Igor Mitic

Inherited Thrombophilia is Associated With Pregnancy Losses That Occur After 12th Gestational Week in Serbian Population

Recurrent fetal loss (RFL) is a significant clinical problem, occurring in 1% to 5% of reproductive females. Inherited or acquired thrombophilia has been diagnosed in 50% to 65% of women with history of unexplained fetal loss. The objective of our study was to determine the prevalence of thrombophilia in women with unexplained RFL in Serbian population and to find out whether the presence of thrombophilia is associated with pregnancy losses that occur later than 12th gestational week. We have examined 147 women with unexplained RFL or intrauterine fetal death and 128 healthy women with at least 1 uncomplicated pregnancy. The antithrombin (AT), protein C (PC), protein S (PS), activated protein C (APC) resistance, factor V (FV) G1691A, factor II (FII) G20210A, and MTHFR C677T were determined. At least 1 inherited thrombophilic defect was found in 54 (36.7%) of 147 women with repeated fetal losses and in 11 (8.59%) of 128 controls (P < .001, OR 6.17, 95% CI 3.06-12.48). The most common thrombophilic abnormalities were homozygosity for MTHFR 677TT, FV Leiden, and FII G20210A. Deficiency of natural anticoagulants occurred in 10 patients, with protein S deficiency being the most frequent one. Thrombophilia was found in 46 of 94 women with RFL that occurred later than the 12th gestational week and in only 8 of 53 with RPL earlier than 12th week (P = .001). Our study has shown the association between the hereditary thrombophilia and RFL that occurred after the 12th gestational week in Serbian population.

Mycophenolate Mofetil in High-Risk Patients with Primary Glomerulonephritis: Results of a 1-Year Prospective Study

Background/Aims: Glucocorticoids and classic immunosuppressive drugs can improve disease activity in primary glomerulonephritis (GN). However, these drugs have serious toxicity and patients frequently experience inadequate response or relapse, so there is a need for alternative agents. This multicenter uncontrolled study analyzed the efficacy and safety of mycophenolate mofetil (MMF) in high-risk patients with primary GN. Methods: A total of 51 patients with biopsy-proven membranous (n = 12), membranoproliferative (n = 15), mesangioproliferative (n = 10), focal segmental glomerulosclerosis (n = 13) and minimal change disease (n = 1) received MMF with low-dose corticosteroids for 1 year. The primary outcome included the number of patients with complete/partial remission. Results: Proteinuria significantly decreased, from its median value of 4.9 g/day (IQR 2.9–8.4) to 1.28 g/day (IQR 0.5–2.9), p < 0.001. The urine protein/creatinine ratio significantly improved, from a median of 3.72 (IQR 2.13–6.48) to 0.84 (IQR 0.42–2.01), p < 0.001. The mean area under the curve for proteinuria significantly decreased, from 4.99 ± 3.46 to 2.16 ± 2.46, between the first (visits 1–2) and last (vists 4–5) treatment periods (p < 0.001). The change was similar for every type of GN, without difference between groups. eGFR slightly increased (62.1 ± 31.8 to 65.3 ± 31.8 ml/min, p = n.s.) and ESR, total proteins, albumins, total- and HDL-cholesterol parameters improved significantly. Systolic, diastolic and mean blood pressure decreased (p < 0.02 for systolic blood pressure). The age of patients was the only independent predictor of complete or partial remission. Conclusion: MMF proved to be efficient in 70% of high-risk patients with primary GN, who reached either complete or partial remission without safety concern after 12 months of treatment. Favorable effects of MMF therapy have to be confirmed in the long term and particularly after discontinuation of the drug.

