Clinical Characteristics of EGPA Patients in Comparison to GPA Subgroup with Increased Blood Eosinophilia from POLVAS Registry.

Objective: To characterize the eosinophilic granulomatosis with polyangiitis (EGPA) population from the POLVAS registry depending on ANCA status and diagnosis onset, including their comparison with the granulomatosis with polyangiitis (GPA) subset with elevated blood eosinophilia (min. 400/µl) (GPA HE) to develop a differentiating strategy. Methods: A retrospective analysis of the POLVAS registry. Results: The EGPA group comprised 111 patients. The ANCA-positive subset (n = 45 [40.54%]) did not differ from the ANCA-negative one in clinics. Nevertheless, cardiovascular manifestations were more common in ANCA-negative patients than in those with anti-myeloperoxidase (MPO) antibodies (46.97% vs. 26.92%, p = 0.045). Patients diagnosed before 2012 (n = 70 [63.06%]) were younger (median 41 vs. 49 years, p < 0.01), had higher blood eosinophilia at diagnosis (median 4,946 vs. 3,200/µl, p < 0.01), and more often ear/nose/throat (ENT) and cardiovascular involvement. GPA HE comprised 42 (13.00%) out of 323 GPA cases with reported blood eosinophil count. Both GPA subsets had a lower prevalence of respiratory, cardiovascular, and neurologic manifestations but more often renal and ocular involvement than EGPA. EGPA also had cutaneous and gastrointestinal signs more often than GPA with normal blood eosinophilia (GPA NE) but not GPA HE. The model differentiating EGPA from GPA HE, using ANCA status and clinical manifestations, had an AUC of 0.92, sensitivity of 96%, and specificity of 95%. Conclusion: Cardiovascular symptoms were more prevalent in the ANCA-negative subset than in the MPO-ANCA-positive one. Since EGPA and GPE HE share similarities in clinics, diagnostic misleading may result in an inappropriate therapeutic approach. Further studies are needed to optimize their differentiation and tailored therapy, including biologics.

Antiphospholipid Syndrome in Renal Allograft Recipients-A Long-Term Multicenter Analysis.

Antiphospholipid syndrome (APS) is a devastating autoimmune disease and in renal transplant recipients may result in allograft thrombosis or in extra-renal manifestation, mostly venous thromboembolism. There are many non- and immune risk factors affecting renal allograft in recipients with APS. However, renal allograft outcome in recipients with APS without APS nephropathy remains unknown. Aim: The aim of the study was to assess renal allograft function and survival in recipients with APS. Methods: Retrospective, multicenter study included 19 adult renal recipients with definite APS (primary or lupus-related) from three Polish transplant centers. Renal allograft function was assessed using serum creatinine concentration (SCr1) at 3rd month post-transplant and at the end of the observation (SCr2) and glomerular filtration rate (GFR) was estimated based on modification of diet in renal disease (MDRD) formula. General linear model was used to assess 12 month GFR change over time. Kaplan-Meier curves and restricted mean survival time were used for allograft survival. Matched control group consisted of 21 stable renal recipients without history of thrombosis and without anticoagulation/antiplatelet treatment. Results: The study group differs in induction therapy (p = 0.019), high-urgency procedure (p = 0.04), proteinuria (p = 0.0058), primary disease (lupus) (p < 0.0001), re-transplantation in primary APS (p = 0.0046) and shorter time since engraftment to SCr2 (p = 0.016). Primary APS was more often diagnosed post-transplant (p = 0.0005). Allograft biopsy revealed thrombotic microangiopathy (TMA) with acute rejection (AR) or isolated AR vs AR or chronic rejection in controls but did not reach significance (p = 0.054). Renal allograft function was inferior in the study group but did not reach significance: mean SCr2 (mg/dL) was 2.18 ± 1.41 and 1.5 ± 0.68 in controls, respectively, p = 0.27; mean GFR2 (ml/min/1.73m2) was 39.9 ± 20.83 and 51.23 ± 19.03, respectively, p = 0.102. Renal allograft duration was inferior in patients with APS and was (in years) 11.22 ± 1.44 vs. 14.36 ± 0.42, respectively, p = 0.037, in patients with primary APS (p = 0.021), in patients with APS diagnosed post-transplant (p = 0.012) but not in lupus-related APS (p = ns). Fifteen year renal allograft survival was inferior in APS vs. controls (73,86% vs. 90.48%, respectively, p = 0.049). Conclusions: Recipients with APS are at higher risk for allograft loss due to immune and non-immune causes. Renal allograft survival was inferior in recipients with APS and renal function remains impaired but stable.

