The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. Although complement activation plays a causal role in atypical hemolytic uremic syndrome and C3 glomerulopathy, over the past decade, a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022, Kidney Diseases: Improving Global Outcomes (KDIGO) convened a Controversies Conference, "The Role of Complement in Kidney Disease," to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of hemolytic uremic syndrome. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified.

Autoantibodies Targeting Nephrin in Podocytopathies.

BACKGROUND: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).

Anti-CFH-associated hemolytic uremic syndrome: do we still need plasma exchange?

BACKGROUND: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. METHODS: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. RESULTS: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. CONCLUSIONS: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.

A novel flow cytometry panel to identify prognostic markers for steroid-sensitive forms of idiopathic nephrotic syndrome in childhood.

Introduction: The clinical evolution of steroid-sensitive forms of pediatric idiopathic nephrotic syndrome (INS) is highly heterogeneous following the standard treatment with prednisone. To date, no prognostic marker has been identified to predict the severity of the disease course starting from the first episode. Methods: In this monocentric prospective cohort study we set up a reproducible and standardized flow cytometry panel using two sample tubes (one for B-cell and one for T-cell subsets) to extensively characterized the lymphocyte repertoire of INS pediatric patients. A total of 44 children with INS at disease onset were enrolled, sampled before and 3 months after standard induction therapy with prednisone and followed for 12 months to correctly classify their disease based on relapses. Age-matched controls with non immune-mediated renal diseases or with urological disorders were also enrolled. Demographical, clinical, laboratory and immunosuppressive treatment data were registered. Results: We found that children with INS at disease onset had significantly higher circulating levels of total CD19+ and specific B-cell subsets (transitional, mature-naïve, plasmablasts/plasmacells, CD19+CD27+, unswitched, switched and atypical memory B cells) and reduced circulating levels of Tregs, when compared to age-matched controls. Prednisone therapy restored most B- and T-cell alterations. When patients were subdivided based on disease relapse, relapsing patients had significantly more transitional, CD19+CD27+ memory and in particular unswitched memory B cells at disease onset, which were predictive of a higher risk of relapse in steroid-sensitive patients by logistic regression analysis, irrespective of age. In accordance, B-cell dysregulations resulted mainly associated with steroid-dependence when patients were stratified in different disease severity forms. Of note, Treg levels were reduced independently from the disease subgroup and were not completely normalized by prednisone treatment. Conclusion: We have set up a novel, reproducible, disease-specific flow cytometry panel that allows a comprehensive characterization of circulating lymphocytes. We found that, at disease onset, relapsing patients had significantly more transitional, CD19+CD27+ memory and unswitched memory B cells and those who are at higher risk of relapse had increased circulating levels of unswitched memory B cells, independently of age. This approach can allow prediction of clinical evolution, monitoring of immunosuppression and tailored treatment in different forms of INS.

Anti-nephrin antibodies in recurrence of focal segmental glomerulosclerosis: closer to discovering the Holy Grail?

Recurrent forms of primary focal segmental glomerulosclerosis (FSGS) pose an unmet challenge to nephrologists, both in terms of understanding the underlying pathophysiology and in terms of identifying an effective management strategy of this disease, which frequently leads to kidney graft loss. In the past few decades, experimental observations both in patients and in animal models have led to the hypothesis of the existence of circulating factors driving the loss of integrity of the glomerular filtration barrier in FSGS. Although different circulating factor candidates have been postulated, none has been unequivocally shown to be pathogenic. In the current study, Shirai et al. propose a new candidate for this role by identifying circulating anti-nephrin autoantibodies in a cohort of patients with post-transplant recurrence of primary FSGS. Recent evidence by Watts et al. has also identified anti-nephrin autoantibodies in the circulation and in the kidney biopsies of patients with minimal change disease. If confirmed, the identification of these autoantibodies would both contribute to identifying the elusive circulating factor in FSGS and increase our understanding of the spectrum of proteinuric glomerular lesions, spanning from minimal change disease to FSGS. The quest for the Holy Grail is perhaps closer to completion.

Iptacopan in Idiopathic Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Protocol of the APPARENT Multicenter, Randomized Phase 3 Study.

