Inflammation In Kidney Disease Research Articles

Great challenges in molecular medicine: toward personalized medicine.

GENE HUNTING, SIGNALING NETWORK, AND MOLECULAR MEDICINE In the 20th century, most researchers investigated WNT signaling in cell and developmental biology by using model animals, such as Drosophila, Xenopus, and mouse. However, I was confident that WNT signaling should be investigated for clinical application by using human samples or cell lines. In 1998, I, together with post-doctoral fellows, started a human WNTome project to comprehensively clone and characterize novel human genes encoding WNT signaling molecules and to establish a “human WNT research” platform (Figure 1A). My group reported the molecular cloning and characterization of FZD1, FZD3, FZD4, FZD6, FZD7, FZD8, FZD10, GIPC2, GIPC3, MFRP, NKD1, NKD2, VANGL1, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT9A (WNT14), WNT9B (WNT14B), and WNT10A as the major products of the human WNTome project [reviewed in Katoh (2002a)] and of other novel human genes, such as FGF20, RhoU, RhoV, and SOX17, as byproducts of the human WNTome project. Most human genes that encode WNT signaling components had been cloned and characterized by 2002, whereas thousands of novel human genes outside of the WNT field still remained to be discovered. In 2003, colleagues and I started a post-WNTome project to identify and characterize novel human genes encoding adhesion molecules, transmembrane proteins, epigenetic regulators, and transcription factors (Figure 1A). My group reported in silico identification and characterization of novel human genes, such as ANO1 (TMEM16A), ANO2 (TMEM16B), ANO3 (TMEM16C), ANO4 (TMEM16D), ANO5 (TMEM16E), ANO6 (TMEM16F), ANO7 (TMEM16G), ANO8 (TMEM16H), ASXL2, ASXL3, BCL9L, CDC50A (TMEM30A), CDC50B (TMEM30B), CDC50C (TMEM30C), CRB2, DACT1 (DAPPER1), DACT2 (DAPPER2), DIXDC1, FAT4, FMNL1, FMNL2, FMNL3, FOXR1 (FOXN5), FOXR2 (FOXN6), HES2, HES3, HES5, JMJD1C (TRIP8), JMJD2A (KDM4A), JMJD2B (KDM4B), JMJD2C (KDM4C), JMJD2D (KDM4D), KIF27, MPP7, PRICKLE1, and PRICKLE2. The human WNTome and postWNTome projects were gene-hunting adventures that utilized molecular biology and computational biology, respectively. Interand intra-cellular signaling networks were simplified to a secondary picture consisting of nodes and edges. Nodes correspond to genes, mRNAs, proteins, or micro-RNAs (miRNAs), while edges correspond to their interactions. I then shifted my interest from the nodes to the edges and the whole picture. In 2007, my laboratory started a stem-cell signaling network project to elucidate mutual interactions of the WNT, FGF, Notch, Hedgehog, TGF-β, and BMP signaling cascades (Figure 1A) (Katoh and Katoh, 2007, 2009; Katoh and Nakagama, 2013). Recently, I was appointed as the chief editor of Frontiers in Molecular Medicine, a subor specialty journal of Frontiers in Cell and Developmental Biology. I would like to contribute to the global scientific community through Frontiers in Molecular Medicine, which aims to address the gap between cell and developmental biology and clinical medicine and to promote development of novel diagnostics and therapeutics for a variety of human diseases, including cancers, cardiovascular diseases, diabetes mellitus, eye diseases, inflammatory bowel diseases, kidney diseases, liver diseases, neurological diseases, and respiratory diseases.

The Characteristics and Significance of Locally Infiltrating B Cells in Lupus Nephritis and Their Association with Local BAFF Expression

Introduction. Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined. Methods. Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN. Results. Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium. Conclusion. As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.

TNFα enhances TLR3‐dependent effects on MMP‐9 expression in human mesangial cells

The role of MMPs (matrix metalloproteinases) in kidney diseases has been widely accepted, where they can regulate inflammatory response because of their effects on both recruitment and survival of inflammatory cells. TNFα (tumour necrosis factor α) has also been implicated in the pathogenesis of inflammatory kidney diseases, including forms of glomerulonephritis associated with viral diseases. Previously, we established the functional linkage between viral receptors of the innate immune system, the TLRs (Toll-like receptors) and control of MMP activity in human MC (mesangial cells). Expression levels of MMP-2, MMP-7, MMP-9, TIMP-1 (tissue inhibitor of metalloproteinase 1) and TIMP-2 in human MC in culture were analysed by RT-PCR (reverse transcription-PCR). TNFα significantly enhanced the TLR3-dependent induction of MMP-9 in human MC. Expression levels of MMP-2, TIMP-1 and TIMP-2 were not significantly affected by the activation of TLR3 or TNFα stimulation. No significant MMP-7 expression was found. We conclude that the role of MMP-9 in chemotaxis, activation and proliferation of inflammatory cells is amplified by TNFα originating from infiltrating cells, especially monocytes, producing a regulatory loop that potentially leads to a self-propagating inflammation.

