RESUMEN
BEN is a primary, chronic tubulointerstitial nephritis characterized with chronic anemia, absence of edema, xantoderma, normal blood pressure and normal findings on the fundus oculi. The disease is distributed in restricted areas in Bulgaria, Romania, Croatia, Bosnia, Former Yugoslavia. Despite numerous studies on genetic and environmental factors and their possible involvement in BEN, its etiopathogenesis still remains elusive. Our recent study aim to elucidate the possible epigenetic component in BEN development. Whole genome DNA array methylation analysis was applied to compare the methylation profiles of male and female BEN patients from endemic regions in Bulgaria and Serbia and healthy controls. All three most prominent candidate genes with aberrations in the epigenetic profile discovered with this study are involved in the inflammatory/immune processes and oncogenesis. These data are in concordance with the reported pathological alterations in BEN. This research supports the role of epigenetic changes in BEN pathology. Exome sequencing of 22.000 genes with Illumina Nextera Exome Enrichment Kit revealed three mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients which encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.
Asunto(s)
Nefropatía de los Balcanes/genética , Metilación de ADN , Epigénesis Genética , Epigenómica , Genoma Humano , Genómica , Nefropatía de los Balcanes/diagnóstico , Nefropatía de los Balcanes/epidemiología , Bulgaria/epidemiología , Estudios de Casos y Controles , Análisis Mutacional de ADN , Epigenómica/métodos , Exoma , Femenino , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genómica/métodos , Proteoglicanos de Heparán Sulfato/genética , Humanos , Masculino , Mutación , Elastasa Pancreática/genética , Fenotipo , Canales de Potasio de Dominio Poro en Tándem/genética , Factores de Riesgo , Serbia/epidemiologíaRESUMEN
Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants--CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.
Asunto(s)
Nefropatía de los Balcanes/genética , Proteoglicanos de Heparán Sulfato/genética , Fallo Renal Crónico/genética , Elastasa Pancreática/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Nefropatía de los Balcanes/patología , Exoma/genética , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fallo Renal Crónico/patologíaRESUMEN
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial kidney disease prevalent in Serbia, Bosnia, Croatia, Bulgaria and Romania. Genetic studies have supported the genetic predisposition to BEN, and some studies in Bulgaria and in the Kolubara region of Serbia have revealed abnormalities of the urinary tract in up to 46% of children from families with BEN. In the present study, urinary excretion of creatinine, an index of muscle mass, was studied in 703 healthy children from endemic and non-endemic areas around the South Morava River. The survey covered a three-year period, and the children were studied three times a year: in the spring, autumn and winter. A urine sample for the period corresponding to 7-10 a.m. was collected during each study period. Evidence has been presented that children from families with BEN excrete significantly less creatinine than those from families without BEN living in the same area, or than children living in villages outside the endemic region or in the city of Nis. This study supports the view that genetic predisposition to BEN is indicated by a smaller muscle mass, although the effect of living conditions and nutrition may also contribute to this.
Asunto(s)
Nefropatía de los Balcanes/orina , Creatinina/orina , Adolescente , Nefropatía de los Balcanes/epidemiología , Nefropatía de los Balcanes/genética , Niño , Estudios de Cohortes , Salud de la Familia , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Encuestas Epidemiológicas , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Tamaño de los Órganos , Población Rural , Estaciones del Año , Población Urbana , Yugoslavia/epidemiologíaRESUMEN
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial kidney disease prevalent in Serbia, Bosnia, Croatia, Bulgaria and Romania. This study investigates the incidence of BEN patients on dialysis with end-stage kidney disease (ESKD), and BEN-associated mortality in endemic areas around the South Morava River in Serbia from 1978 to 1997. In the last 10 years a marked decrease in the incidence of ESRD and BEN-induced mortality has been documented in the region. This study shows a significantly decreased incidence of BEN in endemic areas in South Serbia. Since the effects of etiological agent(s) on renal function in children from families in endemic areas was demonstrated in the early nineties and the disease seems to have an endemic-epidemic profile, the possibility of another epidemic outbreak in the future cannot be excluded.
Asunto(s)
Nefropatía de los Balcanes/epidemiología , Nefropatía de los Balcanes/complicaciones , Nefropatía de los Balcanes/mortalidad , Nefropatía de los Balcanes/terapia , Humanos , Incidencia , Morbilidad/tendencias , Diálisis Renal , Estudios Retrospectivos , Yugoslavia/epidemiologíaAsunto(s)
Nefropatía de los Balcanes/diagnóstico , Nefropatía de los Balcanes/etiología , Exposición a Riesgos Ambientales/efectos adversos , Toxinas Biológicas/efectos adversos , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Dinámica Poblacional , Abastecimiento de AguaRESUMEN
The volume densities of the cortical interstitium (CI), glomeruli and proximal tubular epithelium have been investigated on a sample involving 18 patients suffering from Balkan endemic nephropathy (BEN), classified into three groups with regard to the clearance of 99mTc-DTPA. In comparison with the control group, the evolution of the disease is marked by a significant increase of the CI volume (p<0.001), as well as a significant reduction of glomerular (p<0.01) and tubular volume densities (p<0.001). The most intensive changes of CI and glomerular volumes are characteristic of the initial stage of the disease when glomerular filtration (GF) has shown no signs of deterioration yet. On the other hand, a significant reduction of the tubular epithelium volume density is characteristic of the advanced stages. The specified changes, particularly those taking place at the level of interstitium bear the key responsibility for the BEN progression. However, a number of links constituting the chain of BEN morphogenesis remained insufficiently clarified. This urges for a precise quantification of all histological changes taking place in different stages of the disease, starting from the earliest, in order to get a better insight into the order and dynamics of their occurrence.
