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Background Up to 70% of patients with ANCA-associated vasculitis (AAV) develop GN, with 26% progressing to ESKD. Diagnostic-grade and noninvasive tools to detect active renal inflammation are needed. Urinary soluble CD163 (usCD163) is a promising biomarker of active renal vasculitis, but a diagnostic-grade assay, assessment of its utility in prospective diagnosis of renal vasculitis flares, and evaluation of its utility in proteinuric states are needed. Methods We assessed a diagnostic-grade usCD163 assay in (1) a real-world cohort of 405 patients with AAV and 121 healthy and 488 non-AAV disease controls; (2) a prospective multicenter study of 84 patients with potential renal vasculitis flare; (3) a longitudinal multicenter cohort of 65 patients with podocytopathy; and (4) a cohort of 29 patients with AAV (with or without proteinuria) and ten controls. Results We established a diagnostic reference range, with a cutoff of 250 ng/mmol for active renal vasculitis (area under the curve [AUC], 0.978). Using this cutoff, usCD163 was elevated in renal vasculitis flare (AUC, 0.95) but remained low in flare mimics, such as nonvasculitic AKI. usCD163's specificity declined in patients with AAV who had nephrotic-range proteinuria and in those with primary podocytopathy, with 62% of patients with nephrotic syndrome displaying a "positive" usCD163. In patients with AAV and significant proteinuria, usCD163 normalization to total urine protein rather than creatinine provided the greatest clinical utility for diagnosing active renal vasculitis. Conclusions usCD163 is elevated in renal vasculitis flare and remains low in flare mimics. Nonspecific protein leakage in nephrotic syndrome elevates usCD163 in the absence of glomerular macrophage infiltration, resulting in false-positive results; this can be corrected with urine protein normalization.

Kidney homeostasis is highly dependent upon the correct functioning of myeloid cells. These cells form a distributed surveillance network throughout the kidney, where they play an integral role in the response to organ threat. Dysregulation of resident proinflammatory and profibrotic macrophages leads to kidney structural damage and scarring after kidney injury. Fibrosis throughout the kidney parenchyma contributes to the progressive functional decline observed in CKD, independent of the etiology. Circulating myeloid cells bearing intrinsic defects also affect the kidney substructures, such as neutrophils activated by autoantibodies that cause GN in ANCA-associated vasculitis. The kidney can also be affected by disorders of myelopoiesis, including myeloid leukemias (acute and chronic myeloid leukemias) and myelodysplastic syndromes. Clonal hematopoiesis of indeterminate potential is a common, newly recognized premalignant clinical entity characterized by clonal expansion of hyperinflammatory myeloid lineage cells that may have significant kidney sequelae. A number of existing therapies in CKD target myeloid cells and inflammation, including glucocorticoid receptor agonists and mineralocorticoid receptor antagonists. The therapeutic indications for these and other myeloid cell-targeted treatments is poised to expand as our understanding of the myeloid-kidney interface evolves.

Background. Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV.Methods. sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4(+) T and CD4(+) T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serumsoluble CD25 (ssCD25) add utility to usCD163.Results. usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163positive patients. usCD25 correlated positively with urinary CD4(+) T and CD4(+) TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4(+) T and CD4+ TEMcells.Conclusion. Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.

Objective To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. Methods Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. Results Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15–60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR Conclusion Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

Purpose of program: This paper will provide guidance on how to best manage patients with end-stage kidney disease who will be or are being treated with home dialysis during the COVID-19 pandemic. Sources of information: Program-specific documents, pre-existing, and related to COVID-19; documents from national and international kidney agencies; national and international webinars, including webinars that we hosted for input and feedback; with additional information from formal and informal review of published academic literature. Methods: Members of the Canadian Society of Nephrology (CSN) Board of Directors solicited a team of clinicians and administrators with expertise in home dialysis. Specific COVID-19-related themes in home dialysis were determined by the Canadian senior renal leaders community of practice, a group compromising medical and administrative leaders of provincial and health authority renal programs. We then developed consensus-based recommendations virtually by the CSN work-group with input from ethicists with nephrology training. The recommendations were further reviewed by community nephrologists and over a CSN-sponsored webinar, attended by 225 kidney health care professionals, for further peer input. The final consensus recommendations also incorporated review by the editors at the Canadian Journal of Kidney Health and Disease (CJKHD). Key findings: We identified 7 broad areas of home dialysis practice management that may be affected by the COVID-19 pandemic: (1) peritoneal dialysis catheter placement, (2) home dialysis training, (3) home dialysis management, (4) personal protective equipment, (5) product delivery, (6) minimizing direct health care provider and patient contact, and (7) assisted peritoneal dialysis in the community. We make specific suggestions and recommendations for each of these areas. Limitations: This suggestions and recommendations in this paper are expert opinion, and subject to the biases associated with this level of evidence. To expedite the publication of this work, a parallel review process was created that may not be as robust as standard arms’ length peer-review processes. Implications: These recommendations are intended to provide the best care possible during a time of altered priorities and reduced resources.

