two 375 mg/m2 rituximab infusions at 1 week interval; patients with epitope spreading at month-0 or month-6 with persistent NS will be treated immediately with two 1 g rituximab infusions at 2 week interval). The primary study outcome is the rate of clinical remission at month-12. The secondary outcomes include complete and partial remissions, immunological remissions, relapses, proteinuria, albuminuria, serum creatinine, eGFR, PLA2R1 antibody titers, severe infections, lymphocyte counts and lymphocyte phenotype, residual rituximab levels at month-3 and neutralizing anti-rituximab antibodies at month-6 and month-12 after rituximab treatment. Discussion: The results of this trial will confirm whether personalized treatment of PLA2R1-driven nephrotic MN is more efficient to induce clinical remission than the established GEMRITUX protocol, and may thus contribute to improved remission rates and reduced relapse rates. Trial registration: NCT03804359 trial number. Registered on 15th January 2019.
