- Publikační typ
- tisková chyba MeSH
Arteriální hypertenze představuje jedno z nejběžnějších chronických onemocnění na světě. Udává se, že postihuje třetinu dospělé populace a že v r. 2025 se stane vůbec nejčastější chronickou chorobou. Hypertenze nemá ataky a remise; a pokud vznikne, obvykle neustoupí a vyžaduje dlouhodobou celoživotní léčbu. Přes rozsáhlé a početné studie rizikových faktorů příčinu hypertenze neznáme. Existují tisíce studií zaměřených na různé rizikové faktory vzniku arteriální hypertenze, které zahrnují velmi široké množství vlivů. Žádná z nich neplatí obecně pro celou populaci a neobjasňuje přesně důvody vzniku a progrese onemocnění. V posledních dekádách se v experimentu objevují výsledky, které dokládají vliv komplementu na všechna stadia arteriální hypertenze. Důkazy o tom, že u značné části pacientů s tzv. maligní hypertenzí je trombotická mikroangiopatie vlastně projevem atypického uremického syndromu; přesvědčivě ukazují, že onemocnění je součástí dysregulace komplementu. Tyto skutečnosti posouvají náš pohled na roli komplementu, která je u mnoha chorob včetně hypertenze mnohem významnější, než jsme si dříve mysleli. Adresa pro korespondenci: Doc. MUDr. Eva Honsová, PhD. Unilabs Patologie Evropská 2589/33b 160 00 Praha 6 email: eva.honsova@unilabs.com
Arterial hypertension is one of the most common chronic diseases in the world. It is reported that it affects a third of the adult population and that in 2025 it will become the most common chronic disease. Hypertension does not have attacks and remissions; and if it occurs, it usually does not disappear and requires long-term lifelong treatment. Despite extensive and numerous studies of risk factors, we do not know the cause of hypertension. There are thousands of studies focused on various risk factors for the development of arterial hypertension. None of them apply in general and do not clarify the reasons for the development and progression of the disease. Recent experimental data strongly support a role for complement in all stages of arterial hypertension. Evidence that in a significant proportion of patients with so-called malignant hypertension, thrombotic microangiopathy is a manifestation of atypical hemolytic-uremic syndrome; conclusively shows that the disease is part of complement dysregulation. These facts shift our view of the role of complement, which is much more important in many diseases, including hypertension, than we previously thought.
- MeSH
- hypertenze * etiologie genetika patofyziologie MeSH
- komplement imunologie MeSH
- kuchyňská sůl metabolismus škodlivé účinky MeSH
- ledviny patofyziologie patologie MeSH
- lidé MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- trombotické mikroangiopatie etiologie patofyziologie patologie MeSH
- vazokonstrikce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Komplementový systém je velmi důležitou složkou vrozené (tzv. nespecifické) imunity, která je součástí první linie obrany proti infekcím. Vedle toho hraje komplement významnou roli při odklízení apoptotických a poškozených endogenních buněk a podle nedávných objevů významnou měrou přispívá k homeostáze organismu. Komplementový systém zahrnuje několik desítek solubilních a membránově vázaných proteinů, které po aktivaci fungují jako kaskáda, na jejímž konci je likvidace infekčního agens. K aktivaci komplementu dochází jednou ze 3 cest (klasická, lektinová a alternativní) a všechny 3 cesty vedou k centrální složce C3. Štěpením C3 začíná aktivace tzv. efektorové terminální kaskády, která se prozánětlivými mechanismy, opsonizací a na konci vytvořením kanálu v bazální membráně podílí na eliminaci patogenů. Důležitou roli představuje systematická kontrola aktivace komplementu, protože jde o prevenci před poškozením vlastních tkání. Striktní kontrolu vyžaduje především alternativní cesta, která zajišťuje více než 80 % aktivity terminální kaskády komplementu. Dysregulace komplementu a zvl. jeho alternativní cesty stojí na pozadí mnoha závažných akutních i chronických onemocnění. Adresa pro korespondenci: Doc. MUDr. Eva Honsová, PhD. Unilabs Patologie Evropská 2589/33b 160 00 Praha 6 email: eva.honsova@unilabs.com
The complement system is an important component of innate immunity, which is part of the first line of defense against infections. In addition, complement plays an important role in the removal of apoptotic and damaged endogenous cells and, according to recent discoveries, contributes significantly to the homeostasis of the organism. The complement system includes several dozen soluble and membrane-bound proteins, which, after activation, function as a cascade, at the end of which is the elimination of the infectious agent. Complement activation occurs through one of 3 pathways (classical, lectin, and alternative) and all 3 pathways lead to the central C3 component. The cleavage of C3 starts the activation of the so-called effector terminal cascade, which participates in the elimination of pathogens through pro-inflammatory mechanisms, opsonization and, at the end, the creation of a channel in the basement membrane. The systematic control of complement activation plays an important role, because that represents prevention against damage to one’s own tissues. Especially, the alternative pathway, which provides more than 80% of the activity of the terminal complement cascade, requires tight control. Dysregulation of complement and especially its alternative pathways is behind many acute and chronic diseases.
- MeSH
- aktivace komplementu * fyziologie imunologie MeSH
- alternativní dráha komplementu fyziologie imunologie MeSH
- atypický hemolyticko-uremický syndrom genetika patofyziologie patologie MeSH
- komplement * fyziologie imunologie škodlivé účinky MeSH
- lidé MeSH
- nemoci ledvin patofyziologie patologie MeSH
- trombotické mikroangiopatie genetika patofyziologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
INTRODUCTION: Acute tubulointerstitial nephritis (ATIN) is a well-recognized cause of acute kidney injury (AKI) due to the tubulointerstitial inflammation. The aim of this study was to explore the clinical features, outcomes, and responses to corticosteroid treatment in patients with ATIN. METHODS: Patients with biopsy-proven ATIN, who were diagnosed between 1994 and 2016 at the Department of Nephrology, Charles University, First Faculty of Medicine, and General University Hospital in Prague, were included in the study. Patient demographics, the aetiological and clinical features, the treatment given, and the outcome at 1 year of follow-up were extracted from patient records. RESULTS: A total of 103 ATIN patients were analysed, of which 68 had been treated with corticosteroids. There was no significant difference in the median serum creatinine 280 (169-569) μmol/L in the conservatively managed group versus 374 (249-558) μmol/L in the corticosteroid-treated group, p = 0.18, and dependence on dialysis treatment at baseline at the time of biopsy (10.3 vs. 8.6%). During the 1 year of follow-up, those ATIN patients who had been treated with corticosteroids did better and showed greater improvement in kidney function, determined as serum creatinine difference from baseline and from 1 month over 1-year period (p = 0.001). CONCLUSIONS: This single-centre retrospective cohort study supports the beneficial role of the administration of corticosteroid therapy in the management of ATIN.
- MeSH
- dialýza ledvin * škodlivé účinky MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- intersticiální nefritida * farmakoterapie diagnóza MeSH
- kreatinin MeSH
- ledviny patologie MeSH
- lidé MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
RATIONALE: Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients' needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy. METHODS: We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at - 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH - such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) - to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management. RESULTS: We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS. CONCLUSIONS AND RECOMMENDATIONS IN THE FRAMEWORK OF 3PM: In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa - to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH's pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00381-5.
- Publikační typ
- časopisecké články MeSH
- MeSH
- akutní poškození ledvin * diagnóza patologie terapie MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- rizikové faktory MeSH
- systémová sklerodermie * komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