Respiratory involvement in antineutrophil cytoplasmic antibody-associated vasculitides: a retrospective study based on POLVAS registry.

OBJECTIVES: The study aimed to characterise the Polish population of (ANCA)-associated vasculitides (AAV) with respiratory involvement (RI), in comparison to the subgroup without lung manifestations and the other cohorts. METHODS: Retrospective analysis of the Polish population of AAV with RI was conducted, based on data from the POLVAS registry. Standard descriptive statistics, χ2 test, and Mann-Whitney U test were used to perform comparisons. RESULTS: Among 461 cases qualified to this study, there were 316 cases with RI (68.5%), 206 with granulomatosis with polyangiitis (GPA) (65.2%), 80 with eosinophilic granulomatosis with polyangiitis (EGPA) (25.3%) and 30 with microscopic polyangiitis (MPA) (9.5%). Proportion of RI in GPA, MPA, and EGPA accounted for 67.8%; 40.0%; 97.6%, respectively. The number of relapses was higher in the RI group (median 1.0 vs. 0.0; p=0.01). In the subgroup of combined GPA and MPA with RI, the trends toward higher proportion of deaths (11.7% vs. 5.7%; p=0.07), relapses requiring hospitalisation (52.2% vs. 42.4%, p=0.07) and relapses requiring admission to the intensive care unit (5.6% vs. 1.4%, p=0.09) were observed, median maximal concentration of CRP was higher (46 vs. 25 mg/l; p=0.01) and more aggressive treatment was administered. CONCLUSIONS: Prevalence of RI in the Polish population of AAV is similar to the values reported in the literature, however, the proportion observed in GPA is closer to those presented in Asian than Western European cohorts. RI seems to be associated with a more severe course of disease and its presence prompts more aggressive treatment.

Subphenotypes of ANCA-associated vasculitis identified by latent class analysis.

OBJECTIVES: ANCA-associated vasculitides (AAV) are a heterogeneous group of rare diseases with unknown aetiology and the clinical spectrum ranging from life-threatening systemic disease, through single organ involvement to minor isolated skin changes. Thus, there is an unmet need for phenotype identification, especially among patients with granulomatosis with polyangiitis (GPA). Patients with microscopic polyangiitis (MPA) seem to be clinically much more uniform. Recently, three subcategories of AAV have been proposed and described as non-severe AAV, severe PR3-AAV, and severe MPO-AAV. METHODS: In line with these attempts, we decided to use an unbiased approach offered by latent class analysis (LCA) to subcategorise GPA and MPA in a large cohort of Polish AAV patients included in a multicentre POLVAS registry. RESULTS: LCA of our AAV group identified a four-class model of AAV, including previously proposed three subphenotypes and revealing a fourth (previously not described) clinically relevant subphenotype. This new subphenotype includes only GPA patients, usually diagnosed at a younger age as compared to other groups, and characterised by multiorgan involvement, high relapse rate, relatively high risk of death, but no end-stage kidney disease. CONCLUSIONS: Based on multiple clinical and serological variables, LCA methodology identified 4-class model of AAV. This newly described fourth class of AAV may be of clinical relevance and may require prompt diagnosis and aggressive treatment due to the multiorgan involvement, high risk of relapse and marked mortality among these relatively young GPA subjects.

Pregnancy After Kidney Transplantation With Maternal and Pediatric Outcomes: A Single-Center Experience.

