Hemodialysis Treatment in Patients with Balkan Endemic Nephropathy: An Epidemiological Study

Aim. To analyze hemodialysis (HD) treatment of patients with Balkan endemic nephropathy (BEN) from five endemic villages in the South Morava Region of Serbia. Analyses of patterns of incidence may generate hypotheses about the underlying causes of BEN, and prevalence data provide information on the current and likely future burden on health services for managing BEN. Methods. A total of 143 end-stage kidney disease patients (ESKD) with BEN were admitted to the renal replacement program from 1974 to 2004: 121 to HD, 15 peritoneal dialysis, and 7 kidney transplantation. As a control group, 117 patients with other kidney disease (chronic pyelonephritis, glomerulonephritis, and ischemic nephropathy) admitted to HD at the time of BEN patients and matched by age and gender were studied. Results. Most of the BEN patients (93.4%) treated by HD were born from 1917 to 1941. The majority of patients (79.3%) started HD from 1977 to 1991 (period of 15 years). The mean age of BEN patients starting HD treatment was 49.1 years in the period from 1974 to 1978, and increased steadily in the following years, being 72.5 years in the last period of study (2004–2006) The mean survival time of BEN males was 4.70 (95% CI 3.66–5.75) and for females was 5.02 (95% CI 1.47–4.53). Difference between males and females was not statistically significant (log rank 0.14, p?=?0.7, P > 0.5). Mean survival times of 4.84 (95% CI 3.97–5.70) in BEN patients and 3.1 (95% CI 2.78–3.84) in other kidney disease patients were found. Difference between BEN patients and controls was statistically significant (log rank 8.38, p?=?0.0038, P < 0.01). Conclusion. The population of endemic villages around the South Morava River admitted to HD treatment after 1974 was exposed to environmental toxicant(s) from 1917 to 1941. The most intense effect of environmental exposure was in that period, with ESKD in patients in their forties. The exposure to environmental toxicants has diminished, so ESKD of BEN has become less frequent and manifested in the older age, mean 72.5 in the period from 2004 to 2006. Different type of exposure was registered in some other endemic regions in Serbia and abroad.     

Progression of Kidney Damage in Balkan Endemic Nephropathy: A 15-Year Follow-Up of Patients with Kidney Biopsy Examination

Progression of kidney damage was studied in 18 patients with Balkan endemic nephropathy (BEN), with a mean 15-year follow-up after renal biopsy. According to kidney function, estimated by ^99mTc-DTPA clearance, patients were divided into three groups: with apparently normal kidney function (clearance 103.5 ± 21.3 mL/min/1.73 m²), with incipient renal failure (clearance 65.5 ± 11.3), and with advanced renal failure (clearance 28.0 ± 6.2). The mean yearly decrease of glomerular filtration rate was 2.74 mL/min. In two patients, an increase of kidney function was recorded. Six patients become dialysis dependent, two from the group with incipient renal failure, but all four from the group with advanced renal failure. Three patients died after 8 to 12 years of follow-up, one from causes unrelated to kidney disease and two from end-stage renal failure. This study has shown that BEN is characterized by a slow course and prolonged evolution, modified by medical supervision and treatment.     

Urinary protein patterns in patients with Balkan endemic nephropathy

Purpose

Urinary excretion of beta2-microglobulin (beta2-MG), albumin, immunoglobulin G (IgG) and protein was examined in patients with Balkan endemic nephropathy (BEN), glomerulonephritis (GN) and healthy controls.

Methods

The proteins were measured in morning urine samples from 74 patients with BEN, 50 healthy persons and 22 patients with GN.

Results

In BEN patients, median values for albumin, beta2-MG and protein were above upper normal limits, but median IgG was inside normal range. All patients with GN had microalbuminuria (MAU) and half of them had increased urinary beta2-MG, which was also found in eleven patients with increased urinary IgG. In BEN patients, there were significant negative correlations between eGFR and all measured urinary proteins, the composition of which changed during the course of BEN. In patients with eGFR > 60 ml/min/1.73 m² isolated beta2-MG was the most frequent finding (10/12 patients), but MAU was present in 4/12 patients. In BEN patients with eGFR between 30 and 59 ml/min/1.73 m², beta2-MG appeared as often as the combination of beta2-MG and albumin and isolated MAU. Out of 49 BEN patients with eGFR > 30 ml/min/1.73 m² 15 had increased urinary IgG either alone (1) or together with beta2-MG (3) or albumin (3) or beta2-MG and albumin (8). In BEN patients with GFR < 30 ml/min/1.73 m² only 1/25 had isolated beta2-MG but increased urinary IgG with increased beta2-MG, and albumin was the most frequent.

Conclusion

Although low-molecular weight proteinuria was the most frequent urinary finding in BEN patients, MAU was frequently detected in advanced stages of BEN but also in some patients with eGFR > 60 ml/min/1.73 m². IgG was increasingly found as eGFR decreased.     

