Association between the uremic toxins indoxyl-sulfate and p-cresyl-sulfate with sarcopenia and malnutrition in elderly patients with advanced chronic kidney disease

Abstract Background in patients with chronic kidney disease (CKD) indoxyl sulfate (IS) and p-cresyl sulfate (PCs) may induce sarcopenia either directly or via systemic inflammation. We evaluated whether IS and PCs were associated with: sarcopenia, systemic inflammation and nutritional status. Methods: we examined cross sectionally 93 patients with advanced CKD. Sarcopenia was identified according to EWGSOP2 definition. Malnutrition was assessed by Malnutrition Inflammation Score (MIS) and Protein Energy Wasting syndrome (PEW). Inflammatory status was assessed by dosing: CRP, IL6, TNFα, MCP1, IL10, IL17, IL12p70. Results: we did not find any association of sarcopenia with IS and PCs. IS was associated with LogTNFα and LogMCP-1 in the overall cohort (r = 0.30, p = 0.0043; r = 0.22 p = 0.047) and in not sarcopenic patients (r = 0.32, p = 0.0077; r = 0.25, p = 0.041). PCs was associated with LogIL10 and LogIL12p70 in sarcopenic patients (r = 0.58, p = 0.0042; r = 0.52, p = 0.013). IS was higher in patients without PEW (p = 0.029), while PCs was higher in patients with PEW (p = 0.0040). IS and PCs were not different in patients with normal or increased MIS. Conclusions: IS and PCs were not associated with sarcopenia, although they were both associated with some inflammatory pathways. Notably, we found a positive association of PCs with PEW syndrome

Data Poor Approach for the Assessment of the Main Target Species of Rapido Trawl Fishery in Adriatic Sea

Information on stock status is available only for a few of the species forming the catch assemblage of rapido fishery of the North-central Adriatic Sea (Mediterranean Sea). Species that are caught almost exclusively by this gear, either as target (such as Pectinidae) or accessory catches (such as flatfishes apart from the common sole), remain unassessed mainly due to the lack of data and biological information. Based on cluster analysis, the catch assemblage of this fishery was identified and assessed using CMSY model. The results of this data-poor methodology showed that, among the species analyzed, no one is sustainably exploited. The single-species CMSY results were used as input to an extension of the same model, to test the effect of four different harvest control rule (HCR) scenarios on the entire catch assemblage, through 15-years forecasts. The analysis showed that the percentage of the stocks that will reach Bmsy at the end of the projections will depend on the HCR applied. Forecasts showed that a reduction of 20% of fishing effort may permit to most of the target and accessory species of the rapido trawl fishery in the Adriatic Sea to recover to Bmsy levels within 15 years, also providing a slight increase in the expected catches

Biologia e genetica del podocita

Progresses in podocyte biology have been strictly connected with genetic advances; the identification of genes mutated in familial and sporadic forms of nephrotic syndrome has been followed by functional studies of the encoded proteins, revealing numerous properties of the cell. The molecules uncovered so far belong to three main categories: a) proteins located at the slit diaphragm, the intercellular junction which laterally connects podocyte processes and is responsible for selectivity of the glomerular filter, b) molecules involved in regulation of actin dynamics, which are essential for the maintenance of podocyte structure and function, and c) molecules belonging to intracellular organelles, such as mitochondria and lysosomes, which are central players in podocyte metabolism. Considering the key role of the podocyte in health and disease of the glomerular filter, better knowledge of this cell is a pre-requisite for developing targeted therapies of glomerular diseases

Spontaneous low-protein intake in older CKD patients: one diet may not fit all

BackgroundProtein restriction has been extended to stage 3 chronic kidney disease (CKD) regardless of age in the latest K-DOQI guidelines for the dietary management of patients with CKD. However, in elderly CKD patients there is a tendency to a spontaneous reduction in protein and energy intake that may impair the overall nutritional status. The aim of our study is to assess whether there are differences in malnutrition, exercise capacity and inflammatory status in elderly CKD patients with spontaneously low protein intake (sLPI) compared with patients with normal protein intake (NPI).MethodsWe performed a cross-sectional analysis of 123 incident patients. Malnutrition was assessed using Malnutrition Inflammation Score (MIS) and serum markers; As for physical performance, we used Short Physical Performance Battery (SPPB) and handgrip strength.ResultsWe found that in older patients with advanced CKD, as many as 68% had low spontaneous protein intake, and they were more malnourished evaluated with MIS (25% vs. 10%, p = 0.033), protein-energy wasting (PEW) (43% vs. 14%, p = 0.002) and nPCR (0.63[0.51–0.69] vs. 0.95[0.87–1.1], p < 0.0001). They also had worse body composition, in terms of lower mid-arm muscular circumference (MAMC), fat tissue index (FTI) and higher overhydration (OH). sLPI patients also had higher levels of IL6 (4.6[2.9–8.9] vs. 2.8[0.8–5.1], p = 0.002). Moreover, sLPI patients were frailer (33% vs. 24%, p = 0.037) and had poorer physical performance especially when assessed with (SPPB) (7[5–9] vs. 9[7–10], p = 0.004) and gait test time (6.08 + 2 vs. 7.22 + 2.7, p = 0.04). sLPI was associated with lower physical performance [SPPB OR, 0.79 (0.46–0.97), p = 0.046] and malnutrition [MIS 1.6 (1.05–3.5), p = 0.041] independently from patients’ age and eGFR.ConclusionWe found that in older patients with advanced CKD, up to 68% had low spontaneous protein intake and were frailer, more malnourished and with lower physical performance. These findings emphasize the importance of assessing patients’ needs, and personalized approaches with individual risk–benefit assessments should be sought. To achieve the best possible outcomes, targeted interventions should use all available tools