Outcomes of pregnancies after kidney transplantation were evaluated. Thirty-one pregnancies in 26 women were noted. The mean maternal age at pregnancy was 31 ± 5 years (range, 23-44 years). The interval between transplantation and conception was 54 ± 51 months (range, 7-213 months). The mean serum creatinine concentration before conception was 1.28 ± 0.4 mg/dL (range, 0.8-2.45 mg/dL), and mean estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration) was 62 ± 18 mL/min/1.73 m2 (range, 27-106 mL/min/1.73 m2). There were no maternal deaths. There was 1 case of suspected acute rejection after delivery. There was 1 case of graft loss during pregnancy. Maternal complications included edema (6/26), hypertension (7/26), increase of (2/26) or appearance of proteinuria (5/26), and preeclampsia (4/26). Mean creatinine increase during pregnancy was 0.02 mg/dL. Mean creatinine 1 year after pregnancy was 1.54 mg/dL (±0.8 mg/dL). There were 19 cesarean sections. Fetal outcomes included 25 live births, 4 abortions, and 2 stillbirths. Out of 25 live births, 22 children were considered healthy, 2 children had congenital defects, and there were 2 deaths at neonatal age. Mean pregnancy age was 35 ± 4 weeks (range, 24-40 weeks). The rate of premature deliveries was 15 of 25. Mean neonate birth weight was 2363 ± 1029 grams (range, 490-4100 grams). The rate of babies small for gestational age was 19%. During follow-up (range, 0.5-30 years) 5 of 26 patients lost grafts (between 3 and 15 years after pregnancy); most (20) of the children previously considered healthy had good long-term development. Our results confirm that risk of pregnancy in kidney transplant recipients can be accepted, and children considered healthy at delivery develop well.

Nanodiamond phantoms mimicking human liver: perspective to calibration of T1 relaxation time in magnetic resonance imaging.

Phantoms of biological tissues are materials that mimic the properties of real tissues. This study shows the development of phantoms with nanodiamond particles for calibration of T1 relaxation time in magnetic resonance imaging. Magnetic resonance imaging (MRI) is a commonly used and non-invasive method of detecting pathological changes inside the human body. Nevertheless, before a new MRI device is approved for use, it is necessary to calibrate it properly and to check its technical parameters. In this article, we present phantoms of tissue with diamond nanoparticles dedicated to magnetic resonance calibration. The method of producing phantoms has been described. As a result of our research, we obtained phantoms that were characterized by the relaxation time T1 the same as the relaxation time of the human tissue T1 = 810.5 ms. Furthermore, the use of diamond nanoparticles in phantoms allowed us to tune the T1 value of the phantoms which open the way to elaborated phantoms of other tissues in the future.

Alterations in peripheral blood B cells in systemic lupus erythematosus patients with renal insufficiency.

OBJECTIVE: Systemic lupus erythematosus (SLE) is one of the autoimmune diseases, believed to be closely related to hyperactivity of B cells, overproduction of autoantibodies and immune complex formation and deposition in affected tissue. The autoreactive inflammation leads to multiorgan damage with kidney dysfunction in the forefront. Studies on lupus nephritis (LN), affecting the majority of SLE patients, are mainly focused on cells causing local inflammation. The aim of our work was to detect alterations in more accessible peripheral blood B cells in the course of SLE focusing on the influence of renal insufficiency (RI) on those parameters. METHODS: We performed a comprehensive flow cytometry analysis of B cell subpopulations, analyzed gene expression patterns with qPCR, and examined serum cytokine levels with multiplex cytokine/chemokine assay. RESULTS: We discovered distribution of specific B cell subsets, especially CD38+ cells, plasmablasts, associated with the presence and severity of the disease. Changes in expression of MBD2, DNMT1 and APRIL genes were not only associated with activity of SLE but also were significantly changed in patients with RI. CONCLUSIONS: All these results shed new light on the role of circulating B cells, their subpopulations, function, and activity in the SLE with kidney manifestation.

Transcriptomic and Epigenetic Alterations in Dendritic Cells Correspond With Chronic Kidney Disease in Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a serious autoimmune disease with variety of organ manifestations. The most dreadful one, affecting the majority of SLE patients, is kidney manifestation-lupus nephritis (LN). Dendritic cells (DC) are believed to be one of the culprits of immune dysregulation in LN. Flow cytometry analysis was applied to identify the frequency and activity of peripheral blood DCs subpopulations: myeloid and plasmacytoid, in LN patients. Magnetically isolated mDCs and pDCs were subjected to molecular analysis of genes expression, evaluation of global DNA methylation and histone H3 methylation. We observed distinctive features of DCs associated with the stages of nephritis in LN patients. Lower numbers of pDCs were observed in patients with severe LN, while increased co-stimulatory potential of mDCs was connected with the early, mild stage of this disease. IRF1 transcript upregulation was specific for mDCs from total LN patients, while exceptional amount of IRF1 mRNA was detected in mDCs from severe LN patients. DCs DNA hypermethylation seemed characteristic for severe LN, whereas a decrease in H3K4me3 and H3K27me3 marks was significant for the early stages of LN. These findings present dendritic cell alterations that may reflect renal involvement in SLE, laying foundations for new strategy of diagnosis and monitoring of LN patients, omitting invasive kidney biopsies.