Epidemiology of end‐stage renal disease and hemodialysis treatment in Serbia at the turn of the millennium

The study presents the epidemiological features of patients treated with renal replacement therapy (RRT) in Serbia from 1997 to 2009 and compares the results of hemodialysis treatment in 1999 and 2009. Epidemiological data were obtained from the National Registry of RRT patients and data on hemodialysis treatment from special surveys conducted in 1999 and 2009. Within the period 1997–2009 the incidence of patients on RRT increased from 108 to 179 per million population (pmp), prevalence rose from 435 to 699 pmp, while mortality rate fell from 20.7% to 16.7%. The frequency of patients with glomerulonephritis decreased, while that of patients with diabetes and hypertensive nephropathy increased. In late 2009 there were 5208 patients receiving RRT in Serbia. Within the examined period new hemodialysis and reverse osmosis equipment were purchased, high‐flux dialyzers with synthetic membranes were increasingly used and the number of patients receiving hemodiafiltration increased to 17.6%. Kt/V greater than 1.2 was recorded in 16% of the patients in 1999 but 52% in 2009. Options for correction of anemia and mineral disorders have also improved. The percentage of patients with HbsAg (13.8% vs. 4.8%) as well as anti‐hepatitis C virus antibodies positive patients (23.2% vs. 12.7%) was significantly lower in 2009 than in 1999. Both the incidence and prevalence of RRT patients in Serbia are rising continuously, while the mortality rate is falling. More favorable conditions for dialysis treatment have brought about significant improvement in the results over the last 10 years.

Treatment of Lupus Nephritis by Mycophenolate Mofetil

Background/Aims: Mycophenolate mofetil (MMF) has been increasingly used for the treatment of lupus nephritis (LN). The aim of this study was to examine the efficacy and safety of MMF used with low doses of corticosteroids as maintenance therapy in patients with LN. Methods: The study covered 35 patients, most of them with proliferative types of LN (5 WHO class III, 26 class IV), while 1 had class V and 3 class VI nephritis. MMF was administered in the dose of 1.5–2 g/24 h and prednisone at 10–20 mg/day. The treatment effects were followed over a 12-month period. Results: After 3 months of therapy significant reduction in proteinuria was achieved (2.1 ± 2.4 g/24 h vs. 1.0 ± 1.0 g/24 h, p < 0.01) and maintained to the end of the study. In parallel, a significant rise in serum albumin, a fall of cholesterol and a significant increase in mean glomerular filtration rate were noted. Complete remission was achieved in 16 patients (45.7%), including all patients in class III and V plus 10 patients in class IV. Not a single adverse effect was observed. Conclusion: MMF combined with low doses of steroids is an effective and safe treatment for the maintenance of stable remission of LN.

Splenic peliosis in the course of IgA nephropathy

The immunoglobulin A (IgA) immunoregulation disorders lie at the basis of Henoch-Schönlein purpura nephritis and IgA nephropathy. Peliosis is the condition characterized by cystic formations within the parenchyma of solid organs filled with blood. The authors report a case of a girl presenting with hematuria occurring during the course of respiratory infections since her fifth year. Pathohistological examination was not performed at that time. At the age of 13, the girl was hospitalized for abdominal pain. Computed tomography examination showed the presence of multiple, relatively well-defined nodular formations located in the spleen parenchyma. Splenectomy was performed. Morphological finding completely corresponded to peliosis of the spleen, with the deposits of IgA in the lesions within it. A year and a half following the splenectomy, a typical clinical picture of Henoch-Schönlein purpura nephritis developed. Biopsy findings of the skin and kidneys detected deposits of IgA. This is the first case of a patient suffering from associated IgA and Henoch-Schönlein purpura nephritis complicated by splenic peliosis to be described in the world’s literature.