Influence of Interleukin-17f Gene Polymorphisms on Renal Transplantation Outcome

Interleukin-17 (IL-17) plays an important role in the regulation of cellular and humoral immune responses. Although recent studies suggest a role of IL-17 in transplantation, there has been no report about influence of IL-17 gene polymorphism on renal transplantation outcomes. We investigated whether IL-17F gene polymorphisms have influence on graft outcomes in renal transplantation. We analyzed 227 patients who received living donor renal transplantation at Seoul National University Hospital between Jan 1996 and Jul 2004 and 210 healthy controls. IL-17F single nucleotide polymorphisms (SNPs) at 5 sites were analyzed using direct sequencing for 7384A/G, 7470G/A, and 7489A/G and sequence-specific priming for -1507C/T and 6329C/T polymorphisms. There was no difference in IL-17F ▪ gene polymorphism between patient and control groups. Patients with AA genotype at 7489A/G showed a tendency for higher frequency of underlying inflammatory kidney diseases than those with AG or GG genotypes (70.6% vs. 51.9%, P = 0.061). In addition, patients with G allele at 7384A/G showed a significant decrease of 3-year recurrence-free survival of original renal diseases than those without G allele (80.0% vs. 95.5%, P = 0.002). Patients with CC or CT genotypes at 6329C/T showed a tendency for higher frequency of acute rejection than those with TT genotype (30.2% vs 12.5%, P = 0.09). No other IL-17F gene polymorphism showed association with acute or chronic rejections. In summary, we found that 1) the distribution of IL-17F SNP allele frequencies at 5 sites studied is not different between kidney recipients and healthy controls; 2) 7489A/G and 7384A/G polymorphisms are associated with the occurrence of inflammatory renal disease and the recurrence of underlying disease after renal transplantation, respectively; 3) 6329C/T polymorphism might be associated with acute rejection. Further studies in larger number of patients are needed to confirm the roles of IL17F gene polymorphisms on renal transplantation outcomes or underlying renal diseases.

Platelet-derived growth factor triggers PKA-mediated signalling by a redox-dependent mechanism in rat renal mesangial cells

Inflammatory glomerular kidney diseases are often accompanied with a massive production of reactive oxygen species (ROS) that affect the function of the glomerular filtration barrier and contribute to mesangiolysis via the induction of cell death in mesangial cells. Intriguingly, ROS also trigger fine-tuned signalling processes that affect gene expression and cell proliferation or migration. To define such redox-driven signalling devices, a proteomics approach was performed to identify the formation of protein complexes induced by ROS. To this end, protein lysates of human podocytes were treated with or without hydrogen peroxide (250μM). Thereafter cell lysates were subjected to diagonal 2D gel electrophoresis and putative redox-affected proteins were analysed by MS/MS analysis. Among others, the regulatory subunit of protein kinase A (PKA) could be identified that forms homodimers under oxidative conditions. To evaluate whether ROS dependent dimerization of PKA also occurs in a more physiological setting, rat mesangial cells were treated with platelet-derived growth factor-BB (PDGF-BB) to induce ROS formation. This regimen resulted in a redox dependent dimerization of the R-subunits of PKA. To demonstrate whether PDGF-BB induced ROS formation affects PKA dependent pathways, the effects of PDGF-BB on phosphorylation of serine 157 of vasodilator stimulated protein (VASP) a classical target of PKA were analysed. Interestingly PDGF-BB induced VASP phosphorylation in a ROS dependent manner but independent of changes in cAMP levels. Taken together, we demonstrate a redox-mediated activation of PKA by PDGF-BB thus highlighting a physiological role of ROS as regulator of PKA activity in rat mesangial cells.

