Dosing of Erythropoiesis-Stimulating Agents Can Be Reduced by a New Administration Regimen

Background/Aims:At our hemodialysis (HD) unit, we noted a drop in the treatment dose of erythropoietin-stimulating agents (ESAs) when the frequency of dose adjustment was reduced from weekly, where doses were withheld if hemoglobin was >130 g/l, to monthly, where doses were not withheld. The aim of this study was to find an explanation for this reduction in ESA requirement. Methods: This is a retrospective study on 18 stable HD patients. Comparable follow-up periods of 6 months with the two different ESA adjustment regimens were established and data on ESA dose, hemoglobin and known predictors of ESA response were collected. Results: With the new ESA administration regimen, a 22.5% drop in the total ESA dose was noted. The corresponding fall in the erythropoietin resistance index was 20.0%. Simultaneously, the dialysis dose and transferrin saturation increased significantly. However, in a multivariate linear regression model, changes in these factors did not significantly predict changes in ESA requirement. No relevant changes were noted in other erythropoiesis-modulating factors. Conclusion: Frequent dose adjustments and the current ESA administration practice of withholding ESA doses does not seem to reduce ESA demand. On the contrary, such practice is likely to increase ESA requirement over time

Proteoglycans contribute to the functional integrity of the glomerular endothelial cell surface layer and are regulated in diabetic kidney disease

All capillary endothelia, including those of the glomeruli, have a luminal cell surface layer (ESL) consisting of glycoproteins, glycolipids, proteoglycans (PGs) and glycosaminoglycans. Previous results have demonstrated that an intact ESL is necessary for a normal filtration barrier and damage to the ESL coupled to proteinuria is seen for example in diabetic kidney disease (DKD). We used the principles of ion exchange chromatography in vivo to elute the highly negatively charged components of the ESL with a 1 M NaCl solution in rats. Ultrastructural morphology and renal function were analyzed and 17 PGs and hyaluronan were identified in the ESL. The high salt solution reduced the glomerular ESL thickness, led to albuminuria and reduced GFR. To assess the relevance of ESL in renal disease the expression of PGs in glomeruli from DKD patients in a next generation sequencing cohort was investigated. We found that seven of the homologues of the PGs identified in the ESL from rats were differently regulated in patients with DKD compared to healthy subjects. The results show that proteoglycans and glycosaminoglycans are essential components of the ESL, maintaining the permselective properties of the glomerular barrier and thus preventing proteinuria.publishedVersio

Role of Glomerular Proteoglycans in IgA Nephropathy

Mesangial matrix expansion is a prominent feature of the most common form of glomerulonephritis, IgA nephropathy (IgAN). To find molecular markers and improve the understanding of the disease, the gene and protein expression of proteoglycans were investigated in biopsies from IgAN patients and correlated to clinical and morphological data. We collected and microdissected renal biopsies from IgAN patients (n = 19) and from healthy kidney donors (n = 14). Patients were followed for an average time of 4 years and blood pressure was according to target guidelines. Distinct patterns of gene expression were seen in glomerular and tubulo-interstitial cells. Three of the proteoglycans investigated were found to be of special interest and upregulated in glomeruli: perlecan, decorin and biglycan. Perlecan gene expression negatively correlated to albumin excretion and progress of the disease. Abundant decorin protein expression was found in sclerotic glomeruli, but not in unaffected glomeruli from IgAN patients or in controls. Transforming growth factor beta (TGF-β), known to interact with perlecan, decorin and biglycan, were upregulated both on gene and protein level in the glomeruli. This study provides further insight into the molecular mechanisms involved in mesangial matrix expansion in IgAN. We conclude that perlecan is a possible prognostic marker for patients with IgAN. In addition, the up-regulation of biglycan and decorin, as well as TGF-β itself, indicate that regulation of TGF-β, and other profibrotic markers plays a role in IgAN pathology

Glomerular permselectivity is dependent on adequate serum concentrations of orosomucoid

Glomerular permselectivity is dependent on adequate serum concentrations of orosomucoid. Orosomucoid, or α1-acid glycoprotein, a serum protein known to be an “acute phase reactant” has recently been shown to be needed for the maintenance of normal capillary permeability in skeletal muscle and mesentery. Therefore, we were interested in studying whether the glomerular capillary wall is affected by orosomucoid as well. For this purpose, left and right kidneys from nine rats (group A) were isolated and perfused in situ and in parallel using separate solutions of human albumin (1.8% in Tyrode), differing in their content of orosomucoid, one containing 0.21 g/liter, the other less than 0.005 g/liter. The temperature was kept at 8°C in order to minimize tubular reabsorption of fluid and albumin. The two kidneys showed identical and stable vascular resistances during the experiments. Also the glomerular filtration rates (GFR) were stable between 30 and 33 ml/min/100 g kidney. Initially, the two kidneys showed similar fractional albumin clearance (Θ) values of approximately 0.003. However, in the “absence” of orosomucoid Θ increased to become four- to fivefold higher in the test kidney than in the control kidney at the end of the 1½ hour experiment. This difference was observed in all rats, suggesting that orosomucoid is needed also for the maintenance of the glomerular permselectivity. In a separate group of eight animals (group B), orosomucoid-containing albumin solutions were used in parallel with horse serum solutions to perfuse the two kidneys of each rat, at 8°C. The same protocol as above was used, but no differences could be observed between the two perfusates, indicating that serum proteins other than albumin and orosomucoid are less important for the maintenance of normal capillary permeability. Orosomucoid probably exerts its action on the capillary wall by interacting with the capillary charge barrier. The results indicate that the glomerular barrier has major similarities with that of other capillary beds. Furthermore, the notion that the glomerular permselectivity can be modulated by a serum protein may have pathophysiological implications

Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats

Orellanine is a nephrotoxin found in mushrooms of the Cortinarius family. Accidental intake of this substance may cause renal failure. Orellanine is specific for proximal tubular cells and could, therefore, potentially be used as treatment for metastatic renal cancer, which originates from these cells. However, more information is needed about the distribution and elimination of orellanine from the body to understand its potential use for therapy. In this study, 5 mg/kg orellanine (unlabeled and 3H-labeled) was injected intravenously in rats (Wistar and Sprague Dawley). Distribution was measured (Wistar rats, n = 10, n = 12) using radioluminography and the highest amount of orellanine was found in the kidney cortex and bladder at all time-points investigated. The pharmacokinetic properties of orellanine was investigated using LC-MS/MS and β-scintillation to measure the amount of orellanine in plasma. Three groups of rats were investigated: control rats with intact kidneys (n = 10) and two groups with bilateral renal artery ligation (n = 7) where animals in one of these groups were treated with peritoneal dialysis (n = 8). Using LC-MS/MS, the half-life of orellanine was found to be 109 ± 6 min in the controls. In the groups with ligated renal arteries, orellanine had a half-life of 756 ± 98 min without and 238 ± 28 min with dialysis. Thus, orellanine was almost exclusively eliminated by glomerular filtration as well as by peritoneal dialysis