Crosstalk mechanisms between glomerular endothelial cells and podocytes in renal diseases and kidney transplantation

The glomerular filtration barrier (GFB), composed of endothelial cells, glomerular basement membrane, and podocytes, is a unique structure for filtering blood while detaining plasma proteins according to size and charge selectivity. Structurally, the fenestrated endothelial cells, which align the capillary loops, are in close proximity to mesangial cells. Podocytes are connected by specialized intercellular junctions known as slit diaphragms and are separated from the endothelial compartment by the glomerular basement membrane. Podocyte-endothelial cell communication or crosstalk is required for the development and maintenance of an efficient filtration process in physiological conditions. In pathological situations, communication also has an essential role in promoting or delaying disease progression. Podocytes and endothelial cells can secrete signaling molecules, which act as crosstalk effectors and, through binding to their target receptors, can trigger bidirectional paracrine or autocrine signal transduction. Moreover, the emerging evidence of extracellular vesicles derived from various cell types engaging in cell communication has also been reported. In this review, we summarize the principal pathways involved in the development and maintenance of the GFB and the progression of kidney disease, particularly in kidney transplantation

Podocytes: recent biomolecular developments.

AbstractPodocytes are postmitotic renal glomerular cells with multiple ramifications that extend from the cell body. Processes departing from a podocyte interdigitate with corresponding projections from neighboring cells and form an intricate web that enwraps the glomerular capillary completely. Podocyte processes are interconnected by the slit diaphragm, an adhesion junction mostly formed by Ig-like molecules, cadherins/protocadherins, ephrin/eph, and neurexin molecules organized in an assembly that resembles synaptic junctions. Podocyte failure is primarily or secondarily implicated in all forms of proteinuric glomerular diseases, as confirmed by the morphological changes of their elaborate cell architecture detectable by electron microscopy. Importantly, mutations of podocyte proteins are responsible for the most severe forms of congenital nephrotic syndrome. In the last 15 years, progressive technological advances have aided the study of podocyte biology and pathology, confirming the relevance of podocyte molecules and signaling pathways for the function of the glomerular filter. This review will examine the most important and newest discoveries in the field, which is rapidly evolving, hopefully leading to a detailed knowledge of this fascinating cell and to the development of specific therapeutic options for proteinuric diseases

Urinary mRNA Expression of Glomerular Podocyte Markers in Glomerular Disease and Renal Transplant

The research of novel markers in urinary samples, for the description of renal damage, is of high interest, and several works demonstrated the value of urinary mRNA quantification for the search of events related to renal disease or affecting the outcome of transplant kidneys. In the present pilot study, a comparison of the urine mRNA expression of specific podocyte markers among patients who had undergone clinical indication to renal transplanted (RTx, n = 20) and native (N, n = 18) renal biopsy was performed. The aim of this work was to identify genes involved in podocytes signaling and cytoskeletal regulation (NPHS1, NPHS2, SYNPO, WT1, TRPC6, GRM1, and NEUROD) in respect to glomerular pathology. We considered some genes relevant for podocytes signaling and for the function of the glomerular filter applying an alternative normalization approach. Our results demonstrate the WT1 urinary mRNA increases in both groups and it is helpful for podocyte normalization. Furthermore, an increase in the expression of TRPC6 after all kinds of normalizations was observed. According to our data, WT1 normalization might be considered an alternative approach to correct the expression of urinary mRNA. In addition, our study underlines the importance of slit diaphragm proteins involved in calcium disequilibrium, such as TRPC6

Update on current and potential application of extracellular vesicles in kidney transplantation

: Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy

Assessment of increased glomerular permeability associated with recurrent focal segmental glomerulosclerosis using an in vitro model of the glomerular filtration barrier

The presence of circulating permeability factors (cPFs) has been hypothesized to be associated with recurrence of focal segmental glomerulosclerosis (rFSGS) in renal allografts. The available methods to detect cPFs are complex, not easily repeatable and inappropriate to represent the anatomical characteristics of the three-layer glomerular filtration barrier (GFB). Here we describe a novel method which measures the permeability to bovine serum albumin (BSA) through a three-layer device (3LD). The 3 layers comprise: (1) conditionally immortalized human podocytes (HCiPodo), (2) collagen type IV coated porous membrane and (3) human glomerular endothelial cells (HCiGEnC). Using this method, we found that sera from all rFSGS patients increased albumin permeability, while sera from non recurrent (nrFSGS) and genetic (gFSGS) forms of FSGS did not. The mechanisms underlying the increase of albumin permeability are probably due to endothelial cell damage as an initial event, which was demonstrated by the decrease of Platelet endothelial cell adhesion molecule (PECAM-1 or CD31), while the podocytes’ expressions of synaptopodin and podocin were normal. Furthermore, we also found that the plasmapheretic treatment (PPT) eliminated the effect of increasing BSA permeability in sera from rFSGS patients. These preliminary data suggest that our in vitro GFB model could not only be useful in predicting the recurrence of FSGS after renal transplantation (RTx), but also be a valuable in vitro model to study podocyte and endothelial cell biology