Asunto(s)
Nefropatía de los Balcanes/patología , Riñón/patología , Biopsia , Humanos , Glomérulos Renales/patología , Túbulos Renales Proximales/patologíaRESUMEN
Balkan nephropathy (BEN) is commonly associated with urothelial cancer. Urothelial cancer is manifested in the advanced stage of disease. The aim of this study was to facilitate early detection of urothelial cancer in BEN patients and their family members living in an endemic region by using tumour markers, carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA), and a putative marker, ferritin. Fifteen BEN patients with normal renal function, 17 with renal failure (BEN-RF), 13 healthy members of their families (HFM), 14 patients with glomerulonephritis (GN) and 12 healthy controls (C) were studied. Serum CEA levels in BEN patients were within normal limits, however, in BEN-RF patients they were significantly increased over HFM (p<0.05). Serum TPA levels in BEN and BEN-RF patients were significantly higher than in the C and HFM groups (p<0.05). Urinary CEA was not significantly different between the groups studied. Urinary TPA levels in HFM (median 125 U/l, BEN (236 U/l) and BEN-RF (275 U/l) were significantly increased over C (30 U/l), however, TPA levels were increased also in GN patients (437 U/l). None of the BEN patients studied developed urothelial cancer during the ten years' follow-up. Markedly elevated urinary TPA-like levels in all patients studied (HFM, BEN, BEN-RF, GN) suggest that urinary TPA may not be a reliable tumour marker. However, the clinical relevance of high TPA levels in BEN patients should be evaluated.
Asunto(s)
Nefropatía de los Balcanes/sangre , Biomarcadores de Tumor/sangre , Nefropatía de los Balcanes/orina , Biomarcadores de Tumor/orina , Antígeno Carcinoembrionario/sangre , Antígeno Carcinoembrionario/orina , Ferritinas/sangre , Ferritinas/orina , Humanos , Antígeno Polipéptido de Tejido/sangre , Antígeno Polipéptido de Tejido/orinaRESUMEN
We evaluated the effect of PTH on blood pressure in haemodialysed patients. The correlation was found between systolic, diastolic pressure and PTH. The results have shown that PTH might have the influence on regulation of arterial blood pressure in these patients.
Asunto(s)
Presión Sanguínea , Hormona Paratiroidea/sangre , Diálisis Renal , Adulto , Anciano , Presión Sanguínea/fisiología , Femenino , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana EdadRESUMEN
Most common complications of peritoneal dialysis are those related to anatomic defect of the abdominal wall and peritoneum. The aim of this investigation was to examine the frequency of congenital and acquired wall defects in patients on CAPD treatment causing complications. Fifty patients, 32 women and 18 men, on CAPD treatment for more than two years, were investigated. Most common was a defect in the anterior-lateral abdominal wall predisposing to hernias in 14% of patients. Umbilical and pericatheteral hernias were more common than other, with a mean time of 21 months for the appearance. Persistence of vaginal process of peritoneum related to scrotal oedema was documented in 4% of patients. Communication of peritoneal cavity with the abdominal ostium of tuba uterina was found not to be an important factor for peritonitis.
Asunto(s)
Cavidad Peritoneal/anomalías , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Enfermedades Peritoneales/diagnóstico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Peritonitis is a very serious complication in patients treated by CAPD. The frequent and grave episodes are the main cause for CAPD withdrawal. The effective prevention and adequate therapy of peritonitis are very important for a successful CAPD treatment. The aim of this study was to present our results of peritonitis therapy in CAPD patients using the following protocol: Vancomycin 1.0 g.i.p. immediately after the admission to the unit, 250 mg Ceftriaxon (Longaceph) after a bag exchange for seven days, and the 1.0 g Vancomycin. Using this protocol we treated 97 peritonitis episodes; 74 of them (80%) were treated successfully by this antibiotics combination. The clearness of peritoneal fluid was attained 1-3 days within 56.7% of cases, and 4-6 days within the 29.7% peritonitis episodes (86.4%). A common cause of peritonitis was Staphylococcus epidermidis episodes (28.4%), Staphylococcus aureus (13.5%), and in 39.1% episodes the cultures were sterile. Uneffective antibiotic application according to this protocol was found in cases of pseudomonas and fungal peritonitis. The mentioned antibiotic therapy had no effect in a small number of peritonitides provoked by S. epidermidis (8.7%) and S. aureus (13.0%) This required the application of a third antibiotic. It could be concluded that this antibiotic combination in treatment of peritonitis in patients on CAPD was very effective.
