Renal function is similar in solitary kidneys from patients with and without diabetes.

OBJECTIVES: Due to the shortage of living kidney donors and the current diabetes mellitus (DM) pandemic, studying the association of solitary kidney (SK) with DM is of paramount importance. Our aim was to assess the significance of the association between SK and DM. MATERIALS AND METHODS: Eighty-four patients with SK and DM (group A), with a mean age of 62.46±12.72 years, of whom 36 were males and 48 were females, were enrolled in the study. The control group (group B) comprised 84 SK patients without DM of similar age and duration of existence of a SK. Mean age: 61.58±8.22 years, 23 males and 61 females. Serum creatinine, GFR (CKD-EPI), glycaemia, cholesterol, triglycerides, uric acid, proteinuria/24h, systolic blood pressure (SBP), diastolic blood pressure (DBP) and BMI were assessed. RESULTS: The group of patients with SK and DM (group A) had a higher BMI (p=0.0007), higher metabolic abnormalities (higher glycaemia [p<0.001], triglycerides [p=0.0004], uric acid [p=0.019] and proteinuria/24h [p=0.006]). The study group also had a higher prevalence of hypertension (p=0.003) and coronary artery disease (p=0.031). CONCLUSIONS: We found a higher value of proteinuria in the study group, significant metabolic abnormalities, as well as a higher prevalence of hypertension and coronary artery disease. However, no differences with respect to GFR were found, which could have significant implications for transplantation.

Is ciprofloxacin safe in patients with solitary kidney and upper urinary tract infection?

The solitary kidney (SK) undergoes adaptive phenomena of hyperfunction and hyperfiltration. These secondary adaptive phenomena can make it more vulnerable to potentially nephrotoxic therapies. Adverse reactions of the kidneys to ciprofloxacin are rare, but sometimes severe. Therefore, our study sought to assess the reactions to ciprofloxacin of patients with solitary kidney (SK) and urinary tract infection (UTI) by means of urinary biomarkers. We studied 19 patients with SK and urinary tract infection (UTI) who had been administered a 7-day treatment with intravenous ciprofloxacin. Urinary N-acetyl-beta-d-glucosaminidase, alpha 1-microglobulin, and estimated glomerular filtration rate (eGFR) of these patients were measured at the initiation and at the end of treatment. In 47.37% patients NAG diminished under ciprofloxacin treatment. This observation has the significance of favourable evolution of the tubulointerstitial lesions caused by UTI and lack of nephrotoxic effects; 52.63% cases presented an increase of urinary NAG, a fact that suggests a nephrotoxic effect of ciprofloxacin. The evolution of urinary alpha 1-microglobulin was similar to that one of urinary NAG. Only one of three cases with chronic kidney disease (CKD) stage 5 presented acute kidney injury, associated with increase in the tubular markers. In spite of the high variability of the urinary biomarkers, UTI evolved favourably in these cases; eGFR increased in 16 out of 19 patients, a fact which is indicative of a good outcome of renal function, even in patients with elevated levels of the tubular damage biomarkers. This observation supports the hypothesis that eGFR may be dissociated from the biomarkers which assess tubular injury. In SK patients the occurrence of AKI is not frequent, although the urinary biomarkers rise in some patients treated with ciprofloxacin. This is related not only to the nephrotoxic effect of the drug, but probably to the association of other factors (allergy, individual susceptibility). In SK patients, renal tubular biomarkers, especially NAG, allow monitoring of tubular injury and impose caution in prescribing ciprofloxacin treatment, mainly to patients at risk. Ciprofloxacin is relatively safe regarding its nephrotoxicity, while caution is required in vulnerable patients.

Urinary Biomarkers in the Assessment of Early Diabetic Nephropathy.

Diabetic nephropathy (DN) is a frequent and severe complication of diabetes mellitus (DM). Its diagnosis in incipient stages may allow prompt interventions and an improved prognosis. Towards this aim, biomarkers for detecting early DN can be used. Microalbuminuria has been proven a remarkably useful biomarker, being used for diagnosis of DN, for assessing its associated condition-mainly cardiovascular ones-and for monitoring its progression. New researches are pointing that some of these biomarkers (i.e., glomerular, tubular, inflammation markers, and biomarkers of oxidative stress) precede albuminuria in some patients. However, their usefulness is widely debated in the literature and has not yet led to the validation of a new "gold standard" biomarker for the early diagnosis of DN. Currently, microalbuminuria is an important biomarker for both glomerular and tubular injury. Other glomerular biomarkers (transferrin and ceruloplasmin) are under evaluation. Tubular biomarkers in DN seem to be of a paramount importance in the early diagnosis of DN since tubular lesions occur early. Additionally, biomarkers of inflammation, oxidative stress, podocyte biomarkers, and vascular biomarkers have been employed for assessing early DN. The purpose of this review is to provide an overview of the current biomarkers used for the diagnosis of early DN.

