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BACKGROUND AND HYPOTHESIS: The aim of this study was to quantify hypertension control and evaluate concordance between all commonly available blood pressure modalities in kidney transplant recipients (KTR). METHODS: For this prospective cross-sectional study 89 stable KTR were recruited at the Charité Transplant Outpatient Clinic. For each study participant office (manual office blood pressure 'MOBP' and automated office blood pressure 'AOBP'), 7-day home (HBPM) and 24-hour ambulatory blood pressure measurement (24h-ABPM) were performed. RESULTS: 80 of the 89 patients recruited had sufficient blood pressure recordings. Mean blood pressure for MOBP, AOBP, HBPM and 24h-ABPM was 129/73, 126/71, 131/85 and 130/81 mmHg, respectively. Uncontrolled hypertension, as defined by 24h-ABPM (mean ≥ 130/80 mmHg), was present in 53 (66%) patients. MOBP, AOBP and HBPM classified 19 (24%), 22 (28%) and 41 (51%) patients respectively as 'uncontrolled hypertensive'. The Bland-Altman plot showed good agreement between systolic MOBP, AOBP, HBPM and Daytime-ABPM (mean bias ± SD: -1 ± 13 mmHg, -4 ± 13 mmHg, 1 ± 10 mmHg, respectively). Uncontrolled nighttime hypertension was present in 74 (93%) KTR, with 71 (89%) patients showing a non-physiological dipping pattern. Moderate positive correlation between Daytime-ABPM/HBPM and Nighttime-ABPM (Pearson Correlation Coefficients: 0.62-0.73), followed by MOBP/AOBP (Pearson Correlation Coefficients: 0.49-0.59) was noted. eGFR and proteinuria displayed weak correlation with 24h-, Daytime- and Nighttime-ABPM (absolute values of Pearson Correlation Coefficients: 0.04-0.41). No robust association with either 24h-, Daytime- or Nighttime-ABPM was observed for volume status exams. CONCLUSIONS: Masked hypertension is highly prevalent in KTR, especially due to high rates of uncontrolled nighttime hypertension. HBPM shows the narrowest limits of agreement with Daytime-ABPM. Daytime-ABPM and HBPM show the highest, albeit clinically insufficient, correlation with Nighttime-ABPM. Systematic integration of 24h-ABPM into clinical practice, as proposed by the '2023 ESH Guidelines for the Management of arterial hypertension', should not be withheld for the KTR population. Clinical trials evaluating treatment of hypertension in KTR are urgently needed.
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BACKGROUND: Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1ß-driven disease of unknown etiology. OBJECTIVE: In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease. METHODS: Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signaling reporter assay. RESULTS: Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment. CONCLUSION: Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy.
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Artritis Juvenil , Proteína Antagonista del Receptor de Interleucina 1 , Humanos , Autoanticuerpos , Ensayo de Inmunoadsorción Enzimática , Interleucina-1betaRESUMEN
BACKGROUND: As immunosuppressive therapy has improved in simultaneous pancreas/kidney transplant recipients (SPKTRs), infection has become the major limitation of disease-free survival. METHODS: We studied all SPKTRs and deceased-donor kidney transplant recipients (KTRs) between 2003 and 2015. Thirty-six of 134 SPKTRs (26.9%) were diagnosed with sepsis among which 13/36 SPKTRs (36.1%) developed severe sepsis/septic shock. A control group of 98 SPKTRs without sepsis and 61/538 KTRs (11.3%) with sepsis were used for comparison. RESULTS: Among SPKTRs, female sex, low BMI, CMV seronegativity, CMV disease, and acute cellular rejection increased the risk for sepsis (P < .05). Patient and allograft survival was comparable among SPKTRs with and without sepsis (P > .05), but showed inferior kidney allograft function (P < .05). While urosepsis was less common among SPKTRs (45%), pneumonia (33%) and peritonitis (15%) as site of infections were more frequent (P < .05). Here, gram-positive and fungal sepsis were more common among SPKTRs compared to KTRs (P < .05). SPKTRs showed a higher incidence and an earlier onset of sepsis compared to KTRs (P < .001). SPKTRs with severe sepsis/septic shock were more likely to show pneumonia as site of infection with gram-positive/polymicrobial bacteremia (P < .05). Mortality from severe sepsis was 29% among SPKTRs compared to 58% among KTRs (P < .05). CONCLUSION: Differences in incidence, site, causative pathogens, and onset of sepsis between SPKTRs and KTRs may be attributed to more intense immunosuppression, major surgery, and complications of diabetes among SPKTRs. Lower sepsis-related mortality may reflect younger age and more timely diagnosis, but also supports recent findings of less sepsis-related mortality among recipients of solid organ transplantation.