Asunto(s)
Antibacterianos , Quimioterapia Combinada/uso terapéutico , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Peritonitis/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peritonitis/etiologíaRESUMEN
The estimation of CAPD efficacy presents a complex problem in the patients treated by this method. The most important parameters are: clinical indications, biochemical parameters, Kt/v, PCT, PET indexes, and others. Numerous factors may influence CAPD efficacy. Peritonitis, particularly the frequent episodes, significantly affects permeability and ultrafiltration capacity of the peritoneal membrane. The aim of this paper is to investigate the peritonitis incidence and its influence on some parameters of CAPD efficacy. Forty-four CAPD patients of both sexes, aged 55.7 +/- 13.5 yrs, dialysis duration 19.6 +/- 15 months, were studied. The influence of peritonitis incidence was studied using urea, creatinine, hemoglobin, hematocrit parameters and K t/v, PET indexes. Statistically significant low K t/v values were found in the patients who had four or more peritonitis episodes. Our results, as well as those in the literature, indicate that frequent peritonitis episodes significantly decrease the peritoneal membrane permeability.
Asunto(s)
Diálisis Peritoneal Ambulatoria Continua , Peritonitis/fisiopatología , Adulto , Anciano , Creatinina/metabolismo , Femenino , Humanos , Fallo Renal Crónico/fisiopatología , Masculino , Peritonitis/etiología , Urea/metabolismoRESUMEN
Etiology and pathogenesis of endemic nephropathy (EN) are unknown and in this work the possible pathogenetic role of disturbed antioxidant protection, estimated by the activity of erythrocyte catalase, was evaluated. In patients with EN as well as in clinically healthy members of their families a statistically significant increase in catalase activity (16.7 +/- 0.63 x 10(4) U/g Hb) compared to the control group of the blood bank donors from the city of Nish (11.7 +/- 0.69 x 10 U/g Hb) was found. Increased catalase activity, at the level of significance, was also found in clinically healthy members of EN patients families. The increase of catalase activity was considered compensatory to the increased oxydative capacity.
Asunto(s)
Nefropatía de los Balcanes/sangre , Catalasa/sangre , Eritrocitos/enzimología , Salud de la Familia , HumanosRESUMEN
The aim of this study was to investigate serum levels, urinary excretion and in vitro peripheral blood mononuclear cell (PBMC) production of beta 2-microglobulin in patients with Balkan nephropathy and their families. Increased urinary beta 2-microglobulin excretion was found in Balkan nephropathy, chronic pyelonephritis and glomerulonephritis patients, being highest in the first group. The serum level of beta 2-microglobulin in Balkan nephropathy patients correlated with residual kidney function. Synthesis of beta 2-microglobulin by PBMC, untreated or stimulated by PHA, was not increased in Balkan nephropathy patients or their healthy family members compared to the control group of healthy persons living outside of an endemic region. This study has shown that the increased serum beta 2-microglobulin level in Balkan nephropathy patients is the consequence of the glomerular filtration rate (GFR) reduction. Urinary beta 2-microglobulin excretion was found increased not only in patients but in some healthy members of nephropathic families. beta 2-microglobulin therefore can serve as a marker of the early tubular damage in Balkan nephropathy. However, urinary beta 2-microglobulin is not specific for Balkan nephropathy, lacking specificity required for screening purposes. The different patterns of serum and urinary beta 2-microglobulin, and other urinary proteins, in patients with Balkan nephropathy from patients with chronic pyelonephritis and glomerulonephritis favor the opinion that Balkan nephropathy is a separate clinical entity.
Asunto(s)
Nefropatía de los Balcanes/sangre , Microglobulina beta-2/metabolismo , Albuminuria/orina , Nefropatía de los Balcanes/orina , Glomerulonefritis/sangre , Glomerulonefritis/orina , Humanos , Técnicas In Vitro , Leucocitos Mononucleares/metabolismo , Pielonefritis/sangre , Pielonefritis/orina , Albúmina Sérica/metabolismo , Microglobulina beta-2/orinaRESUMEN
The aim of this investigation was to study the frequency of urinary tract tumors (UTT) in settlements around the South Morava River and its tributaries where Balkan nephropathy is endemic. For this purpose 659 surgery and autopsy records of patients with UTT were reviewed. The records came from 25 counties and 1279 settlements classified as endemic, hypoendemic and nonendemic. Upper tract urothelial, urinary bladder and kidney tumors were included in the evaluation. A highly significant geographic correlation between Balkan nephropathy and UTT localized in renal pelvis and ureter was noted in the South Morava River valley. These tumors were 57 and 61.8 times more frequent in endemic settlements than in control rural and city populations free of Balkan nephropathy. The frequency of urinary bladder tumors in endemic settlements was also increased compared with the nonendemic villages and large cities, up to 11.9 and 8.5 times, respectively. In endemic settlements, upper urinary tract tumors were five times and tumors of urinary bladder were seven times more frequent in families with Balkan nephropathy than in those without, and up to 224 times more frequent than in the city families. Familial clustering of UTT was also noted. The geographic correlation between Balkan nephropathy and UTT supports the speculation that these disorders share a common etiology.