Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group.

The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.

Diagnosis and management of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.

AI's Threat to the Medical Profession.

This Viewpoint discusses the potential drawbacks of the use of artificial intelligence (AI) in medicine, for example, the loss of certain skills due to the reliance on AI, and how physicians should consider how to take advantage of the potential benefits of AI without losing control over their profession.

Ultrastructural Examination of Glomerular Fibrillary Deposits in Diabetic Nephropathy.

Glomerular fibrillary deposits have occasionally been reported in diabetic nephropathy, but no large-scale, ultrastructural evaluation of these deposits has been reported so far. Here, we report our study of glomerular non-Congophilic, DnaJ homolog subfamily B member 9 negative fibrillary deposits in diabetic nephropathy as characterized by transmission electron microscopy. Clinical data from 55 patients with biopsy-confirmed diabetic nephropathy and 18 healthy living donors were reviewed, and their biopsies were evaluated by light microscopy, immunofluorescence, and electron microscopy. Small fibrillary structures with a diameter of 10 ± 1 nm were present in all cases with diabetic nephropathy, regardless of the histologic class. In addition, glomerular fibrillary structures with a diameter of 23 ± 5 nm or 30 ± 7 nm were present in 35 cases. Interestingly, especially the small- and medium-sized fibrils, usually without apparent organization, were comparable with fibrils in fibrillary glomerulopathy. We conclude that glomerular fibrillary deposits occur far more commonly in renal biopsies of patients with diabetic nephropathy than generally considered. This is an important finding because their similarity to fibrils in fibrillary glomerulonephritis may complicate the histologic diagnostic process, especially in cases of overlapping clinical manifestations. Therefore, when encountering fibrillary deposits on electron microscopy, it is important to consider diabetic nephropathy as an alternative diagnosis.

Glomerular Diseases Across Lifespan: Key Differences in Diagnostic and Therapeutic Approaches.

Glomerular diseases are common causes of chronic kidney disease in childhood, adolescence, and adulthood. The epidemiology of glomerular diseases differs between different age groups, with minimal change disease being the leading cause of nephrotic syndrome in childhood, while membranous nephropathy and focal segmental glomerulosclerosis are more common in adulthood. IgA vasculitis is also more common in childhood. Moreover, there is a difference in disease severity with more children presenting with a relapsing form of nephrotic syndrome and a more acute presentation of antineutrophil cytoplasmic antibody-associated vasculitis and concomitant glomerulonephritis, as highlighted by the higher percentage of cellular crescents on kidney biopsy specimens in comparison with older patients. There is also a female preponderance in antineutrophil cytoplasmic antibody-associated vasculitis and more children present with tracheobroncholaryngeal disease. This article aims to summarize differences in the presentation of different glomerular diseases that are encountered commonly by pediatric and adult nephrologists and potential differences in the management.

Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.

The Sound of Interconnectivity; The European Vasculitis Society 2022 Report.

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

Increased microchimerism in peripheral blood of women with systemic lupus erythematosus: relation with pregnancy.

OBJECTIVES: We aimed to determine the presence, amount and origin of microchimerism in peripheral blood of pregnant and non-pregnant parous women with systemic lupus erythematosus (SLE) as compared to control subjects. METHODS: We performed a comparative study in which peripheral blood was drawn from eleven female non-pregnant SLE-patients and 22 control subjects, and from six pregnant SLE-patients and eleven control subjects during gestation and up to six months postpartum. Quantitative PCR for insertion-deletion polymorphisms and null alleles was used to detect microchimerism in peripheral blood mononuclear cells and granulocytes. RESULTS: Microchimerism was detected more often in non-pregnant SLE-patients than control subjects (54.4% vs. 13.6%, respectively; p=0.03). When present, the median total number of foetal chimeric cells was 5 gEq/106 in patients and 2.5gEq/106 in control subjects (p=0.048). Microchimerism was mostly foetal in origin; maternal microchimerism was detected in one patient and one control subject. In control subjects, microchimerism was always derived from only one source whereas in 50% of patients it originated from multiple sources. The pregnant patients had a significantly higher median number of foetal chimeric cells in the granulocyte fraction just after delivery than control subjects (7.5 gEq/106 vs. 0 gEq/106, respectively; p=0.02). CONCLUSIONS: Just after delivery, SLE-patients had more microchimerism than control subjects. Three months post-partum, microchimerism was no longer detectable, only to reappear many years after the last pregnancy, more often and at higher levels in SLE-patients than in control subjects. This suggests that these chimeric cells may originate from non-circulating foetal chimeric stem cells.

Use of Glomerular CD68+ Cells as a Surrogate Marker for Endocapillary Hypercellularity in Lupus Nephritis.

