Identification of inflammatory biomarkers in IgA nephropathy using the NanoString technology: a validation study in Caucasians.

OBJECTIVE AND DESIGN: Immunoglobulin A nephropathy (IgAN) is a kidney disease characterized by the accumulation of IgA deposits in the glomeruli of the kidney, leading to inflammation and damage to the kidney. The inflammatory markers involved in IgAN remain to be defined. Gene expression analysis platforms, such as the NanoString nCounter system, are promising screening and diagnostic tools, especially in oncology. Still, their role as a diagnostic and prognostic tool in IgAN remains scarce. In this study, we aimed to validate the use of NanoString technology to identify potential inflammatory biomarkers involved in the progression of IgAN. SUBJECTS: A total of 30 patients with biopsy-proven IgAN and 7 cases of antineutrophil cytoplasmic antibody (ANCA)-associated pauci-immune glomerulonephritis were included for gene expression measurement. For the immunofluorescence validation experiments, a total of 6 IgAN patients and 3 controls were included. METHODS: Total RNA was extracted from formalin-fixed paraffin-embedded kidney biopsy specimens, and a customized 48-plex human gene CodeSet was used to study 29 genes implicated in different biological pathways. Comparisons in gene expression were made between IgAN and ANCA-associated pauci-immune glomerulonephritis patients to delineate an expression profile specific to IgAN. Gene expression was compared between patients with low and moderate risk of progression. Genes for which RNA expression was associated with disease progression were analyzed for protein expression by immunofluorescence and compared with controls. RESULTS: IgAN patients had a distinct gene expression profile with decreased expression in genes IL-6, INFG, and C1QB compared to ANCA patients. C3 and TNFRSF1B were identified as potential biomarkers for IgAN progression in patients early in their disease course. Protein expression for those 2 candidate genes was upregulated in IgAN patients compared to controls. Expression of genes implicated in fibrosis (PTEN, CASPASE 3, TGM2, TGFB1, IL2, and TNFRSF1B) was more pronounced in IgAN patients with severe fibrosis compared to those with none. CONCLUSIONS: Our findings validate our NanoString mRNA profiling by examining protein expression levels of two candidate genes, C3 and TNFRSF1B, in IgAN patients and controls. We also identified several upregulated mRNA transcripts implicated in the development of fibrosis that may be considered fibrotic markers within IgAN patients.

Minimal Change Disease With Severe Acute Kidney Injury Following the Oxford-AstraZeneca COVID-19 Vaccine: A Case Report.

We report a case of minimal change disease (MCD) with severe acute kidney injury (AKI) following the first injection of the ChAdOx1 nCoV-19 (AZD1222) vaccine from Oxford-AstraZeneca against coronavirus disease 2019 (COVID-19). A 71-year-old man with a history of dyslipidemia and a baseline serum creatinine of 0.7mg/dL presented with nephrotic syndrome, AKI, and severe hypertension 13 days after receiving the Oxford-AstraZeneca vaccine. Refractory hyperkalemia and hypervolemia with oligoanuria prompted initiation of hemodialysis. His serum albumin was 2.6g/dL and his urinary protein-creatinine ratio was 2,321mg/mmol. Given a high suspicion for rapidly progressive glomerulonephritis, empirical glucocorticoid treatment was initiated (3 methylprednisolone pulses followed by high-dose prednisone). A kidney biopsy showed MCD and acute tubular injury. Kidney function and proteinuria subsequently improved, and hemodialysis was discontinued 38 days after the start of therapy. This case describes de novo MCD after the Oxford-AstraZeneca vaccine. It adds to the few published case reports of MCD after the Pfizer-BioNTech COVID-19 vaccine. Further reports and studies will be needed to elucidate whether MCD is truly associated with COVID-19 vaccination.

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease.

RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

Pharmacodynamics of 250 mg and 500 mg oral furosemide in peritoneal dialysis
.

Residual renal function and diuresis preservation are associated with improved volume control and lower mortality in peritoneal dialysis (PD). Loop diuretics are used to maintain diuresis, although their optimal dosage remains unclear. This study aimed to compare the pharmacodynamics of a 250-mg and a 500-mg dose of oral furosemide in PD patients. 12 patients with a diuresis > 100 mL per day were randomized in a crossover pattern to successively receive an oral dose of 250 mg and 500 mg of furosemide. Twelve-hour natriuresis and diuresis were measured before and after each furosemide dose. Fractional excretion of sodium (FENa) and absolute sodium excretion increased after each dose, although these rises were not statistically significantly different (5.8% (250 mg) vs. 6.9% (500 mg), p = 0.57 for FENa and 42.6 mmol/12h (250 mg) vs. 70.8 mmol/12h (500 mg), p = 0.07 for absolute sodium excretion). Urinary volume was significantly increased after the 500-mg dose, whilst the difference did not reach statistical significance after the 250-mg dose. Furthermore, the higher dose was associated with a greater increase in diuresis than the lower dose (226 mL (250 mg) vs. 522 mL (500 mg), p = 0.04). Furosemide could be used at oral single doses reaching 500 mg in PD patients requiring greater volume control.

Impact of Arteriovenous fistula creation on estimated glomerular filtration rate decline in Predialysis patients.