Label-free optical detection of cyclosporine in biological fluids.

In this paper, a spectroscopic method for determination of cyclosporine concentrations in biological fluids is presented. Blood plasma and hemoglobin solutions are chosen for the experiment. For various cyclosporine concentrations in blood plasma and hemoglobin, absorbance measurements in spectra range from 600 to 1100 nm are performed. The measurement results are analyzed by the use of a dedicated algorithm. The obtained data are characterized by a high coefficient of correlation R2 , which is equal to 0.9461 and 0.9808 for blood plasma and hemoglobin, respectively. The proposed method enables the selective detection of cyclosporine level and could be applied in medicine and laboratory diagnostics. The obtained result can be the base to build the point-of-care CsA level detection optical sensor.

Optical-Spectrometry-Based Method for Immunosuppressant Medicine Level Detection in Aqueous Solutions.

In this paper, an investigation into detecting immunosuppressive medicine in aqueous solutions using a spectrometry-based technique is described. Using optical transmissive spectrometry, absorbance measurements in the spectra range from 250 nm to 1000 nm were carried out for different cyclosporine A (CsA) concentrations in aqueous solutions. The experiment was conducted for samples both with and without interferent substances—glucose and sodium chloride. Using a dedicated algorithm, the measured data was analyzed and a high correlation coefficient R² = 0.8647 was achieved. The experiment showed that the described technique allowed for the detection of various CsA concentration levels in a selective, label-free and simple way. This method could be used in medicine, veterinary medicine and laboratory diagnostics.

The usefulness of histopathological examinations of non-renal biopsies in the diagnosis of granulomatosis with polyangiitis.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is a rare, ANCA-associated, systemic disease characterized by necrotizing small and medium vessel vasculitis of unknown etiology associated with granulomatous inflammation affecting the renal, pulmonary, upper airways, ocular systems and other tissues. Histological proof of the granulomatosis with polyangiitis (GPA) can be obtained by biopsy of clinically involved sites. The main purpose of this study was to examine histopathological changes in non-renal biopsies from patients with established diagnosis of GPA and evaluated the histological confirmation at diagnosis of this disease. MATERIAL AND METHODS: A retrospective analysis was performed in patients with GPA diagnosed and treated in clinics of the University Clinical Center (UCK) in Gdansk in 1988-2009. RESULTS: In the analyzed group of GPA patients the histopathological examination of biopsies taken from involved tissues (except kidney) was performed in 60% of patients. Thirty-six out of 93 biopsies (39%) were diagnosed as typical of GPA, 10 (10.7%) were suggestive and 51 (54.8%) were non-specific. Considering all biopsies, the diagnosis was confirmed in 24 patients (57% of patients in whom biopsies were taken). Epitheloid cell granulomas were present in 33 biopsies (43%), characteristic necrosis in 27 biopsies (35%), small vessel vasculitis in 18 biopsies (23%), while multinucleated giant cells were identified only in 9 biopsies (12%). CONCLUSIONS: Histopathological examination of the affected tissues remains the gold standard of the diagnosis of GPA. Its usefulness increases, particularly in ANCA-negative patients, in the initial phase of the disease, or in patients with atypical clinical presentation. In many cases, it is necessary to repeat biopsy to establish the diagnosis. The role of the histopathological examination seems to be particularly important when ANCA is negative or clinical symptoms are atypical of GPA.

Kidney disease in the elderly: biopsy based data from 14 renal centers in Poland.

