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 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.
Depressive disorders are highly prevalent among subjects suffering from chronic kidney disease (CKD). The aim of the present study is to evaluate clinical and biochemical factors associated with ...depressive disorders in a sample of older CKD patients, with a focus on advanced glycation end products (AGEs) and their soluble receptors (sRAGEs). A total of 115 older subjects affected by CKD (stages 3 to 5, not in dialysis) were selected for this study. These patients were divided into two groups according to the presence of depressive disorders defined by a score ≥ 10 on the 30-item Geriatric Depression Scale (GDS). The two groups were compared by independent sample t tests for continuous variables and χsup.2 tests for qualitative ones. Significant variables at univariate analyses were then inserted as predictors of a binary logistic regression model, with the presence or absence of depressive disorders as a dependent variable. The binary logistic regression model showed that patients with concomitant depressive disorders were more frequently of female gender (p < 0.01) and had lower MCP1 (p < 0.01) and AGE circulating levels (p < 0.01) than their counterparts. Depressive disorders in older CKD patients are more prevalent in women and seem to be inversely associated with systemic inflammation and circulating AGEs.
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.
Proteinuria is a common symptom of glomerular diseases and is due to leakage of proteins from the glomerular filtration barrier, a three-layer structure composed by two post-mitotic highly ...specialized and interdependent cell populations, i.e. glomerular endothelial cells and podocytes, and the basement membrane in between. Despite enormous progresses made in the last years, pathogenesis of proteinuria remains to be completely uncovered. Studies in the field could largely benefit from an in vitro model of the glomerular filter, but such a system has proved difficult to realize. Here we describe a method to obtain and utilize a three-dimensional podocyte–endothelial co-culture which can be largely adopted by the scientific community because it does not rely on special instruments nor on the synthesis of devoted biomaterials. The device is composed by a porous membrane coated on both sides with type IV collagen. Adhesion of podocytes on the upper side of the membrane has to be preceded by VEGF-induced maturation of endothelial cells on the lower side. The co-culture can be assembled with podocyte cell lines as well as with primary podocytes, extending the use to cells derived from transgenic mice. An albumin permeability assay has been extensively validated and applied as functional readout, enabling rapid drug testing. Additionally, the bottom of the well can be populated with a third cell type, which multiplies the possibilities of analyzing more complex glomerular intercellular signaling events. In conclusion, the ease of assembly and versatility of use are the major advantages of this three-dimensional model of the glomerular filtration barrier over existing methods. The possibility to run a functional test that reliably measures albumin permeability makes the device a valid companion in several research applications ranging from drug screening to intercellular signaling studies.
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The Death Ligand TRAIL in Diabetic Nephropathy LORZ, Corina; BENITO-MARTIN, Alberto; EGIDO, Jesus ...
Journal of the American Society of Nephrology,
05/2008, Letnik:
19, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of ...genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death-related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-kappaB, and inhibition of NF-kappaB sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN.
Although patients with chronic renal failure are increasing worldwide, many aspects of kidney biology remain to be elucidated. Recent research has uncovered several molecular properties of the ...glomerular filtration barrier, in which podocytes, highly differentiated, ramified cells that enwrap the glomerular basement membrane, have been reported to be mainly responsible for filter's selectivity. We previously described that podocytes express Rab3A, a GTPase restricted to cell types that are capable of highly regulated exocytosis, such as neuronal cells. Here, we first demonstrate by a proteomic study that Rab3A in podocytes coimmmunoprecipitates with molecules once thought to be synapse specific. We then show that podocytes possess structures resembling synaptic vesicles, which contain glutamate, coexpress Rab3A and synaptotagmin 1, and undergo spontaneous and stimulated exocytosis and recycling, with glutamate release. Finally, from the results of a cDNA microarray study, we describe the presence of a series of neuron- and synapse-specific molecules in normal human glomeruli and confirm the glomerular protein expression of both metabotropic and ionotropic glutamate receptors. These data point toward a synaptic-like mechanism of communication among glomerular cells, which perfectly fits with the molecular composition of the glomerular filter and puts in perspective several previous observations, proposing a different working hypothesis for understanding glomerular signaling dynamics.-- Rastaldi, M. P., Armelloni, S., Berra, S., Calvaresi, N., Corbelli, A., Giardino, L. A., Li, M., Wang, G. Q., Fornasieri, A., Villa, A., Heikkila, E., Soliymani, R., Boucherot, A., Cohen, C. D., Kretzler, M., Nitsche, A., Ripamonti, M., Malgaroli, A., Pesaresi, M., Forloni, G. L., Schlöndorff, D., Holthofer, H., D'Amico, G. Glomerular podocytes contain neuron-like functional synaptic vesicles.
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