Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).

Pembrolizumab-Induced Anti-GBM Glomerulonephritis: A Case Report.

Immune checkpoint inhibitors are known to have a wide range of autoimmune toxicities, such as acute interstitial nephritis. Immunotherapy induced glomerulonephritis has been described, but anti-glomerular basement membrane disease (anti-GBM) is rarely reported. We present a case report of a 60-year-old woman with squamous cell carcinoma of the cervix who was treated with pembrolizumab, an anti-programmed cell death protein 1, and who developed severe acute kidney injury 4 months after therapy initiation. The immune workup showed a positive serum anti-GBM antibody (24 U/mL). The kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G2 glomerular basement membrane staining, compatible with anti-GBM glomerulonephritis. The patient was treated with plasmapheresis, IV steroids, and cyclophosphamide, but she developed kidney failure, necessitating dialysis. Few case reports, such as the present case, provide a possible link between anti-GBM glomerulonephritis and immune checkpoint inhibitors, warranting early clinical suspicion and investigation in patients who are treated with these agents and subsequently develop acute kidney injury.

Clinical Characteristics and Outcome of Canadian Patients Diagnosed With Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, heterogeneous disease of uncontrolled activation of the alternative complement pathway that is difficult to diagnose. We have evaluated the Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. OBJECTIVE: To evaluate Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. METHODS: The Global aHUS Registry is an observational, noninterventional, multicenter study that has prospectively and retrospectively collected data from patients of all ages with an investigator-made clinical diagnosis of aHUS, irrespective of treatment. Patients of all ages with a clinical diagnosis of aHUS were eligible and invited for enrollment, and those with evidence of Shiga toxin-producing Escherichia coli infection, or with ADAMTS13 activity ≤10%, or a subsequent diagnosis of thrombotic thrombocytopenic purpura were excluded. Data were collected at enrollment and every 6 months thereafter and were analyzed descriptively for categorical and continuous variables. End-stage renal disease (ESRD)-free survival was evaluated using Kaplan-Meier estimates, and ESRD-associated risk factors of interest were assessed using Cox proportional hazards regression models. Patients were censored at start of eculizumab for any outcome measures. RESULTS: A total of 37 Canadian patients were enrolled (15 pediatric and 22 adult patients) between February 2014 and May 2017; the median age at initial aHUS presentation was 25.9 (interquartile range = 6.7-51.7) years; 62.2% were female and 94.6% had no family history of aHUS. Over three-quarters of patients (78.4%) had no conclusive genetic or anti-complement factor H (CFH) antibody information available, and most patients (94%) had no reported precipitating factors prior to aHUS diagnosis. Nine patients (8 adults and 1 child) experienced ESRD prior to the study. After initial presentation, there appears to be a trend that children are less likely to experience ESRD than adults, with 5-year ESRD-free survival of 93 and 56% (P = .05) in children and adults, respectively. Enrolling physicians reported renal manifestations in all patients at initial presentation, and 68.4% of patients during the chronic phase (study entry ≥6 months after initial presentation). Likewise, extrarenal manifestations also occurred in more patients during the initial presenting phase than the chronic phase, particularly for gastrointestinal (61.1% vs 15.8%) and central nervous system sites (38.9% vs 5.3%). Fewer children than adults experienced gastrointestinal manifestations (50.0% vs 70.0%), but more children than adults experienced pulmonary manifestations (37.5% vs 10.0%). CONCLUSIONS: This evaluation provides insight into the diagnosis and management of aHUS in Canadian patients and the challenges faced. More genetic or anti-CFH antibody testing is needed to improve the diagnosis of aHUS, and the management of children and adults needs to consider several factors such as the risk of progression to ESRD is based on age (more likely in adults), and that the location of extrarenal manifestations differs in children and adults.

