No description available.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormalities in multiple components of the immune system resulting in progressive damage to multiple organs. Current treatments for SLE are often intensive and result in side effects and the potential for continued flares and progression of disease. Histone deacetylase (HDAC) enzymes control multiple cellular functions by removing acetyl groups from lysine residues in various proteins. HDAC inhibitors have been investigated as a potential treatment for SLE with promising results, however selective HDAC6 inhibition (HDAC6i) has become a leading candidate for pharmacologic inhibition to reduce the potential for side effects. We hypothesize that HDAC6i will decrease SLE disease by targeting substrates of HDAC6 in multiple components of immunity and organ systems. NZB/W mice were treated with ACY-738 or ACY-1083, followed by evaluation of multiple disease parameters and mechanisms involved in disease pathogenesis within the kidney, bone marrow, and spleen. Within the kidney, HDAC6i decreased glomerular pathology scores, proteinuria, and IgG and C3 deposition. Within glomerular cells, HDAC6i increased alpha-tubulin acetylation and decreased nuclear NF-κB. Within the spleen, there was a dose-dependent decrease in the frequency of Th17 cells and a mild decrease in the frequency of Treg cells. Concurrently, there were decreased levels of IL-12/IL-23 and minimal decreases in TGF-β in the serum. Within the bone marrow, B cell development through Hardy fractions exhibited accelerated progression through later stages as NZB/W mice aged. This accelerated progression may allow B cells to bypass important regulatory checkpoints in maintaining immune tolerance and contribute to autoimmunity. Treatment with an HDAC6i corrected the aberrant B cell development in the bone marrow and RNAseq analysis unveiled six genes (Cebpb, Ccr9, Spib, Nfil3, Lgals1, and Pou2af1) that may play a role in the aforementioned abnormalities. Overall, these findings show that HDAC6i decreased disease in NZB/W mice by targeting multiple components of the immune response, including glomerular cells, T cell subsets in the spleen, and bone marrow B cells. In conclusion, selective HDAC6i is an excellent candidate for pharmacologic therapy for SLE because it targets multiple immune abnormalities involved in SLE pathogenesis while remaining selective and safe. / Ph. D.

Aufgrund einer hohen Rate von Nierenveränderungen in einem bayrischen Schlachtunternehmen, welche jedoch nicht immer zum Ausschluss des jeweiligen Organs führten, war das Ziel dieser Arbeit, den Anteil an makroskopisch veränderten bzw. unveränderten sowie für untauglich zum menschlichen Verzehr bewerteten Nieren von Schlachtschweinen im Rahmen der Fleischuntersuchung zu erheben. Darüber hinaus sollten die Veränderungen sowohl der tauglichen als auch der untauglichen Nieren mittels pathologisch-anatomischer Untersuchung charakterisiert werden. Um zukünftige Entscheidungen bezüglich „tauglich/untauglich“ am Schlachtband zu erleichtern, erfolgte an ausgewählten typischen Läsionen eine histopathologische Untersu-chung zur Verifizierung der makroskopischen Diagnose. Des Weiteren sollte eine makroskopische und histo-logische Charakterisierung des „Status quo“ einer Schweineniere im Jahre 2012 anhand dieser Stichprobe unternommen und mit Beschreibungen in der Literatur verglichen werden. Im Untersuchungszeitraum (zwei mal fünf Tage im Juli und August 2012) wurden die Nieren von insgesamt 6235 Schlachtschweinen (120-130 kg) aus dem „Einzugsgebiet Oberbayern“ untersucht. Weitere 98 Nieren dienten als Kontrolle und der Charakterisierung einzelner Veränderungen. Am Schlachtband wurden 12 237 Nieren nach äußerer Adspektion in die Gruppen „ohne besonderen makroskopischen Befund“ (o.b.B.), „Ein-ziehungen im Bereich der Nierenrinde mit und ohne Beteiligung der Kapsel“ (E.R.m./o.K.) ohne Berücksichti-gung weiterer, eventuell zusätzlich vorliegender Befunde, „Vorliegen einer persistierenden fetalen Lappung“ (p.f.L.) und „sonstige Befunde“ unterteilt. Eine ausführliche pathologisch-anatomische Untersuchung erfolgte an insgesamt 2010 von den amtlichen Fachassistenten untauglich bewerteter Nieren. 