Urinary enzymatic markers (N-acetyl-beta-D-glucosaminidase) in assessing the tubulointerstitial compartment in chronic glomerulonephritis related to odontogenic foci.

Chronic glomerulonephritis is related to focus infection. Odontogenic foci are frequently involved in glomerulonephritis. The relationship with the odontogenic focus infection can be demonstrated by the occurrence or aggravation of the symptoms of glomerulonephritis: proteinuria, haematuria, high blood pressure and oedema. Glomerular impairment in glomerulonephritis occurs together with inflammatory alterations of the tubulointerstitial compartment that can play an important part in the evolution of the disease. Tubular urinary markers can indicate the activation of this compartment during an infection of a focus, an odontogenic focus in our study.The paper aims at demonstrating the relationship between the odontogenic focus infection and tubulointerstitial lesions, assessed by a tubular urinary marker, N-acetyl beta-D glucosaminidase (NAG).We investigated the urinary N-acetyl beta-D glucosaminidase of 20 patients with chronic glomerulonephritis who presented odontogenic focus infections, comparing them with patients with chronic glomerulonephritis without odontogenic foci and of 20 controls, clinically healthy persons.Chronic glomerulonephritis patients with odontogenic focus infection presented clearly increased values as compared to clinically healthy control persons of urinary N-acetyl beta-D glucosaminidase.These patients underwent surgical intervention on the odontogenic focus under antibacterial prophylactic treatment. In 75% cases, the values of N-acetyl beta-D glucosaminidase diminished, indicating the favourable effect of the treatment of the odontogenic focus on the tubulointerstitial compartment in patients with chronic glomerulonephritis. In 25% cases this therapeutic treatment was associated with an increase of the values of urinary N-acetyl beta-D glucosaminidase, expressing its unfavourable effect on chronic glomerulonephritis.Urinary N-acetyl beta-D glucosaminidase indicated an etiopathogenetic relationship between the odontogenic focus and the tubulointerstitial compartment in chronic glomerulonephritis.

Familial versus environmental factors in Balkan endemic nephropathy in Mehedinti county, Romania, by means of albuminuria and tubular biomarkers: preliminary study.

INTRODUCTION AND AIMS: Balkan endemic nephropathy (BEN), a regional tubulointerstitial kidney disease encountered in South-Eastern Europe, with still undefined etiology and inexorable evolution towards end stage renal disease, raises the question of the relative contribution of family and environmental factors in its etiology. In order to evaluate the intervention of these factors, markers of tubular injury have been assessed, this lesion being considered an early renal involvement in BEN. METHODS: The paper studies relatives of BEN patients currently included in dialysis programmes (for involvement of the family factor) and their neighbors (for involvement of environmental factors) and analyzes them with regard to tubular injury by means of tubular biomarkers (N-acetyl-beta-d-glucosaminidase-NAG and alpha-1-microglobulin), and albuminuria. At the same time, glomerular filtration rate (GFR) (CKD-EPI) was measured. It is considered that, in order to acquire the disease, one should have lived for 20 years in the BEN area. The relatives have been classified according to this criterion. RESULTS: More evident tubular injury was found in the neighbors of BEN patients living for more than 20 years in the endemic area, which argues in favor of environmental factors. Higher levels of urinary alpha-1-microglobulin and albumin in relatives of BEN patients who had been living for more than 20 years in the area than in relatives with a residence under 20 years, plead for the same hypothesis. GFR was lower in persons who had been living for more than 20 years in the BEN area (neighbors and relatives). CONCLUSIONS: Environmental factors could be more important in BEN than family factors.

Surprising good antioxidant status in patients with Balkan Endemic Nephropathy on hemodialysis undergoing vitamin C therapy. A pilot study.