BACKGROUND: Arteriovenous fistula (AVF) is the vascular access of choice for patients on hemodialysis. Recent evidence suggests that AVF creation may slow estimated glomerular filtration rate (eGFR) decline. The study objective was to assess the impact of the AVF creation on eGFR decline, after controlling for key confounding factors. METHODS: This retrospective cohort study included adult patients followed in a single-center predialysis clinic between 1999 and 2016. Patients with a patent AVF were followed up to 2 years pre- and post-AVF creation. Estimated GFR trajectory was reported using linear mixed models adjusted for demographic characteristics, comorbidities and use of renin-angiotensin-aldosterone blockade. RESULTS: A total of 146 patients were studied with a median age 68.7 (60.5-75.4) years and a median eGFR at time of AVF creation of 12.8 (11.3-13.9) mL/min/1.73m2. The crude annual eGFR decline rates were - 3.60 ± 4.00 mL/min/1.73 m2 pre- and - 2.28 ± 3.56 mL/min/1.73 m2 post-AVF, resulting in a mean difference of 1.28 mL/min/1.73 m2 (95% CI 0.49, 2.07). In a mixed effect linear regression model, monthly eGFR decline was - 0.63 (95% CI -0.81, - 0.46; p <  0.001) mL/min/1.73m2/month. The period after AVF creation was associated with a relatively higher eGFR (ß 0.94, 95% CI 0.61-1.26, p <  0.001). There was a significant association between follow-up time and the period pre/post AVF (ß 0.19, 95% CI 0.16, 0.22; p <  0.001) such that eGFR decline was more attenuated each month after AVF creation. CONCLUSIONS: In this cohort, AVF creation was associated with a significant reduction of eGFR decline. Further prospective studies are needed to confirm this association.

Association of erythropoiesis-stimulating agents and the incidence risk of cancer diagnosis among chronic dialysis patients: a nested case-control study.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the cornerstone of the treatment for anemia in end-stage renal disease (ESRD) patients. Although a correlation has been established between ESAs and increased tumor growth among patients with cancer-related anemia, an association with a higher incidence of cancer among chronic dialysis patients remains relatively unclear. METHODS: We completed a nested case-control study in a cohort of 4574 patients who began chronic dialysis treatment between 1 January 2001 and 31 December 2007 in Quebec, Canada, utilizing dialysis registry and administrative databases exclusively to extract our data. We excluded patients with a prior diagnosis of cancer. Eligible cases were identified by the time of initial cancer diagnosis obtained from either the hospital's discharge or physician billing form. We then randomly selected up to 10 controls for each case. ESA exposure was evaluated between 6 and 9 months prior to the initial cancer diagnosis. The mean weekly exposure was used to categorize ESA usage as either a low dose (<30 µg/week), moderate dose (30-70 µg/week) or high dose (>70 µg/week). We estimated the association between ESAs and the risk of developing cancer using a multivariable conditional logistic regression. RESULTS: We identified 419 cases of cancer and 3895 matched controls during the study period. The use of ESAs was associated with a higher risk of cancer {odds ratio [OR] 1.04 [95% confidence interval (CI) 1.02-1.07]}. Specifically, patients in the high exposure group (>70 µg/week) had an increased risk of developing cancer [OR 1.77 (95% CI 1.18-2.66)] compared with patients in the unexposed group. CONCLUSION: High-dose ESA was associated with an increased incidence risk of new cancer diagnosis among chronic dialysis patients.

Association between acetylsalicylic acid and the risk of dialysis-related infections or septicemia among incident hemodialysis patients: a nested case-control study.

BACKGROUND: Vascular access-related infections and septicemia are the main causes of infections among hemodialysis patients, the majority of them caused by Staphylococcus species. Acetylsalicylic acid (ASA) has recently been reported with a probable antistaphylococcal activity. This study aimed to evaluate the effect of ASA on the risk of dialysis-related infection and septicemia among incident chronic hemodialysis patients. METHODS: In a nested case-control study, we identified 449 cases of vascular access-related infections and septicemia, and 4156 controls between 2001 and 2007 from our incident chronic hemodialysis patients' cohort. Cases were defined as patients hospitalized with a main diagnosis of vascular access-related infection or septicemia on the discharge sheet (ICD-9 codes). Up to ten controls per case were selected by incidence density sampling and matched to cases on age, sex and follow-up time. ASA exposure was measured at the admission and categorized as: no use, low dose (80-324 mg/d), high dose (≥325 mg/d). Odds ratios (OR) for infections were estimated using multivariable conditional logistic regression analysis, adjusting for potential confounders. RESULTS: Compared to no use, neither dose of ASA was associated with a decreased risk of infection: low dose (OR 1.03, 95 % CI 0.82-1.28) and high dose (OR 1.30, 95 % CI 0.96-1.75). However, diabetes (OR = 1.32, 95 % CI = 1.07-1.62) and anticoagulant use (OR = 1.62, 95 % CI = 1.30-2.02) were associated with a higher risk. CONCLUSION: Among hemodialysis patients, ASA use was not associated with a reduced risk of hospitalizations for dialysis-related infections or septicemia. However, ASA may remain beneficial for its cardiovascular indications.

Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease.