400 Proben wurden histopathologisch mittels H.-E.-Färbung und teils unter Anwendung von Spezialfärbungen (PAS-Reaktion, Movat-Versilberung, Azan-Färbung) sowie immunhistochemischer Methoden (CD3, CD79a, MAC387, Lami-nin, PCV-2-Antigen) beurteilt. Dabei erfolgte sowohl die Charakterisierung der makroskopisch sichtbaren Läsionen, als auch die Befundung angrenzender, makroskopisch unauffälliger Parenchymanteile. Daneben standen die Daten über Konfiskatabzüge bei Lungen, Herzen und Lebern der Tiere zur Verfügung. An 75,35 % aller Nieren konnten makroskopische Befunde erhoben werden, wobei 16,91 % der Organe un-tauglich beurteilt wurden. 70,52 % der 10 168 tauglichen Nieren zeigen bei der äußeren Adspektion Läsionen (64,93 % E.R.m./o.K.; 3,10 % p.f.L.; 2,49 % sonstige Befunde). Während die Rate untauglicher Nieren zwi-schen den Untersuchungswochen (UW) vergleichbar war (15,96 % bzw. 17,90 %) traten zwischen den Un-tersuchungstagen (UT) deutliche Abweichungen (9,70 %–26,96 %) auf. Ähnliches wurde bei den tauglichen Nieren ohne einen makroskopischen Befund beobachtet (17,67 %–37,59 % pro UT bzw. 28,33 % 1. UW und 19,81 % 2. UW). Der Anteil an Schweinen mit zusätzlichen Konfiskatabzügen bei Lunge, Herz und/oder Le-ber war bei Tieren mit mindestens einer untauglichen Niere bzw. zwei tauglichen Organen nahezu gleich groß (25,62 % bzw. 23,72 %), bei solchen mit zwei tauglichen o.b.B.-Nieren betrug er 29,19 %. 2010 näher unter-suchte Nieren wiesen in 0,35 % keinen, in 21,59 % einen bzw. in 78,26 % mehr als einen (bis zu sechs) unterschiedliche Befunde auf. Bis auf das Vorliegen von Nephrosen, akuter Glomerulonephritiden sowie einiger Entwicklungsstörungen konnten alle in der Literatur beschriebenen Nephropathien der Schweineniere nachgewiesen werden. Trotz identischem makroskopischem Bild variierten die histologischen Befunde bei ausgewählten Veränderungen. Die häufigsten Läsionen untauglicher Nieren waren E.R.m.K. (bei 72,09 %), welche sich histologisch als in Binde- und Fettgewebe eingebettete arterielle, venöse und Lymphgefäße dar-stellten und am ehesten als Missbildungen zu betrachten sind. Die bei 33,88 % beobachteten E.R.o.K. zeig-ten histologisch eine Fibrose oder eine chronische interstitielle (interst.) Nephritis, wobei vermutlich prä- und postnatale Insulte an der Entstehung beteiligt waren. An schlachtungsbedingte Petechien erinnernde Herde auf der Rindenoberfläche stellten sich in 96,8 % als entzündungsassoziierte Blutungen um teils alterierte Gefäße dar. Die unterschiedlichen Formen einer nicht-eitrigen interstitiellen Nephritis (multifokal, diffus, teils mit Fibrose) konnten makroskopisch bei ca. 13,5 % der untauglichen Nieren beobachtet werden, wobei histo-logisch teils die in der Literatur beschriebenen „Entzündungspattern“, aber auch teilweise kein histomorpho-logisches Korrelat nachgewiesen werden konnte. Während die makroskopische Diagnose einer embolisch-eitrigen Herdnephritis (0,1 %) und Pyelonephritis (0,2 %) sicher gestellt werden konnte, bereitete die einer solitären Pyelitis Schwierigkeiten. Makroskopisch als akute/subakute sowie chronische „infarktähnlich“ ange-sprochene Läsionen (bei insgesamt 9,66 %) wiesen nicht das klassische histologische Bild eines Infarktes auf, sondern passen zum Teil zu vaskulopathiebedingten „Subinfarkten“ oder stellten sich als fokale interst. Nephritiden dar. In makroskopisch unveränderten Nieren (Kontrollnieren) bzw. in unveränderten Bereichen veränderter Nieren (untaugliche, taugliche veränderte Nieren) zeigten über 96 %, unabhängig vom makro-skopischen Befund, eine