Are xenogeneic anti-tissue transglutaminase antibodies the holy grail for celiac patients?

Celiac disease is an immune mediated disorder, the only one with a well-established origin, resulting from a permanent gluten intolerance. Although a gluten-free diet is currently the "safe" and appropriate therapy for celiac disease, this is not always an easy and simple option as "harmful" gluten may contaminate food during the processing and preparation phases. There are also further social pressures, which might be more pressing for young celiac patients, in following a strict gluten-free diet. Therefore, a new therapeutic approaches are sought which would permit celiacs to "peacefully" coexist with gluten. Presently, the most promising looks search for genetically modified wheat lacking toxic gluten peptides and the use of oral endopeptidases in attempt to curb gluten toxicity. Recently discovered role of anti-tissue transglutaminase antibodies in celiac pathogenesis has brought a prospect for a new hypothetical therapeutic approach, an oral immunization of celiacs with xenogeneic anti-tissue transglutaminase antibodies.     

Folliculo-stellate cells – Potential mediators of the inflammaging-induced hyperactivity of the hypothalamic–pituitary–adrenal axis in healthy elderly individuals

Some evidence has suggested that, with age, the hypothalamic–pituitary–adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood–brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they secrete paracrine agents that act locally to modulate pituitary responses to hypothalamic and peripheral signals. There is evidence of cytokines characteristically involved in inflammaging. For example, IL-1 and TNF-α are thought to stimulate folliculo-stellate cells to release various paracrine agents, including IL-6, IL-11, leukemia inhibitory factor, and macrophage migration inhibitory factor. Through different mechanisms, these agents induce ACTH release by corticotropes. Therefore, it can be concluded that folliculo-stellate cells may act as potent mediators of the age-related HPA axis hyperactivity induced by cytokines characteristic of the inflammaging phenomenon in healthy elderly individuals.     

Progression of kidney damage in Balkan endemic nephropathy: a 15-year follow-up of patients with kidney biopsy examination

Progression of kidney damage was studied in 18 patients with Balkan endemic nephropathy (BEN), with a mean 15-year follow-up after renal biopsy. According to kidney function, estimated by 99mTc-DTPA clearance, patients were divided into three groups: with apparently normal kidney function (clearance 103.5+/-21.3 mL/min/1.73 m2), with incipient renal failure (clearance 65.5 +/- 11.3), and with advanced renal failure (clearance 28.0+/-6.2). The mean yearly decrease of glomerular filtration rate was 2.74 mL/min. In two patients, an increase of kidney function was recorded. Six patients become dialysis dependent, two from the group with incipient renal failure, but all four from the group with advanced renal failure. Three patients died after 8 to 12 years of follow-up, one from causes unrelated to kidney disease and two from end-stage renal failure. This study has shown that BEN is characterized by a slow course and prolonged evolution, modified by medical supervision and treatment.     

Quantitative analysis of the nephron during human fetal kidney development

BACKGROUND: The development of human kidney is a complex process. The number, shape, size, and distribution of nephrons as functional units in a kidney, provide some important information about the organization of the kidney. The aim of this study was to extend the knowledge of the developing human kidney by studying nephrons in the kidney's cortex during gestation. METHODS: Kidney tissue specimens of 32 human fetuses, the gestational age from IV lunar month (LM IV) to LM X, were analysed. Specimens were divided in ten groups based on gestational age. Stereological methods were used at the light microscopic level to estimate the volume densities of the corpuscular and tubular components of the nephron in the cortex of the developing human kidney. RESULTS: Nephron polymorphism was the main characteristic of the human fetal kidney during development. In younger fetuses, just below the renal capsule, there was a wide nephrogenic zone. It contained the condensed mesenchyme and terminal ends of the ureteric bud. Nephrons, in the different stages of development, were located around the ureteric bud which branched in the cortical nephrogenic zone and induced nephrogenesis. More mature nephrons were located in the deeper part of the cortex, close to the juxta-medullary junction. During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Glomeruli changed their size and shape, while the tubules changed their length and convolution. Renal cortex became wider and contained the more mature glomeruli and the more convoluted tubules. The volume density of the tubular component of the nephron increased continually from 10.53% (LM IVa) to 27.7% (LM X). Renal corpuscles changed their volume density irregularly during gestation, increasing from 13% (LM IVa) to 15.5% (LM IVb). During the increase of gestational age, the volume density of corpuscular component of the nephron decreased to 11.7% (LM VIII), then went on increasing until the end of the intrauterine development (LM X) when corpuscles occupied 16.73% of the cortical volume. The volume density of the developing nephrons (corpuscular and tubular portion) showed the significant positive correlation (r = 0.85; p<0.01) with gestational age. CONCLUSION: The present study was one of few quantitative studies of the human developing nephron. Knowledge about the normal development of the human kidney should be important for the future medical practice.