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The article discusses the use of exome sequencing (ES) as a potential alternative to kidney biopsies in diagnosing undetermined kidney diseases (UKD). While kidney biopsies are invasive and carry risks, recent studies have shown that genetic variants may explain a significant portion of UKD cases. ES involves sequencing the coding regions of all protein-coding genes in the human genome and has been successful in diagnosing certain genetic kidney disorders. However, the study emphasizes that ES does not provide a definitive diagnosis in all cases, and kidney biopsies should still be considered in certain situations. [Extracted from the article]

Years of standing still have ended, and the field of nephrology has seen a plethora of clinical trials, changing the therapeutic landscape of chronic kidney disease (CKD) and immune-mediated kidney disease management. POP inhibition might be carried forward to develop therapies that aim to reduce the damage to kidneys caused by ischemia and reperfusion injury, such as after kidney transplantation. Overall, the provided results will further help to increase our understanding of kidney disease in more detail and will eventually lead to individualized treatment approaches for the plethora of kidney diseases. Kidney biopsies remain valuable to a final diagnosis and have achieved enormous value in predicting prognosis in several kidney diseases, such as anti-neutrophil cytoplasmic antibody (ANCA)-glomerulonephritis [[1]]. [Extracted from the article]

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 <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. 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. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide   Coronavirus disease 2019 (COVID-19) vaccine platforms are becoming available and are the most promising strategy to curb the spread of severe acute respiratory syndrome coronavirus 2 infections. However, numerous uncertainties exist regarding the pros and cons of vaccination, especially in patients with (immune-mediated) kidney diseases on immunosuppressive drugs. Here, members of the Immunonephrology Working Group of the European Renal Association–European Dialysis and Transplant Association discuss 13 frequently asked questions regarding the safety and efficacy of the most promising vaccine candidates. Post-marketing surveillance should be performed to estimate the rate of vaccine response (humoral and cellular) of different vaccine platforms and disease activity following the administration of COVID-19 vaccines. Some of the candidates induce signalling pathways, which also promote autoimmune kidney diseases, e.g. type I interferons in systemic lupus erythematosus. Efficacy estimates would thus far favour the use of selected COVID-19 vaccines, such as BNT162b2, mRNA-1273 or Gam-COVID-Vac. Humoral immune response after vaccination should be monitored using appropriate assays. Even in the absence of neutralizing antibodies, patients might be protected by a sufficient cellular immune response capable of reducing the severity of COVID-19. A reduced vaccine response after the use of CD20-depleting agents is anticipated and it is particularly important to discuss strategies to improve vaccine response with these patients. Distancing and shielding measures remain important, as not all vaccines fully protect from coronavirus infection. In-depth information about the most pressing vaccine questions is essential to reduce vaccine hesitancy of patients. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic poses important challenges to the care of patients with immune-mediated kidney diseases and to kidney transplant recipients. Here, we discuss the management of immunosuppression for these patients during the pandemic and suggest potential approaches that could be considered in the absence of validated strategies. [ABSTRACT FROM AUTHOR]

Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50–100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens. [ABSTRACT FROM AUTHOR]

Glucocorticoid exposure remains a major contributor to morbidity and mortality in patients with immune-mediated kidney disease. Recent clinical trials have tested novel potential therapies for these patients and showed that glucocorticoid doses can be reduced without compromising efficacy. Key advances: C5a receptor antagonism with avacopan is effective in combination with cyclophosphamide or rituximab for inducing and maintaining remission in severe anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and reduces glucocorticoid requirements. Reducing glucocorticoid dose with rituximab for the induction of remission in AAV does not compromise short-term efficacy and reduces serious infections. Use of the calcineurin inhibitor voclosporin with mycophenolate mofetil (MMF) and glucocorticoids improves renal response in patients with class III–V lupus nephritis and eGFR >45 ml/min/1.73 m2. Obinutuzumab combined with MMF and glucocorticoids increases renal response in patients with class III–IV lupus nephitis. Inhibition of sodium–glucose co-transporter 2 with dapagliflozin in proteinuric IgA nephropathy improves renal outcomes. [ABSTRACT FROM AUTHOR]

