Since the re-classification of membranoproliferative glomerulonephritis the new disease entity C3 glomerulopathy is diagnosed if C3 deposition is clearly dominant over immunoglobulins in ...immunohistochemistry or immunofluorescence. Although this new definition is more orientated at the pathophysiology as mediated by activity of the alternative complement pathway C3 glomerulopathy remains a heterogenous group of disorders. Genetic or autoimmune causes are associated in several but not in all patients with this disease. However, prognosis is poorly predictable, and clinicians cannot directly identify patients that might benefit from therapy. Moreover, therapy may range from supportive care alone, unspecific immune suppression, plasma treatment, or plasma exchange to complement inhibition. The current biopsy based diagnostic approaches sometimes combined with complement profiling are not sufficient to guide clinicians neither (i) whether to treat an individual patient, nor (ii) to choose the best therapy. With this perspective, we propose an interdisciplinary diagnostic approach, including detailed analysis of the kidney biopsy for morphological alterations and immunohistochemical staining, for genetic analyses of complement genes, complement activation patterning in plasma, and furthermore for applying novel approaches for convertase typing and complement profiling directly in renal tissue. Such a combined diagnostic approach was used here for a 42-year-old female patient with a novel mutation in the Factor H gene, C3 glomerulopathy and signs of chronic endothelial damage. We present here an approach that might in future help to guide therapy of renal diseases with relevant complement activation, especially since diverse new anti-complement agents are under clinical investigation.
Th1 and Th17 subtype effector CD4+ T cells are thought to play a critical role in the pathogenesis of human and experimental crescentic glomerulonephritis. The time course, mechanism, and functions ...of Th1 and Th17 cell recruitment, and their potential interaction in glomerulonephritis, however, remain to be elucidated. We performed interventional studies using IL-17- and IFN-γ-gene-deficient mice, as well as neutralizing antibodies that demonstrated the importance of the Th17-mediated immune response during the early phase of the disease. At a later stage, we found that Th1 cells were critical mediators of renal tissue injury. Early recruitment of IL-17-producing Th17 cells triggered expression of the chemokine CXCL9 in the kidney that drove the infiltration of Th1 cells bearing its receptor CXCR3. At a later stage, Th1 cell–derived IFN-γ was found to inhibit local chemokine CCL20 expression, acting through its receptor CCR6 on Th17 cells, thereby limiting the renal Th17 immune response. Thus, our findings provide mechanistic evidence for a cytokine–chemokine-driven feedback loop that orchestrates the observed differential Th1 and Th17 cell infiltration into the inflamed kidney. This contributes to the observed time-dependent function of these two major pathogenic effector CD4+ T cell subsets in crescentic glomerulonephritis.
The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane or podocytes frequently ...underlies renal protein loss. There is an increasing belief in the involvement of the complement system, a part of the innate immune system, in these conditions. Understanding the interactions between the complement system and glomerular structures continually evolves, challenging the traditional view of the blood-urine barrier as a passive filter. Clinical studies suggest that a precise inhibition of the complement system at various points may soon become feasible. However, a thorough understanding of current knowledge is imperative for planning future therapies in nephrotic glomerular diseases such as membranous glomerulopathy, membranoproliferative glomerulonephritis, lupus nephritis, focal segmental glomerulosclerosis, and minimal change disease. This review provides an overview of the complement system, its interactions with glomerular structures, and insights into specific glomerular diseases exhibiting a nephrotic course. Additionally, we explore new diagnostic tools and future therapeutic approaches.
Among numerous other immune-mediated diseases, glomerulonephritis has also been suspected to be an extrahepatic manifestation of HEV infection. In this prospective study, we tested 108 patients with ...glomerulonephritis and 108 age- and sex-matched healthy controls at the University Hospital Hamburg Eppendorf, Hamburg, Germany, for anti-HEV IgG (Wantai test) as a marker for previous HEV exposure. A total of 24 patients (22%) tested positive for anti-HEV IgG. Males tended to be more frequently anti-HEV IgG positive (29%) in comparison to females (16%). However, this does not reach statistical significance (
= 0.07). Anti-HEV IgG positive patients were older in comparison to negative patients (mean 53 vs. 45 years,
= 0.05). The kidney function seems to be slightly decreased in anti-HEV IgG positive patients in comparison to and anti-HEV IgG negative patients basing on creatinine (
= 0.04) and glomerular filtration rate (GFR) (
= 0.05). Slightly higher values of bilirubin could be found in IgG positive patients (
= 0.04). Anti-HEV-IgG seropositivity rate (22%) in glomerulonephritis patients, did not differ significantly in comparison to an age- and sex-matched control cohort of healthy blood donors (31/108 positive, 29%). A total of 2/2 patients with membranoproliferative glomerulonephritis (MPGN) tested anti-HEV IgG positive (
= 0.002 in comparison to glomerulonephritis patients with other subtypes). In conclusion, our findings indicate that previous HEV exposure in a region where GT3 is endemic is not associated with glomerulonephritis in general. However, the subgroup of MPGN patients should be investigated in future studies. Furthermore, future studies are needed to investigate whether the observed association between anti-HEV IgG positivity and reduced GFR in glomerulonephritis patients is HEV associated or is an age-related effect.
Thrombotische Mikroangiopathien Schmidt, Tilman; Huber, Tobias B.