Compliance with guidelines and predictors of mortality in hemodialysis. Learning from Serbia patients

OBJECTIVES The aims of the study were to determine the percentage of patients on regular hemodialysis (HD) in Serbia failing to meet KDOQI guidelines targets and find out factors associated with the risk of time to death and the association between guidelines adherence and patient outcome. METHODS A cohort of 2153 patients on regular HD in 24 centers (55.7% of overall HD population) in Serbia were followed from January 2010 to December 2012. The percentage of patients failing to meet KDOQI guidelines targets of dialysis dose (Kt/V>1.2), hemoglobin (>110g/L), serum phosphorus (1.1-1.8mmol/L), calcium (2.1-2.4mmol/L) and iPTH (150-300pg/mL) was determined. Cox proportional hazards analysis was used to select variables significantly associated with the risk of time to death. RESULTS The patients were on regular HD for 5.3±5.3 years, dialyzed 11.8±1.9h/week. Kt/V<1.2 had 42.4% of patients, hemoglobin <110g/L had 66.1%, s-phosphorus <1.1mmol/L had 21.7% and >1.8mmol/L 28.6%, s-calcium <2.1mmol/L had 11.7% and >2.4mmol/L 25.3%, iPTH <150pg/mL had 40% and >300pg/mL 39.7% of patients. Using Cox model (adjustment for patient age, gender, duration of HD treatment) age, duration of HD treatment, hemoglobin, iPTH and diabetic nephropathy were selected as significant independent predictors of time to death. When targets of five examined parameters were included in Cox model, target for KtV, hemoglobin and iPTH were found to be significant independent predictors of time to death. CONCLUSION Substantial proportion of patients examined failed to meet KDOQI guidelines targets. The relative risk of time to death was associated with being outside the targets for Kt/V, hemoglobin and iPTH.

The role of TNF-α superfamily members in immunopathogenesis of sepsis

Background Members of TNF&agr; superfamily, A proliferation inducing ligand (APRIL), B‐cell activating factor (BAFF) and Transmembrane activator and calcium cyclophylin interactor (TACI) are main regulators of B‐cell function. The aim of this study was to evaluate concentrations of APRIL, BAFF and soluble TACI (sTACI) receptor in septic patients compared to healthy controls and compare concentrations of these biomarkers depending on sepsis severity and outcome. Materials and methods A total of 115 septic patients and 30 healthy volunteers were included and concentrations of APRIL, BAFF and sTACI were determined in all subjects at the admission (ELISA R&D Systems tests). Concentrations of these biomarkers in function of sepsis severity (sepsis n = 94 and septic shock n = 21) and outcome (lethal n = 40, recovery n = 75) were tested, as well as correlations with APACHE II and SOFA scores, immunoglobulins, complement, PCT and CRP concentrations. Results Concentrations of all three biomarkers were significantly increased in septic patients compared to controls (AUCAPRIL = 0.982, AUCBAFF = 0.873, AUCsTACI = 0.683). Higher concentrations of APRIL and sTACI (p = 0.033, p = 0.037), and lower concentrations of BAFF (p = 0.005) were observed in patients with septic shock compared to sepsis. BAFF concentrations correlated positively with IgM, C3 and C4 levels. sTACI and APRIL were shown to be predictors of lethal outcome (p = 0.003, p = 0.049). Conclusions Concentrations of observed TNF&agr; superfamily members are significantly increased in septic patients, confirming their role in sepsis pathogenesis. Higher concentrations of anti‐inflammatory sTACI receptor correlated with severity of sepsis and poorer prognosis, thus potentially indicating domination of anti‐inflammatory response in septic patients with worse outcome. HighlightsHigh concentrations of TNF‐&agr; superfamily members point to prompt activation of B cells in sepsis.APRIL, BAFF and sTACI are good predictors of septic shock and lethal outcome in sepsis.Their concentrations correlate well with SOFA, but do not correlate with PCT.Lower BAFF and higher sTACI concentrations suggest increased apoptosis of B cells in septic shock.sTACI is an anti‐inflamatory cytokine that had the highest AUC in outcome prediction.

