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.
•In older patients with advanced chronic kidney disease IS and PCs are not associated with sarcopenia.•In older patients with advanced chronic kidney disease IS and PCs are associated with different inflammatory patterns in sarcopenic and not sarcopenic individuals.•In older patients with advanced chronic kidney disease PCs is higher in patients with protein energy wasting syndrome (PEW), while IS was not associated with PEW.
Kidney transplantation (KT) is the best treatment for End-Stage Kidney Disease (ESKD). However, early diagnosis of graft injury remains challenging, mainly because the lack of accurate and ...noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as the development of innovative therapies is needed. Many research efforts are focusing on Extracellular Vesicles (EVs), 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 cargos, they act in damage response and immune modulation. In transplantation, they possibly be used to determine organ quality and ageing, the presence of Delayed Graft Function (DGF), rejection and many other transplant-related pathologies. Also, their low immunogenicity and safe profile make them ideal for drug delivery and development of therapies to improve KT outcomes. In this review, we summarize current evidence about EVs in KT, starting from 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.
The relative contribution of genetic factors and dietary patterns to glomerular damage in healthy individuals and prediabetic conditions is currently unclear. All Rab3A knockout (KO) mice ...spontaneously develop macroalbuminuria, but only male mice exhibit a glucose-intolerant phenotype, thus making the model suitable to examine the impact of a diet on preexisting podocyte damage.
Male and female Rab3A KO and wild-type (WT) mice were chronically fed a high-glucose diet (HGD). Biochemical tests, histology and immunohistochemistry were periodically performed whilst primary podocytes served for in vitro analyses.
Chronic administration of an HGD did not induce de novo alterations in WT kidneys but caused progressive worsening of podocyte and glomerular damage in both male and female Rab3A KO. Though glomerular lesions, reminiscent of human diabetic nephropathy, were more severe in male mice, overt proteinuria and renal damage were also evident in female mice. The in vitro analysis of Rab3A WT and KO podocytes revealed diminished actin plasticity in the cell processes of KO podocytes. Furthermore, a modest increase in glucose concentration induced profound cytoskeletal changes only in Rab3A KO cells.
Our data show that chronic administration of an HGD to Rab3A KO mice that have a genetic defect that impairs podocyte actin plasticity results in increased podocyte damage and leads to overt proteinuria. If the same diet is given to male Rab3A KO animals, with additionally altered glucose homeostasis, this results in renal lesions similar to those of human diabetic nephropathy.
Chronic kidney disease (CKD) is a disabling condition associated with different medical comorbidities including depression and cognitive impairment. We investigated the association between ...malnutrition, inflammation and depressive/cognitive symptoms in elderly subjects with advanced CKD.
We evaluated cross-sectionally 132 elderly subjects (age ≥65 years) with advanced CKD (stage 4–5, non-dialytic-ND) in regular follow up at the outpatient clinic of nephrology. Blood and urinary samples were collected after an overnight fast. All patients were evaluated by Geriatric Depression Scale (GDS)-30 items for severity of depressive symptoms, Mini Mental State Examination (MMSE) and the Clock Drawing Test (CDT) for cognition. Nutritional status was assessed by Malnutrition Inflammation Score (MIS). Different linear regression models were performed to study the association between clinical variables, diet and inflammatory parameters with the above mentioned rating scale scores. A final linear regression model with only previous statistically significant variables was performed for GDS scores.
Our cohort consisted of 95 males and 37 females with a mean age of 78 ± 7. Female gender (B = 3.20, p < .01), higher MIS (B = 0.29, p = .02) and higher IL-12p70 serum levels (pg/mL) (B = 0.37, p = .03) were associated with severity of depressive symptoms. MIS was associated with the severity of cognitive impairment as assessed by MMSE (B = −0.19, p < .01) and CDT (B = 0.10, p = .03).
In elderly subjects affected by CKD the severity of depressive symptoms and cognitive impairment is associated with specific inflammatory and nutritional parameters. These results have to be considered as preliminary and need replication by further studies.
•We ask if depression and cognition in patients with chronic kidney disease (CKD) are modulated by diet and inflammation.•Malnutrition and increased cell-mediated inflammation are associated with severity of depression in old patients with CKD.•In elderlies with CKD, depression and dyscognition are associated with specific inflammatory and nutritional patterns.
