Podocyte Infolding Glomerulopathy, First Case Report From North America.

RATIONALE: Podocyte infolding glomerulopathy (PIG) is a newly described condition with only 37 cases reported worldwide. Due to its rarity, the pathogenesis and evolution of this disease is unclear. This case report contributes to our collective knowledge about the clinical and histological progression of this disease. PRESENTING CONCERNS OF THE PATIENT: Over the course of a year, a 52-year-old Malaysian woman with no known prior medical history developed progressively worsening edema and other findings consistent with nephrotic syndrome. DIAGNOSIS: Unlike most patients with PIG, this patient did not have any autoimmune disease. She was Hepatitis B core antibody positive with a Hepatitis B surface antibody >1000, suggesting prior Hepatitis B infection with immunity. A renal biopsy was performed which was consistent with PIG. A second renal biopsy was done 2 years later which again showed characteristic findings of PIG with worsened podocyte effacement but no interval change in chronicity. INTERVENTIONS: The patient was treated with blood pressure control and renin-angiotensin-aldosterone system (RAAS) blockade with irbesartan and spironolactone. She was also treated with prednisone at 1 mg/kg for 2 months followed by a taper for a total of 7 months of prednisone treatment. OUTCOMES: The patient had a partial response to a course of prednisone. However, since stopping steroids, her proteinuria and renal function has been gradually worsening. TEACHING POINTS: PIG is mostly found in patients of East Asian descent. It presents as proteinuria and is often associated with autoimmune disease but can be idiopathic. It is characterized on renal biopsy by infolding or protrusion of podocyte cytoplasm into glomerular basement membrane, as well as intramembranous cytoplasmic microspherules or microtubules. Atypical membranous nephropathy should be ruled out prior to diagnosis. Unlike membranous nephropathy, PIG usually responds at least partially to steroid monotherapy. To our knowledge, this is the first reported case of PIG from North America. Furthermore, it is the first case of PIG with repeat biopsy showing interval worsening of PIG rather than either resolution of PIG or transformation of PIG to a different diagnosis.

FONDEMENT: La glomérulonéphrite due à l'involution des podocytes (GIP) est une affection nouvellement décrite; seuls 37 cas ont été signalés jusqu'à présent dans le monde. La pathogenèse et l'évolution de cette maladie rare sont donc encore nébuleuses. Ce rapport de cas ajoute au savoir collectif sur sa progression clinique et histologique. PRÉSENTATION DU CAS: Une Malaisienne de 52 ans sans antécédents médicaux connus qui, sur une période d'un an, a développé un œdème s'étant aggravé progressivement et présenté d'autres résultats concordant avec un syndrome néphrotique. DIAGNOSTIC: Contrairement à la plupart des patients ayant reçu un diagnostic de GIP, cette patiente ne présentait aucune maladie auto-immune concomitante. Un résultat positif pour les anticorps anti-HBc et un compte supérieur à 1 000 pour les anticorps de surface contre l'hépatite B suggéraient une infection antérieure par l'hépatite B avec immunité. Une biopsie rénale avait montré un résultat compatible avec une GIP. Une deuxième biopsie rénale effectuée deux ans plus tard a également montré des résultats caractéristiques d'une GIP et une aggravation de l'épanchement des podocytes, mais aucun changement d'intervalle en terme de chronicité. INTERVENTIONS: La patiente a été traitée par maîtrise de la tension artérielle et blocage du SRAA avec irbésartan et spironolactone. Elle a également reçu une dose de 1 mg/kg de prednisone pendant deux mois, qui a par la suite été progressivement réduite. Le traitement à la prednisone s'est étalé sur un total de sept mois. RÉSULTATS: La patiente a répondu partiellement au traitement à la prednisone. Mais depuis l'arrêt des stéroïdes, une aggravation de la protéinurie et une altération de la fonction rénale progressives ont été observées. ENSEIGNEMENTS TIRÉS: La GIP affecte principalement des patients originaires de l'Asie de l'Est. Cette maladie se présente sous la forme d'une protéinurie et elle est souvent associée à une maladie auto-immune, bien qu'elle puisse aussi être idiopathique. À la biopsie rénale, la GIP se caractérise par un repli ou une protrusion du cytoplasme des podocytes dans la membrane basale glomérulaire, de même que par des microsphérules ou des microtubules cytoplasmiques intramembranaires. Une néphropathie membranaire atypique doit être exclue avant de poser le diagnostic. Contrairement à la néphropathie membranaire, la GIP répond généralement, au moins partiellement, aux stéroïdes en monothérapie. À notre connaissance, il s'agit du premier cas signalé de GIP en Amérique du Nord. Il s'agit en outre du premier cas de GIP avec biopsie répétée montrant une aggravation de la maladie pendant l'intervalle plutôt qu'une résolution ou une transformation de la maladie en un diagnostic différent.