Medizinische Klinik, Intensivmedizin und Notfallmedizin,
02/2023, Volume:
118, Issue:
1
Journal Article
Zusammenfassung
Im Kollektiv der Notfallpatient:Innen ist die Kombination von Anämie und Thrombopenie keine Seltenheit. Auch wenn diese Befunde sich häufig aus dem medizinischen Kontext heraus ...erklären lassen, ist eine thrombotische Mikroangiopathie eine wichtige Differenzialdiagnose. Hierbei führt der Verschluss der kleinsten Gefäße zu einer Funktionseinschränkung der betroffenen Organe. Nicht selten sind es die Symptome der Organfehlfunktion, z. B. an Niere oder Gehirn, durch die die Patient:Innen in der Notfall- und Intensivmedizin vorstellig werden. Charakteristisch ist eine Coombs-negative Hämolyse mit Fragmentierung von Erythrozyten. Es zeigt sich eine Laktatdehydrogenaseerhöhung und ein Verbrauch an Thrombozyten und Haptoglobin. Die Differenzialdiagnosen, die sich hinter einer thrombotischen Mikroangiopathie verbergen können, sind zahlreich und divers in ihrer Pathogenese. Eine gerichtete und schnelle Aufarbeitung ist dringend notwendig, da mitunter rasch eine spezifische Therapie eingeleitet werden muss. So führt die thrombotisch-thrombozytopenische Purpura unbehandelt in etwa 90 % der Fälle zum Tod. Durch Rekonstitution des zugrunde liegenden Mangels von ADAMTS13 („a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13“) mittels Plasmaaustausch lässt sich das Überleben in den meisten Fällen jedoch sichern. Auch das komplementvermittelte hämolytisch-urämische Syndrom sollte in Betracht gezogen und bei entsprechendem Verdacht mittels einer medikamentösen Komplementinhibition behandelt werden. In vielen Fällen ist eine thrombotische Mikroangiopathie Ausdruck einer anderweitigen Störung und kann Manifestation einer schweren Hypertonie oder einer Gerinnungsstörung, wie der disseminierten intravasalen Gerinnung oder dem Antiphospholipidsyndrom, sein. Sie wird auch als Folge medikamentöser Therapien oder metabolischer Störungen beobachtet.
CD4
T cells are important drivers of tissue damage in immune-mediated renal diseases, such as anti-glomerular basement membrane glomerulonephritis, anti-neutrophil cytoplasmic antibody-associated ...glomerulonephritis, and lupus nephritis. The discovery of a distinct, IL-17-producing CD4
T-cell lineage termed T helper type 17 (T
17) cells has markedly advanced current understanding of the pathogenic mechanisms of organ-specific immunity and the pathways that lead to target organ damage. T
17 cells are characterized by the expression of the transcription factor RORγt, the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-22, and high expression of the chemokine receptor C-C-motif chemokine receptor 6 (CCR6). An emerging body of evidence from experimental models and human studies supports a key role for these cells in the development of renal damage, and has led to the identification of targets to inhibit the production of T
17 cells in the intestine, their migration, or their actions within the kidney. Here, we describe the identification, regulation, and function of T
17 cells and their associated pathways in immune-mediated kidney diseases, with a particular focus on the mechanisms underlying renal tissue injury. We also discuss the rationale for the translation of these findings into new therapeutic approaches in patients with autoimmune kidney disease.
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease is induced by antibodies, which are directed against the podocyte protein phospholipase A
2
receptor 1 (PLA
...2
R1-ab) in 80% of cases. B cell depleting treatments, most notably rituximab, a chimeric CD20-antibody, are often effective for treatment of MN. However, in 35–40% of patients rituximab fails to induce remission of disease and relapses after rituximab-induced remission are frequent. Therefore, alternative treatment options are necessary. Over the past years optimized antibodies targeting CD20 were designed to overcome side effects or sensitization to the murine fractions of rituximab and potentially improve B cell depletion. Ocrelizumab is a humanized B cell depleting antibody, approved for treatment of multiple sclerosis (MS). Here, we report the case of a patient who was diagnosed with MS and, 8 years later, developed PLA
2
R1-associated MN. Treatment for MS was switched to the CD20-antibody ocrelizumab, which was expected to deplete B cells and potentially induce remission of MN. After treatment with ocrelizumab PLA
2
R1-ab disappeared from the circulation and the patient developed remission of proteinuria. Ocrelizumab might be an efficacious treatment alternative for patients with MN who fail to achieve remission or are immunologically sensitized to rituximab.
The mobile impurity in a Bose-Einstein condensate (BEC) is a
paradigmatic many-body problem. For weak interaction between the
impurity and the BEC, the impurity deforms the BEC only slightly and
it ...is well described within the Fröhlich model and the Bogoliubov
approximation. For strong local attraction this standard approach,
however, fails to balance the local attraction with the weak
repulsion between the BEC particles and predicts an instability
where an infinite number of bosons is attracted toward the impurity.
Here we present a solution of the Bose polaron problem beyond the
Bogoliubov approximation which includes the local repulsion
between bosons and thereby stabilizes the Bose polaron even near and
beyond the scattering resonance. We show that the Bose polaron
energy remains bounded from below across the resonance and the size
of the polaron dressing cloud stays finite. Our results demonstrate
how the dressing cloud replaces the attractive impurity potential
with an effective many-body potential that excludes binding. We
find that at resonance, including the effects of boson repulsion,
the polaron energy depends universally on the effective
range. Moreover, while the impurity contact is strongly peaked at
positive scattering length, it remains always finite. Our solution
highlights how Bose polarons are self-stabilized by repulsion,
providing a mechanism to understand quench dynamics and
nonequilibrium time evolution at strong coupling.
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