Showing papers by "Maria Dolores Sanchez-Niño published in 2014"

Unilateral ureteral obstruction: beyond obstruction

Abstract: Unilateral ureteral obstruction is a popular experimental model of renal injury. However, the study of the kidney response to urinary tract obstruction is only one of several advantages of this model. Unilateral ureteral obstruction causes subacute renal injury characterized by tubular cell injury, interstitial inflammation and fibrosis. For this reason, it serves as a model both of irreversible acute kidney injury and of events taking place during human chronic kidney disease. Being a unilateral disease, it is not useful to study changes in global kidney function, but has the advantage of a low mortality and the availability of an internal control (the non-obstructed kidney). Experimental unilateral ureteral obstruction has illustrated the molecular mechanisms of apoptosis, inflammation and fibrosis, all three key processes in kidney injury of any cause, thus providing information beyond obstruction. Recently this model has supported key concepts on the role in kidney fibrosis of epithelial-mesenchymal transition, tubular epithelial cell G2/M arrest, the anti-aging hormone Klotho and renal innervation. We now review the experimental model and its contribution to identifying novel therapeutic targets in kidney injury and fibrosis, independently of the noxa.

TWEAK and the progression of renal disease: clinical translation

Abstract: Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance The effects of TWEAK in tubular cells have been explored in most detail In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis Similar actions were observed on glomerular mesangial cells In vivo TWEAK actions on healthy kidneys mimic cell culture observations Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored

Mitochondria-targeted therapies for acute kidney injury.

Abstract: Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.

p-Cresyl sulphate has pro-inflammatory and cytotoxic actions on human proximal tubular epithelial cells

Abstract: Background. p-Cresyl sulphate (p-CS) and p-cresyl glucuronide (p-CG) are uraemic toxins that exhibit pro-inflammatory features in leukocytes and are associated with the progression of chronic kidney disease (CKD). Tubular cells are key targets of nephrotoxic agents and tubular cell death and activation contribute to the progression of CKD. However, the potential toxicity of these compounds on tubular cells is not fully understood. More specifically, apoptosis has never been studied. Methods. HK-2 human proximal tubular epithelial cells were studied. Cell death was evaluated by flow cytometry of DNA content and by morphology. Gene expression was studied by real-time (RT)-PCR. Protein expression was studied by western blot and flow cytometry. Results. Long-term (7 days) exposure to p-CS induced apoptosis in HK-2 cells in a concentration-dependent manner. In addition, short-term (3 h) exposure to p-CS promoted the expression of the TWEAK receptor Fn14, cooperated with TWEAK in promoting cell death and increased inflammatory gene expression. Albumin was cytotoxic and increased the inflammatory response to p-CS concentrations found in the circulation of non-dialysis CKD patients. In contrast, no biological actions of p-CG were observed on HK-2 cells, either alone or in combination with p-CS. Conclusions. This study demonstrates for the first time that p-CS has pro-apoptotic and pro-inflammatory effects on tubular cells. These results identify mechanisms by which uraemic toxicity may contribute to CKD progression.

Deferasirox nephrotoxicity—the knowns and unknowns

Abstract: In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

Osteoprotegerin and kidney disease

Abstract: Vascular calcification in chronic kidney disease (CKD) patients is associated to increased mortality. Osteoprotegerin (OPG) is a soluble tumor necrosis factor (TNF) superfamily receptor that inhibits the actions of the cytokines receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) by preventing their binding to signaling receptors in the cell membrane. OPG-deficient mice display vascular calcification while OPG prevented calcification of cultured vascular smooth muscle cells and protected kidney cells from TRAIL-induced death. OPG may be a biomarker in patients with kidney disease. Circulating OPG is increased in predialysis, dialysis and transplant CKD patients and may predict vascular calcification progression and patient survival. By contrast, circulating OPG is decreased in nephrotic syndrome. In addition, free and exosome-bound urinary OPG is increased in human kidney disease. Increased urinary OPG has been associated with lupus nephritis activity. Despite the association of high OPG levels with disease, experimental functional information available suggests that OPG might be protective in kidney disease and in vascular injury in the context of uremia. Thus, tissue injury results in increased OPG, while OPG may protect from tissue injury. Recombinant OPG was safe in phase I randomized controlled trials. Further research is needed to fully define the therapeutic and biomarker potential of OPG in patients with kidney disease.