Immunoglobulin A vasculitis (IgAV) is a small vessel vasculitis with skin, joint, gastrointestinal and renal manifestations. Our understanding of the natural history of this disease is limited due to the overall low incidence of IgAV in adults and a lack of consensus regarding diagnostic criteria. In this review, we describe IgAV in the adult population, focusing on diagnostic and classification systems, and treatments strategies. Recent data from larger longitudinal adult cohorts demonstrate that IgAV is associated with significant morbidity and mortality. Treatment regimen remains controversial but emerging retrospective observational data support potential benefit of immunosuppression. As illustrated in trials of IgA nephropathy, immunosuppression carries significant risks of toxicity. Treatment regimen and selection of patients who will benefit from treatment remains challenging. Prospective treatment trials are needed to elucidate both the patient populations that will derive benefit and what treatment is most efficacious.

Summary Innate lymphocyte populations, such as innate lymphoid cells (ILCs), γδ T cells, invariant natural killer T (iNK T) cells and mucosal-associated invariant T (MAIT) cells are emerging as important effectors of innate immunity and are involved in various inflammatory and autoimmune diseases. The aim of this study was to assess the frequencies and absolute numbers of innate lymphocytes as well as conventional lymphocytes and monocytes in peripheral blood from a cohort of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV) patients. Thirty-eight AAV patients and 24 healthy and disease controls were included in the study. Patients with AAV were sampled both with and without immunosuppressive treatment, and in the setting of both active disease and remission. The frequencies of MAIT and ILC2 cells were significantly lower in patients with AAV and in the disease control group compared to healthy controls. These reductions in the AAV patients remained during remission. B cell count and frequencies were significantly lower in AAV in remission compared to patients with active disease and disease controls. Despite the strong T helper type 2 (Th) preponderance of eosinophilic granulomatosis with polyangiitis, we did not observe increased ILC2 frequency in this cohort of patients. The frequencies of other cell types were similar in all groups studied. Reductions in circulating ILC2 and MAIT cells reported previously in patients with AAV are not specific for AAV, but are more likely to be due to non-specific manifestations of renal impairment and chronic illness. Reduction in B cell numbers in AAV patients experiencing remission is probably therapy-related.

Immunoglobulin A nephropathy (IgAN) is the world's commonest primary glomerular disease with variable clinical presentation and progression rates that are dependent on clinical-pathologic phenotype and duration of follow-up. Overall 4-40% of patients progress to end-stage kidney disease (ESKD) by 10 years. Treatment decisions remain a challenge due to these variations. The ultimate goal of management is to prevent progression to ESKD and of vital importance is the potential reversible early detection of active glomerular inflammation prior to scarring. IgAN is globally, is the most common biopsy proven glomerulonephritis and a leading cause of ESKD. The Oxford pathological classification was devised by a collaborative pathology and nephrology network to provide an evidence-based scoring system with reproducible independent pathology features of predictive value. Clinical variables that alter prognosis include male sex, increasing age, increased body weight, smoking, Pacific Asian ethnicity, hypertension, proteinuria, and complement deficiency. Excellent conservative therapy is the cornerstone of therapy with tight blood control, renin-angiotensin system inhibition, and statin therapy. The role of immunosuppressive therapy including corticosteroids in IgAN remains open with ongoing clinical trials of low dose oral corticosteroids and enteric coated budesonide. Complement activation contributes to the pathogenic process of IgAN with evidence from genetic, serological, histological and in-vitro studies. This knowledge has translated to clinical trials of investigational agents directly targeting the alternative pathway.

C3 glomerulopathy, a newly designated entity, is characterized by glomerular disease associated with dysregulation of the alternative complement pathway and is a rare cause of end-stage kidney disease. Overall disease characteristics that include clinical presentation, laboratory assessment, histopathology and genetic background have only been unravelled in recent years and have led to the development of anti-complement therapies targeting different levels of the alternative pathway. We describe the long-term outcomes following kidney transplantation in an Irish family with familial C3 glomerulopathy due to a hybrid CFHR3-1 gene.