AIMS: End Stage Renal Disease (ESRD) represents a microinflammatory state accompanied by oxidative stress and an imbalance between pro- and antioxidants. Vitamin C is a highly effective antioxidant, acting to lessen oxidative stress. The aim of our study was to assess the Antioxidant Capacity of Water soluble substances (ACW) and the Antioxidant Capacity of Liposoluble substances (ACL) in patients with Balkan Endemic Nephropathy (BEN) on hemodialysis undergoing Vitamin C therapy as compared to healthy controls. METHODS: Twenty-one patients with BEN on hemodialysis (HD), mean age: 63.33 +/- 5.42 years, 6 M and 15 F, were enrolled into the study. All patients received 10 vials of Vitamin C 750 mg/5 ml every 2 months. Eleven apparently healthy subjects, mean age: 63.73 +/- 5.21 years, 6 M and 5 F, served as controls. The photochemiluminescence assay was used to measure the antioxidant activity of plasma samples. The results are presented in equivalent concentration units of Vitamin C for water soluble antioxidants and in equivalent concentration units of Trolox (synthetic Vitamin E) for lipid soluble antioxidants. Both concentrations are expressed in micromols/L. Statistical analysis (non-parametric Wilcoxon test) was performed using NCSS. RESULTS: Mean duration since BEN diagnosis was: 8.24 +/- 3.5 years. Mean duration since HD initiation was: 4.92 +/- 3.4 years. Smoking status was negative in all patients. Hypertension was present in 15 patients (71.42%), cardiovascular disease in 10 (47.61%), HCV infection in 13 (61.9%), 1 patient had HBV + HCV infection, 1 had renal tuberculosis, 1 had upper urinary tract cancer, 1 genital cancer, and I autoimmune thyroid disease. The Antioxidant Capacity of Water soluble substances (ACW) in patients with BEN was 477.6 +/- 177.63 micromols/L, significantly higher as compared to controls: 198.05 +/- 196.63 micromols/L; p = 0.01, whereas the Antioxidant Capacity of Liposoluble substances (ACL) in patients with BEN was 33.9 +/- 22.99 micromols/L, non-significantly different as compared to controls: 27.38 +/- 4.21 micromols/L; p = 0.22. CONCLUSIONS: We conclude that Vitamin C therapy in patients with BEN on HD significantly increases the Antioxidant Capacity of Water soluble substances (ACW) as compared to controls and could be used to counter oxidative stress in patients with ESRD.

Are other factors besides albuminuria important for the progression of HCV chronic hepatitis towards CKD? A survey from a hepatology department in western Romania.

UNLABELLED: HCV is an important cause of renal disease. Taal and Brenner have identified risk factors for CKD and have suggested that these risk factors be incorporated into a renal risk score analogous to the Framingham cardiovascular score. Given the high HCV-renal disease comorbidity, we sought to assess risk factors for CKD in patients with HCV chronic hepatitis. METHODS: One hundred-seventeen patients with HCV chronic hepatitis (mean age: 50.68 +/- 9.14 years; 86 female and 31 male) hospitalized in the Department of Hepatology during 2009 were enrolled into the study. All patients were assessed for the risk factors for CKD proposed by Taal and Brenner: albuminuria, diabetes mellitus, hypertension, obesity, anemia, hypercholesterolemia, hypertriglyceridemia, nephrotoxins, primary renal disease, associated urological disorder, cardiovascular disease and family history of CKD. Renal function (GFR-CKD-Epi) was also evaluated. STATISTICAL ANALYSIS: Pearson's correlation coefficient and Odds Ratio (OR) was performed using SPSS17 and Epi 3.2.2. RESULTS: The prevalence of albuminuria was 21.36%, of hypertension was 20.51%, of obesity was 21.36%, and hypercholesterolemia was present in 41.02% of the cases. Renal function was as follows: 10.25% (12/117) of the patients had a GFR < 60 mL/min/1.73 sqm.; 64.95% (76/117) of the patients had a GFR between 60-89 mL/min/1.73 sqm.; and 24.78% (29/117) had a GFR > or = 90 mL/min/1.73 sqm. CONCLUSIONS: Our study shows that HCV chronic hepatitis is associated with renal function impairment in a high percentage of patients. Prominent risk factors for CKD are present in these patients, such as albuminuria, hypertension, obesity, and hypercholesterolemia, which need to be actively searched and addressed therapeutically.

Urinary biomarkers in assessing the nephrotoxic potential of gentamicin in solitary kidney patients after 7 days of therapy.