graduell variable mononukleäre interstitielle Nephritis. Der Nachweis von tertiärem lymphatischen Gewebe („Follikel“) schwankt, abhängig vom makroskopischen (Haupt-)Befund der Niere, zwischen 0 % und 85 % (Kontrollnieren 30 %). Darüber hinaus zeigten ca. 78 % aller Proben eine Proliferation der Mesangiumzellen und/oder Endothelzellen sowie 100 % aller Proben eine graduell variable Sklerose und/oder Hyalinose („Minimal Change Nephrotic Syndrome“). Es kann festgestellt werden, dass das in der anatomischen Literatur beschriebene makroskopische Bild der Schweineniere nur in ca. 25 % aller Nieren an diesem Schlachthof vorliegt. Bezüglich der Entscheidung „tauglich/untauglich“ am Schlachtband erweist sich die pathologisch-anatomische Untersuchung als ausrei-chend und nötig. Hinsichtlich einer exakten pathologischen und ätiologischen Diagnose sind dieser Methode jedoch Grenzen gesetzt. Die histologischen Untersuchungen zeigen, dass von dezenten nicht-eitrigen interst. Nephritiden und Pyelitiden in nahezu jeder Niere am Schlachthof auszugehen ist, was, zusammen mit den glomerulären Veränderungen und dem Auftreten des tertiären lymphatischen Gewebes, für eine chronische Immunstimmulation bzw. für subklinische Infektionen der untersuchten Schweine spricht. Von einem Ge-sundheitsrisiko für den Verbraucher dürfte beim Großteil der Läsionen nicht auszugehen sein, doch zeigt die Unsicherheit in der fleischhygienerechtlichen Bewertung angeborener oder degenerativer Defekte die Not-wendigkeit eines „Positivkataloges“ für Organe von Schlachttieren. Ob und inwieweit diese interst. Nephritis in Zukunft lebensmittelrechtlich relevant wird, bleibt abzuwarten. Diese Arbeit sollte Anlass zu aktuellen ver-gleichenden Studien geben, um regionale, epidemiologische und genetische Einflüsse auf bestimmte Läsio-nen zu untersuchen, wie sie durch NIEBERLE und COHRS (1970) vor Jahrzehnten durchgeführt wurden.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Percutaneous kidney biopsies have been performed since 1944 to establish diagnoses and treatment. Risk factors based on a limited amount of data have shown age, blood pressure, kidney function and needle size as some risk factors for biopsy complications. Although the techniques of biopsy have improved over the years, it is still an invasive procedure and serious complications can occur. The overall aim of this thesis was to obtain a large series of data from biopsy procedures and to use these to bring further light on risk factors to help minimize the risk for patients and to optimize diagnostics. Specific aims were to clarify if different factors, such as gender, diagnoses, localization of biopsies, needle types and sizes, could be useful to help minimize complication risks in native kidney biopsies (Nkb) and transplant kidney biopsies (Txb). Another point to investigate was the value of the Resistive Index (RI) obtained at ultrasound before performing Txb. Materials and methods: A protocol for prospective multicentre registration of various factors and complications associated with Nkb and Txb was designed. Consecutive data were obtained from seven hospitals. All biopsies, except one computer tomography-guided Nkb, were performed using real-time ultrasound guidance and an automated spring-loaded biopsy device. For the biopsies 14- to 20- Gauge (G) needles were used. The kidney function level, i.e. estimated glomerular filtration rate (eGFR), was calculated using the Modification of Diet in Renal Disease (MDRD) formula (GFR in mL/min per 1.73m2). For statistical analyses the IBM SPSS Statistic 22 (Armonk, NY, USA) and OpenEpi (Open Source Epidemiologic Statistics for Public Health, www.OpenEpi.com) were used. Data were presented as Odds Ratio (OR), Risk Ratio (RR) and Confidence Intervals (CI). A two sided p-value of <0.05 was considered significant. In total 1299 consecutive biopsies (1039 native and 260 transplant