Introduction: Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultra-rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Dysregulation of the alternative complement pathway is implicated in the pathophysiology of IC-MPGN; and currently, there are no approved targeted treatments. Iptacopan is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the alternative pathway (AP). Methods: This randomized, double-blind, placebo-controlled phase 3 study (APPARENT; NCT05755386) will evaluate the efficacy and safety of iptacopan in patients with idiopathic (primary) IC-MPGN, enrolling up to 68 patients (minimum of 10 adolescents) aged 12 to 60 years with biopsy-confirmed IC-MPGN, proteinuria ≥1 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplant, progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily (bid) or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg bid for all patients for 6 months. The primary objective of the study is to evaluate the efficacy of iptacopan versus placebo in proteinuria reduction measured as urine protein-to-creatinine ratio (UPCR) (24-h urine) at 6 months. Key secondary end points will assess kidney function measured by eGFR, patients who achieve a proteinuria-eGFR composite end point, and patient-reported fatigue. Conclusion: This study will provide evidence toward the efficacy and safety of iptacopan in idiopathic (primary) IC-MPGN.

Childhood-onset IgA nephropathy: is long-term recovery possible?

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. While studies have primarily focused on identifying risk factors for disease progression, very few data exist on the likelihood of achieving complete recovery from the disease. METHODS: We conducted a single-center retrospective study on all consecutive patients with biopsy-proven IgAN diagnosed between 1986 and 2018 in our pediatric center. Biopsies were classified according to the MEST-C Oxford classification score. "Complete clinical remission" was defined as the absence of proteinuria, hematuria, and hypertension in patients with normal kidney function who had been off therapy for more than 2 years. RESULTS: Overall, 153 patients with age at onset of 10.6 ± 4 years were enrolled in the study. Of these, 41 achieved "complete clinical remission." The estimated probability of complete clinical remission at 10 years was 43% (95%CI 33-54). However, seven patients relapsed within 10 years. Multivariable analysis showed that higher age at onset (HR 0.89, 95%CI 0.80-0.98, p = 0.017) and segmental glomerulosclerosis lesions (HR 0.28, 95%CI 0.10-0.79, p = 0.017) decreased significantly the chances of achieving complete clinical remission. Immunosuppressive therapy was not significantly associated with clinical outcomes. CONCLUSIONS: Approximately one-third of patients with pediatric-onset IgAN achieve prolonged remission, in particular, very young children at disease onset without sclerotic glomerular lesions. Longer term follow-up is needed to assess if these patients have achieved permanent remission.

Complement inhibitors in pediatric kidney diseases: new therapeutic opportunities.

Historically, the complement system (classical, lectin, alternative, and terminal pathways) is known to play a crucial role in the etiopathogenesis of many kidney diseases. Direct or indirect activation in these settings is revealed by consumption of complement proteins at the serum level and kidney tissue deposition seen by immunofluorescence and electron microscopy. The advent of eculizumab has shown that complement inhibitors may improve the natural history of certain kidney diseases. Since then, the number of available therapeutic molecules and experimental studies on complement inhibition has increased exponentially. In our narrative review, we give a summary of the main complement inhibitors that have completed phase II and phase III studies or are currently used in adult and pediatric nephrology. The relevant full-text works, abstracts, and ongoing trials (clinicaltrials.gov site) are discussed. Data and key clinical features are reported for eculizumab, ravulizumab, crovalimab, avacopan, danicopan, iptacopan, pegcetacoplan, and narsoplimab. Many of these molecules have been shown to be effective in reducing proteinuria and stabilizing kidney function in different complement-mediated kidney diseases. Thanks to their efficacy and target specificity, these novel drugs may radically improve the outcome of complement-mediated kidney diseases, contributing to an improvement in our understanding of their underlying pathophysiology.

Kidney manifestations of pediatric Sjögren's syndrome.

Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5-20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6-96.2%), and anti-Ro/SSA (36.4-84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature.

Childhood nephrotic syndrome.

