Vladisav Stefanovic

Etiology of Balkan endemic nephropathy and associated urothelial cancer.

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression to terminal renal failure. Evidence has accumulated that BEN is an environmentally induced disease. There are three actual theories attempting to explain the environmental cause of this disease: (1) the aristolochic acid hypothesis, which considers that the disease is produced by chronic intoxication with Aristolochia, (2) the mycotoxin hypothesis, which considers that BEN is produced by ochratoxin A, and (3) the Pliocene lignite hypothesis, which proposes that the disease is caused by long-term exposure to polycyclic aromatic hydrocarbons and other toxic organic compounds leaching into the well drinking water from low-rank coals in the vicinity to the endemic settlements. Moreover, it was suggested that BEN risk is influenced by inherited susceptibility. Therefore, it has been expected that molecular biological investigations will discover genetic markers of BEN and associated urothelial cancer, permitting early identification of susceptible individuals who may be at risk of exposure to the environmental agents. Since kidney pathophysiology is complex, gene expression analysis and highly throughput proteomic technology can identify candidate genes, proteins and molecule networks that eventually could play a role in BEN development. Investigation of gene-gene and gene-environment interactions could be the content of further studies determining the precise risk for BEN.

Balkan endemic nephropathy and associated urothelial cancer

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease described only in some rural parts of southeastern Europe. One of its most peculiar characteristics is a strong association with upper urothelial cancer (UUC). BEN-related UUC has the same histological features as other forms of UUC in general, but is more frequently bilateral, less frequently affects the bladder and has a sex ratio close to 1. BEN and BEN-associated UUC share the same etiology. Over time, incidence of these conditions has been declining. Since BEN was first described, around half a century ago, socioeconomic changes (in housing, farming, living standards, etc.) have been profound and have obscured the factors responsible for the observed reduction in incidence. Whatever the causes of BEN, the disease might not be restricted only to southeastern Europe. Rather, the intensity of exposure to risk factors for BEN and, consequently, clustering of cases has more likely determined our knowledge of topographical distribution of an etiological entity that is much more widespread, or that might even be ubiquitous in its sporadic form.

Health-Related Quality of Life in Different Stages of Renal Failure

Measures of health-related quality of life (HRQoL) have a significant predictive value on patient survival and hospitalizations, especially in patients with chronic kidney disease (CKD). In this review, some of the major studies performed in patients with different stages of renal failure are presented. The most used instrument for measuring HRQoL is the Short form health survey questionnaire (SF-36). Patients with predialysis CKD had higher SF-36 scores than a large cohort of hemodialysis (HD) or peritoneal dialysis (PD) patients, but lower scores than those reported for the adult population. Kidney transplantation offers better HRQoL than dialysis. Hemoglobin level predicted both physical and mental domain scores of the SF-36. HRQoL of HD and PD patients were compared in only a few studies, mostly because these studies are difficult to interpret. PD patients generally have lower comorbidity scores at the onset of end-stage renal disease (ESRD), independent of other factors influencing modality selection. Comorbid medical conditions are common in patients with ESRD, and are an important contributing factor to clinical outcomes and quality of life. Depression occurs in about 20-30% of dialysis patients. This is important because of the negative impact depression has on quality of life, but also because depression is now established as a factor that can significantly affect morbidity and mortality in ESRD patients. Sexual life satisfaction showed marked deterioration in all age groups. Patients aged over 65 scored significantly better than younger patients on dialysis stress scales, and were generally more satisfied with life. Longitudinal studies are needed to define periods at risk for decline in HRQoL during progression of CKD.