kidneys) in 1178 patients (456 women and 722 men) were used for investigation. The median age of patients was 55 years (range 16 to 90 years). Major (require an intervention) and minor biopsy complications (no need of intervention) were registered. Results: The overall frequency of biopsy complications for Nkb was 8.8% (major 6.7%, minor 2.1%) and for Txb was 6.5% (major 3.8%, minor 2.7%); no death. Women had a higher risk for development of major (10.7% versus 4.7%, OR 2.4, CI 1.4-4.2) and overall biopsy complications (13.2% versus 6.5%, OR 2.2, CI 1.4-3.5) compared to men in Nkb. In Nkb, major complications were more common after biopsies from the right kidney in women versus men (10.8% vs 3.1%, OR 3.7, CI 1.5–9.5), in patients with lower versus higher BMI (25.5 vs 27.3, p=0.016) and for younger versus older age (44.8 vs 52.3 years, p=0.002). Lower (90 mmHg) compared to higher (98 mmHg) mean arterial pressure in Txb indicated a risk of major complications (p=0.039). Factors such as number of passes and kidney function did not influence complication rates. Biopsy needles of 16 G compared to 18 G showed more glomeruli per pass in Nkb (11 vs 8, p<0.001) and in Txb (12 vs 8, p<0.001). Sub-analysis revealed that 18 G 19 mm side-notch needles in Nkb resulted in more major (11.3% vs 3%, OR 4.1, CI 1.4-12.3) and overall complications (12.4% vs 4.8%, OR 2.8, CI 1.1-7.1) in women than in men. If the physician had performed less compared to more than four Nkb per year, minor (3.5% vs 1.4%, OR 2.6, CI 1.1-6.2) and overall complications (11.5% vs 7.4%, OR 1.6, CI 1.1-2.5) were more common. The localization of biopsy within the kidney (Nkb and Txb) was not a risk factor for complications. Patients with IgA-nephritis compared to patients with other diseases had a higher risk of major complications (11.7% vs 6.4 %, OR 1.8, CI 1.1–3.2). More major complications were found in Nkb if they had higher versus lower degree of glomerulosclerosis (31% vs 20 %, p=0.008) and in Txb if there was a higher versus lower degree of interstitial fibrosis (82% vs 33%, p<0.001). Re-biopsies (Nkb) were more common in patients with IgA-nephritis than those with other diseases (4.7% vs 1.3 %, OR 4, CI 1.5–11), in younger versus older age (42.6 vs 52.3 years, p=0.031), and in those with a higher versus lower degree of interstitial fibrosis (63% vs 34 %, p=0.046). In Txb, a RI≥0.8 compared to RI<0.8 predicted major (13.3% vs 3.2%, RR 4.2, CI 1.3-14.1) and overall biopsy complications (16.7% vs 5.3%, RR 3.2, CI 1.2-8.6). In the group <0.8, RI correlated with age (rs=0.28, p<0.001) and systolic blood pressure (rs=0.18, p=0.02). In the group ≥0.8, RI correlated with degree of interstitial fibrosis (rs=0.65, p=0.006) and systolic blood pressure (rs=0.40, p=0.03). The multiple regression analysis showed that the <0.8 RI group correlated only with age (p<0.001), whereas the ≥0.8 RI group correlated only with the degree of interstitial fibrosis (p=0.003). Conclusions: The present results motivate greater attention to be paid to the possibility of major side-effects after Nkb in women and biopsies from their right side, but as well in younger patients, and in those with lower BMI. This also applies for patients with presumptive IgA-nephritis and higher degree of glomerulosclerosis. In Txb, patients with higher degree of interstitial fibrosis had a greater risk of major complications. Moreover, the present data indicate that Nkb and Txb should be preferably taken with 16 G needles with 20 mm sample size. This results in better histological quality and there is a lower risk for major complications as compared to 18 G needles. The localization of biopsy within the kidney (Nkb and Txb) does not alter complication rates. For Nkb there were fewer complications if the physician had performed at least four biopsies per year. A RI≥0.8 in Txb indicates a greater risk for major and overall complications.

