Gener Ismail

Prostate cancer proteomics: Current trends and future perspectives for biomarker discovery

The clinical and fundamental research in prostate cancer - the most common urological cancer in men - is currently entering the proteomic and genomic era. The focus has switched from one single marker (PSA) to panels of biomarkers (including proteins involved in ribosomal function and heat shock proteins). Novel genetic markers (such as Transmembrane protease serine 2 (TMPRSS2)-ERG fusion gene mRNA) or prostate cancer gene 3 (PCA3) had already entered the clinical practice, raising the question whether subsequent protein changes impact the evolution of the disease and the response to treatment. Proteomic technologies such as MALDI-MS, SELDI-MS, i-TRAQ allow a qualitative/quantitative analysis of the proteome variations, in both serum and tumor tissue. A new trend in prostate cancer research is proteomic analysis of prostasomes (prostate-specific exosomes), for the discovery of new biomarkers. This paper provides an update of novel clinical tests used in research and clinical diagnostic, as well as of potential tissue or fluid biomarkers provided by extensive proteomic research data.

Antiphospholipase A2 Receptor Autoantibodies: A Step Forward in the Management of Primary Membranous Nephropathy

Since the identification of PLA2R (M-type phospholipase A2 receptor) as the first human antigenic target in primary membranous nephropathy (MN), perpetual progress has been made in understanding the pathogenesis of this disease. Accumulating clinical data support a pathogenic role for the anti-PLA2R antibodies (PLA2R ABs), but confirmation in an animal model is still lacking. However, PLA2R ABs were related to disease activity and outcome, as well as to response therapy. Accordingly, PLA2R ABs assay seems to be promising tool not only to diagnose MN but also to predict the course of the disease and could open the way to personalize therapy. Nevertheless, validation of a universal assay with high precision and definition of cut-off levels, followed by larger studies with a prolonged follow-up period, are needed to confirm these prospects.

Identification of Subgingival Periodontal Pathogens and Association with the Severity of Periodontitis in Patients with Chronic Kidney Diseases: A Cross-Sectional Study

Background. The aim of our study was to assess the subgingival profile of 9 periodontal pathogens, by means of real-time PCR, in a group of predialysis chronic kidney disease patients with and without periodontal disease and to identify the risk factors associated with periodontal disease in these patients. Material and Methods. This is a single centre cross-sectional cohort study performed on 70 CKD patients. Patients received a full-mouth periodontal examination and the following parameters were assessed: periodontal pocket depth (PPD), clinical attachment level, bleeding on probing, and plaque index; subgingival biofilm samples were collected from the deepest periodontal pocket of each quadrant and were pooled in one transporting unit. Clinical data were drawn from the medical file of the patients. Results. T. denticola (P = 0.001), T. forsythia (P < 0.001), and P. micros (P = 0.003) are significantly associated with periodontal disease in CKD subjects but in a multivariate model only age and T. forsythia remain independent risk factors for periodontal disease in patients with CKD. Conclusions. In our cohort, age and T. forsythia are independently associated with periodontitis in CKD patients. Within the limits of this study, CKD was not significantly associated with a particular subgingival periodontal pathogens profile in periodontitis patients.

Validation study of Oxford Classification of IgA Nephropathy: the significance of extracapillary hypercellularity and mesangial IgG immunostaining

The Oxford classification (OC) of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as predictors of outcome. We aimed to validate the OC and to investigate the clinical significance of extracapillary hypercellularity and IgG immunostaining. We examined the renal outcome at December 31, 2014, of 121 adult patients with biopsy proven primary IgAN between 2003 and 2013. The primary endpoint was doubling of serum creatinine or renal replacement therapy initiation. The mean observation period was 59.7 months. Thirty‐one percent of the patients presented with a grade of extracapillary hypercellularity. In comparison with the group with no crescents, they had higher grade of inflammation, lower eGFR and increased proteinuria. There were no differences between the IgA and IgA&IgG immunostaining groups regarding the disease progression risk factors. Mean kidney survival time for the entire cohort was 10.6 (9.1, 12.0) years. In the Cox regression model, the independent predictors of decreased renal survival were eGFR at time of biopsy, S1 and the presence of crescents. Our study showed that extracapillary proliferation and S1 had the greatest importance in establishing the renal prognosis of patients with IgAN.