Clinical efficiency of intravenous immunoglobulin at pregnants with infection of urinary tract

The problem of infection of urinary tract at pregnant women does not lose the urgency now. The inefficiency of treatment of this pathology is connected with physiological decrease in immuni-ty at such patients. Additional using of intravenous immunoglobulin in the form of a preparation Biovenum Моnоfor treatment of pregnant women with pyelonephritis is offered. 75 patients with gestational pyelonephritis or exacerbation of chronic pyelonephritis which have developed at them during II trimester of pregnancy have been surveyed. The 1-st group was formed by 40 persons who received the standard treatment, the 2-nd group was generated by 35 women who in addition received Biovenum Моnо.After the suffering for infectious diseases of kidneys during pregnancy, its further course is characterized by increase of frequency of threatening abortion and premature deliveries, gestosis and placentary dysfunction; during labors a premature rupture of amniotic membranes and distress of fetus was more widespread. At such patients the placenta in many cases had both ultrasonic, and histological attributes of infection. Occurrence during the pregnancy of inflammatory diseases of kidneys was accompanied by significant distribution of the pathology connected with intra-uterine infection among newborns. Additional application of a preparation Biovenum Моnо for treatment of pyelonephritis during the second trimester of pregnancy in comparison with the standard treatment leads to authentic decrease in frequency both obstetrical complications and perinatal pathology.

Human Lipoxygenase: Developments in its Structure, Function, Relevance to Diseases and Challenges in Drug Development

Human lipoxygenases (LOXs) are the enzymes participating in the metabolism of the polyunsaturated fatty acids and catalyzing their oxidation to a variety of eicosanoids, which as the secondary signal transducers have a major impact on human homeostasis. They are involved in many diseases such as inflammatory responses, cancers, cardiovascular and kidney diseases, neurodegenerative disorders and metabolic syndrome. This review summarizes recent developments concerning human 12S-LOX and rabbit 15-LOX projected upon available structural data of LOX and COX oxidoreductases, with conclusions that might apply to LOX family of enzymes in general. Namely: (i) Human lipoxygenases might act as oligomers consisting of active and apo monomers. (ii) Sequential homodimers might act as structural heterodimers with the dimeric interface formed by the interactions resembling the leucine zipper in the coiled-coil superstructure. (iii) Two commonly recognized domains are not sufficient to explain LOX flexibility. Molecular architecture should contain assignment of another regulatory domain of alpha-beta character, possibly important in molecular signaling, which might provide another avenue for targeted drug development. (iv) Allosteric mechanism might involve orchestrated conformational changes and flexibility of the coils connecting the structured elements and ligands binding in more than one monomer.

Notch‐3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury

Kidney diseases impart a vast burden on affected individuals and the overall health care system. Progressive loss of renal parenchymal cells and functional decline following injury are often observed. Notch-1 and -2 receptors are crucially involved in nephron development and contribute to inflammatory kidney diseases. We specifically determined the participation of receptor Notch-3 following tubulointerstitial injury and in inflammatory responses. Here we show by heat map analyses that Notch-3 transcripts are up-regulated in human kidney diseases. A similar response was corroborated with kidney cells following TGF-β exposure in vitro. The murine unilateral ureteral obstruction (UUO) model mirrors hallmarks of tubulointerstitial injury and damage. A subset of tubular and interstitial cells demonstrated up-regulated Notch-3 receptor expression in diseased animals. We hypothesized a relevance of Notch-3 receptors for the chemotactic response. To address this question, animals with genetic ablation of receptor Notch-3 were analysed following UUO. As a result, we found that Notch-3-deficient animals are protected from tubular injury and cell loss with significantly reduced interstitial collagen deposition. Monocytic cell infiltration was significantly reduced and retarded, likely due to abrogated chemokine synthesis. A cell model was set up that mimics enhanced receptor Notch-3 expression and activation. Here a pro-mitogenic response was seen with activated signalling in tubular cells and fibroblasts. In conclusion, Notch-3 receptor fulfils non-redundant roles in the inflamed kidney that may not be replaced by other Notch receptor family members. Thus, specific blockade of this receptor may be suitable as therapeutic option to delay progression of kidney disease.

IL-6 and Lipocalin2/Neutrophil Gelatinase-Associated Lipocalin May Mediate Podocyte Dysfunction in Inflammatory Kidney Disease

IL-6 and Lipocalin2/Neutrophil Gelatinase-Associated Lipocalin May Mediate Podocyte Dysfunction in Inflammatory Kidney Disease

Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction

Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72 h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.