Several recent studies have focused on similarities between glomerular podocytes and neurons because the two cells share a specialized cytoskeletal organization and several expression-restricted ...proteins, such as nephrin and synaptopodin. In neurons, the small guanosine triphosphatase Rab3A and its effector rabphilin-3A form a complex required for the correct docking of synaptic vesicles to their target membrane. Because rabphilin-3A binds in neurons to cytoskeletal proteins also important for podocyte homeostasis, and the complex rabphilin-3A-Rab3A has been demonstrated in neurons and neuroendocrine cells, the aim of our work was to investigate their possible expression and regulation in podocytes. Normal kidneys from mouse, rat, and human were studied by immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction to evaluate the expression of Rab3A and rabphilin-3A. Double-staining immunohistochemistry and immunogold electron microscopy were then used to precisely localize the two proteins at the cellular and subcellular levels. Rab-3A and rabphilin-3A regulations in disease were then analyzed in growth hormone-transgenic mice, a well established model of focal and segmental glomerulosclerosis, and in human biopsies from proteinuric patients. Our results demonstrated that rabphilin-3A and Rab3A are present in normal mouse, rat, and human kidneys, with an exclusively glomerular expression and a comma-like pattern of positivity along the glomerular capillary wall, suggestive for podocyte staining. Co-localization of both molecules with synaptopodin confirmed their presence in podocytes. By immunogold electron microscopy both proteins were found around vesicles contained in podocyte foot processes. Their expression was increased in growth hormone-transgenic mice compared to their wild-type counterpart, and in a subset of biopsies from proteinuric patients. Our data, demonstrating the presence of two synaptic proteins in podocytes, further supports similarities between cytoskeletal and vesicular organization of podocytes and neurons. The altered expression observed in mouse and human proteinuric diseases suggests a possible role for these molecules in glomerulopathies.
Abstract
BACKGROUND AND AIMS
Current guidelines do not clarify whether older patients with advanced chronic kidney disease may benefit of low protein diet if they are at risk of malnutrition. We ...compared the effects of normo-calorie/normo-protein (NP) and normo-calorie/low protein diet (LP) on nutritional status and metabolic complications related to the progression of kidney damage in these patients.
METHOD
This pilot study had an open label randomized-controlled design (ClinicalTrials.gov Id: NCT05015647). Thirty-five patients were treated for six months with two different diets (LP = 17) and (NP = 18). Malnutrition was assessed by Malnutrition Inflammation Score and International Society of Renal Nutrition and Metabolism criteria. Renal function was assessed by creatinine and cystatin C based eGFR.
RESULTS
At the end of the study, Malnutrition Inflammation Score was improved in both LP and NP groups (respectively: 3 ± 3 versus 6 ± 1.5, P = 0.020 and 3 ± 2.5 versus 6 ± 2, P = 0.012), and prevalence of protein energy wasting syndrome decreased only in LP. LP group had higher eGFRcys-C (17 ± 6 versus 12 ± 4 mL/min/1.73 m2; P < 0.05), lower serum urea (105 ± 65 versus 138 ± 30 mg/dL; P < 0.05) and lower PTH (68 ± 10 versus 99 ± 61 ng/L; P < 0.05) than NP. Serum and urinary phosphorous did not change while FGF23-intact and FGF23 c-terminal increased in both groups (FGF23-intact in LP: 7048;98 versus 12690;410 pg/mL, P < 0.01 and in NP: 8657;194 versus 143119;186 pg/mL, P < 0.01; FGF23 c-terminal in LP: 7730.3;112 versus 11163;384 RU/mL, P < 0.01 and in NP: 14256.6;175 versus 15776.7;281 RU/mL, P < 0.01).
CONCLUSION
LP diet has a favorable impact on nutritional status as much as NP diet with possible greater benefits on the progression of kidney disease and some of its metabolic complications.
Abstract
Background and Aims
Idiopathic focal segmental glomerular sclerosis (FSGS) is characterized by progressive damage to the renal parenchyma leading to end-stage renal disease, frequent ...recurrence after kidney transplantation and no specific therapeutic intervention. Since the podocytes (PODO) are the principal target of FSGS injury, their protection could be an efficient, targeted therapy. In this context, we investigated a potential therapeutic approach based on a new peptide, UPARANT, capable of modulating the Urokinase-type plasminogen activator receptor (uPAR) on PODO.
Method
PODO were activated with 4% sera of 5 patients with recurrent FSGS for 48 h and then treated with 100 nM of UPARANT for 48 h. Proteins were then extracted for TMT proteomics. The Gene Ontology system database, valid for large-scale analysis, was used to identify the significantly enriched biological pathways and molecular functions. An in vitro model of a glomerular filtration barrier composed of PODO-endothelial co-culture was used to assess the change in filtration capacity by albumin (BSA) permeability test. The difference from baseline BSA percentage was measured after damage induced with sera from three FSGS patients and after 48 h of treatment with UPARANT.
Results
First, we found that UPARANT could counteract the BSA permeability induced by FSGS sera in the PODO-endothelial co-culture (P = .04, P = .03, and P = .02, respectively). The proteomic analysis of PODO indicated that UPARANT induced the positive regulation of plasma membrane repair mechanisms (Annexin 2 P = .007 and AHNAK P = .03); this process was strongly linked to the activation of molecular functions related to both S100 and calcium-dependent proteins. Moreover, UPARANT induced the overexpression of Endophilin-B1 (P = .02) and Vimentin (P = .02), both involved in the assembly and organization of the actin filament.
Conclusion
We demonstrated that UPARANT efficiently counteracts in vitro the effects of FSGS sera on PODO, leading to the recovery of the spatial organization of PODO, acting on the structural integrity of the plasma membrane and restoring cytoskeletal plasticity and dynamism. This might result in vivo in the protection of the integrity of the filtration barrier.
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.
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