Clinical characteristics of Polish patients with ANCA-associated vasculitides-retrospective analysis of POLVAS registry.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare small to medium-size vessel systemic diseases. As their clinical picture, organ involvement, and factors influencing outcome may differ between countries and geographical areas, we decided to describe a large cohort of Polish AAV patients coming from several referral centers-members of the Scientific Consortium of the Polish Vasculitis Registry (POLVAS). METHODS: We conducted a systematic multicenter retrospective study of adult patients diagnosed with AAV between Jan 1990 and Dec 2016 to analyze their clinical picture, organ involvement, and factors influencing outcome. Patients were enrolled to the study by nine centers (14 clinical wards) from seven Voivodeships populated by 22.3 mln inhabitants (58.2% of the Polish population). RESULTS: Participating centers included 625 AAV patients into the registry. Their distribution was as follows: 417 patients (66.7%) with GPA, 106 (17.0%) with MPA, and 102 (16.3%) with EGPA. Male-to-female ratios were almost 1:1 for GPA (210/207) and MPA (54/52), but EGPA was twice more frequent among women (34/68). Clinical manifestations and organ involvement were analyzed by clinical phenotype. Their clinical manifestations seem very similar to other European countries, but interestingly, men with GPA appeared to follow a more severe course than the women. Fifty five patients died. In GPA, two variables were significantly associated with death: permanent renal replacement therapy (PRRT) and respiratory involvement (univariate analysis). In multivariate analysis, PRRT (OR = 5.3; 95% confidence interval (CI) = 2.3-12.2), respiratory involvement (OR = 3.2; 95% CI = 1.06-9.7), and, in addition, age > 65 (OR = 2.6; 95% CI = 1.05-6.6) were independently associated with death. In MPA, also three variables were observed to be independent predictors of death: PRRT (OR = 5.7; 95% CI = 1.3-25.5), skin involvement (OR = 4.4; 95% CI = 1.02-19.6), and age > 65 (OR = 6.3; 95% CI = 1.18-33.7). CONCLUSIONS: In this first multicenter retrospective study of the Polish AAV patients, we have shown that their demographic characteristics, disease manifestations, and predictors of fatal outcome follow the same pattern as those from other European countries, with men possibly suffering from more severe course of the disease.

Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD.

Prevalence and correlates of suicidal thoughts in patients with neuropsychiatric lupus.

BACKGROUND: Suicidal ideation is observed in patients with systemic lupus erythematosus (SLE). No study on this notable phenomenon in neuropsychiatric SLE (NPSLE) is available so far. METHODS: Participants were 53 consecutive outpatients with NPSLE (48 women; mean age 43.8 years) diagnosed according to the American College of Rheumatology nomenclature for SLE neuropsychiatric syndromes. A Neuropsychiatric Questionnaire (NP-Q) concerning 45 neurological, cognitive and psychiatric symptoms was used to assess the prevalence of self-perceived neuropsychiatric symptoms. The Modified Hospital Anxiety and Depression Scale (HADS-M) was used to assess the level of anxiety, depression and irritability. Formal neuropsychological examination was performed. Clinical data were collected by means of medical charts review and structured interview. RESULTS: Suicidal thoughts were present in 25% of patients with NPSLE, irrespective of sex, age, education, work status, disease duration and steroid treatment. Suicidal ideation was connected with elevated levels of depression, anxiety and irritability. In patients with suicidal ideation the prevalence of cognitive, psychiatric and neurological self-perceived problems was significantly higher. CONCLUSIONS: Suicidal thoughts are common in patients with NPSLE. Neuropsychiatric manifestation per se, depression, anxiety and patients' subjective complaints can be risk factors for suicidal ideation. Screening for suicidal thoughts is vital in routine care of SLE patients.

Lung Ultrasonography in the Evaluation of Interstitial Lung Disease in Systemic Connective Tissue Diseases: Criteria and Severity of Pulmonary Fibrosis - Analysis of 52 Patients.