Altered expression of microRNA miR-146a correlates with the development of chronic renal inflammation

MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that act as post-transcriptional regulators of target mRNA. In this study, we sought to identify the microRNA underlying local inflammation in a murine model of chronic kidney disease (CKD). In microarray analysis of kidneys, the expression of miR-146a/b was elevated in B6.MRLc1 CKD mice that spontaneously develop renal inflammation with age. Primary-microRNA analysis found that elevated miR-146a/b expression in the kidneys of B6.MRLc1 mice was mainly derived from miR-146a rather than miR-146b, and this expression increased with the development of CKD. Histopathological scores for glomerular and interstitial lesions, mRNA expression of inflammatory mediators, and macrophage infiltration were significantly higher in B6.MRLc1 than C57BL/6 mice and were positively correlated with miR-146a expression. In situ hybridization and laser microdissection-RT-PCR showed that miR-146a expression in interstitial lesions containing inflammatory cells was higher than in the glomerulus. The increased expression of the inflammatory-associated genes RELA, IRAK1, IL1B, IL10, and CXCLs was noted in miR-146a/b-silenced human monocytes. The amount of miR-146a was higher in urine sediments of B6.MRLc1 than of C57BL/6 mice. Thus, miR-146a expression in the kidneys and its urinary excretion was specifically associated with the development of interstitial lesions and correlated with inflammatory cell infiltration.

Resistin: functional roles and therapeutic considerations for cardiovascular disease

Resistin, originally described as an adipocyte-specific hormone, has been suggested to be an important link between obesity, insulin resistance and diabetes. Although its expression was initially defined in adipocytes, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages, spleen and bone marrow cells. Increasing evidence indicates that resistin plays important regulatory roles apart from its role in insulin resistance and diabetes in a variety of biological processes: atherosclerosis and cardiovascular disease (CVD), non-alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and chronic kidney disease. As CVD accounts for a significant amount of morbidity and mortality in patients with diabetes and without diabetes, it is important to understand the role that adipokines such as resistin play in the cardiovascular system. Evidence suggests that resistin is involved in pathological processes leading to CVD including inflammation, endothelial dysfunction, thrombosis, angiogenesis and smooth muscle cell dysfunction. The modes of action and signalling pathways whereby resistin interacts with its target cells are beginning to be understood. In this review, the current knowledge about the functions and pathophysiological implications of resistin in CVD development is summarized; clinical translations, therapeutic considerations and future directions in the field of resistin research are discussed. This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.

Association of Intrarenal B-Cell Infiltrates with Clinical Outcome in Lupus Nephritis: A Study of 192 Cases

Background. Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined. Methods. Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies. Results. Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (all P < 0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (all P < 0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies. Conclusion. It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.

Leading causes of death and concomitant pathology in patients with type 2 diabetes mellitus according to autopsy data

Aims. The aim of this study was to estimate the prevalence rate of concomitant pathology and its influence on leading causes of death in patients withtype 2 diabetes mellitus according to clinical charts and pathologist's reports. Materials and methods. We have studied the database of Moscow City Hospital №50 in order to pick out confirmed cases of type 2 DM, treated inthe period from 2006 to 2008 years (302 patients, 9,97%). Prevalence rate of concomitant pathology and leading causes of death were then carefullystudied on this ground. Results. We examined clinical charts of 302 patients with type 2 DM - 219 female (72.5%) at the age of 76 [70;80] and 83 male at theage of 75 [68;80]. Cardiovascular pathology and cerebrovascular disease (acute cerebrovascular event and/or postinfarction encephalic cysts,discirculatory encephalopathy) (50.66%) showed high prevalence. Respiratory system diseases (25.8%), excessive body weight and obesity (21.5%),gallstone disease (19.86%), malignant neoplasm (16.2%), prostatic hyperplasia (found in 35 male patients, 42.17%), gynecologic pathology (foundin 23 female patients, 10.5%) and infectious inflammatory diseases of kidneys and urinary tract (8.6%) were also disclosed. Leading causes of deathwere found to be acute cerebrovascular events (28.8%), postinfarction cardiosclerosis (23.18%), acute/recurring myocardium infarction (19.54%)and malignant neoplasm (14.57%). High polypathy prevalence was discovered in studied cohort, and in one third of cases patients perished fromcombination of concurrent diseases.Conclusion: High prevalence rate of intercurrent diseases and polymorbidity in patients with type 2 diabetes mellitus substantiate the need for thoroughexamination at different stages of medical care, treatment of existing malfunctions, as well as preventive measures against complications.