INTRODUCTION: The solitary kidney (SK) may present increased vulnerability to nephrotoxicity because of adaptive phenomena. AIMS: Assessing the vulnerability of the SK with urinary tract infections (UTI) to gentamicin by means of urinary biomarkers (N-acetyl-beta-D-glucosaminidase (NAG) and urinary alpha-1-microglobulin), as well as glomerular filtration rate (GFR). METHODS: We studied 14 patients with SK with UTI (group A) (mean age 58.07 ± 13.61 years, mean duration of SK 13.55 ± 12.33 years) who were administered gentamicin for 7 days. Group B consisted by 17 patients with SK without any other associated renal pathology (average age 51.17 ± 9.39 years, average existence period of a single kidney 33.23 ± 21.73 years). We also included a third group (group C) represented by nine healthy individuals, with two kidneys. RESULTS: Increased values of urinary NAG were found in group B as compared to group C and alpha-1 microglobulin in group A as compared to group B. During treatment with gentamicin, increased values of both NAG and alpha-1-microglobulin in group A were found on day 7 as compared to values before treatment (day 7 NAG=18.99 ± 14.07 U/g creat versus day 0, NAG=5.15 ± 6.54 U/g creat, p=0.004; day 7 alpha-1-microglobulin=20.88 ± 18.84 mg/g creat versus day 0, urinary alpha-1-microglobulin=4.96 ± 6.57 mg/g creat, p=0.003). No statistically significant alterations of GFR were noticed after 7 days of treatment. CONCLUSIONS: We found the nephrotoxic effects of gentamicin at tubular level, but not at glomerular level. The nephrotoxic potential of gentamicin in patients with a SK can be monitored by assessing urinary biomarkers during treatment of UTI.

Is the urinary biomarkers assessment a non-invasive approach to tubular lesions of the solitary kidney?

INTRODUCTION: The solitary kidney (SK) is currently debated in the literature, as living kidney donation is extensively used and the diagnosis of congenital SK is frequent. Tubulointerstitial lesions associated with adaptive phenomena may occur early within the SK. AIMS: Analysis of the significance of urinary biomarkers in the assessment of tubulointerstitial lesions of the SK. METHODS: A cross-sectional study of 37 patients with SK included 18 patients-acquired SK (mean age 56.44 ± 12.20 years, interval from nephrectomy 10.94 ± 9.37 years), 19 patients-congenital SK (mean age 41.52 ± 10.54 years). Urinary NAG, urinary alpha-1-microglobulin, albuminuria, eGFR (CKD-EPI equation) were measured. RESULTS: In acquired SK, NAG increased in 60.66%, urinary alpha 1-microglobulin in 16.66%, albuminuria in 55.55% of patients. Inverse correlation with eGFR presented NAG (R(2 )= 0.537, p = 0.022), urinary alpha 1-microglobulin (R(2 )= 0.702, p = 0.001), albuminuria (R(2 )= 0.655, p = 0.003). In congenital SK, NAG increased in 52.63%, urinary alpha 1-microglobulin in 5.26%, albuminuria in 47.36% of patients. In this group, urinary biomarkers correlated inversely with eGFR: NAG (R(2 )= 0.743, p < 0.001), urinary alpha 1-microglobulin (R(2 )= 0.701, p = 0.001), albuminuria (R(2 )= 0.821, p < 0.001). Significant correlations were found between the urinary biomarkers in both groups. CONCLUSIONS: Urinary biomarkers allow a non-invasive, sensitive, early assessment of the tubular lesions of the SK. Urinary biomarkers of PT injury parallel renal function decline, thus complementing the estimation of GFR. Monitoring of PT dysfunction is mandatory in patients with SK.

The dynamics of urinary N-acetyl-ß-D-glucosaminidase (NAG), a marker of renal tubular dysfunction, in patients with lupus nephritis undergoing oral prednisone therapy.