The administration of iodinated contrast medium (CM) has immediate negative impact on multiple levels of the nephron, including vasoconstriction, an increase in apoptotic pathways and oxidative stress. Therefore, contrast-induced acute kidney injury (CI-AKI) remains an important cause of sudden impairment of renal function. Far from being just a transient phenomenon, CI-AKI has consistently been shown to be associated with adverse outcomes. The phenomenon of chronic kidney disease (CKD) following AKI might explain why this entity portends a poor prognosis in the long run. While it is generally acknowledged that in individuals with normal renal function, the risk of CI-AKI is negligible, pre-existing renal disease is its greatest independent risk factor. Although several recent publications have challenged the dogma of CI-AKI as a stand-alone disease entity, these trials, despite careful propensity matching, are hampered by their retrospective nature. In this article, we concede that there is always a trade-off and that administration of CM may be justified if its diagnostic value is believed to outweigh its associated risks. However, we reason that despite considerable progress in the field, the risk of CI-AKI is still high in the modern era and that CM-based imaging should be employed with great restraint in patients with CKD. [ABSTRACT FROM AUTHOR]

A better understanding of the pathophysiology of autoimmune disorders is desired to allow tailored interventions. Despite increased scientific interest a direct pathogenic factor in autoimmune renal disease has been described only in a minority like membranous nephropathy or ANCA-associated vasculitis. Nonetheless the initial step leading to the formation of these antibodies is still obscure. In this review we will focus on the possible role of microbial factors in this context. Staphylococcus aureus may be a direct pathogenetic factor in granulomatosis with polyangiitis (GPA). Chronic bacterial colonization or chronic infections of the upper respiratory tract have been proposed as trigger of IgA vasculitis and IgA nephropathy. Interventions to remove major lymphoid organs, such as tonsillectomy, have shown conflicting results but may be an option in IgA vasculitis. Interestingly no clear clinical benefit despite similar local colonization with bacterial strains has been detected in patients with IgA nephropathy. In systemic lupus erythematosus injection of bacterial lipopolysaccharide induced progressive lupus nephritis in mouse models. The aim of this review is to discuss and summarize the knowledge of microbial antigens in autoimmune renal disease. Novel methods may provide insight into the involvement of microbial antigens in the onset, progression, and prognosis of autoimmune kidney disorders. [ABSTRACT FROM AUTHOR]

Treatment of nephrotic syndrome due to minimal change disease and focal segmental glomerulosclerosis remains a challenge since steroid dependence, steroid resistance and a relapsing disease course exhibits a high cumulative steroid dosage. The necessity of using alternative steroid-sparing immunosuppressive agents with potential toxic side effects also restricts their long-term use. Rituximab, a monoclonal antibody targeting CD20, has been increasingly used in the therapy of difficult-to-treat nephrotic syndrome. A clinical response has been shown for patients with steroid-dependent or frequently relapsing nephrotic syndrome, whereas the benefit seems to be limited in steroid-resistant patients, especially those with underlying focal segmental glomerulosclerosis. No potentially life-threatening adverse events have been observed in the treatment of adult minimal change disease and focal segmental glomerulosclerosis following rituximab administration. Since most reports are retrospective and evidence of efficacy is derived from small case series, more prospective trials in a controlled, randomized manner are highly desirable to delineate the use of rituximab or other B cell-depleting agents in steroid-dependent, frequently relapsing or steroid-resistant patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The author reflects on the involvement of the kidneys in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Other topics are the renal involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and its impact on mortality and morbidity, as well as in majority of patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation, leading to autoantibody production. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. Alterations of kidney function in Sjögren syndrome, systemic scleroderma (SSc), auto-immune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus (SLE), antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that. In SLE, renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings. Patients with scleroderma renal crisis (SRC), which is usually characterized by severe hypertension, progressive decline of renal function and thrombotic microangiopathy, show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome, auto-immune myopathies, APSN and RA. In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions. [ABSTRACT FROM AUTHOR]