OBJECTIVES: Patients with a diagnosed systemic connective tissue disease require regular monitoring from the point of view of interstitial lung disease. The main aim of this work is a description of the criteria for pulmonary fibrosis and the degree of the severity of the fibrosis during the course of interstitial lung disease through the TLU (transthoracic lung ultrasound). MATERIALS AND METHODS: 52 patients with diagnosed diffuse interstitial lung disease were qualified for this research, together with 50 volunteers in the control group. The patients in both groups were over 18 years of age and were of both sexes. The results of the TLU of the patients underwent statistical analysis and were compared to High-Resolution Computed Tomography (HRCT) results. RESULTS: As a consequence of the statistical analysis, we defined our own criteria for pulmonary fibrosis in TLU: irregularity of the pleura line, tightening of the pleura line, the fragmentary nature of the pleura line, blurring of the pleura line, thickening of the pleura line, artifacts of line B ≤ 3 and ≥ 4, artifacts of Am line and subpleural consolidations < 5 mm. As a result of the conducted research, a scale of severity of pulmonary fibrosis in TLU was devised (UFI - Ultrasound Fibrosis Index), enabling a division to be made into mild, moderate and severe cases. CONCLUSIONS: Transthoracic Lung Ultrasonography (TLU) gives a new outlook on the diagnostic possibilities, non-invasive and devoid of ionising radiation, of pulmonary fibrosis. This research work has allowed to discover two new ultrasound symptoms of pulmonary fibrosis (blurred pleural line and Am lines).

Pregnancy after kidney transplantation: a single-center experience and review of the literature.

After kidney transplantation (KT), pregnancy is possible, although the risk of maternal and fetal complications is much higher than in the general population. Outcome of 22 pregnancies in 17 patients transplanted in the Gdansk center in the period 1980-2012 was studied. Mean maternal age at pregnancy was 30 ± 5 (range, 23-39) years, interval between transplantation and conception 3.4 ± 2.5 (range, 0.6-11) years. Mean creatinine concentration before conception was 1.29 ± 0.36 (range, 0.8-2.45) mg/dL and was stable during 1 year preceding pregnancy (mean increase, 0.01 mg/dL). Nine of the 17 patients received 1 and 4 received ≥2 antihypertensive drugs, and 1 had proteinuria. Twelve of the 17 patients were primagravidas, 1 was pregnant 3 times, and 14 times. At the time of conception, 20 patients received CNI (14 cyclosporine, 6 tacrolimus), 15 antimetabolites (3 mycophenolate mofetil [MMF], 12 azathioprine), 1 mammalian target of rapamycin inhibitor (mTORi; sirolimus), and all prednisone. MMF and mTORi were discontinued before or during the 1st weeks of pregnancy. Maternal outcome: all survived the pregnancy. None experienced rejection or graft loss as a direct result of pregnancy. Maternal complications included edema (5/17), worsening of blood pressure control (5/17), and worsening (1/17) or new onset of proteinuria (2/17). Mean creatinine decrease during pregnancy was 0.06 mg/dL. Mean creatinine 1 year after pregnancy was 1.49 ± 0.53 mg/dL. There were 12 cesarean sections. Fetal outcomes: 17 live births (2 with serious congenital defects), 2 spontaneous and 1 induced abortion, 2 stillbirths. Mean pregnancy age and neonate birth weights were 35 ± 4 (range, 23-39) weeks and 2,552 ± 629 (range, 1,480-3,420) g, respectively. During mean 8.5 (range, 1-25) years of follow-up after pregnancy, 4/17 patients lost grafts. Grafts were lost in the 3rd to 7th years after pregnancy. We conclude that pregnancy does not exert a direct negative influence on patient and graft survivals; 68% of all pregnancies resulted in delivering healthy neonates.

Rapamycin as a therapy of choice after renal transplantation in a patient with tuberous sclerosis complex.