Adapting Nephrology Training Curriculum in the Era of COVID-19.

PURPOSE OF REVIEW: The COVID-19 pandemic has widespread implications not only for clinical practice but also for academic medicine and postgraduate training. The need to promote physical distancing and flexibility within our department has generated important revisions to the core curriculum for the Adult Nephrology Training Program in Vancouver, Canada. SOURCES OF INFORMATION: We reviewed available educational resources and objectives to develop curricular adaptations informed by staff and trainee feedback. METHODS: Many facets of the program including clinical rotations, scholarly activities, evaluation, and wellness have been impacted, and thus revised for online delivery where possible. Trainees have personalized a learning plan based on individual goals and supplemented by a list of internet-based resources for independent review. Changes in learning objectives and methods for specific rotations have occurred and are described. Ongoing evaluation will be undertaken. KEY FINDINGS: Curriculum adaptation in the era of COVID-19 is necessary to ensure ongoing high-quality education for future nephrologists. We describe existing changes to formal training in British Columbia (BC), which will be tailored as the pandemic evolves, and anticipate them to have lasting impact on the way we structure training programs in the future. Standardization and harmonization of modified curriculum may be possible across Canada with sharing of these learnings. LIMITATIONS: Formal evaluation of these changes in terms of knowledge acquisition and examination performance has not yet been undertaken. Next steps will include assessing and documenting the impact of this curricular transformation to further optimize scheduling, educational yield, and trainee wellness.

Eligibility of real-world patients with chemo-refractory, K-RAS wild-type, metastatic colorectal cancer for palliative intent regorafenib monotherapy.

The CORRECT trial demonstrated survival benefits with regorafenib monotherapy in patients with treatment-refractory, metastatic colorectal cancer (mCRC). However, the trial's stringent eligibility criteria for regorafenib may limit its external validity. We aimed to examine treatment attrition rates and eligibility for regorafenib in routine practice. We identified patients at the British Columbia Cancer Agency diagnosed with mCRC who demonstrated disease progression or intolerable toxicity on 2 or more lines of systemic therapy. During the study timeframe, panitumumab and cetuximab were only used in the chemo-refractory setting. Data on clinicopathologic variables and patient outcomes were ascertained and analyzed. Eligibility was determined using the CORRECT trial criteria. A total of 391 patients were identified, among whom only 39% were eligible for regorafenib: 35% in the panitumumab group and 51% in the cetuximab group. The main reasons for ineligibility in all patients were Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 1 (69%), an elevated total bilirubin (21%), and thromboembolic events in the past 6 months (10%). No difference in eligibility for regorafenib was observed between patients previously receiving panitumumab or cetuximab (P = 0.914; 95% CI 0.550-1.951). Kaplan-Meier analyses showed that regorafenib-eligible compared to regorafenib-ineligible patients had an increased median overall survival of 5.3 versus 2.1 months, respectively (P < 0.001). However, Cox proportional hazard analyses showed that only ECOG PS rather than trial eligibility was correlated with outcomes. The strict eligibility criteria disqualify most patients with treatment-refractory mCRC for regorafenib therapy. Future trials should broaden the eligibility criteria to improve external validity.

Tyrosine Residues Regulate Multiple Nuclear Functions of P54nrb.

The non-POU-domain-containing octamer binding protein (NONO; also known as p54nrb) has various nuclear functions ranging from transcription, RNA splicing, DNA synthesis and repair. Although tyrosine phosphorylation has been proposed to account for the multi-functional properties of p54nrb, direct evidence on p54nrb as a phosphotyrosine protein remains unclear. To investigate the tyrosine phosphorylation status of p54nrb, we performed site-directed mutagenesis on the five tyrosine residues of p54nrb, replacing the tyrosine residues with phenylalanine or alanine, and immunoblotted for tyrosine phosphorylation. We then preceded with luciferase reporter assays, RNA splicing minigene assays, co-immunoprecipitation, and confocal microscopy to study the function of p54nrb tyrosine residues on transcription, RNA splicing, protein-protein interaction, and cellular localization. We found that p54nrb was not phosphorylated at tyrosine residues. Rather, it has non-specific binding affinity to anti-phosphotyrosine antibodies. However, replacement of tyrosine with phenylalanine altered p54nrb activities in transcription co-repression and RNA splicing in gene context-dependent fashions by means of differential regulation of p54nrb protein association with its interacting partners and co-regulators of transcription and splicing. These results demonstrate that tyrosine residues, regardless of phosphorylation status, are important for p54nrb function. J. Cell. Physiol. 232: 852-861, 2017. © 2016 Wiley Periodicals, Inc.