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Trasplante de Riñón/efectos adversos , Trasplante de Páncreas/efectos adversos , Complicaciones Posoperatorias , Sepsis/etiología , Cuidados Críticos , Humanos , Estudios Retrospectivos , Factores de Riesgo , Sepsis/mortalidad , Choque SépticoRESUMEN
BACKGROUND: Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with cytomegalovirus (CMV) infection being the most important viral infection with adverse impact on patient and allograft outcomes. METHODS: We studied all primary SPKTRs and deceased-donor kidney transplant recipients (KTRs) between 2008 and 2015 for the development of CMV infection. A total of 21/62 SPKTRs (33.9%) and 90/335 KTRs (26.9%) were diagnosed with CMV infection. A control group of 41 SPKTRs without CMV infection was used for comparison. RESULTS: SPKTRs showed an increased incidence of CMV infection compared with KTRs. SPKTRs were more likely to develop CMV disease, CMV pneumonia, recurrent CMV infection, higher initial and peak CMV loads, and more need for intravenous antiviral therapy compared with KTRs (P<.05). High-risk CMV serostatus (D+R-) and 2 HLA-B/-DR mismatches increased the risk of CMV infection in SPKTRs (P<.05). No differences were observed for patient and allograft outcomes (P>.05). SPKTRs with CMV infection were more likely to show concomitant Epstein-Barr virus (EBV) viremia compared with SPKTRs without CMV infection (P<.05). SPKTRs with CMV infection showed higher incidences of concomitant BK polyomavirus-associated nephropathy, EBV viremia, and sepsis compared with KTRs with CMV infection (P<.05). CONCLUSION: Our results suggest a higher incidence and more severe course of CMV infection in SPKTRs compared with KTRs. The increased incidence of concomitant infectious complications among SPKTRs with CMV infection suggests an overall impaired immunity, and calls for more intense screening.
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Infecciones por Citomegalovirus/etiología , Trasplante de Riñón/efectos adversos , Trasplante de Páncreas/efectos adversos , Adolescente , Adulto , Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacología , Infecciones por Citomegalovirus/inmunología , Femenino , Humanos , Inmunosupresores , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/métodos , Estudios Retrospectivos , Factores de Riesgo , Carga Viral , Viremia , Adulto JovenAsunto(s)
Acidosis Tubular Renal/etiología , Consumo de Bebidas Alcohólicas/efectos adversos , Alcoholismo/complicaciones , Túbulos Renales/fisiopatología , Cuadriplejía/etiología , Acidosis Tubular Renal/fisiopatología , Acidosis Tubular Renal/terapia , Abstinencia de Alcohol , Terapia Combinada , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora , Cuadriplejía/diagnóstico , Cuadriplejía/fisiopatología , Cuadriplejía/terapia , Recuperación de la Función , Resultado del TratamientoRESUMEN
BACKGROUND: Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with BK polyomavirus (BKV)-associated nephropathy (BKVN) being the most important infectious cause of allograft loss. Comparisons of BKVN with kidney transplant recipients (KTRs), however, are lacking. METHODS: We studied all SPKTRs and KTRs at our transplant centre between 2003 and 2012. Eleven of 106 SPKTs (10.4%) and 21 of 1062 KTRs (2.0%) were diagnosed with BKVN with allograft loss in 1 SPKTR (9.1%) and 2 KTRs (9.5%). A control of 95 SPKTRs without BKVN was used for comparison. RESULTS: SPKTRs showed an increased incidence of BKVN compared with KTRs (P < 0.001). Onset of BKVN in SPKTRs was significantly later compared with KTRs (P = 0.033). While 67% of KTRs showed early-onset BKVN, 64% of SPKTRs developed late-onset BKVN. Older recipient age and male gender increased the risk of BKVN in SPKTRs (P < 0.05). No differences were observed for patient and allograft survival (P > 0.05). However, SPKTRs with BKVN showed inferior estimated glomerular filtration rate and a higher incidence of de novo donor-specific antibodies compared with SPKTRs without BKVN in long-term follow-up (P < 0.05). SPKTRs showed higher peak BKV loads, a need for more intense therapeutic intervention and were more likely not to recover to baseline creatinine after BKVN (P < 0.05). CONCLUSIONS: Our results suggest a higher incidence, more severe course and inferior outcome of BKVN in SPKTRs. An increased vulnerability of the allograft kidney due to inferior organ quality may predispose KTRs to early-onset BKVN. In contrast, SPKTRs present with late-onset BKVN in the presence of high-dose immunosuppression.
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Virus BK , Rechazo de Injerto/virología , Enfermedades Renales/virología , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virología , Adulto , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Huésped Inmunocomprometido , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Incidencia , Estimación de Kaplan-Meier , Enfermedades Renales/inmunología , Enfermedades Renales/mortalidad , Enfermedades Renales/cirugía , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Trasplante de Páncreas , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/mortalidad , Modelos de Riesgos Proporcionales , Receptores de Trasplantes , Trasplante Homólogo , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/mortalidadRESUMEN
Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody-positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin-antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCß1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the conversion of PGRN, and is strongly associated with the occurrence of neutralizing, proinflammatory PGRN-antibodies, indicating immunogenicity of this alternative secondary modification.