CONTEXTE: Le syndrome hémolytique et urémique atypique (SHUa) se caractérise par l'activation incontrôlée de la voie alternative du complément. Il s'agit d'une maladie rare, hétérogène et très difficile à diagnostiquer. Nous avons évalué les patients Canadiens inscrits au registre international du SHUa afin d'offrir une perspective canadienne sur le diagnostic et la prise en charge du SHUa, de même que sur les défis posés par la maladie. OBJECTIF: Évaluer les patients Canadiens inscrits au registre international du SHUa afin d'offrir une perspective canadienne sur le diagnostic et la prise en charge du SHUa, de même que sur les défis posés par la maladie. MÉTHODOLOGIE: Le registre international du SHUa est une étude observationnelle, non interventionnelle et multicentrique ayant recueilli, de façon rétrospective et prospective, des données auprès de patients de tous âges ayant reçu un diagnostic clinique de SHUa, quel que soit le traitement. Tous ces patients étaient admissibles et ont été invités à participer à l'étude. Les patients présentant une infection diagnostiquée à Escherichia coli producteur de shigatoxine, une activité de l'ADAMTS13 inférieure ou égale à 10 % ou un diagnostic subséquent de purpura thrombocytopénique thrombotique ont été exclus. Les données colligées à l'inclusion et à tous les six mois par la suite ont fait l'objet d'une analyze descriptive des variables catégorielles et continues. Des estimations de Kaplan-Meier ont été employées pour évaluer la survie sans insuffisance rénale terminale (IRT) et des modèles de régression à risques proportionnels de Cox ont servi à évaluer les facteurs de risques associés à l'IRT. Les patients ont été censurés au début du traitement par l'eculizumab pour la mesure des résultats. RÉSULTATS: Au total, 37 patients canadiens ont été inscrits (15 enfants et 22 adultes) entre février 2014 et mai 2017. L'âge médian lors de l'épisode initial était de 25,9 ans (intervalle interquartile: 6,7­51,7); 62,2 % des sujets étaient de sexe féminin et 94,6 % n'avaient pas d'antécédents familiaux de SHUa. Plus des trois quarts des patients (78,4 %) ne disposaient d'aucune information génétique ou relative aux anticorps anti-complément du facteur H concluante, et aucun facteur précipitant n'avait été rapporté avant le diagnostic pour la majorité des patients (94 %). Neuf patients (8 adultes et 1 enfant) avaient souffert d'IRT avant l'étude. Une tendance semble indiquer qu'après l'épisode initial, les enfants seraient moins susceptibles que les adultes de progresser vers l'IRT (survie sans IRT après 5 ans: 93 % et 56 % respectivement; P = 0,05). Les médecins-recruteurs ont observé des manifestations rénales chez tous les patients lors de l'épisode initial de SHUa et chez 68,4 % des patients au cours de la phase chronique (inscription à l'étude au moins 6 mois après l'épisode initial). Parallèlement, les manifestations extra-rénales sont également survenues chez davantage de patients lors de l'épisode initial que lors de la phase chronique, particulièrement pour les manifestations gastro-intestinales (61,1 % contre 15,8 %) et du système nerveux central (38,9 % contre 5,3 %). Les enfants ont été moins nombreux que les adultes à subir des manifestations gastro-intestinales (50,0 % contre 70,0 %), mais ont subi davantage de manifestations pulmonaires (37,5 % contre 10,0 %). CONCLUSION: Cette étude offre un éclairage sur le diagnostic et la prise en charge du SHUa chez les patients canadiens, de même que sur les défis posés par la maladie. Davantage de dépistage génétique et de dépistage des anticorps anti-CFH sont requis pour améliorer le diagnostic du SHUa. La prise en charge de la maladie doit tenir compte de plusieurs facteurs, notamment du risque de progression vers l'IRT qui varie selon l'âge (plus probable chez l'adulte) et du fait que le site des manifestations extrarénales diffère chez l'enfant et l'adulte.

Clinicopathologic correlation in IgA nephropathy.

IgA nephropathy is the most common biopsy-proven pattern of glomerulonephritis in the world. Many factors, both clinical and histologic, have been suggested to impact on prognosis. We review the wide variations in how patients with immunoglobulin A nephropathy can present and the important differences derived from the clinical pathologic setting through the description of 4 cases. These include the clinical scenarios of modest proteinuria, acute kidney injury, and the nephrotic syndrome.

Remission of proteinuria in primary glomerulonephritis: we know the goal but do we know the price?

Membranous nephropathy, focal segmental glomerulosclerosis and IgA nephropathy are the most commonly recognized types of primary glomerulonephritis that progress to end-stage renal disease. Persistent proteinuria is a major determinant of such progression. Reduction of proteinuria slows progression of renal disease and improves renal survival, but many of the agents used to reduce proteinuria carry a considerable risk of toxicity. The assessment of benefit versus risk of these medications can be further complicated by the temporal disconnect between the onset of benefit and of serious adverse events. In addition, relapses are common in these disorders and there is often a need for retreatment. Such retreatment might lead to repeated and/or prolonged drug exposure and to the oversight or underestimation of the cumulative dose of these agents because of the potentially extended interval between relapses. Consequently, it is very important to constantly review each patient's status and take into account their age, comorbid conditions and cumulative drug exposure when assessing treatment options. The potentially delayed development of adverse events also emphasizes the need for long-term surveillance of patients who receive immunosuppressive treatment for glomerular disease, often well beyond their drug exposure period and even when the treatment has been successful.

A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR).

BACKGROUND: Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. METHODS AND DESIGN: Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with i.v. rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. DISCUSSION: This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy.

Incidence and severity of early electrolyte abnormalities following autologous haematopoietic stem cell transplantation.

BACKGROUND: Haematopoietic stem cell transplantation (HSCT) has gained worldwide acceptance as a therapeutic option for many haematological and non-haematological conditions. Local experience supports that electrolyte abnormalities are quite common; however, the incidence and timing of these abnormalities are unknown. METHOD: We conducted a retrospective descriptive study of 48 consecutive adult patients in order to study the incidence and the timing of electrolyte abnormalities following autologous HSCT. Clinical and pharmacological data were collected by the review of patient charts. Potassium, magnesium, calcium, phosphorus and albumin levels were retrieved from the laboratory. RESULTS: HSCT was performed for multiple myeloma (28/48), lymphoma (8/48), Hodgkin disease (4/48), amyloidosis (4/48) and other neoplasia (4/48). At baseline, 21% of patients (10/48) had low electrolyte levels. Following autologous HSCT, hypokalaemia occurred in 81% (39/48), hypomagnesaemia in 67% (32/48), hypocalcaemia in 49% (17/35) and hypophosphataemia in 91% (39/43) of the patients. The nadir of the electrolyte levels occurred between day 8 and 10 after stem cell transplant while the engraftment occurred at day 11.6+/-0.6. The use of amphotericin B and furosemide was associated with more pronounced hypokalaemia and hypomagnesaemia. Hypocalcaemia was more pronounced in patients with multiple myeloma. High levels of electrolytes occurred in only 25% of the patients, none of which required specific treatment. CONCLUSION: We conclude that low electrolyte levels are extremely common after HSCT and the pathophysiology of these abnormalities are complex and multifactorial.