Herein we have reported the use of rapamycin in immunosuppressive treatment after renal transplantation as a therapy of choice in a patient with diagnosis of tuberous sclerosis complex (TSC). TSC is a genetic disorder, caused by mutations of TSC1 or TSC2 genes. Products of these genes, hamartin and tuberin, create a complex that inhibits mammalian target of rapamycin (mTOR), a key protein engaged in regulation of the cell cycle. Mutations of TSC genes lead to constitutive activation of mTOR resulting in uncontrolled proliferation, differentiation, and migration of cells. As a consequence malformations of many organs arise. We have presented a case of a 47-year-old female TSC patient with multisystem involvement (skin, brain, lungs, and kidneys), who developed end-stage renal disease ESRD due to angiomyolipomas with subsequent bilateral nephrectomy. At the age of 44 years, she started hemodialysis treatments and 10 months later underwent kidney transplantation. Immunosuppressive treatment included the mTOR inhibitor rapamycin. Since the patient was discharged from hospital, she has remained in good clinical condition with stable graft function. Clinical evaluation after 2 years treatment with rapamycin revealed significant regression of skin lesions. Brain, chest, and abdominal cavity computed tomography images remained stable. No complications of immunosuppressive treatment or TSC were observed. Experimental and clinical studies have confirmed that rapamycin exerts beneficial effects in TSC, providing a new therapeutic option. Therefore an immunosuppressive regimen with rapamycin should be considered as the treatment of choice after kidney transplantation among patients with TSC seeking to avoid development or progression of disease complications.

Renal allograft protection with angiotensin II type 1 receptor antagonists.

The renal benefits of agents inhibiting the renin-angiotensin-aldosterone system in renal transplant recipients, i.e. preventing the development of chronic graft nephropathy, are supposed but not finally proven. In a double-blind, placebo-controlled, cross-over study, we evaluated the influence of losartan on surrogate markers of tubular injury, urine excretion of transforming growth factor beta-1 (TGF-beta1) and amino-terminal propeptide of type III procollagen (PIIINP) in 16 patients after transplantation. The patients received randomly either losartan (50-100 mg daily) or the beta-blocker carvedilol (12.5-25 mg) for 8 weeks, allowing a placebo washout between treatments. The target office through blood pressure (BP) was below 130/85 mmHg. The BP did not differ in the treatment periods. Losartan significantly decreased N-acetyl-beta-d-glucosaminidase and alfa-1 microglobulin excretion relative to placebo and carvedilol. Urine excretion of TGF-beta1 and PIIINP was significantly lower after losartan. In conclusion, losartan reduces urine excretion of proteins associated with tubular damage and graft fibrosis.

Influence of predialysis oxidative stress on peroxidation processes after renal transplantation.

Oxidative stress occurs as a result of reactive oxygen species (ROS) overproduction. The content of carbonyl groups (CG), malonyldialdehyde, 4-hydroxynonenal (MDA, 4-HNE) represent markers of protein and lipid peroxidation processes, respectively. The aim of the present study was to determine CG and MDA/4-HNE in the serum of 30 hemodialyzed patients (-HD; 13 men, 17 women of mean age 47.7 +/- 15.3 years) before and after a hemodialysis session, of 20 transplant patients (TX; 10 men, 10 women of mean age 40.7 +/- 11.3 years) before and after the procedure (RT), and of a control group (n = 47; including 30 women, 17 men of mean age 38.7 +/- 14.0 years). The CG content was evaluated using the 2,4-dinitrophenylhydrazine assay and MDA/4-HNE by the Oxis Bioxytech colorimetric method. Among the HD group the concentrations of MDA/4-HNE and CG were higher than control subjects (P <.05). In the HD group CG concentrations before and after dialysis session were similar while MDA/4-HNE concentrations were higher before the dialysis session (P <.01). One day after RT, MDA/4-HNE and CG concentrations had increased but at 7 days they had decreased and the CG level was increased. A high production of ROS can be assumed in dialysis patients. MDA/4-HNE concentrations, however, decreased after the dialysis treatment, because as low-weight molecules they diffused across the dialysis filter. On the first day after RT a high intensity of lipid and protein peroxidation was observed. During the first week after RT, accumulation of protein peroxidation products was observed but simultaneously lipid peroxidation product concentrations decreased due to quick metabolism. The intensity of lipooxidation during first day after RT seems to be dependent upon the ischemia time.