BACKGROUND: Albuminuria is an early manifestation of sickle cell nephropathy. Prior small case series suggests benefit of hydroxyurea in reducing albuminuria, with a similar trend noted in pediatric studies. We aimed to comprehensively evaluate hydroxyurea use and prevalence of albuminuria in adult sickle cell patients. METHODS: We performed a cross-sectional study of 149 adult patients followed between 2000 and 2011 in a comprehensive sickle cell clinic. All patients were assessed for albuminuria either by direct measurement or by urinary chemical strip (dipstick) testing. Urinary albumin-to-creatinine ratios (UACRs) were available for 112 patients. Hydroxyurea exposure was defined as ≥3 months of therapy before the assessment of albuminuria. Albuminuria was defined as either UACR ≥30 mg/g or ≥1+ proteinuria on two separate dipsticks. We constructed a multivariate logistic regression model to assess the association between hydroxyurea and albuminuria. RESULTS: The prevalence of albuminuria was lower among patients on hydroxyurea (34.7 versus 55.4%; P = 0.01) as was median albumin excretion (17.9 versus 40.5 mg/g; P = 0.04). In multivariate analysis, hydroxyurea was associated with a lower likelihood of albuminuria (odds ratio 0.28, 95% CI: 0.11-0.75, P = 0.01), adjusting for age, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, tricuspid regurgitant jet velocity, hypertension and acute chest syndrome. CONCLUSIONS: In our population of sickle cell patients, those using hydroxyurea were less than one-third as likely to exhibit albuminuria. Hydroxyurea use may prevent development of overt nephropathy or the progression of sickle cell disease nephropathy to end-stage renal disease, and its use for this indication merits further investigation.

Podocyte-associated gene mutation screening in a heterogeneous cohort of patients with sporadic focal segmental glomerulosclerosis.

BACKGROUND: The utility of genetic testing in sporadic focal segmental glomerulosclerosis (FSGS) is unclear. We sought to determine the frequency of podocyte-related gene mutations in a heterogeneous population of adults and children with biopsy-proven FSGS. METHODS: The prevalence of pathogenic mutations in five genes (NPHS2, TRPC6, ACTN4, INF2 and PLCE1) and of APOL1 risk alleles (G1 and G2) was ascertained in children and adults diagnosed between 1984 and 2011 with FSGS by renal biopsy. Clinical data were extracted from medical records. RESULTS: A total of 65 patients (28 children, 37 adults) with sporadic FSGS were identified (34 females, 31 males), with a mean age of 25 ± 16 years (range from 3 to 62 years). The majority of patients were African American (39 African American, 21 White and 2 Hispanic). We identified biallelic pathogenic NPHS2 mutations in 2 of 28 (7.1%) children, both of whom were of non-Hispanic Caucasian background. A homozygous NPHS2 p.R138Q/p.R138Q mutation was detected in a 5-year-old Caucasian female. Two compound heterozygous NPHS2 mutations p.R138Q/p.R229Q were identified in a 7-year-old Caucasian male patient. One novel, potentially pathogenic non-synonymous variant in INF2 was identified in an African American patient. The proportion of African Americans with two APOL1 risk alleles was 69.2%. CONCLUSIONS: This study delineates a role for genetic testing for NPHS2 in children with biopsy-proven sporadic FSGS. Further studies which specify clinical and pathological details of patients will help further define whether there are specific populations that warrant systematic testing of other podocyte-related genes in sporadic FSGS.

Association between vitamin D receptor activator and the risk of infection-related hospitalizations among incident hemodialysis patients: a nested case-control study.

BACKGROUND: Patients suffering from chronic kidney disease are at greater risk of developing infection than the normal population, and infections are the second cause of mortality after cardiovascular complications in this population. Some reports suggest that the intake of active vitamin D might be beneficial to prevent infections. Therefore, we aimed to determine if the oral intake of vitamin D receptor activator (VDRA) is associated with a lower risk of infection-related hospitalization (IRH) among incident chronic hemodialysis patients. METHODS: We conducted a nested case-control study in a cohort of 4933 patients initiating chronic hemodialysis between 1 January 2001 and 31 December 2007 in Quebec, Canada, using administrative databases. We identified cases of hospital admission indicating an infection as main diagnosis on the hospital's discharge sheet. Up to 10 controls were randomly selected for each case. Association between oral VDRA use and risk of IRH was estimated using conditional logistic regression. RESULTS: We identified 1136 cases of IRH and 10396 controls during the study period. The intake of VDRA was not associated with the risk of being hospitalized due to an infection (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.95-1.20). Using the prior 6-month cumulative dose of VDRA, we also found that a cumulative VDRA dose of less than 45 mcg (OR, 1.05; 95%CI, 0.92-1.19) or greater than 45 mcg (OR, 1.15; 95%CI, 0.96-1.36) was not associated with the IRH risk. CONCLUSIONS: The oral intake of VDRA was not associated with the risk of IRH in incident hemodialysis patients.

Is health-related quality of life trajectory associated with dialysis modality choice in advanced chronic kidney disease?