Effects of Aerobic Exercise on Microalbuminuria and Enzymuria in Type 2 Diabetic Patients

Increased urinary albumin excretion is a strong predictor for the development of overt diabetic nephropathy and overall cardiovascular morbidity and mortality in patients with type 2 diabetes. In a previous study, regular aerobic physical activity in overweight/obese patients with type 2 diabetes mellitus was found to have significant beneficial effects on glycemic control, insulin resistance, cardiovascular risk factors, and oxidative stress. The aim of the present study was to investigate the effects of aerobic exercise in the same cohort of type 2 diabetic patients on urinary albumin excretion, serum levels and urinary excretion of enzymes, tubular damage, and metabolic control markers in type 2 diabetic patients. Changes from baseline to 3 and 6 months of aerobic exercise were assessed for urinary albumin excretion, serum activities, and urinary excretion of N-acetyl-β-D-glucosaminidase (NAGA), plasma cell glycoprotein 1 (PC-1) and aminopeptidase N (APN), as well as their association with insulin resistance, cardiovascular risk factors, and oxidative stress parameters in 30 male type 2 diabetic patients (aged 54.8 ± 7.3 years, with a mean BMI of 30.8 ± 3.0 kg/m2). Microalbuminuria was found in six (20%) diabetic patients at baseline, three of them (10%) after three months, and only one patient (3.33%) at the end of the study period. A significant correlation was found for urinary albumin excretion at baseline both with sulfhydryl-groups and catalase, but not for urinary albumin excretion with MDA and glutathione. The prevalence of microalbuminuria tended to decrease after six months of aerobic exercise in type 2 diabetic patients, independently of any improvement in insulin resistance and oxidative stress parameters. Neither between-group nor within-group changes were found for urinary PC-1, APN, and NAGA activity. Serum NAGA was significantly increased (p < 0.05) over the control level in diabetic patients at baseline, but it decreased to the normal level after six months of exercise. This study has shown that a six-month aerobic exercise, without any change in the medication, tended to decrease microalbuminuria without changing enzymuria. However, further studies are needed not only to confirm those findings, but to elucidate potential mechanisms that would clarify the beneficial effects of exercise.

Fifty years of research in Balkan endemic nephropathy: where are we now?

Despite broad investigations into the possible role of genetic factors, environmental agents and immune mechanisms, the etiology of Balkan endemic nephropathy (BEN) is only partially understood. An increased incidence of upper urothelial cancer in patients with BEN and in populations from endemic settlements has been demonstrated. Genetic studies have landed support for genetic predisposition to BEN. The similarity of the morphological and clinical pattern of BEN and Chinese herbs nephropathy has raised the possibility of a common etiologic agent, aristolochic acid (AA), described in 1969 by Ivić and confirmed by a recent study of AA-DNA adducts. Ochratoxin A (OTA) is studied extensively as the etiologic agent of BEN. Weathering of low-rank coals nearby the endemic villages produces water-soluble polycyclic aromatic hydrocarbons and aromatic amines, similar to metabolic products of acetaminophen, which has a causal relationship with analgesic nephropathy. AA is confirmed as the etiologic agent of BEN; however, it may not be the sole risk factor. More research is needed on the patterns of BEN over time and between different endemic places. Therefore, it is important to test etiological hypotheses in different endemic foci, preferably as a multicentric research. An international approach to solving the etiology of BEN is needed in the coming years. The geographic correlation and presence of AA-DNA adducts in both BEN and associated urothelial cancer support the hypothesis that these diseases share a common etiology.

Viral Infection in Renal Transplant Recipients

Viruses are among the most common causes of opportunistic infection after transplantation. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses have also affected outcomes. In some cases, preventive measures such as pretransplant screening, prophylactic antiviral therapy, or posttransplant viral monitoring may limit the impact of these infections. Recent advances in laboratory monitoring and antiviral therapy have improved outcomes. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections. This paper will summarize the major viral infections seen following transplant and discuss strategies for prevention and management of these potential pathogens.

Diagnostic criteria for Balkan endemic nephropathy: proposal by an international panel.

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression to terminal renal failure. Diagnostic criteria for BEN have been described more than 40 years ago. Research groups on BEN use one of at least three described lists of criteria. Comparison of studies using such criteria is difficult, and a recent meeting of investigators (Zagreb, October 2006) has suggested that unified criteria have to be elaborated. In this paper, an International Panel of BEN Investigators agreed on criteria appropriate to epidemiologic studies and clinical investigations of BEN. A screening procedure of BEN in endemic settlements is proposed.