Hemolytic anemia after renal transplantation: analysis of case reports.

Hemolysis after renal transplantation in some cases is clearly related to hemolytic-uremic syndrome (HUS) and usually attributed to cyclosporine (CsA) treatment. Acute hemolysis in other recipients is related to anti-erythrocyte autoantibodies. In most cases these patients have received ABO-compatible, although ABO-nonidentical, organs, mostly from O blood group donors. We report three cases of autoimmune hemolytic anemia after renal transplantation. Two patients (patients: 1 and 2; ABO-compatible, but nonidentical kidneys) suffered acute hemolysis in the third week after transplantation. One patient (patient 3: ABO-identical kidney) suffered a chronic, subclinical course of disease beginning 5 months after transplantation. The clinical picture of this disease was completely different from HUS. The existence of severe anemia (patients 1 and 2), hyperbilirubinemia (particularly high in patient 3), increased serum lactic dehydrogenase levels, and decreased serum haptoglobin in the presence of good graft function suggested an hemolytic anemia. In all patients the direct antiglobulin test was positive. The acute or chronic symptoms of hemolysis disappeared, at 2 and 5 weeks, respectively, after conversion from CsA to tacrolimus. Hemolysis in these patients probably relates to alloantibodies derived from passenger B lymphocytes transplanted with the organs. Because hemolysis has been most frequently related to CsA therapy, it is suggested that B lymphocytes proliferated and produced antibodies because CsA effects to inhibit T-cell function generally spares B-cell activity. It is proposed that a subtype of B cells, which are resistant to CsA, produces anti-A and/or anti-B antibodies. Treatment with tacrolimus appears to be successful, probably due to its alternate, and likely more effective, manner of B-cell suppression.

Influence of spontaneous platelet aggregation on progression of glomerular disease.

UNLABELLED: Platelet secretion products may play an important role in the pathogenesis and progression of the kidney disease. Amongst the parameters describing platelet hyperactivity the measurement of spontaneous platelet aggregation (SPA) seems particularly useful. In this study SPA as well as mean platelet volume (MPV), modal platelet volume (PLT Mode) and platelet count (PLT) were investigated in 60 patients with biopsy proven primary glomerulonephritis. SPA was measured using the turbidimetric method according to Born with no enhancers added. Serum creatinine concentration (Cr), reciprocal serum creatinine concentration (1/Cr) and endogenous creatinine clearance (Cl(Cr)) were used for the renal function estimation. Protein and lipid profiles as well as coagulo-fibrinolytic balance were measured in parallel. The investigated group consisted of 30 non-nephrotic patients (CGN) - in 9, SPA was found (CGN-B) while 21 had SPA <10% (CGN-A), and 30 nephrotic patients (CGN+NS) - 19 with SPA (CGN+NS-B) and 11 without (CGN+NS-A). SPA was found to be a constant platelet feature in patients with chronic glomerulopathy. The group remained under observation for 36 months. 41 patients were included in the 3-year prospective study which revealed the significant influence of the blood platelet hyperaggregability on the renal disease progression. A significantly increased serum creatinine concentration, decreased 1/Cr parameter and decreased glomerular filtration rate (Cl(Cr)) were noted in subgroups showing SPA. A significant correlation between SPA and (Delta)Cr/month (r = 0.41), (Delta)1/Cr/month (r = 0.38) as well as (Delta)Cl(Cr)/month (r = 0.52) was found. The platelet activity and thus SPA can be altered by various factors: albumin and fibrinogen plasma concentrations, thrombosis activation and possibly lipoprotein metabolism disturbances. A characteristic feature of spontaneously aggregating platelet is their increased volume (MPV). CONCLUSION: Platelet hyperaggregation in one of nonimmunological factors stimulates the progression of glomerulonephritis.