INTRODUCTION AND AIMS: N-Acetyl-ß-D-glucosaminidase (NAG), a marker of renal tubular dysfunction, is increased in patients with lupus nephritis. In addition to the toxic effects of proteinuria, patients with lupus nephritis may exhibit other factors that contribute to tubular dysfunction, such as pathogenic antitubular basement membrane antibodies. The aim of our study was to assess urinary NAG, proteinuria, and glomerular filtration rate (GFR) before treatment and after 7 and 30 days of oral prednisone therapy in patients with lupus nephritis. METHODS: Ten patients with lupus nephritis, all females, mean age: 29.4 ± 10.17 years, were enrolled into the study. All the patients received oral prednisone 1 mg/kg. Twenty healthy subjects served as controls. We measured urinary NAG before treatment and after 7 and 30 days of oral prednisone therapy. Proteinuria, GFR, blood pressure, and side effects of therapy were also followed up. Urinary NAG was measured using the colorimetrical method and expressed as units per gram of creatinine (U/gCr). Statistical analysis (Wilcoxon signed ranks test and Wilcoxon rank sum test) was performed using SPSS 17. RESULTS: In the 10 patients with lupus nephritis, urinary NAG before treatment was 16.9 ± 13.39 U/gCr (P = 0.005 compared with controls). NAG in controls was 1.73 ± 0.51 U/gCr. Proteinuria before treatment was 3.84 ± 1.93 g/24 h. The GFR before treatment was 50.48 ± 11.98 mL/min/1.73 m². After 7 days of prednisone, urinary NAG was 23.55 ± 25.25 U/gCr (P = 0.878 compared with baseline, and P = 0.02 compared with controls). Proteinuria was 2.94 ± 1.3 g/24 h (P = 0.005 compared with baseline), and the GFR was 58.11 ± 13.64 mL/min/1.73 m² (P = 0.005 compared with baseline). After 30 days of prednisone, urinary NAG was 11.77 ± 12.18 U/gCr (P = 0.203 compared with baseline, P = 0.022 compared with the value after 7 days of prednisone, and P = 0.01 compared with controls). Proteinuria was 1.73 ± 0.68 g/24 h (P = 0.005 compared with baseline, and P = 0.005 compared with the value after 7 days of prednisone), and the GFR was 67.49 ± 16.42 mL/min/1.73 m² (P = 0.005 compared with baseline and P = 0.009 compared with the value after 7 days of prednisone). Blood pressure measurements did not show any significant changes. No major side effects of steroid therapy were noticed. CONCLUSIONS: Urinary NAG showed a significant reduction between 7 and 30 days of therapy. The reduction in urinary NAG set in later than the decline in proteinuria and the improvement in GFR. Further studies incorporating a longer follow-up are needed to observe whether the reduction in NAG persists upon continuation of prednisone therapy.

Genetic and epigenetic biomarkers for early detection, therapeutic effectiveness and relapse monitoring in bladder cancer.

Urinary bladder cancer is the fifth most common cancer in the Western world and is responsible for about 3% of all cancer-related deaths. Because most advanced invasive or metastatic cancers have low cure rates, risk assessment and early detection of the clinically occult premalignant phases of neoplasia are a particular importance. Many tumor biomarkers for bladder cancer have been evaluated for use in detecting and monitoring bladder cancers tissue specimens, bladder washes, and urine specimens but, none of the biomarkers reported to date has shown sufficient sensitivity and specificity to detect the entire spectrum of bladder cancers in routine clinical practice. The limitations of established prognostic markers requires us to identify better molecular parameters that could be of interest in predicting the prognosis of bladder cancer patients, in particular, the high-risk patient groups that are at risk of progression and recurrence. Methylation is an important molecular mechanism in the development of bladder cancer and could be used as a prognostic and diagnostic biomarker, because hypermethylation of several gene promoters was detected in urine sediment DNA from bladder cancer patients. Aberrant patterns of epigenetic modification could be, in the near future, crucial indicators in cancer diagnosis, prognosis, and additionally could be good targets for developing novel therapies while maintaining quality of life.

Does the antiviral therapy of patients with chronic hepatitis exert nephrotoxic effects?