Noninvasive Markers of Improvement of Liver Steatosis Achieved by Weight Reduction in Patients with Nonalcoholic Fatty Liver Disease

Abstract Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance and metabolic syndrome, which are linked to obesity. The aim of the study was to assess if weight reduction through 12 months of lifestyle intervention and exercise would lead to improvement of steatosis. Methods. In a prospective observational study 86 overweight subjects (51 men, 35 women) with steatosis were recruited, after excluding other etiologies. Patients were assigned a caloric goal and a daily fat goal. Physical activity focused on moderate-intensity activities. Blood samples (biochemistry, HOMA-IR, cytokine levels, steatotest) were collected at entry and months 6 and 12. All subjects underwent abdominal CT scan before commencement and after 12 months to assess visceral and subcutaneous adipose tissue (VAT/SAT) area. Results. After 12 months baseline descriptive characteristics (weight, BMI, waist circumference) decreased significantly. Biochemical parameters that decreased significantly were: GGT (40.0 ± 18.0 vs 31.1 ± 13; p = 0.01), ALT (58.5 ± 23.5 vs 32,7 ± 14.8; p = 0.001), cholesterol (236.4 ± 54.8 vs 204.8 ± 91; p = 0.05), LDL (160.1 ± 47.4 vs 125.3 ± 40; p = 0.05) and HOMA-R (4.86 ± 0.63 vs 3 ± 0.41; p = 0.018). Steatotest improved significantly (0.68 ± 0.16 vs 0.38 ± 0.14; p = 0.02). Modification of adipocytokines was significant for leptin (p = 0.018) and adiponectin (p = 0.003). Factors associated with regression of steatosis were weight, BMI, ALT, waist circumference, GGT, HOMA, leptin, VAT and steatotest. Multivariate logistic regression showed the following factors related to improved steatosis: BMI < 25 kg/m2, ALT < 42 U/L, leptin < 10.5 ng/ml and adiponectin > 8.4 μg/ml. Conclusions. Overweight persons who achieve significant reductions in body weight through 12 months of physical activity and low caloric diet can decrease liver fat, VAT and SAT. Even in those with minimal weight loss ALT levels, steatosis, adipokines and cardiovascular risk factors improved. Abstract Ficatul gras non-alcoolic este puternic asociat cu rezistenţa la insulină şi cu sindromul metabolic, care sunt legate de obezitate. Scopul studiului a fost de a evalua dacă scăderea ponderală obţinută prin 12 luni de intervenţie asupra stilului de viaţă şi exerciţii fizice ar conduce la ameliorarea steatozei hepatice. Metode. Am recrutat într-un studiu prospectiv, observaţional, 86 subiecţi supraponderali (51 bărbaţi, 35 femei) cu steatoză, după excluderea altor etiologii. Pacienţilor li s-a atribuit o ţintă calorică şi o ţintă zilnică de grăsimi. Activitatea fizică s-a bazat pe activităţi de intensitate moderată. S-au recoltat probe de sânge (biochimie, HOMA-IR, citokine, steatotest) la înrolare şi după 6 şi 12 luni. La toţi subiecţii s-a efectuat examen CT la început şi după 12 luni pentru a evalua suprafaţa ţesutului adipos visceral şi subcutanat (VAT/SAT). Rezultate. După 12 luni, caracteristicile descriptive de la înrolare (greutate, IMC, circumferinţa abdominală) au scăzut semnificativ. Parametrii biochimici care au scăzut semnificativ au fost: GGT (40,0 ± 18,0 vs 31,1 ± 13; p = 0,01), ALT (58,5 ± 23,5 vs 32,7 ± 14,8; p = 0,001), colesterol (236,4 ± 54,8 vs 204,8 ± 91; p = 0,05), LDL (160,1 ± 47,4 vs 125,3 ± 40; p = 0,05) şi HOMA-IR (4,86 ± 0,63 vs 3 ± 0,41; p = 0,018). Steatotest s-a ameliorat semnificativ (0,68 ± 0,16 vs 0,38 ± 0,14; p = 0,02). Modificările nivelurilor adipocitokinelor au fost semnificative pentru leptină (p = 0,018) şi adiponectină (p = 0,003). Factorii asociaţi cu regresia steatozei au fost greutatea, IMC, ALT, circumferinţa abdominală, GGT, HOMA, leptina, VAT şi steatotest. Regresia logistică multivariată a evidenţiat următorii factori legaţi de ameliorarea steatozei: IMC < 25 kg/m2, ALT < 42 U/L, leptina < 10,5 ng/ml şi adiponectina > 8,4 μg/ml. Concluzii. Persoanele supraponderale care obţin reduceri semnificative ale greutăţii corporale prin 12 luni de activitate fizică şi dietă hipocalorică îşi pot scădea grăsimea hepatică, VAT şi SAT. Chiar şi la cei cu scădere ponderală minimă s-au ameliorat nivelurile ALT, steatoza, adipokinele şi factorii de risc cardiovasculari.