Post-transplant lymphoproliferative disorder after kidney transplantation

Online first: March 31, 2017 SUMMARY Introduction Post-transplant lymphoproliferative disorder (PTLD) is one of the most severe and often fatal complications observed after solid organ and bone marrow transplantations. Case outline We present a case of a patient born in 1989 who underwent a living related donor renal transplantation at the age of 16. Induction therapy implied the administration of anti-thymocyte globulin and corticosteroids, and maintenance therapy encompassed a combination of three immunosuppressive agents – tacrolimus, mycophenolate mofetil, and corticosteroid. The patient experienced first complications six months after transplantation, manifested as aggravation of tonsillitis symptoms and subsequent dysphagia. Histopathological and immunohistochemical finding of tonsillectomy specimens suggested polymorphic PTLD (with high expression of Epstein–Barr virus latent membrane protein antigen). Definitive diagnosis of diffuse large B-cell lymphoma (CD20+) was established upon analysis of oesophageal bioptate. Antiviral therapy was applied, along with rituximab and a combination of cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine, and prednisolone (CHOP therapy), whilst the dosage of basic immunosuppressive drugs was reduced. Complex diagnostic procedures confirmed the absence of disease recurrence and stable graft function five years after completing the PTLD therapy. Conclusion The presented case of our patient, who developed PTLD after renal transplantation, demonstrated that appropriate early diagnosis, reduction of immunosuppressive regimens, and vigilant application of immunomodulatory and chemotherapy could result in complete disease remission, yet preserving and maintaining the stable function of the transplant.

Erratum to: Vascular access registry of Serbia: a 4-year experience

Nasta, Jelacic Rosa, Kostic Mirjana, Kovacevic Miodrag, Lazarevic Tatjana, Markovic Rodoljub, Micunovic Vesna, Milenkovic Olgica, Milenkovic Radomir, Milenkovic Srboljub, Milicevic Biserka, Milicevic Olivera, Nikolic Zora, Obrenovic Slavica, Orescanin Mira, Pavlovic Stevan, Pesic Snezana, Petkovic Dobrila, Pilipovic Dragana, Prokopovic Miomir, Radovanovic Zoran, Rakic Nenad, Rangelov Vanja, Sefer Kornelija, Sibalic Simin Marija, Stefanovic Nikola, Stojanovic Dragoslav, Stojanovic Stanojevic Marina, Tirmenstajn Jankovic Biserka, Vasic Jovanovic Vesna, Vasilic Kokotovic Olivera, Vojinovic Goran, Vuckovic Dragana, Vukelic Vesna, Vukic Jasmina, Zagorac Nikola, Zec Nenad. Erratum to: Int Urol Nephrol DOI 10.1007/s11255‐016‐1378‐9

Interleukin-17A Levels Increase in Serum of Children With Juvenile Idiopathic Arthritis

Objectives This study aims to determine the serum levels of interleukin-17A (IL-17A) in children with juvenile idiopathic arthritis (JIA) and analyze the correlation between IL-17A values and disease activity, certain clinical features, and laboratory markers of inflammation. Patients and methods The study included 30 children (7 boys, 23 girls; mean age 8.8±5.3 years; range 1 to 18 years), who had been diagnosed with JIA (18 children were diagnosed during the study period and 12 children were diagnosed before the start of the study) and had active disease during the study period. Control group included 30 healthy, age- and sex- matched children (9 boys, 21 girls; mean age 8.3±4.8 years; range 1 to 18 years). The enzyme-linked immunosorbent assay was used to assess the serum IL-17A levels of children with JIA in the active phase of the disease and control group. Clinical and laboratory features of the disease were evaluated for the children with JIA. Results Serum levels of IL-17A in children with JIA were significantly higher in comparison to control group. In children with JIA who were prospectively monitored, statistically significantly decreased IL-17A level was recorded in the inactive phase of the disease. The incidence of arthritis of coxofemoral joints was significantly more common, and the mean levels of erythrocyte sedimentation rate and C-reactive protein were significantly higher in the group of children with JIA with detectable levels of IL-17A. Children with JIA and detectable levels of IL-17A had significantly higher values of Juvenile Arthritis Disease Activity Score-27 in comparison to children with JIA and non-detectable IL-17A. Conclusion Assessment of serum IL-17A levels in early phases of JIA gives an opportunity for early detection of children that have higher risk for worse functional outcome.