In recent decades, insights into the molecular pathways involved in disease have revolutionized the treatment of autoimmune diseases. A plethora of targeted therapies have been identified and are at varying stages of clinical development in renal autoimmunity. Some of these agents, such as rituximab or avacopan, have been approved for the treatment of immune-mediated kidney disease, but kidney disease lags behind more common autoimmune disorders in new drug development. Evidence is accumulating as to the importance of adaptive immunity, including abnormalities in T-cell activation and signaling, and aberrant B-cell function. Furthermore, innate immunity, particularly the complement and myeloid systems, as well as pathologic responses in tissue repair and fibrosis, play a key role in disease. Collectively, these mechanistic studies in innate and adaptive immunity have provided new insights into mechanisms of glomerular injury in immune-mediated kidney diseases. In addition, inflammatory pathways common to several autoimmune conditions exist, suggesting that the repurposing of some existing drugs for the treatment of immune-mediated kidney diseases is a logical strategy. This new understanding challenges the clinical investigator to translate new knowledge into novel therapies leading to better disease outcomes. This review highlights promising immunomodulatory therapies tested for immune-mediated kidney diseases as a primary indication, details current clinical trials and discusses pathways that could be targeted in the future. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic revealed that our understanding of infectious complications and strategies to mitigate severe infections in patients with glomerular diseases is limited. Beyond COVID-19, there are several infections that specifically impact care of patients receiving immunosuppressive measures. This review will provide an overview of six different infectious complications frequently encountered in patients with glomerular diseases, and will focus on recent achievements in terms of vaccine developments and understanding of the use of specific antimicrobial prophylaxis. These include influenza virus, Streptococcus pneumoniae , reactivation of a chronic or past infection with hepatitis B virus in cases receiving B-cell depletion, reactivation of cytomegalovirus, and cases of Pneumocystis jirovecii pneumonia in patients with anti-neutrophil cytoplasmic antibody–associated vasculitis. Varicella zoster virus infections are particularly frequent in patients with systemic lupus erythematosus and an inactivated vaccine is available to use as an alternative to the attenuated vaccine in patients receiving immunosuppressants. As with COVID-19 vaccines, vaccine responses are generally impaired in older patients, and after recent administration of B-cell depleting agents, and high doses of mycophenolate mofetil and other immunosuppressants. Strategies to curb infectious complications are manifold and will be outlined in this review. [ABSTRACT FROM AUTHOR]

In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies. [ABSTRACT FROM AUTHOR]

Patients with immune-mediated kidney diseases are at increased risk of severe coronavirus disease 2019 (COVID-19). The international rollout of COVID-19 vaccines has provided varying degrees of protection and enabled the understanding of vaccine efficacy and safety. The immune response to COVID-19 vaccines is lower in most patients with immune-mediated kidney diseases; either related to immunosuppression or comorbidities and complications caused by the underlying disease. Humoral vaccine response, measured by the presence of antibodies, is impaired or absent in patients receiving rituximab, mycophenolate mofetil (MMF), higher doses of glucocorticoids and likely other immunosuppressants, such as cyclophosphamide. The timing between the use of these agents and administration of vaccines is associated with the level of immune response: with rituximab, vaccine response can only be expected once B cells start to recover and patients with transient discontinuation of MMF mount a humoral response more frequently. The emergence of new COVID-19 variants and waning of vaccine-induced immunity highlight the value of a booster dose and the need to develop mutant-proof vaccines. COVID-19 vaccines are safe, exhibiting a very low risk of de novo or relapsing immune-mediated kidney disease. Population-based studies will determine whether this is causal or coincidental. Such cases respond to standard management, including the use of immunosuppression. The Immunonephrology Working Group and European Vasculitis Society recommend that patients with immune-mediated kidney diseases follow national guidance on vaccination. Booster doses based on antibody measurements could be considered. [ABSTRACT FROM AUTHOR]