Idiopathic nephrotic syndrome is the most common glomerular disease in children. Corticosteroids are the cornerstone of its treatment, and steroid response is the main prognostic factor. Most children respond to a cycle of oral steroids, and are defined as having steroid-sensitive nephrotic syndrome. Among the children who do not respond, defined as having steroid-resistant nephrotic syndrome, most respond to second-line immunosuppression, mainly with calcineurin inhibitors, and children in whom a response is not observed are described as multidrug resistant. The pathophysiology of nephrotic syndrome remains elusive. In cases of immune-mediated origin, dysregulation of immune cells and production of circulating factors that damage the glomerular filtration barrier have been described. Conversely, up to a third of cases of steroid-resistant nephrotic syndrome have a monogenic origin. Multidrug resistant nephrotic syndrome often leads to kidney failure and can cause relapse after kidney transplant. Although steroid-sensitive nephrotic syndrome does not affect renal function, most children with steroid-sensitive nephrotic syndrome have a relapsing course that requires repeated steroid cycles with significant side-effects. To minimise morbidity, some patients require steroid-sparing immunosuppressive agents, including levamisole, mycophenolate mofetil, calcineurin inhibitors, anti-CD20 monoclonal antibodies, and cyclophosphamide. Close monitoring and preventive measures are warranted at onset and during relapse to prevent acute complications (eg, hypovolaemia, acute kidney injury, infections, and thrombosis), whereas long-term management requires minimising treatment-related side-effects. A subset of patients have active disease into adulthood.

A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome.

BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.

Age and memory B cells at baseline are associated with risk of relapse and memory B-cell reappearance following anti-CD20 treatment in pediatric frequently-relapsing/steroid-dependent nephrotic syndrome.

B-cell depleting anti-CD20 monoclonal antibodies, such as rituximab, have proven efficacy in children with frequently-relapsing/steroid-dependent nephrotic syndrome (FR/SDNS). However, drug-free remission is variable and specific baseline markers predictive of relapse after anti-CD20 treatment are still being defined. To clarify these, we performed a bicentric observational study in a large cohort of 102 children and young adults with FR/SDNS treated with anti-CD20 monoclonal antibodies (rituximab and ofatumumab). Sixty-two patients (60.8%) relapsed during a 24-month period (median [interquartile range] relapse-free survival, 14.4 months [7.9-24.0]). A lower risk of relapse was significantly associated with an older age (over 9.8 years, hazard ratio, 0.44; 95% confidence interval, 0.26-0.74) and a higher risk of relapse was significantly associated with higher circulating levels of memory B cells (1.14; 1.09-1.32) at time of anti-CD20 infusion, independent of time elapsed from onset, previous anti-CD20 treatment, type of administered anti-CD20 monoclonal antibodies, and previous or maintenance oral immunosuppression. Patients younger than 9.8 years at anti-CD20 infusion had a subsequent higher recovery of total, transitional, mature-naïve and memory B-cell subsets independent of previous anti-CD20 treatment and maintenance immunosuppression. Significantly, younger age and higher circulating levels of memory B cells at time of anti-CD20 infusion were also independently associated with the recovery of memory B cells by linear mixed-effects modelling. Thus, both younger age and higher circulating levels of memory B cells at time of infusion are independently associated with a higher risk of relapse and an earlier recovery of memory B cells following anti-CD20 treatment in children with FR/SDNS.

Successful treatment with avacopan (CCX168) in a pediatric patient with C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis (C3GN) is a subtype of C3 glomerulopathy (C3G), characterized by dysregulation of the alternative pathway of complement and by dominant C3 by immunofluorescence on the kidney biopsy. There is no approved treatment for patients with C3G. Immunosuppressive drugs as well as biologics have been used with limited success. In recent decades, substantial advances in the understanding of the complement system have led to the development of new complement inhibitors. Avacopan (CCX168) is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a, one of the most potent pro-inflammatory mediators of the complement system. CASE REPORT: We describe a child with biopsy-proven C3GN treated with avacopan. She was enrolled in the ACCOLADE double-blind placebo-controlled Phase 2 study (NCT03301467), where during the first 26 weeks she was randomized to receive an avacopan-matching placebo orally twice daily, while in the following 26 weeks, the study was open-label and she received avacopan. After a wash-out period, she was restarted on avacopan through an expanded access program. CONCLUSIONS: In this case, use of avacopan in a pediatric patient with C3GN was safe and well tolerated. On avacopan, the patient was able to discontinue mycophenolate mofetil (MMF) while maintaining remission.