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Autoanticuerpos/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Precursores de Proteínas/inmunología , Serina/inmunología , Animales , Autoanticuerpos/genética , Autoanticuerpos/metabolismo , Sitios de Unión/genética , Western Blotting , Línea Celular , Línea Celular Tumoral , Citometría de Flujo , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mutagénesis Sitio-Dirigida , Fosforilación , Progranulinas , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Proteína Quinasa C beta/genética , Proteína Quinasa C beta/inmunología , Proteína Quinasa C beta/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/inmunología , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Serina/genética , Serina/metabolismoRESUMEN
INTRODUCTION: Psoriatic arthritis (PsA) is a distinctive inflammatory arthritis which may typically develop in a subgroup of individuals suffering from psoriasis. We recently described progranulin autoantibodies (PGRN-Abs) in the sera of patients with different autoimmune diseases including seronegative polyarthritis. In the present study we investigated the occurrence of PGRN-Abs in PsA. METHODS: PGRN-Abs were determined in 260 patients with PsA, 100 patients with psoriasis without arthritic manifestations (PsC) and 97 healthy controls using a recently described ELISA. PGRN plasma levels were determined from subgroups by a commercially available ELISA-kit. Possible functional effects of PGRN-antibodies were analysed in vitro by tumour necrosis factor (TNF)-α mediated cytotoxicity assays using WEHI-S and HT1080 cells. RESULTS: PGRN-Abs were detected with relevant titres in 50/260 (19.23%) patients with PsA, but in 0/100 patients with psoriasis without arthritic manifestations (P = 0.0001). All PGRN-Abs belonged to immunoglobulin G (IgG). PGRN-Abs were significantly more frequent in PsA patients with enthesitis or dactylitis. PGRN-Abs were also more frequent in PsA patients receiving treatment with TNF-α-blockers than in patients treated without TNF-α-blockers (20.8% versus 17.4%; P = 0.016). PGRN plasma levels were significantly lower in PGRN-Ab-positive patients with PsA than in healthy controls and patients with psoriasis without arthritic manifestations (P < 0.001), indicating a neutralizing effect of PGRN-Abs. Moreover cytotoxicity assays comparing PGRN-antibody positive with negative sera from matched patients with PsA, clearly showed a proinflammatory effect of PGRN antibodies. CONCLUSION: Neutralizing PGRN-Abs occur with relevant titres in a subgroup of patients with PsA, but not in patients without arthritic manifestations (PsC). PGRN-Ab-positive patients had more frequent enthesitis or dactylitis. TNF-α-induced cytotoxicity assays demonstrated that the protective effects of progranulin were inhibited by serum containing PGRN-Abs. This suggests that PGRN-Ab might not only be useful as a diagnostic and prognostic marker, but may provide a proinflammatory environment in a subgroup of patients with PsA.
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Artritis Psoriásica/sangre , Artritis Psoriásica/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Autoantígenos/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Progranulinas , Adulto JovenRESUMEN
Systemic vasculitides constitute a heterogeneous group of diseases. Autoimmunity mediated by B lymphocytes and their humoral effector mechanisms play a major role in ANCA-associated vasculitis (AAV) as well as in non-ANCA associated primary systemic vasculitides and in the different types of autoimmune connective tissue disorders and rheumatoid arthritis. In order to detect autoantibodies in systemic vasculitides, we screened protein macroarrays of human cDNA expression libraries with sera from patients with ANCA-associated and ANCA-negative primary systemic vasculitides. This approach led to the identification of antibodies against progranulin, a 88 kDA secreted glycoprotein with strong anti-inflammatory activity in the course of disease of giant-cell arteritis/polymyalgia rheumatica (14/65), Takayasu's arteritis (4/13), classical panarteritis nodosa (4/10), Behcet's disease (2/6) and in the course of disease in granulomatosis with polyangiitis (31/75), Churg-Strauss syndrome (7/23) and in microscopic polyangiitis (7/19). In extended screenings the progranulin antibodies were also detected in other autoimmune diseases such as systemic lupus erythematosus (39/91) and rheumatoid arthritis (16/44). Progranulin antibodies were detected only in 1 of 97 healthy controls. Anti-progranulin positive patients with systemic vasculitides, systemic lupus erythematosus or rheumatoid arthritis had significant lower progranulin plasma levels, indicating a neutralizing effect. In light of the anti-inflammatory effects of progranulin, progranulin antibodies might exert pro-inflammatory effects thus contributing to the pathogenesis of the respective autoimmune diseases and might serve as a marker for disease activity. This hypothesis is supported by the fact that a positive progranulin antibody status was associated with active disease in granulomatosis with polyangiitis.