Introdução: Pancreatite é uma manifestação incomum e com risco de vida no lúpus eritematoso sistêmico juvenil (LESJ). Objetivo: Estudar a classificação da pancreatite em pacientes com LESJ de acordo com as definições do Grupo Internacional de Estudos de Pancreatite Pediátrica (INSPPIRE) e determinar prevalência geral, características clínicas, alterações laboratoriais e prognóstico do primeiro episódio. Métodos: Um estudo de coorte retrospectivo multicêntrico incluiu 852 pacientes com LESJ estudados em 10 serviços de referência terciária de reumatologia pediátrica. Resultados: Pancreatite foi diagnosticada em 22 de 852 (2.6%) pacientes com LESJ. Foram classificados como pancreatite aguda em 20 (91%), pancreatite aguda recorrenteem 2 (9%), e nenhum deles apresentou pancreatite crônica. Nenhum deles tinha cálculos biliares, pancreatite traumática, ou relatou o uso de álcool e/ou tabagismo. A comparação dos pacientes com pancreatite (primeiro episódio) e sem esta complicação, revelou uma menor duração da doença [1 (0-10) vs. 4 (0-23) anos, P < 0,0001] e maior mediana do Índice de Atividade de Doença do LES 2000 [21 (0-41) vs. 2 (0-45), P < 0,0001]. A frequência de febre (P < 0,0001), perda de peso (P < 0,0001), serosite (P < 0,0001), nefrite (P < 0,0001), hipertensão arterial (P < 0,0001), insuficiência renal aguda (P < 0,0001), síndrome de ativação macrofágica (P < 0,0001), e morte (P=0,001) foram maiores em pacientes com pancreatite. A freqüência de metilprednisolona endovenosa (P < 0,0001) e a mediana da prednisona [55 (15-60) vs. 11 (1-90) mg/dia, P < 0,0001] foram significantemente maiores em pacientes com pancreatite. Dois pacientes apresentavam pancreatite aguda recorrente com dois episódios distintos, com intervalo sem dor entre os dois episódios de 1 e 4 anos. Conclusão: Este foi o primeiro estudo classificando a pancreatite usando as definições do Grupo Internacional de Estudos de Pancreatite Pediátrica em pacientes com LESJ mostrando uma predominância da pancreatite aguda associado ao tratamento com glicocorticóide e atividade grave da doença / Introduction: Pancreatitis is a rare and a life-threatening systemic lupus erythematosus (SLE) manifestation in childhood-onset SLE (cSLE). Objective: To study the classification of pancreatitis in cSLE according to the International Study Group of Pediatric Pancreatitis and determine the overall prevalence, clinical features, laboratory, and first episode outcomes. Methods: A multicenter cohort study in 10 pediatric rheumatology centers, included 852 patients with cSLE. Results: Pancreatitis was diagnosed in 22 of 852 (2.6%) patients with cSLE. It was classified as acute pancreatitis in 20 (91%), acute recurrent pancreatitis in 2 (9%), and none of them had chronic pancreatitis. None of them had gallstones, traumatic pancreatitis, or reported alcohol/tobacco use. The comparison of patients with pancreatitis (first episode) and without this complication revealed a shorter disease duration [1 (0-10) vs. 4 (0-23) anos, P<0.0001] and higher median of Systemic Lupus Erythematosus Disease Activity Index 2000 [21 (0-41) vs. 2 (0-45), P < 0.0001]. The frequencies of fever (P < 0.0001), weight loss (P < 0.0001), serositis (P < 0.0001), nephritis (P < 0.0001), arterial hypertension (P < 0.0001), acute renal failure (P < 0.0001), macrophage activation syndrome (P < 0.0001), and death (P=0.001) were also higher in patients with pancreatitis. The frequencies of intravenous methylprednisolone use (P < 0.0001) and the median of prednisone dose [55 (15-60) vs. 11 (1-90) mg/dia, P<0.0001] were significantly higher in patients with pancreatitis. Of note, the 2 patients with acute recurrent pancreatitis had 2 episodes, with pain free interval of 1 and 4 years. Conclusions: This was the first study characterizing pancreatitis using the International Study Group of Pediatric Pancreatitis standardized definitions in patients with cSLE showing that the predominant form is acute pancreatitis seen in association with glucocorticoid treatment and active severe disease