Persistently active interferon-γ pathway and expansion of T-bet+ B cells in a subset of patients with childhood-onset systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease causing significant morbidity and mortality, despite important improvements in its management in the last decades. The objective of this work is to investigate the role of IFN-γ in the pathogenesis of childhood-onset systemic lupus erythematosus (cSLE), evaluating the crosstalk between IFN-α and IFN-γ and the expression of T-bet, a transcription factor induced by IFN-γ, in B cells of patients with cSLE. Expression levels of both IFN-α and IFN-γ-induced genes were upregulated in patients with cSLE. We found increased serum levels of CXCL9 and CXCL10 in patients with cSLE. Type I IFN score decreased with initiation of immunosuppressive treatment; conversely, type II IFN score and levels of CXCL9 were not significantly affected by immunosuppressive treatment. Type II IFN score and CXCL9 were significantly higher in patients with lupus nephritis. We observed the expansion of a population of naïve B cells expressing T-bet in a cluster of patients with cSLE. IFN-γ, but not IFN-α, induced the expression of T-bet in B cells. Our data suggest that IFN-γ is hyperactive in cSLE, especially in patients with lupus nephritis, and it is not modulated by therapy. Our data reinforce the potential of IFN-γ as a therapeutic target in SLE.

Renal involvement in monogenic autoinflammatory diseases: A narrative review.

Autoinflammatory diseases (AIDs) are mostly caused by dysfunctions in single genes encoding for proteins with a prominent role in the regulation of innate immunity, such as complement factors, inflammasome components, tumour necrosis factor (TNF)-α, and proteins belonging to type I-interferon (IFN) signalling pathways. Due to the deposition of amyloid A (AA) fibrils in the glomeruli, unprovoked inflammation in AIDs frequently affects renal health. In fact, secondary AA amyloidosis is the most common form of amyloidosis in children. It is caused by the extracellular deposition of fibrillar low-molecular weight protein subunits resulting from the degradation and accumulation of serum amyloid A (SAA) in numerous tissues and organs, primarily the kidneys. The molecular mechanisms underlying AA amyloidosis in AIDs are the elevated levels of SAA, produced by the liver in response to pro-inflammatory cytokines, and a genetic predisposition due to specific SAA isoforms. Despite the prevalence of amyloid kidney disease, non-amyloid kidney diseases may also be responsible for chronic renal damage in children with AIDs, albeit with distinct characteristics. Glomerular damage can result in various forms of glomerulonephritis with distinct histologic characteristics and a different underlying pathophysiology. This review aims to describe the potential renal implications in patients with inflammasomopathies, type-I interferonopathies, and other rare AIDs in an effort to improve the clinical course and quality of life in paediatric patients with renal involvement.

Rituximab-associated hypogammaglobulinemia in children with idiopathic nephrotic syndrome: results of an ESPN survey.

BACKGROUND: There is paucity of information on rituximab-associated hypogammaglobulinemia (HGG) and its potential infectious consequences in children treated for idiopathic nephrotic syndrome (INS). METHODS: A survey was distributed by the European Society Pediatric Nephrology to its members. It addressed the screening and management practices of pediatric nephrology units for recognizing and treating RTX-associated HGG and its morbidity and mortality. Eighty-four centers which had treated an overall 1328 INS children with RTX responded. RESULTS: The majority of centers administered several courses of RTX and continued concomitant immunosuppressive therapy. Sixty-five percent of centers routinely screened children for HGG prior to RTX infusion, 59% during, and 52% following RTX treatment. Forty-seven percent had observed HGG prior to RTX administration, 61% during and 47% >9 months following treatment in 121, 210, and 128 subjects respectively. Thirty-three severe infections were reported among the cohort of 1328 RTX-treated subjects, of whom 3 children died. HGG had been recognized in 30/33 (80%) of them. CONCLUSIONS: HGG in steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS) children is probably multifactorial and can be observed prior to RTX administration in children with SDNS/FRNS. Persistent HGG lasting >9 months from RTX infusion is not uncommon and may increase the risk of severe infections in this cohort. We advocate for the obligatory screening for HGG in children with SDNS/FRNS prior to, during, and following RTX treatment. Further research is necessary to identify risk factors for developing both HGG and severe infections before recommendations are made for its optimal management. A higher resolution version of the Graphical abstract is available as Supplementary information.