Craniofacial bone tissue engineering

There are numerous conditions, such as trauma, cancer, congenital malformations, and progressive deforming skeletal diseases, that can compromise the function and architectonics of bones of craniofacial region. The need to develop new approaches for treatment of these disorders arises from the fact that conventional therapeutic strategies face many obstacles and limitations. The use of tissue engineering in regeneration of craniofacial bone structures is a very promising possibility and a great challenge for researchers and practitioners. Developments in stem cell biology and engineering have led to the discovery of different stem cell populations and biodegradable materials with suitable properties. This review summarizes the current achievements in tissue engineering of craniofacial bone, temporomandibular joint, and periodontal ligament.

REVERSAL OF EXPERIMENTAL MYOGLOBINURIC ACUTE RENAL FAILURE WITH BIOFLAVONOIDS FROM SEEDS OF GRAPE

Rhabdomyolysis may account for about 10% of all cases of acute renal failure (ARF). This study was performed to explore the protective influence of proanthocyanidins from seeds of grape in an experimental model of myoglobinuric ARF. Rats were injected with 50% glycerol (8 mL/Kg, im) followed immediately and daily in the next three days by ip proanthocyanidins (20 mg/kg) or saline. After 96 h rats were sacrificed and kidney morphology, kidney cortex peptidase activities, and malondialdehyde (MDA) content were determined. A moderate renal failure was produced by glycerol injection with blood urea of 31.8 ± 11.0 vs. 7.68 ± 0.24 mmol/L, and serum creatinine of 153.6 ± 38.2 vs. 39.6 ± 9.0 μmol/L, in glycerol-induced ARF vs. control rats, respectively. Rats that received proanthocyanidins in addition to glycerol had significantly lower (p < 0.01) blood urea and serum creatinine levels compared to those receiving glycerol alone. These functional differences between the glycerol and glycerol plus proanthocianidins groups were also confirmed histologically. Kidney cortex dipeptidylpeptidase IV (DPP IV) activity was not significantly changed in glycerol-induced ARF, however, markedly increased after proanthocyanidins treatment. Kidney cortex malondialdehyde content was found significantly increased in glycerol-induced ARF over control level, and was markedly reduced by proanthocyanidin treatment. Taken together, these results provide strong evidence for the protective role of proanthocyanidins from seeds of grape in glycerol-induced ARF. The effect is probably due to the antioxidant activity of proanthocyanidins and to increased expression of kidney cortex DPP IV with effective degradation of TNF-α. This may provide therapeutic opportunities of preventing and/or treating myoglobinuric ARF in humans.

Oxidative stress parameters as possible urine markers in patients with diabetic nephropathy

OBJECTIVE Reactive oxygen species play a crucial role in the pathogenesis of diabetic nephropathy (DN). The present study was performed to assess oxidative stress parameters-thiobarbituric acid reactive substances (TBARS), reactive carbonyl derivates (RCDs), and total sulfhydryl groups (TSHGs)-in serum and urine of patients with DN. METHODS All parameters were determined in patients with type 2 and type 1 diabetes mellitus and microalbuminuria (DMT2-MIA, DMT1-MIA, respectively) and patients with type 2 diabetes mellitus and macroalbuminuria (DMT2-MAA) compared to healthy controls. RESULTS Serum and urine TBARS levels were higher in all patients with DN and microalbiminuria compared to the control group. RCD levels significantly increased in serum of patients with DMT2 relative to the controls as well as in urine of patients with DMT2-MAA and DMT1-MIA. In all groups of patients, TSHGs decreased in serum but not in urine of patients with DMT2-MAA. CONCLUSION Urine TBARS, RCDs, and TSHGs could be proposed as possible markers for oxidative damage of kidney in DN.