BACKGROUND: Patients with advanced chronic kidney disease have lower health-related quality of life (HRQOL) than the general population. There is uncertainty regarding patterns of HRQOL changes before dialysis initiation. This study aimed to characterise HRQOL trajectory and assess its potential association with intended dialysis modality. METHODS: This prospective single-centre cohort study followed adults with an estimated glomerular filtration rate ≤15 mL/min/1.73 m2 for one year. Patients were allocated into one of two groups based on their intended treatment modality, 'home dialysis' (peritoneal dialysis or home haemodialysis (HD)) and 'other' (in-centre HD or conservative care). Follow-up was for up to 1 year or earlier if initiated on kidney replacement therapy or died. Kidney Disease Quality of Life - Short Form (KDQOL-SF) was completed every 6 months. Predictors of changes in KDQOL-SF components were modelled using mixed effect multivariable linear regressions. RESULTS: One hundred and nine patients were included. At baseline, crude physical composite summary (PCS) (45 ± 10 vs. 39 ± 8) was higher in patients choosing home dialysis (n = 41), while mental composite summary (MCS) was similar in both groups. After adjustment, patients choosing home dialysis had an increase in MCS (B = 8.4 per year, p = 0.007) compared to those selecting in-centre HD/conservative care. This translates into an annual increase in MSC by 3 points for the 'home dialysis' group, compared to an annual decline by 5.4 points in the 'other' group. There was no difference in PCS trajectory through time. CONCLUSIONS: Patients choosing home dialysis had improved MCS over time compared to those not selecting home dialysis. More work is needed to determine how differences in processes of care and/or unmeasured patient characteristics modulate this association.

Kidney Biopsy Findings Among Allogenic Hematopoietic Stem Cell Transplant Recipients With Kidney Injury: A Case Series.

Rationale and Objective: The incidence of kidney disease is high in patients after allogeneic hematopoietic cell transplantation (aHCT). Although rarely performed, kidney biopsy may be useful to make a precise diagnosis because several mechanisms and risk factors can be involved, and to adjust the treatment accordingly. This case series aimed to report the spectrum of biopsy findings from patients with kidney injury after aHCT. Study Design: Single-center retrospective case series. Setting and Participants: All individuals who underwent a native kidney biopsy, among all adult patients who received aHCT in a tertiary hospital in Montreal (Canada) from January 1, 2010, to December 31, 2020, were identified, and the clinical data were extracted from their medical records. Results: A total of 17 patients were included. Indications for biopsy included acute kidney injury (n=6), chronic kidney disease (n=5), nephrotic syndrome (n=4), and subnephrotic proteinuria (n=2). Pathologic findings from the kidney biopsy were heterogenous: 10 patients showed evidence of thrombotic microangiopathy (TMA), 5 of acute tubular injury, and 4 of membranous nephropathy. Cases of acute interstitial nephritis, BK virus nephropathy, immune complex nephropathy, focal and segmental glomerulosclerosis, minimal change disease, and karyomegalic-like interstitial nephritis were also described. Limitations: There was no systematic kidney biopsy performed for all patients with kidney injury after aHCT. Only a small proportion of patients with kidney damage underwent biopsy, making the results less generalizable. Conclusions: Kidney biopsy is useful in patients with kidney disease after aHCT to make a precise diagnosis and tailor therapy accordingly. This series is one of the few published studies describing pathologic findings of biopsies performed after aHCT in the context of acute kidney injury and chronic kidney disease. TMA was widely present on biopsy even when there was no clinical suspicion of such a diagnosis, suggesting that the current clinical criteria for a diagnosis of TMA are not sensitive enough for kidney-limited TMA.

Focused Jurisdictional Scan of Glomerulonephritis Medication Access in Canada: A Program Report.

Purpose of Program: Glomerulonephritis (GN) is a group of rare kidney diseases that is increasingly being managed with higher cost immunosuppressive (IS) agents in Canada. Ontario Health's Ontario Renal Network (ORN) oversees the management and delivery of GN services in the province. Stakeholder surveys previously conducted by ORN identified that both clinicians and patients do not perceive access to GN medications as comprehensive or timely. The program conducted a focused jurisdictional scan among 7 provinces to inform ORN initiatives to improve access to GN medications. Specifically, the program examined clinician experience with GN access, public drug coverage criteria, and timelines for public coverage for select IS agents (ie, tacrolimus, cyclosporine, mycophenolate mofetil [MMF], mycophenolate sodium, rituximab, and eculizumab) used to manage GN in adults who live in Canada. Methods: For the selected IS agents, a focused jurisdictional scan on medication access was conducted by ORN in 2018 and updated in July 2022. Information was obtained by searching the gray literature and/or credible online sources for public funding policies and eligibility criteria. Findings were supplemented by personal communications with provincial drug programs and consulting GN clinical experts from 7 provinces (ie, Alberta, British Columbia, Saskatchewan, Manitoba, Ontario, Nova Scotia, and Quebec). Key Findings: Clinicians from different provinces prescribe IS agents similarly for GN indications, despite distinctions in public drug funding policies. While patients can obtain public funding for many IS agents, for GN, most provinces rely on case-by-case review processes. In addition, provinces can vary in their funding criteria and which IS agents are listed on the public formulary. For IS agents that require prior authorization or case-by-case review, timelines vary by province with decisions taking a few days to weeks. British Columbia, with a GN-specific drug formulary, had the most integrated and efficient system for patients and prescribers. Limitations: This scan primarily relied on publicly available information for drug coverage criteria and clinician experience with access in their province. Since this scan was conducted, public drug coverage criteria and/or application processes may have changed. Implications: While patients in most provinces have similar needs and nephrologists similar prescribing patterns, gaps still exist for publicly funded GN medications. Interprovincial differences in the drugs funded, funding criteria, and application process may affect timely and equitable access to GN medications across Canada. Given the rarity of GN, a pan-Canadian funding approach may be warranted to improve the current state.