Proteinúria é a principal manifestação da nefrite lúpica (NL) e reflete lesão no podócito. Análise dos biomarcadores do podócito foi realizada com o objetivo de identificar se o fenótipo podocitário é distinto na NL membranosa pura e proliferativa. Expressão de sinaptopodina, proteína 1 do tumor de Wilms (Wilms tumor protein 1 - WT1), proteína epitelial glomerular 1 (glomerular epitelial protein 1 - GLEPP1) e nefrina foi avaliada em 52 biópsias de NL por imunohistoquímica. Expressão preservada de sinaptopodina foi observada em apenas 10 (19,2%) de todas as biópsias enquanto que 42 (80,8%) apresentavam expressão reduzida. Ambos os grupos tinham proteinúria semelhante no momento da biópsia (p = 0,22), porém, no seguimento médio de quatro anos houve uma tendência para menores níveis médios de proteinúria nos pacientes com marcação preservada de sinaptopodina (0,26 ± 0,23 vs 0,84 ± 0,90 g/24 h, p = 0,05) do que naqueles com expressão reduzida. Trinta e nove (75%) biópsias foram classificadas como proliferativa e treze (25%) como membranosa pura. Comparação dos biomarcadores do podócito demonstrou predomíno de marcação preservada de sinaptopodina (69,2%), WT1 (69,2%), GLEPP1 (53,9%) e nefrina (60%) no grupo membranosa pura enquanto apenas < 10% das proliferativas apresentaram expressão preservada. Nossos dados sugerem que nas classes proliferativas parece haver lesão estrutural do podócito, enquanto que na membranosa pura o padrão predominantemente preservado sugere uma lesão funcional do podócito que pode ser responsável pelo melhor prognóstico a longo prazo do desfecho da proteinúria / Proteinuria is a major feature of lupus nephritis (LN) and reflects podocyte injury. Analysis of podocyte biomarkers was performed attempting to identify if podocyte phenotype is distinct in pure membranous and proliferative LN. Expression of synaptopodin, Wilms tumor protein 1 (WT1), glomerular epithelial protein 1 (GLEPP1) and nephrin was evaluated in 52 LN biopsies by immunohistochemistry. Preserved synaptopodin expression was observed in only 10 (19,2%) of all biopsies while 42 (80,8%) had a reduced expression. Both groups had comparable proteinuria at the time of biopsy (p=0,22), however, in the mean follow-up of four years there was a tendency to lower mean levels of proteinuria in patients with preserved synaptopodin staining (0,26 ± 0,23 vs. 0,84 ± 0,90 g/24 h, p=0,05) than those with diminished expression. Thirty-nine (75%) biopsies were classified as proliferative and thirteen (25%) as pure membranous. Comparison of podocyte biomarkers demonstrated a predominance of preserved staining of synaptopodin (69,2%), WT1 (69,2%), GLEPP1 (53,9%) and nephrin (60%) in the pure membranous group whereas only < 10% of the proliferative showed preserved expression. Our data suggest that in proliferative forms there seems to occur structural podocyte damage, whereas in the pure membranous the predominant preserved pattern suggests a dysfunctional podocyte lesion that may account for the better long-term prognosis of proteinuria outcome