OBJECTIVES: Glucocorticoids (GCs) are a mainstay of treatment for patients with ANCA-associated vasculitis (AAV) but are associated with significant adverse effects. Effective remission induction in severe AAV using extremely limited GC exposure has not been attempted. We tested an early rapid GC withdrawal induction regimen for patients with severe AAV. METHODS: Patients with active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune glomerulonephritis were included. Induction treatment consisted of two doses of rituximab, 3 months of low-dose CYC and a short course of oral GC (for between 1 and 2 weeks). Clinical, biochemical and immunological outcomes as well as adverse events were recorded. RESULTS: A total of 49 patients were included, with at least 12 months of follow-up in 46. All patients achieved remission, with decreases observed in creatinine, proteinuria, CRP, ANCA level and BVAS. Three patients requiring dialysis at presentation became dialysis independent. Two patients required the introduction of maintenance GC for treatment of vasculitis. Overall outcomes were comparable to those of two matched cohorts (n = 172) from previous European Vasculitis Society (EUVAS) trials, but with lower total exposure to CYC and GCs (P < 0.001) and reduced rates of severe infections (P = 0.02) compared with the RITUXVAS (rituximab versus cyclophosphamide in AAV) trial. We found no new cases of diabetes in the first year compared with historic rates of 8.2% from the EUVAS trials (P = 0.04). CONCLUSION: Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.

Background Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). Methods Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. Results Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8–1.2] in remission and 1.4 mg/dL (IQR 1.0–1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79–337), 44 (17–104) and 38 (7–76), respectively (P Conclusion A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.

Purpose of program: To provide guidance on the management of patients with advanced chronic kidney disease (CKD) not requiring kidney replacement therapy during the COVID-19 pandemic. Sources of information: Program-specific documents, pre-existing, and related to COVID-19; documents from national and international kidney agencies; national and international webinars, including webinars that we hosted for input and feedback; with additional information from formal and informal review of published academic literature. Methods: Challenges in the care of patients with advanced CKD during the COVID-19 pandemic were highlighted within the Canadian Senior Renal Leaders Forum discussion group. The Canadian Society of Nephrology (CSN) developed the COVID-19 rapid response team (RRT) to address these challenges. They identified a lead with expertise in advanced CKD who identified further nephrologists and administrators to form the workgroup. A nation-wide survey of advanced CKD clinics was conducted. The initial guidance document was drafted and members of the workgroup reviewed and discussed all suggestions in detail via email and a virtual meeting. Disagreements were resolved by consensus. The document was reviewed by the CSN COVID-19 RRT, an ethicist and an infection control expert. The suggestions were presented at a CSN-sponsored interactive webinar, attended by 150 kidney health care professionals, for further peer input. The document was also sent for further feedback to experts who had participated in the initial survey. Final revisions were made based on feedback received until April 28, 2020. Canadian Journal of Kidney Health and Disease (CJKHD) editors reviewed the parallel process peer review and edited the manuscript for clarity. Key findings: We identified 11 broad areas of advanced CKD care management that may be affected by the COVID-19 pandemic: (1) clinic visit scheduling, (2) clinic visit type, (3) provision of multidisciplinary care, (4) bloodwork, (5) patient education/support, (6) home-based monitoring essentials, (7) new referrals to multidisciplinary care clinic, (8) kidney replacement therapy, (9) medications, (10) personal protective equipment, and (11) COVID-19 risk in CKD. We make specific suggestions for each of these areas. Limitations: The suggestions in this paper are expert opinion, and subject to the biases associated with this level of evidence. To expedite the publication of this work, a parallel review process was created that may not be as robust as standard arms’ length peer-review processes. Implications: These suggestions are intended to provide guidance for advanced CKD directors, clinicians, and administrators on how to provide the best care possible during a time of altered priorities and reduced resources.

A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SW strongly expressed CD163 protein. In 479 individuals, including patients with SW, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SW, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SW.

Background: As renal biopsies are not routinely repeated to monitor treatment response in anti-neutrophil cytoplasm antibody (ANCA)-associated glomerulonephritis, serum creatinine (SC) and proteinuria assessed by urine protein:creatinine ratio (UPCR) measurements are relied upon to provide a non-invasive estimate of disease activity within the kidney. However, sparse information exists about the time to achieve maximal improvement in these parameters, which has important implications for treatment decisions and disease-scoring systems. Methods: We analysed patients with ANCA-associated glomerulonephritis and renal impairment from cohorts in the United Kingdom and Ireland, with the primary objective of determining actuarial time to nadir SC and UPCR. Time to disappearance of haematuria was analysed as a secondary objective. Results: Ninety-four patients fulfilled our selection criteria, with 94 (100%) and 66 (70%) having reached their nadir SC and UPCR respectively during the follow-up period. Nadir SC was achieved after a median of 88 days (95% CI 74-102), UPCR at 346 days (95% CI 205-487). Those of Indo-Asian ethnic origin reached their nadir SC faster (34 days) than other ethnicities (p < 0.01). There were no significant differences in time to nadir SC or UPCR on the basis of gender, clinical diagnosis, ANCA positivity or renal biopsy findings. Conclusion: In this retrospective study, nadir creatinine and proteinuria occur later than other signs of clinical remission, suggesting that ongoing renal recovery continues for a significant time after diagnosis. It may benefit disease-scoring systems to take into account SC levels beyond the initial assessment.