Next-Generation Phosphate Binders: Focus on Iron-Based Binders

Abstract: Phosphate excess is associated with increased mortality in patients with chronic kidney disease (CKD) and has recently been linked to accelerated aging. Oral phosphate binders are prescribed to patients with CKD to prevent absorption of dietary phosphate. Currently available binders have been associated with impaired outcomes (calcium-based binders) or are expensive (non-calcium-based binders). Iron-based phosphate binders represent a new class of phosphate binders. Four iron-based phosphate binders have undergone testing in clinical trials. The development of fermagate and SBR759 is currently on hold due to suboptimal and adverse effect profiles in at least some clinical trials. Ferric citrate and sucroferric oxyhydroxide (PA21) are at different stages of application for regulatory approval after being found safe and efficacious in decreasing serum phosphate. Iron from ferric citrate is more readily absorbed than that from sucroferric oxyhydroxide. Sucroferric oxyhydroxide was launched in the USA in 2014 for the treatment of hyperphosphatemia in adult dialysis patients. Ferric citrate may be more suited for chronic treatment of hyperphosphatemia in CKD patients requiring iron supplements but its use may have to be limited in time because of potential for iron overload in patients not needing iron or not receiving erythropoiesis-stimulating agents. In contrast, sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplements.

TWEAK promotes peritoneal inflammation.

Abstract: Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r=0.491, p=0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.

Macrophages and Recently Identified Forms of Cell Death

Abstract: Recent advances in cell death biology have uncovered an ever increasing range of cell death forms. Macrophages have a bidirectional relationship with cell death that modulates the immune response. Thus, macrophages engulf apoptotic cells and secrete cytokines that may promote cell death in parenchymal cells. Furthermore, the presence of apoptotic or necrotic dead cells in the microenvironment elicits differential macrophage responses. Apoptotic cells elicit anti-inflammatory responses in macrophages. By contrast macrophages may undergo a proinflammatory form of cell death (pyroptosis) in response to damage-associated molecular patterns (DAMPs) released from necrotic cells and also in response to pathogen-associated molecular patterns (PAMPs). Pyroptosis is a recently identified form of cell death that occurs predominantly in subsets of inflammatory macrophages and is associated to the release of interleukin-1β (IL-1β) and IL-18. Deregulation of these processes may result in disease. Thus, failure of macrophages to engulf apoptotic cells may be a source of autoantigens in autoimmune diseases, excessive macrophage release of proapoptotic factors or sterile pyroptosis may contribute to tissue injury and failure of pathogen-induced pyroptosis may contribute to pathogen survival. Ongoing research is exploring the therapeutic opportunities resulting this new knowledge.

Differential effects of oral and intravenous l-carnitine on serum lipids: is the microbiota the answer?

Abstract: l-carnitine (free carnitine) transports cytosolic long-chain fatty acids as acylcarnitines across the inner mitochondrial membrane for β-oxidation and subsequent ATP production in the mitochondria. The endogenous carnitine pool comprises free l-carnitine as well as short-, medium- and long-chain fatty acid esters (acyl-carnitines) and depends on absorption of l-carnitine from dietary sources, endogenous biosynthesis and renal tubular reabsorption from glomerular filtrate [1]. More than 99% of the carnitine pool is located outside of plasma. Carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation, such as heart and muscle. Myocytes have one of the highest intracellular carnitine concentrations in the body, and red meat is a rich source of dietary carnitine. Absorption of orally administered l-carnitine is very variable and ranges from 5 to 18% for pharmacological doses of up to 75% for dietary l-carnitine. The low bioavailability depends both on transport kinetics and on l-carnitine metabolism by intestinal bacteria [1, 2]. The renal clearance of l-carnitine (1–3 mL/min) is much lower than the glomerular filtration rate because of extensive (98–99%) tubular reabsorption. The lack of reabsorption during the haemodialysis procedure results in large losses of l-carnitine in dialysate. The existence of a threshold concentration for tubular reabsorption results in much higher renal clearances after intravenous administration of high doses [3].