In recent decades, several important advances have taken place in the understanding of the pathogenesis underlying membranous nephropathy (MN) that have sparked renewed interest in its management. Four landmark trials in MN and a fifth clinical trial—which was a pilot study—have been published in recent years. The results from some of these trials have had a significant impact on the recommendations included in the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases, representing a significant step forward compared with the previous guideline in several aspects, including diagnosis, disease monitoring and treatment strategies. However, considering the rapidly evolving advances in the knowledge of MN and the recent publication of the STARMEN and RI-CYCLO trials, several recommendations contained in the guideline warrant updates. This article provides a perspective of the Immunonephrology Working Group of the European Renal Association regarding the management of MN in native kidneys of adult patients. [ABSTRACT FROM AUTHOR]

Patients with kidney diseases should be prioritized for COVID-19 vaccination and the available data suggest that replication-defective viral-vectored vaccines and mRNA vaccines are safe to use. As vaccine responses are likely to be lower in patients with kidney diseases than in the general population, highly potent vaccines should be preferred. [ABSTRACT FROM AUTHOR]

Matricellular proteins in the kidney have been associated with the development of tubulointerstitial fibrogenesis and the progression of renal disease. This study investigated potential antifibrotic effects of the cytokine oncostatin M (OSM) in human proximal tubule cells (PTC), particularly with regard to inhibition of profibrotic events initiated by TGF-β1. In human PTC, OSM diminished transforming growth factor (TGF)-β1-induced expression of the transcriptional epithelial-mesenchymal transition mediator FoxC2. Furthermore, exposure to OSM attenuated basal and TGF-β1-induced expression of the matricellular proteins SPARC, TSP-1, TNC, and CTGF regardless of the sequence of ligand administration. OSM was shown to result in rapid and sustained phosphorylation of both Stat1 and Stat3 and also in transient phosphorylation of Smad2/3 in contrast to TGF-β1, which demonstrated a gradually building phosphorylation of Smad2/3 and a brief phosphorylation of Smad1/5/8. Utilizing receptor-blocking molecules, we found the inhibitory effect of OSM on TGF-β1-induced CTGF mRNA expression occurs independently of Smad2/3 signaling and present evidence that this effect may be partially driven by OSM receptor-mediated Stat1 and/or Stat3 signaling pathways, thereby providing a mechanism whereby OSM can contribute to tubulointerstitial protection. [ABSTRACT FROM AUTHOR]

Peripheral blood eosinophilia (PBE), defined as 500 eosinophils or above per microliter (µL) blood, is a condition that is not uncommon but often neglected in the management of patients with chronic kidney disease (CKD), acute kidney injury (AKI), or patients on renal replacement therapy (RRT). The nature of PBE in the context of kidney diseases is predominantly secondary or reactive and has to be distinguished from primary eosinophilic disorders. Nonetheless, the finding of persistent PBE can be a useful clue for the differential diagnosis of underdiagnosed entities and overlapping syndromes, such as eosinophilic granulomatosis with polyangiitis (EGPA), IgG4-related disease (IgG4-RD), acute interstitial nephritis (AIN), or the hypereosinophilic syndrome (HES). For patients on RRT, PBE may be an indicator for bio-incompatibility of the dialysis material, acute allograft rejection, or Strongyloides hyperinfection. In a subset of patients with EGPA, eosinophils might even be the driving force in disease pathogenesis. This improved understanding is already being used to facilitate novel therapeutic options. Mepolizumab has been licensed for the management of EGPA and is applied with the aim to abrogate the underlying immunologic process by blocking interleukin-5. The current article provides an overview of different renal pathologies that are associated with PBE. Further scientific effort is required to understand the exact role and function of eosinophils in these disorders which may pave the way to improved interdisciplinary management of such patients. [ABSTRACT FROM AUTHOR]