Predictive Factors for Natural Pregnancy after Microsurgical Reconstruction in Patients with Primary Epididymal Obstructive Azoospermia

Primary epididymal obstructive azoospermia (OA) is the most prevalent form of OA in nonvasectomized patients and has been less studied. We aim to assess the results with microsurgical vasoepididymostomy used in the treatment of men diagnosed with primary epididymal obstructive azoospermia and to identify the factors associated with natural pregnancy occurring after microsurgical reconstruction. This prospective study included consecutive patients with epididymal OA who underwent microsurgical reconstruction in our center. Clinical and biological data were obtained every three months during follow-up. Occurrence of natural pregnancy was the primary study outcome. In total, 36 patients underwent microsurgical reconstruction. The mean age was 34 ± 4.5 years (range 24–46 years). Median follow-up time was 15 [IQR 12–21] months. The total patency rate was 77.7% (n = 28). During follow-up, 8 (22.2%) natural pregnancies occurred. The overall live birth rate was 100%. Low FSH levels (HR: 0.22; 95% CI: 0.052–0.88; P = 0.032) and higher total motile sperm count (TMSC) (HR: 1.001; 95% CI 1–1.001; P = 0.012) were associated with a higher rate of natural pregnancy. Our data suggest that microsurgical vasoepididymostomy is an effective therapy of primary epididymal OA. Baseline lower FSH and higher TMSC were independent predictors for natural pregnancy occurrence.

Histological predictors of renal outcome in lupus nephritis: the importance of tubulointerstitial lesions and scoring of glomerular lesions:

Introduction Lupus nephritis (LN) affects nearly 60% of patients with systemic lupus erythematosus and up to 30% of them will progress to end-stage renal disease (ESRD), despite receiving aggressive immunosuppressive therapy. The prognostic value of ISN/RPS classification is controversial. Therefore, we aimed to identify clinical and pathological predictors of outcome in LN patients independent of this classification. Material and methods Thirty-seven patients with LN who underwent percutaneous kidney biopsy between 1997 and 2016 were included in this study. Twenty clinical and twenty histological variables were tested for their association with a composite end-point of doubling of serum creatinine, ESRD and death. Univariate and multivariate Cox proportional hazard regression analysis were performed to identify independent predictors of outcome. Results During a median follow-up period of 48 months (IQR: 17.5–120 months), 21.6% of patients reached the composite end-point. The overall survival rate of our cohort was 89% at one year, 86% at five years, 74% at 10 years and 64% at 20 years. Patients with Class IV LN showed the worst prognosis with 44% survival at 10 years, while those who additionally showed crescents and global sclerosis on kidney biopsy had an even lower survival of 21% and 0% at 10 years, respectively. After multivariate adjustment, we identified estimated glomerular filtration rate at baseline (HR, 0.91 per ml/min /1.73 m2; 95% CI, 0.84 to 0.99), 24-hour proteinuria at baseline (HR, 2.04 per g/d; 95% CI, 1.19 to 3.5), crescents (HR, 1.068 per %; 95% CI, 1.003 to 1.091), global sclerosis (HR, 1.036 per %; 95% CI, 0.984 to 1.091), presence of adhesions (HR, 9.2; 95% CI, 1.38 to 61.2) and tubulitis (HR, 13.1; 95% CI; 1.3 to 131) as independent predictors of outcome in our cohort of LN. Conclusions Our study identified glomerular (crescents, global sclerosis, adhesions) and tubulointerstitial (tubulitis) lesions, in addition to clinical variables (renal function, 24-hour proteinuria), as important predictors of renal outcome, independent of the ISN/RPS classification. We suggest that the ISN/RPS classification could be improved by a quantitative assessment of glomeruli with active and chronic lesions and by a greater emphasis given to tubulointerstitial lesions.