Objectif du programme: Les glomérulonéphrites (GN) sont un groupe de néphropathies rares qui sont de plus en plus fréquemment traitées avec les agents immunosuppresseurs (IS) coûteux au Canada. Le Réseau rénal de l'Ontario (ORN­Ontario Renal Network) de Santé Ontario supervise la gestion et la prestation des services liés à la GN dans cette province. Des enquêtes menées précédemment par l'ORN auprès des parties prenantes ont révélé que tant les cliniciens que les patients ne percevaient pas l'accès aux médicaments pour traiter la GN comme complet ou opportun. Le programme a mené une analyse ciblée des territoires de compétences dans sept provinces afin d'orienter les initiatives de l'ORN ayant pour objectif d'améliorer l'accès aux médicaments pour traiter la GN. Plus précisément, le programme a examiné l'expérience des cliniciens en matière d'accès aux médicaments pour traiter la GN, les critères d'admissibilité au régime public d'assurance-médicaments et les délais de couverture publique de certains agents IS (p. ex., tacrolimus, cyclosporine, mycophénolate mofétil [MMF], mycophénolate sodique, Rituximab, éculizumab) utilisés pour traiter la GN chez les adultes canadiens. Méthodologie: Une analyse ciblée des territoires de compétences quant à l'accès aux médicaments a été réalisée par l'ORN en 2018 et mise à jour en juillet 2022. L'information quant aux politiques de financement public et aux critères d'admissibilité a été obtenue en effectuant une recherche dans la littérature grise et des sources crédibles en ligne. Les résultats ont été complétés par des communications directes avec les régimes provinciaux d'assurance-médicaments et des experts cliniques de la GN de sept provinces (Alberta, Colombie-Britannique, Saskatchewan, Manitoba, Ontario, Nouvelle-Écosse et Québec). Principaux résultats: Les cliniciens des différentes provinces prescrivent des agents IS de façon similaire pour les indications liées à la GN, malgré des distinctions dans les politiques publiques de financement des médicaments. Bien que les patients bénéficient d'une couverture publique pour de nombreux agents IS, pour le traitement de la GN, la plupart des provinces s'appuient sur des processus d'examen au cas par cas. De plus, il peut exister des différences entre les provinces en ce qui concerne les critères de financement et les agents IS qui figurent sur leur formulaire public. Dans le cas des agents IS nécessitant une autorisation au préalable ou un examen au cas par cas, les délais varient d'une province à l'autre; les décisions pouvant prendre de quelques jours à quelques semaines. La Colombie-Britannique, qui dispose d'un formulaire de médicaments pour traiter spécifiquement la GN, présente le système le plus intégré et le plus efficace pour les patients et les prescripteurs. Limites: Cette analyse s'est principalement appuyée sur des renseignements accessibles au public en ce qui concerne les critères de couverture des médicaments et l'expérience des cliniciens en matière d'accès dans leur province. Les critères de couverture des médicaments publics et les processus de demande pourraient avoir changé depuis que cette analyse a été effectuée. Conclusion: Bien que les patients de la plupart des provinces aient des besoins similaires et que les néphrologues aient des habitudes de prescription similaires, des lacunes subsistent en ce qui concerne le financement public des médicaments pour traiter la GN. Les différences interprovinciales entre les médicaments financés, les critères de financement et le processus de demande peuvent avoir une incidence sur l'accès opportun et équitable aux médicaments pour traiter la GN à travers le Canada. Étant donné la rareté de cette maladie, une approche de financement pancanadienne pourrait être justifiée afin d'améliorer l'état actuel.

CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes.

Glomerular diseases (GDs) represent the third leading cause of end-stage kidney disease (ESKD) in the US Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research in DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient-reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD, and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 mL/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of GDs and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population.

Effects of chronic renal failure on brain drug transporters in rats.

Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30-50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.

Assisted Peritoneal Dialysis Implementation: A Pilot Program From a Large Dialysis Unit in Quebec.