BACKGROUND: Longer life expectancy is associated with an increasing prevalence of kidney disease. Aging itself may cause renal damage, but the spectrum of kidney disorders that affect elderly patients is diverse. Few studies, mostly form US, Asia and West Europe found differences in the prevalence of some types of kidney diseases between elderly and younger patients based on renal biopsy findings, with varied proportion between glomerulopathies and arterionephrosclerosis as a dominant injury found. Here, for the first time in Eastern Europe we analyzed native kidney biopsy findings and their relationship to clinical characteristics at the time of biopsy in elderly individuals (aged ≥65) in comparison to younger adults (aged 18-64). METHODS: Biopsy and clinical data from 352 patients aged ≥65 were retrospectively identified, analyzed and compared with a control group of 2214 individuals aged 18-64. All kidney biopsies studied were examined at Medical University of Warsaw in years 2009-14. RESULTS: In elderly patients the leading indication for biopsy was nephrotic range proteinuria without hematuria (34.2%) and the most prevalent pathologic diagnoses were: membranous glomerulonephritis (MGN) (18.2%), focal segmental glomerulosclerosis (FSGS) (17.3%) amyloidosis (13.9%) and pauci immune glomerulonephritis (12.8%). Hypertension and age-related lesions very rarely were found an exclusive or dominant finding in a kidney biopsy (1.7%) and a cause of proteinuria (1.1%) in elderly individuals. There were 18.2% diabetics among elderly individuals, and as much as 75% of them had no morphologic signs of diabetic kidney disease in the renal biopsy. Amyloidosis, MGN, pauci immune GN, crescentic GN and light and/or heavy chain deposition disease (LCDD/HCDD) were more frequent whereas IgA nephropathy (IgAN), lupus nephritis (LN) and thin basement membrane disease (TBMD) were less common among elderly than in younger patients. CONCLUSIONS: Proteinuria, a dominating manifestation in elderly patients subjected to kidney biopsy was most commonly related to glomerulopathies. The relatively high prevalence of potentially curative kidney diseases in elderly individuals implicates the importance of renal biopsy in these patients.

Gastrointestinal tract involvement in granulomatosis with polyangiitis.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is a necrotising vasculitis of small arteries and veins. In its classical manifestation GPA affects the upper and lower respiratory tract and kidneys. However, other organs, including those of the gastrointestinal tract, may be affected as well. AIM: To present the clinical manifestations of gastrointestinal tract involvement in patients with GPA. MATERIAL AND METHODS: We analysed case records of 34 patients with GPA treated in the Department of Nephrology, Transplantology, and Internal Medicine of the Medical University of Gdansk from 1991 to 2009. RESULTS: In 9 of 34 patients, 2 men and 7 women, aged 18 to 74 years, gastrointestinal complications were observed in the course of GPA. In two of them a localised and in seven a generalised type of GPA was diagnosed. The main symptoms relating to gastrointestinal tract were: oral mucosa ulcerations, gum mucosa hypertrophy, dyspepsia, vomiting, stomachache, gastrointestinal haemorrhage, diarrhoea, and symptoms of gastrointestinal tract perforation. Two patients required urgent surgical treatment. In 2 of the 5 patients who developed gastrointestinal bleeding, it was the direct cause of death. The histopathological confirmation of specificity of changes in gastrointestinal tract was established only in 2 cases. Tissue samples collected during endoscopy usually revealed only nonspecific inflammation or the presence of ulcers. CONCLUSIONS: Therapeutic strategies accepted for GPA treatment are effective in treating patients with gastrointestinal involvement in the course of the disease. Some complications require surgical intervention.

[Mycophenolate mofetil--20 years of experience in treatment of rheumatic diseases]. / Mykofenolan mofetylu - 20 lat doswiadczen w leczeniu chorób reumatycznych

Mycophenolate mofetil (MMF) has been used in rheumatology for over 20 years. When transformed to the active metabolite of mycophenolic acid, it is a potent, selective, reversible inhibitor of inosine monophosphate dehydrogenase, a key enzyme of de novo purine synthesis, exerting a cytostatic effect on T and B cells. It also induces apoptosis of antigen-activated T cell clones, reduces the production of antibodies to inhibit the expression of adhesion molecules, reducing the influx of leukocytes and monocytes to inflammatory sites, and has anti-fibrotic properties. Although the main branch of medicine that uses MMF is transplantation, rheumatologists experienced in application of this drug confirmed its usefulness in the treatment of connective tissue diseases. In comparison with immunosuppressives available in rheumatology, MMF has a very good safety profile and is well tolerated by patients. Through multi-center, randomized, controlled clinical trials, MMF has become well established in the treatment of lupus nephritis. Conclusions about its effectiveness in other rheumatologic indications are not entirely clear, being derived from small clinical trials, observational studies and case reports. They suggest that MMF may also be used to treat extrarenal symptoms of SLE, interstitial lung disease in the course of SSc (systemic sclerosis), PM/DM (polymyositis/dermatomyositis), and skin lesions in these diseases, myositis and systemic vasculitis. It should be emphasized that MMF has proved effective in many cases complicated by multidrug resistance to immunosuppressive therapy and has allowed a significant reduction of long-term corticotherapy or its withdrawal.