Does immunosuppressive regimen influence the lipid disturbances in kidney recipients?

Though it is said that some immunosuppressive agents are implicated in the development of hyperlipidemia in kidney recipients, this subject is still controversial. Main plasma lipid parameters, as well as apolipoproteins A1 and B were measured periodically in 39 kidney first cadaveric, nondiabetic recipients during 24 months of clinic follow-up after transplantation. Standard triple immunosuppressive therapy: prednisone + cyclosporine + azathioprine was administrated from the beginning. After the second year of kidney transplantation, a significant reduction refers to values of TC, LDL, apo A1 and apo B. In the group with antirejection - methylprednisolone therapy, and without it only TG in the 24th month and apo B in the 1st month were statistically lower in the latter group (both p < 0.05). In the multiple regression test, a linear coincidence was observed between apo A1, apo B and prednisone cumulative dosage after the 1st month, TG and cyclosporine in the 6th month and LDL and cyclosporine in the 12th month after transplantation. It appears that steroids had an impact on lipids directly after transplantation, while cyclosporine did so thereafter.

Correlation between plasma carnitine, muscle carnitine and glycogen levels in maintenance hemodialysis patients.

Chronic hemodialysis (HD) may lead to losses of carnitine from plasma and muscle. Plasma carnitine does not reflect the body content of carnitine. The purpose of this study was the evaluation of total and free plasma and muscle carnitine concentrations (TPC, FPC, TMC, FMC), muscle glycogen and the relationship between plasma and tissue carnitine content and the basic indices of lipid metabolism in HD patients. The studies were conducted in two groups: the first one consisted of 37 HD patients (19 F, 18 M), the second one served as the control and was composed of 29 (10 F, 19 M) patients with healthy kidneys. Tissue specimens in HD patients were taken during surgery on arterio-venous fistula from brachioradial muscle. Carnitine and glycogen measurements were performed using enzymatic methods according to Cederblad and Huijng respectively. Total cholesterol (CH), HDL-CH, and triglycerides were assayed by enzymatic commercial test system (Boehringer-Mannheim, Germany). To summarise, we found the following phenomena in our HD patients in comparison with the controls: 1) In plasma: similar TPC but decreased FPC levels and FPC/TPC ratio which may suggest free carnitine deficiency. 2) In muscle: significantly lower TMC and FMC levels but normal FMC/ITMC ratio. 3) Negative correlation between TMC and FMC levels and duration of dialysis treatment. 4) No correlation between plasma and muscle camitine concentration. 5) Significantly higher concentration of muscle glycogen which could be explained by the changes in the structure of muscle fibres in HD patients and/or lower physical activity. 6) A positive correlation between FPC/APC or FPC/TPC ratio and HDL-CH in HD patients which may suggest that an appropriate proportion between free and acylcarnitines may influence HDL-CH levels in that population.

[The concentration of adenine nucleotides in platelets of patients with primary chronic glomerulonephritis]. / Stezenie nukleotydów adeninowych w plytkach krwi chorych z pierwotnymi klebuszkowymi zapaleniami nerek.

UNLABELLED: Nephrotic syndrome (n.s.) is associated with numerous blood coagulation abnormalities and a marked predisposition to thromboembolism. Increased aggregation and activation of platelets in patients with glomerulonephritis (g.l.n. p.t.s.) may partly explain this status. The aim of this study was to measure the platelets adenine nucleotides concentration. The study was performed in 57 patients with a renal biopsy confirmed primary glomerulonephritis and 24 sex and age matched healthy volunteers which served as a control group. The patients were divided into two subgroups: subgroup I/A--36 patients with the symptoms of the nephrotic syndrome and subgroup I/B--21 patients with chronic glomerulonephritis and proteinuria but without the symptoms of nephrotic syndrome. Concentration of adenine nucleotides in platelets was measured using HPLC. In the subgroup I/A significantly lower levels of ATP, ADP and AMP concentrations in platelets were observed comparing to control subjects. Simultaneously significant correlation between both ATP and ADP concentration and plasma levels of albumin, total cholesterol, LDL-cholesterol, triglycerides and fibrinogen were found in g.l.n. p.t.s. SUMMARY AND CONCLUSIONS: 1. Significantly lower concentrations of adenine nucleotides in platelets of gln pts with the nephrotic syndrome may result from their activation. 2. Protein and lipid metabolism as well as fibrinogen seem to influence ATP and ADP concentrations in platelets of g.l.n. p.t.s.