Background: Kidney failure prevalence is increasing in older patients for whom dialysis initiation can be challenging. Assisted peritoneal dialysis (PD), where PD is performed with the help of a healthcare worker, can facilitate PD for frailer patients who may not be candidate otherwise. Objectives: This study aimed to assess the feasibility of implementing the first pilot assisted PD program in Quebec (Canada) and to evaluate the characteristics and outcomes of the PD cohort before and after assisted PD availability. Design: Observational retrospective cohort study. Setting and Population: All adult patients initiating PD between 2015 and 2020 in a single-center dialysis unit were included. Measurements: Incidence, characteristics, and outcomes of patients with PD were compared between (1) the "pre" (2015-2017) and the "post" assisted PD era (2018-2020) and (2) patients with assisted PD and independent PD in the more recent period. Methods: The primary outcome was peritonitis rate over the first year. Secondary outcomes included hospitalization, transfers to in-center hemodialysis (HD) and mortality. Results: Overall, 124 patients initiated PD with an annual incidence of 17 ± 3 patients during the "pre" and 24 ± 8 patients during the "post" assisted PD era (P = .18). First-year peritonitis rate was similar over the 2 eras. Years of PD initiation and use of assisted PD were not associated with risk peritonitis (over total follow-up) after adjustment. Adjusted hazard of transfer to HD or death was higher during the "post" era (hazard ratio [HR]: 2.77; 95% confidence interval [CI]: 1.42-5.58). Seventeen patients received assisted PD including 13 (18%) of the 72 patients initiated between 2018 and 2020. Patients with assisted PD were older than those with independent PD (72 [64-84] vs. 59 [47-67], P = .006) and received assistance for 0.8 (0.4-1.5) years. When comparing assisted and independent cohorts, there were no differences in crude rates of peritonitis or hospitalization. Limitations: Single-center study with small sample size. Conclusion: This study shows the feasibility of implementing an assisted PD program, with favorable overall outcomes including similar rates of peritonitis during the first year after PD initiation.

Contexte: La prévalence de l'insuffisance rénale augmente chez les patients plus âgés chez qui l'initiation de la dialyse peut être difficile. La dialyse péritonéale (DP) assistée, soit avec l'aide d'un professionnel de la santé, peut faciliter cette modalité chez les patients fragiles qui, autrement, ne seraient pas candidats. Objectifs de l'étude: Cette étude visait deux objectifs: 1) évaluer la faisabilité de la mise en œuvre du premier program pilote de DP assistée au Québec (Canada) et, 2) évaluer les caractéristiques et les résultats de la cohorte avant et après l'accès à la DP assistée. Conception: Étude de cohorte observationnelle rétrospective. Cadre et participants: Ont été inclus tous les patients adultes ayant initié une DP entre 2015 et 2020 dans l'unité de dialyse d'un center hospitalier. Mesures: L'incidence de la DP, ainsi que les caractéristiques et les résultats des patients sous DP ont été comparés entre [1] les patients « pré ¼ (2015-2017) et « post ¼ DP assistée (2018-2020) et entre [2] les patients sous DP assistée et sous DP autonome au cours de la période la plus récente. Méthodologie: Le principal critère d'évaluation était le taux de péritonite dans la première année. Les résultats secondaires comprenaient hospitalisation, les transferts à l'hémodialyse (HD) en centre et le taux de mortalité. Résultats: En tout, 124 patients ont amorcé un traitement de DP avec une incidence annuelle de 17 ± 3 patients au cours de la période « pré ¼ et de 24 ± 8 patients au cours de la période « post ¼ (p = 0,18). Le taux de péritonite dans la première année était semblable pour les deux périodes. Après ajustement, les années d'initiation et l'utilisation de la DP assistée n'étaient pas associées à un risque de péritonite accru (pour la période totale de suivi). Le risque ajusté de transfert à l'HD ou de décès était plus élevé durant la période « post ¼ (RR 2,77; IC 95 %: 1,42-5,58). Dix-sept patients ont reçu la DP assistée, dont 13 (18 %) des 72 patients initiés entre 2018 et 2020. Les patients sous DP assistée étaient plus âgés que ceux sous DP autonome (72 [64-84] ans c. 59 [47-67] ans; p = 0,006) et ont reçu de l'aide pendant 0,8 (0,4-1,5) an. Aucune différence n'a été observée dans les taux bruts de péritonite ou d'hospitalization lors de la comparaison des cohortes assistée et autonome. Limites: Étude menée dans un seul center, sur un faible échantillon de patients. Conclusion: Cette étude montre que la mise en œuvre d'un program de DP assistée est faisable et qu'elle donne de bons résultats, notamment des taux similaires de péritonite dans l'année suivant l'initiation de la DP.

SMOC2 promotes an epithelial-mesenchymal transition and a pro-metastatic phenotype in epithelial cells of renal cell carcinoma origin.

Renal Cell Carcinoma (RCC) is the most common form of all renal cancer cases, and well-known for its highly aggressive metastatic behavior. SMOC2 is a recently described non-structural component of the extracellular matrix (ECM) that is highly expressed during tissue remodeling processes with emerging roles in cancers, yet its role in RCC remains elusive. Using gene expression profiles from patient samples, we identified SMOC2 as being significantly expressed in RCC tissue compared to normal renal tissue, which correlated with shorter RCC patient survival. Specifically, de novo protein synthesis of SMOC2 was shown to be much higher in the tubular epithelial cells of patients with biopsy-proven RCC. More importantly, we provide evidence of SMOC2 triggering kidney epithelial cells into an epithelial-to-mesenchymal transition (EMT), a phenotype known to promote metastasis. We found that SMOC2 induced mesenchymal-like morphology and activities in both RCC and non-RCC kidney epithelial cell lines. Mechanistically, treatment of RCC cell lines ACHN and 786-O with SMOC2 (recombinant and enforced expression) caused a significant increase in EMT-markers, -matrix production, -proliferation, and -migration, which were inhibited by targeting SMOC2 by siRNA. We further characterized SMOC2 activation of EMT to occur through the integrin ß3, FAK and paxillin pathway. The proliferation and metastatic potential of SMOC2 overexpressing ACHN and 786-O cell lines were validated in vivo by their significantly higher tumor growth in kidneys and systemic dissemination into other organs when compared to their respective controls. In principle, understanding the impact that SMOC2 has on EMT may lead to more evidence-based treatments and biomarkers for RCC metastasis.