Introdução: Pancreatite é uma manifestação incomum e com risco de vida no lúpus eritematoso sistêmico juvenil (LESJ). Objetivo: Estudar a classificação da pancreatite em pacientes com LESJ de acordo com as definições do Grupo Internacional de Estudos de Pancreatite Pediátrica (INSPPIRE) e determinar prevalência geral, características clínicas, alterações laboratoriais e prognóstico do primeiro episódio. Métodos: Um estudo de coorte retrospectivo multicêntrico incluiu 852 pacientes com LESJ estudados em 10 serviços de referência terciária de reumatologia pediátrica. Resultados: Pancreatite foi diagnosticada em 22 de 852 (2.6%) pacientes com LESJ. Foram classificados como pancreatite aguda em 20 (91%), pancreatite aguda recorrenteem 2 (9%), e nenhum deles apresentou pancreatite crônica. Nenhum deles tinha cálculos biliares, pancreatite traumática, ou relatou o uso de álcool e/ou tabagismo. A comparação dos pacientes com pancreatite (primeiro episódio) e sem esta complicação, revelou uma menor duração da doença [1 (0-10) vs. 4 (0-23) anos, P < 0,0001] e maior mediana do Índice de Atividade de Doença do LES 2000 [21 (0-41) vs. 2 (0-45), P < 0,0001]. A frequência de febre (P < 0,0001), perda de peso (P < 0,0001), serosite (P < 0,0001), nefrite (P < 0,0001), hipertensão arterial (P < 0,0001), insuficiência renal aguda (P < 0,0001), síndrome de ativação macrofágica (P < 0,0001), e morte (P=0,001) foram maiores em pacientes com pancreatite. A freqüência de metilprednisolona endovenosa (P < 0,0001) e a mediana da prednisona [55 (15-60) vs. 11 (1-90) mg/dia, P < 0,0001] foram significantemente maiores em pacientes com pancreatite. Dois pacientes apresentavam pancreatite aguda recorrente com dois episódios distintos, com intervalo sem dor entre os dois episódios de 1 e 4 anos. Conclusão: Este foi o primeiro estudo classificando a pancreatite usando as definições do Grupo Internacional de Estudos de Pancreatite Pediátrica em pacientes com LESJ mostrando uma predominância da pancreatite aguda associado ao tratamento com glicocorticóide e atividade grave da doença / Introduction: Pancreatitis is a rare and a life-threatening systemic lupus erythematosus (SLE) manifestation in childhood-onset SLE (cSLE). Objective: To study the classification of pancreatitis in cSLE according to the International Study Group of Pediatric Pancreatitis and determine the overall prevalence, clinical features, laboratory, and first episode outcomes. Methods: A multicenter cohort study in 10 pediatric rheumatology centers, included 852 patients with cSLE. Results: Pancreatitis was diagnosed in 22 of 852 (2.6%) patients with cSLE. It was classified as acute pancreatitis in 20 (91%), acute recurrent pancreatitis in 2 (9%), and none of them had chronic pancreatitis. None of them had gallstones, traumatic pancreatitis, or reported alcohol/tobacco use. The comparison of patients with pancreatitis (first episode) and without this complication revealed a shorter disease duration [1 (0-10) vs. 4 (0-23) anos, P<0.0001] and higher median of Systemic Lupus Erythematosus Disease Activity Index 2000 [21 (0-41) vs. 2 (0-45), P < 0.0001]. The frequencies of fever (P < 0.0001), weight loss (P < 0.0001), serositis (P < 0.0001), nephritis (P < 0.0001), arterial hypertension (P < 0.0001), acute renal failure (P < 0.0001), macrophage activation syndrome (P < 0.0001), and death (P=0.001) were also higher in patients with pancreatitis. The frequencies of intravenous methylprednisolone use (P < 0.0001) and the median of prednisone dose [55 (15-60) vs. 11 (1-90) mg/dia, P<0.0001] were significantly higher in patients with pancreatitis. Of note, the 2 patients with acute recurrent pancreatitis had 2 episodes, with pain free interval of 1 and 4 years. Conclusions: This was the first study characterizing pancreatitis using the International Study Group of Pediatric Pancreatitis standardized definitions in patients with cSLE showing that the predominant form is acute pancreatitis seen in association with glucocorticoid treatment and active severe disease