Recombinant human erythropoietin stimulates production of interleukin 2 by whole blood cell cultures of hemodialysis patients.

The impairment of function of human T lymphocytes, leading to an inappropriate cytokine production, is partially responsible for defective immunological response in hemodialysis patients (HD). Recent data suggest that recombinant human erythropoietin (rhEPO) may exert immunological effects. The aim of this study was to find out whether rhEPO treatment of the HD patients may have an effect on the interleukin 2 (IL-2) production by their whole blood cell cultures. The study was carried out in 10 HD patients receiving rhEPO for 6 months. Compared with the levels seen before the treatment, the concentration of IL-2 increased in the phytohemagglutinin-stimulated whole blood cell cultures of 7 of 10 patients under study. Addition of rhEPO in vitro to the whole blood cell cultures of the HD patients before implementation of erythropoietin confirmed that rhEPO is able to directly stimulate IL-2 production. Our studies show that the therapy with rhEPO affects IL-2 secretion.

[Lipoprotein metabolism disturbances in patients with kidney diseases]. / Zaburzenia metabolizmu lipoproteiny(a) u chorych z chorobami nerek.

Lipoprotein(a) was discovered over 30 years age and it is an independent risk factor for atherosclerosis, coronary artery disease and peripheral vascular diseases. Among patients with end stage renal failure lipoprotein(a) levels are higher than in general population and being independent of the type of treatment. Cardiovascular diseases are the most important cause of mortality in ESRD patients. Moreover we have interesting information about possibility of influence of Lp(a) serum levels.

[Retroperitoneal fibrosis and chronic peri-aortitis--new hypothesis]. / Zwlóknienie zaotrzewnowe a przewlekle zapalenie okoloaortalne--nowa hipoteza.

Retroperitoneal fibrosis is characterised by the development of fibrotic mass surrounding the abdominal aorta and its branches. In the one third of cases, the causes of this disease include ergot-derivative drugs, retoperitoneal haemorrhage or urine extravasation and desmoplastic response to a variety of tumours. Retroperitoneal fibrosis is idiopathic in two thirds of cases and is found most commonly as an isolated fibrotic plague centered over the lumbar spine and entrapping one or both ureters. It has been postulated that fibrosis in idiopathic cases is caused by a chronic inflammatory or autoimmune response to antigens leaking into retroperitoneum from atheromatous plagues in the aorta or common iliac arteries. Many findings indicate the active nature of aortic adventitial chronic inflammation associated with human advanced atherosclerosis ("chronic periaortitis") and show its possible progressive potential to the clinically important disease termed "idiopathic retroperitoneal fibrosis" and "inflammatory aneurysm". A definitive differential diagnosis requires not only CT and NMR but also histologic confirmation. Treatment may be surgical or medical, with the best outcome observed in patient receiving both.

[Infected abdominal aneurysm with retroperitoneal fibrosis--a case successfully treated conservatively]. / Zapalny tetniak aorty brzusznej ze zwlóknieniem zaotrzewnowym-przypadek pomyslnie leczony zachowawczo.

53 year old men suffered from abdominal pain, vomiting, lack of appetite, loss of weight, with ESR > 100 mm Hg and moderate anaemia was presented. Many diagnostic procedures were without results and finally laparotomy was taken. The microscopic examination of specimen of periaortic tissue revealed retroperitoneal fibrosis accompanying atherosclerotic aortae. Corticotherapy and antilipemic drugs were given. After 3 years a complete remission of periaortic pathologic mass was observed. This case could prove the autoimmunological hypothesis of retroperitoneal fibrosis.