Risk of hospitalization, technique failure, and death with increased training duration in 3-days-a-week home hemodialysis.

INTRODUCTION: Quality training is a core component of successful home hemodialysis (HHD) and training duration varies significantly between dialysis centers as well as at the patient level. This study aimed to assess the adverse outcomes associated with HHD training duration. METHODS: All HHD patients successfully trained in a single dialysis center between January 2005 and July 2017 were included. A multivariable multiple-events (Andersen-Gill) survival model was built to evaluate the association between training time and main adverse events, including hospitalizations, technique failure, and death on HHD. Potential confounding factors were defined a priori (age, diabetes, coronary artery disease, and year of training start). Adjusted risk of vascular interventions (arteriovenous fistula angioplasties and central venous catheter replacements) was assessed as the secondary outcome in a negative binomial regression. FINDINGS: Forty-eight patients were included in the study. Median HHD training duration was 86 (67-108) days, using a thrice weekly training schedule. Over a follow-up median time of 2.0 (0.7-3.3) years, three patients died while on HHD, 10 had a definitive transfer to HD, and 18 experienced a least 1 hospitalization (38 hospitalizations in total). Training duration was associated with a higher risk of hospitalization, technique failure, and death in unadjusted (hazard ratio [HR] 1.16 per month, 95% confidence interval [CI] 1.08-1.24) and adjusted multiple events model (HR 1.21, 95% CI 1.04-1.43). Risk of vascular access intervention was also significantly higher with increased training time (adjusted incidence rate ratio 1.31, 95% CI 1.03-1.64, per training month). DISCUSSION: In this single-center observational study, HHD training duration was associated with a higher risk of adverse events including, death, technique failure, hospitalizations, and vascular access intervention. Enhanced clinical follow-up and home support should be offered to these more vulnerable patients to mitigate this heightened risk.

Qualitative and Quantitative Dosage of the Anti M-Type Phospholipase A2 Receptor Autoantibody: One-Year Experience in Quebec's Reference Center.

BACKGROUND: Quantification of the M-type phospholipase A2 receptor antibodies (anti-PLA2R) is now an essential tool for diagnosis and management of primary membranous nephropathy (MN). Since October 2018, Hôpital Maisonneuve-Rosemont (HMR) has been designated as Quebec's reference center for serum anti-PLA2R antibody testing by the Institut National d'Excellence en Santé et Services Sociaux (INESSS), the regulatory body on drugs and tests usage in Quebec. OBJECTIVES: To describe the 2-step method of serum qualitative and quantitative anti-PLA2R antibody testing during its first year of use in Quebec and analyze its diagnostic value in the province's population. DESIGN: Retrospective cohort study. SETTING: Single-center academic teaching hospital in Quebec, Canada. PATIENTS: All patients who had a serum anti-PLA2R antibody test analyzed at HMR from October 1, 2018, to October 1, 2019, were included in the study. MEASUREMENTS: Serum anti-PLA2R antibodies were screened by indirect immunofluorescence tests. If results were positive or undetermined, it was followed by a quantitative enzyme-linked immunosorbent assay (ELISA) test. Both tests were based on a commercial kit developed by the same company. METHODS: We calculated sensitivity, specificity, predictive value, and likelihood ratio for both tests, using kidney biopsy findings performed at HMR as the gold standard. RESULTS: In Quebec, a total of 1690 tests were performed among 1025 patients during the study year. A small proportion of these patients (8%) were followed at HMR. Patients tested at HMR and in the rest of Quebec had similar characteristics. Test validity was only characterized for patients tested at HMR. Sensitivity and specificity were, respectively, 58% and 100% for the qualitative test, and 71% and 100% for the quantitative test. The combined net sensitivity was 42% and the net specificity 100%. The net positive and negative predictive value were 100% and 84% respectively, whereas the net negative likelihood ratio was 0.58. LIMITATIONS: As the detailed analysis was only possible in the small proportion of patients clinically followed at HMR, there is a possible selection bias. Another potential selection bias was the focus on patients who were selected to have a kidney biopsy, probably because of more severe disease, higher probability of glomerulonephritis, or lesser number of comorbidities. Given the retrospective nature of this study, there was no systematic kidney biopsy or serum PLA2R antibody testing performed. Finally, we were unable to provide detailed information on the timing between immunosuppressive therapy and anti-PLA2R results. CONCLUSIONS: Serum anti-PLA2R antibody testing was widely used in Quebec during its first year of availability. A 2-step approach, using a qualitative test first, followed by a quantitative test if the results are positive or undetermined, appears efficient to avoid useless quantitative testing in negative patients and to better characterize undetermined results on immunofluorescence. TRIAL REGISTRATION: Due to the retrospective nature of this study, no trial registration was performed.