Proteinúria é a principal manifestação da nefrite lúpica (NL) e reflete lesão no podócito. Análise dos biomarcadores do podócito foi realizada com o objetivo de identificar se o fenótipo podocitário é distinto na NL membranosa pura e proliferativa. Expressão de sinaptopodina, proteína 1 do tumor de Wilms (Wilms tumor protein 1 - WT1), proteína epitelial glomerular 1 (glomerular epitelial protein 1 - GLEPP1) e nefrina foi avaliada em 52 biópsias de NL por imunohistoquímica. Expressão preservada de sinaptopodina foi observada em apenas 10 (19,2%) de todas as biópsias enquanto que 42 (80,8%) apresentavam expressão reduzida. Ambos os grupos tinham proteinúria semelhante no momento da biópsia (p = 0,22), porém, no seguimento médio de quatro anos houve uma tendência para menores níveis médios de proteinúria nos pacientes com marcação preservada de sinaptopodina (0,26 ± 0,23 vs 0,84 ± 0,90 g/24 h, p = 0,05) do que naqueles com expressão reduzida. Trinta e nove (75%) biópsias foram classificadas como proliferativa e treze (25%) como membranosa pura. Comparação dos biomarcadores do podócito demonstrou predomíno de marcação preservada de sinaptopodina (69,2%), WT1 (69,2%), GLEPP1 (53,9%) e nefrina (60%) no grupo membranosa pura enquanto apenas < 10% das proliferativas apresentaram expressão preservada. Nossos dados sugerem que nas classes proliferativas parece haver lesão estrutural do podócito, enquanto que na membranosa pura o padrão predominantemente preservado sugere uma lesão funcional do podócito que pode ser responsável pelo melhor prognóstico a longo prazo do desfecho da proteinúria / Proteinuria is a major feature of lupus nephritis (LN) and reflects podocyte injury. Analysis of podocyte biomarkers was performed attempting to identify if podocyte phenotype is distinct in pure membranous and proliferative LN. Expression of synaptopodin, Wilms tumor protein 1 (WT1), glomerular epithelial protein 1 (GLEPP1) and nephrin was evaluated in 52 LN biopsies by immunohistochemistry. Preserved synaptopodin expression was observed in only 10 (19,2%) of all biopsies while 42 (80,8%) had a reduced expression. Both groups had comparable proteinuria at the time of biopsy (p=0,22), however, in the mean follow-up of four years there was a tendency to lower mean levels of proteinuria in patients with preserved synaptopodin staining (0,26 ± 0,23 vs. 0,84 ± 0,90 g/24 h, p=0,05) than those with diminished expression. Thirty-nine (75%) biopsies were classified as proliferative and thirteen (25%) as pure membranous. Comparison of podocyte biomarkers demonstrated a predominance of preserved staining of synaptopodin (69,2%), WT1 (69,2%), GLEPP1 (53,9%) and nephrin (60%) in the pure membranous group whereas only < 10% of the proliferative showed preserved expression. Our data suggest that in proliferative forms there seems to occur structural podocyte damage, whereas in the pure membranous the predominant preserved pattern suggests a dysfunctional podocyte lesion that may account for the better long-term prognosis of proteinuria outcome

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 3 uppsatser.