INTRODUCTION: HBV and HCV chronic hepatitis can be accompanied by secondary renal disease. In addition, these patients receive antiviral drugs with potential nephrotoxicity. It is known that interferon (IFN) therapy in HCV-infected kidney transplant recipients is followed by rejection of the transplant in 50% of the cases. Ribavirin is contraindicated in hemodialyzed patients and in patients with a GFR <50 ml/min/1.73 m(2). IFN therapy requires dosage reduction and close monitoring in patients with a GFR <50 ml/min/1.73 m(2) and in patients with end stage renal disease. The aim of our study was to assess the nephrotoxicity of antiviral drugs in patients with chronic hepatitis by measuring three renal biomarkers: urinary albumin, N-acetyl-ß-D-glucosaminidase (NAG) and α 1-microglobulin, as well as glomerular filtration rate (GFR-MDRD4) before and at 6 months of therapy. METHODS: Fifty-five patients (28 male and 27 female, with a mean age of 47.85 ± 12.03 years) with chronic hepatitis (40 patients with HCV, 13 patients with HBV, 1 patient with HBV+HCV, and 1 patient with HBV+HDV) were enrolled into the study. Different antiviral drug associations were used on a case-by-case basis. The 40 patients with HCV chronic hepatitis received either Peg-IFN-α 2a+Ribavirin (37 patients) or Peg-IFN-α 2b+Ribavirin (3 patients). The 13 patients with HBV chronic hepatitis received Peg-IFN-α 2a (9 patients), Lamivudine (2 patients), Entecavir (1 patient), or Adefovir (1 patient). The patient with HBV+HCV chronic hepatitis received Peg-IFN-α 2a+Ribavirin. The patient with HBV+HDV chronic hepatitis received IFN-α 2a. Urinary albumin (ELISA), NAG (colorimetrical method), α 1-microglobulin (ELISA), and serum creatinine were measured before and at 6 months of antiviral therapy. Urinary markers were expressed as either mg/gCr (for albumin and α 1-microglobulin) or U/gCr (for NAG). Statistical analysis (Pearson's correlation coefficient, paired t-test and χ(2)-test) was performed. RESULTS: At 6 months of therapy urinary albumin/gCr did not increase significantly: 16.58 ± 23.39 vs. 15.85 ± 24.96 mg/gCr before therapy, p = 0.87. Urinary NAG/gCr did not increase significantly: 4.21 ± 3.37 vs. 3.83 ± 3.2 U/gCr before therapy, p = 0.53. Urinary α 1-microglobulin/gCr was almost unchanged: 4.38 ± 4.47 vs. 4.38 ± 3.57 mg/gCr before therapy, p = 0.99. The GFR did not decline significantly: 92.41 ± 22.21 vs. 94.59 ± 36.1 ml/min/1.73 m(2) before therapy, p = 0.7. Ten patients (18.18%) were albuminuric before therapy, and 14 patients (25.45%) were albuminuric at 6 months of therapy, a non-significant increase (p = 0.35). We found a correlation between urinary albumin/gCr and NAG/gCr and between urinary albumin/gCr and α 1-microglobulin/gCr both at baseline and at 6 months of therapy: r = 0.54, p = 0.0005; r = 0.29, p = 0.03; r = 0.51, p = 0.0005; and r = 0.4, p = 0.002, respectively. In the patient receiving Adefovir, a known nephrotoxic drug, two of the three biomarkers (urinary albumin/gCr and NAG/gCr) increased, most notably NAG/gCr. Both HCV and HBV chronic hepatitis therapy were associated with non-significant changes in renal biomarker excretion and GFR. CONCLUSIONS: With the exception of Adefovir, all of the drug associations used in this study were safe.

Therapeutic remedies based on Aristolochia clematitis in the main foci of Balkan endemic nephropathy in Romania.

Balkan endemic nephropathy (BEN) is a disease found in Romania and neighboring countries in the Balkan area. In Romania, BEN is most prevalent in Mehedinti County, located in the South of Romania near the Danube River. The etiology of the disease is as yet unknown. One of the current hypotheses concerning BEN etiology is an involvement of aristolochic acid (AA). BEN bears many similarities to aristolochic nephropathy, which is developed due to the use of Chinese herbs as therapeutic remedies in slimming diets. This paper analyzes the involvement of therapeutic remedies based on AA in the BEN found in Mehedinti County, where these herbs have been traditionally used. The presence of AA in the plasma of BEN patients as well as of other subjects, including healthy relatives of these patients and other persons from the BEN-affected area, has been analyzed. No AA was detected in the plasma of the studied subjects. This proves the absence, at the current time, of an AA contribution in the analyzed subjects. Therapeutic remedies based on AA have been used in the BEN-affected area. We were not able to reveal direct relationships between these remedies and either the development of BEN in dialyzed patients or the development of urinary-tract tumors in dialyzed patients with urothelial tumors. Therapeutic remedies based on Aristolochiaclematitis may play a stimulating role in BEN with regard to its development and the development of urinary-tract tumors. There may be a relationship between BEN and cumulative previous exposure to low doses of AA due to the consumption of contaminated foodstuffs, which could add to any contributions by therapeutic remedies.

The importance of clinical application of molecular biomarkers in bladder cancer detection.

It is known that high throughput technologies facilitate the identification of new molecular targets and biomarkers specific for bladder cancer.The new field of molecular medicine promises that clinical outcomes will be improved by directing therapy toward the molecular mechanisms and targets associated with the growth of the patient's tumor.The great challenge remains to improve the measurement of these targets and to translate this wealth of discovery into clinical management of bladder cancer.