CONTEXTE: La quantification des anticorps des récepteurs de la phospholipase A2 de type M (anti-PLA2R) est désormais un outil essentiel pour le diagnostic et la prise en charge de la glomérulonéphrite extra-membraneuse primaire (GEMp). Depuis octobre 2018, l'Hôpital Maisonneuve-Rosemont (HMR) a été désigné par l'Institut National d'Excellence en Santé et Services Sociaux (INESSS)­l'organisme règlementant l'usage des médicaments et des tests au Québec­comme le centre hospitalier de référence dans la province pour le dépistage des anticorps sériques anti-PLA2R. OBJECTIFS: Décrire la méthode en deux étapes du test qualitatif et quantitatif des anticorps anti-PLA2R sériques au cours de sa première année d'utilisation au Québec et évaluer sa valeur diagnostique dans la population de la province. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Un centre hospitalier universitaire du Québec (Canada). SUJETS: Ont été inclus tous les patients dont le test des anticorps sériques anti-PLA2R a été analysé à HMR entre le 1er octobre 2018 et le 1er octobre 2019. MESURES: Les anticorps sériques anti-PLA2R ont été détectés par immunofluorescence indirecte. Les résultats positifs ou indéterminés ont été suivis d'un test ELISA quantitatif. Les deux tests ont été réalisés à l'aide de trousses commerciales développées par la même entreprise. MÉTHODOLOGIE: Nous avons analysé la sensibilité, la spécificité, la valeur prédictive et le rapport de vraisemblance des deux tests avec comme référence des résultats de biopsie rénale obtenus à HMR. RÉSULTATS: Au Québec, au cours de l'année de l'étude, 1 690 tests ont été effectués sur 1 025 patients; une faible proportion de ces patients (8 %) étaient suivis à HMR. Les patients, qu'ils aient été testés à HMR et ailleurs au Québec, présentaient des caractéristiques semblables. La validité du test n'a été caractérisée que pour les patients testés à HMR. La sensibilité et la spécificité s'établissaient respectivement à 58 % et à 100 % pour le test qualitatif, et à 71 % et 100 % pour le test quantitatif. La sensibilité nette combinée était de 42 % et la spécificité nette, de 100 %. Les valeurs prédictives nettes, positive et négative, étaient respectivement de 100 % et de 84 %, alors que le ratio net de probabilité négative était de 0,58. LIMITES: L'étude présente un possible biais de sélection puisque l'analyse détaillée n'était possible que pour la faible proportion de patients suivis à HMR. L'accent mis sur les patients sélectionnés pour une biopsie rénale, probablement en raison d'une maladie plus grave, d'une probabilité plus élevée de glomérulonéphrite ou d'un moins grand nombre de comorbidités, constitue un autre possible biais de sélection. Aucune biopsie rénale ou test d'anticorps de PLA2R sérique systématique n'a été effectué puisque l'étude est rétrospective. Enfin, il n'a pas été possible de fournir des informations détaillées sur le temps écoulé entre le traitement immunosuppresseur et les résultats du test d'anticorps anti-PLA2R. CONCLUSION: Le test d'anticorps sériques anti-PLA2R a été largement utilisé au Québec au cours de sa première année de disponibilité. Une approche en deux étapes, constituée d'un test qualitatif suivi d'un test quantitatif si le résultat est positif ou indéterminé, semble efficace pour éviter de procéder inutilement à des tests quantitatifs chez les patients négatifs et pour caractériser plus précisément les résultats indéterminés par immunofluorescence. ENREGISTREMENT DE L'ESSAI: L'essai n'a pas été enregistré puisqu'il s'agit d'une étude rétrospective.

Arteriovenous Fistula Creation and Estimated Glomerular Filtration Rate Decline in Advanced CKD: A Matched Cohort Study.

Background: Kidney failure is associated with a high burden of morbidity and mortality. Previous studies have raised the possibility that arteriovenous fistula (AVF) creation may attenuate eGFR decline. This study aimed to compare eGFR decline in predialysis patients with an AVF, matched to patients oriented toward peritoneal dialysis (PD). Methods: Predialysis patients with an AVF and those oriented toward PD were retrospectively matched using a propensity score. Time zero was defined as the "AVF creation date" for the AVF group and the "date when eGFR was closest to the matched patient's eGFR at AVF creation" for the PD group. Crude and predicted eGFR decline in AVF and PD groups were compared before and after time zero using mixed-effect linear regressions. Results: In total, 61 pairs were matched. Crude annual eGFR decline before AVF creation/time zero was -4.1 ml/min per m2 per year in the AVF group versus -5.3 ml/min per m2 per year in the PD group (P=0.75) and after time zero, -2.5 ml/min per m2 per year in the AVF group versus -4.5 ml/min per m2 per year in the PD group (P=0.02). The predicted annual decline decreased from -5.1 ml/min per m2 per year in the AVF group before AVF creation to -2.8 ml/min per m2 per year after (P<0.01), whereas there was no difference in the PD group (-5.5 versus -5.1 ml/min per m2 per year respectively, P=0.41). Conclusions: In this matched study, AVF creation was associated with a deceleration of kidney function decline compared with a control PD-oriented group. Prospective studies are needed to assess the potential mechanisms between vascular access creation and eGFR slope attenuation.