Inferior Vena Cava and Renal Vein Thrombosis Associated with Thymic Carcinoma

Thymic tumors are rare mediastinal tumors that can present with a wide variety of symptoms. They can cause distant manifestations and are frequently associated with paraneoplastic syndromes. In our case, we describe the evolution of a 68-year-old male whose first manifestation was thrombosis of the inferior vena cava and renal veins. Thrombosis of large abdominal veins is rare, especially without being associated with any other comorbidity or risk factors.

A Rare Cause of Acute Kidney Injury in a Female Patient with Breast Cancer Presenting as Renal Colic

Renal infarction is a rare cause of acute kidney injury which could lead to permanent loss of renal function. A prompt diagnosis is necessary in order to achieve a successful revascularization of the occluded artery. Given the rarity of the disease and the paucity of the reported cases in the previous literature a high index of suspicion must be maintained not only in the classical cardiac sources of systemic emboli (atrial fibrillation, dilated cardiomyopathy, or endocarditis), but also in the situations when a hypercoagulable state is presumed. The unspecific presenting symptoms often mask the true etiology of the patients complaints. We present here a rare case of renal infarction that occurred in the setting of a hypercoagulable state, in a female patient with a history of breast cancer and documented hepatic metastases.

Kidney involvement by IgG4-related sclerosing disease

A 54-year-old Caucasian woman was admitted due to persistent febrile syndrome, sweating and abdominal pain. Fever marked the onset of the patients medical history 10 years earlier. The physical examination revealed normal findings. Laboratory data showed normal white blood cell count, mild microcytic anaemia with a normal reticulocyte count, important inflammatory syndrome (C-reactive protein 40 mg/L, IL-6 23 pg/mL), normal renal function and no urinary abnormalities. Autoimmune serology was negative. An abdominal computed tomography scan revealed multiple nodular masses in the right kidney associated with a large lumboaortic adenopathic mass (Figure 1). A renal biopsy showed severe interstitial fibrosis and tubular atrophy. The borders of the sclerotic lesion were heavily infiltrated by lymphocytes and plasma cells (Figure 2). The morphology and anatomic distribution of the lesions raised the differential diagnosis of tubulointerstitial nephritis versus a lymphoma or plasma cell dyscrasia (Figure 3). Immunohistochemistry and in situ hybridization studies (including CD3, CD20, CD68, CD138, lambda LC, kappa LC, PAX5, desmin, ALK-1, AE1/AE3 cytokeratin, HMB-45) did not support a lymphoproliferative process. CD20 and PAX5 highlighted well-formed follicles and occasional germinal centres, while CD3 stained primarily small, mature-appearing T-cells. CD138 + plasma cells were abundant and kappa/lambda ISH showed polytypic distribution. Reed-Sternberg and/or Hodgkin cells were not identified, although focally, eosinophils were prominent. However, IgG4 immunostaining showed a marked increase in IgG4-positive plasma cells at the borders of the sclerotic lesions. We made a diagnosis of IgG4-related sclerosing autoimmune disease. Evolution was favourable following immunosuppressive therapy (prednisone and cyclophosphamide), with an important decrease in the size of the lumboaortic adenophatic mass and right kidney nodular masses, and remission of fever and of the inflammatory syndrome. Fig. 1. Computed tomography scan of the abdomen: nodular masses in the right kidney associated with a large lumboaortic adenopathic mass. Fig. 2. Renal biopsy: a fibroinflammatory process extensively replaces normal renal interstitium. The borders of the sclerotic lesion are heavily invaded by a dense lymphoplasmacytic infiltrate. (haematoxylin–eosin stain; original magnification, ×20) ... Fig. 3. (A) Normal kidney architecture (right) is replaced by severe inflammatory cell infiltration and fibrosis (left). (B) Well-formed follicles are visible in the inflammatory cell infiltration (high magnification of the red square marked area in A)