Introduction: Lupus nephritis (LN) class III or IV is strongly related to patient mortality and morbidity. The interobserver agreement of endocapillary hypercellularity by routine light microscopy, one of the most important lesions determining whether class III or IV is present, is moderate. In IgA nephropathy (IgAN), the presence of glomerular CD68+ cells was found to be a good surrogate marker for endocapillary hypercellularity. We investigated whether the presence of glomerular CD68+ cells could serve as a surrogate marker for endocapillary hypercellularity as well in LN. Methods: A total of 92 LN biopsies were scored for the number of glomerular CD68+ cells using CD68 staining, including endocapillary hypercellularity and the activity index (AI). A new AI was calculated in which CD68+ cells replaced endocapillary hypercellularity. Clinical parameters were obtained from time of biopsy, 1 year after, and 2 years after. Results: The number of glomerular CD68+ cells significantly correlated with endocapillary hypercellularity. A cutoff value of 7 for the maximum number of CD68+ cells within 1 glomerulus in a biopsy yielded a sensitivity of 88% and a specificity of 67% for the presence of endocapillary hypercellularity. Both endocapillary hypercellularity and CD68+ cells correlated with renal function during follow-up. The current and the new AI correlated equally well with the clinical outcome. Conclusion: In LN, CD68+ cells can be used as a surrogate marker for endocapillary hypercellularity.

Impact of Consensus Definitions on Identification of Glomerular Lesions by Light and Electron Microscopy.

INTRODUCTION: In 2020, a working group of 13 renal pathologists published consensus definitions for 47 individual glomerular lesions found on light microscopy (LM) and 47 glomerular lesions and 9 normal structures found on electron microscopy (EM). METHODS: To test the impact of these definitions on identification of these lesions and structures, 2 surveys were circulated to all members of the Renal Pathology Society (RPS), each having 32 images (19 LM, 13 EM) and accompanying questions with 5 multiple-choice answers, one being the consensus choice of the working group. The first survey (survey 1 [S1]), answered by 297 RPS members, was sent in September 2020, before publication of the consensus definitions. The second (survey 2 [S2]), with images of the same lesions and structures (but not the same images) and the same questions and multiple choices in different order, was sent in April 2020, 5 months after the publication of the definitions. RESULTS: S2 was taken by 181 RPS members; 64% also took S1 and 61% reported having read the definitions paper (def. paper). Mean agreement with the consensus answers increased modestly between the 2 surveys (65.2% vs. 72.0%, P = 0.097); the increase was greater and significant when only respondents to S2 who read the def. paper were considered (65.2% vs. 74.8%, P = 0.026). Furthermore, in S2 agreement with consensus answers was greater among respondents who read this paper versus those who did not (66.9% vs. 74.8%, P < 0.0001). CONCLUSIONS: Publication of the consensus definitions modestly improved interobserver agreement in identification of glomerular lesions.

The COVID-19 pandemic and ANCA-associated vasculitis - reports from the EUVAS meeting and EUVAS education forum.

The Coronavirus Disease 2019 (COVID-19) pandemic influenced the management of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A paucity of data exists on outcome of patients with vasculitis following COVID-19, but mortality is higher than in the general population and comparable to patients undergoing haemodialysis or kidney transplant recipients (reported mortality rates of 20-25%). Delays in diagnosis have been reported, which are associated with sequelae such as dialysis-dependency. Management of ANCA-associated vasculitis has not changed with the aim to suppress disease activity and reduce burden of disease. The use of rituximab, an important and widely used agent, is associated with a more severe hospital course of COVID-19 and absence of antibodies following severe acute respiratory syndrome (SARS)-CoV-2 infections, which prone patients to re-infection. Reports on vaccine antibody response are scarce at the moment, but preliminary findings point towards an impaired immune response, especially when patients receive rituximab as part of their treatment. Seropositivity was reported in less than 20% of patients when rituximab was administered within the prior six months, and the antibody response correlated with CD19+ B-cell repopulation. A delay in maintenance doses, if disease activity allows, has been suggested using a CD19+ B-cell guided strategy. Other immunosuppressive measures, which are used in ANCA-associated vasculitis, also impair humoral and cellular vaccine responses. Regular measurements of vaccine response or a healthcare-policy time-based strategy are indicated to provide additional doses ("booster") of COVID-19 vaccines. This review summarizes a recent educational forum and a recent virtual meeting of the European Vasculitis Society (EUVAS) focusing on COVID-19.

Reappraisal of Renal Arteritis in ANCA-associated Vasculitis: Clinical Characteristics, Pathology, and Outcome.

BACKGROUND: Renal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail. METHODS: In a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value. RESULTS: We included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival (P=0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status (P=0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype. CONCLUSIONS: Our findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed.

Machine learning in medicine: Medical droids, tricorders, and a computer named Hal 9000.

The usage of artificial intelligence to evaluate histological images was recently explored in many different areas of pathology. Studies focusing on nephropathology demonstrated that algorithms could be trained to identify various structures of the kidney, like glomeruli and interstitium, as well as performing a classification task just as good as highly experienced pathologists. It is conceivable that further development of digitalized pathology in combination with all opportunities that artificial intelligence and machine learning have to offer, will rapidly change the work of the clinical pathologist in a substantial way.

Reduced Glomerular Endothelial Thrombomodulin Is Associated with Glomerular Macrophage Infiltration in Diabetic Nephropathy.

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin.

Consensus definitions for glomerular lesions by light and electron microscopy: recommendations from a working group of the Renal Pathology Society.

Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.

Developments in the Histopathological Classification of ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.