Norepinephrine reduces ω-conotoxin-sensitive Ca2+ currents in renal afferent neurons in rats

Sympathetic efferent and peptidergic afferent renal nerves likely influence hypertensive and inflammatory kidney disease. Our recent investigation with confocal microscopy revealed that in the kidney sympathetic nerve endings are colocalized with afferent nerve fibers (Ditting T, Tiegs G, Rodionova K, Reeh PW, Neuhuber W, Freisinger W, Veelken R. Am J Physiol Renal Physiol 297: F1427-F1434, 2009; Veelken R, Vogel EM, Hilgers K, Amman K, Hartner A, Sass G, Neuhuber W, Tiegs G. J Am Soc Nephrol 19: 1371-1378, 2008). However, it is not known whether renal afferent nerves are influenced by sympathetic nerve activity. We tested the hypothesis that norepinephrine (NE) influences voltage-gated Ca(2+) channel currents in cultured renal dorsal root ganglion (DRG) neurons, i.e., the first-order neuron of the renal afferent pathway. DRG neurons (T11-L2) retrogradely labeled from the kidney and subsequently cultured, were investigated by whole-cell patch clamp. Voltage-gated calcium channels (VGCC) were investigated by voltage ramps (-100 to +80 mV, 300 ms, every 20 s). NE and appropriate adrenergic receptor antagonists were administered by microperfusion. NE (20 μM) reduced VGCC-mediated currents by 10.4 ± 3.0% (P < 0.01). This reduction was abolished by the α-adrenoreceptor inhibitor phentolamine and the α(2)-adrenoceptor antagonist yohimbine. The β-adrenoreceptor antagonist propranolol and the α(1)-adrenoceptor antagonist prazosin had no effect. The inhibitory effect of NE was abolished when N-type currents were blocked by ω-conotoxin GVIA, but was unaffected by other specific Ca(2+) channel inhibitors (ω-agatoxin IVA; nimodipine). Confocal microscopy revealed sympathetic innervation of DRGs and confirmed colocalization of afferent and efferent fibers within in the kidney. Hence NE released from intrarenal sympathetic nerve endings, or sympathetic fibers within the DRGs, or even circulating catecholamines, may influence the activity of peptidergic afferent nerve fibers through N-type Ca(2+) channels via an α(2)-adrenoceptor-dependent mechanism. However, the exact site and the functional role of this interaction remains to be elucidated.

TNF receptor subtype 2 induction by viral dsRNA involves IP-10 and TNF-α in glomerular mesangial inflammation

the ubiquitously important immunoregulator tumor necrosis factor-α (TNF-α) mediates its effects via two distinct receptors, TNFR1 and TNFR2. Although the exact roles of these receptors are not yet completely understood and may differ depending on organ type, they are known to participate in the

A hospital-based cost minimization study of the potential financial impact on the UK health care system of introduction of iron isomaltoside 1000

Background:The clinical need to be able to administer high doses of intravenous iron conveniently in a single rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. Ferric carboxymaltose can be administered at 15 mg/kg body weight to a maximum dose of 1000 mg, whereas iron isomaltoside 1000 can be administered at 20 mg/kg body weight. The ability to give high doses of iron is important in the context of managing iron deficiency anemia in a number of clinical conditions where demands for iron are high (including chronic blood loss associated with inflammatory bowel disease, menorrhagia, and chronic kidney disease). It is also an important component in the strategy as an alternative to a blood transfusion. Affordability is a key issue for health services.Methods:This study was a comparative analysis of the costs of administering the newly available intravenous iron formulations against standard practice (blood transfusion, intravenous iron sucrose) by considering the cost of this treatment option plus nursing costs associated with administration, equipment for administration, and patient transportation in the secondary care (hospital) setting across three dosage levels (600 mg, 1000 mg, and 1600 mg).Results and conclusion:The analysis indicates that the use of iron isomaltoside 1000 results in a net saving when compared with iron sucrose, blood, and ferric carboxymaltose. At 600 mg and 1000 mg doses, it is cheaper than low-molecular-weight iron dextran but more expensive at a dose of 1600 mg. However, it takes six hours to administer low-molecular-weight iron dextran at this dose level, which is inconvenient and reduces patient throughput (productivity).

Glucocorticoid enhances hypoxia- and/or transforming growth factor-β-induced plasminogen activator inhibitor-1 production in human proximal renal tubular cells

Glucocorticoid (GC) treatment reportedly exaggerates renal fibrosis in progressive kidney diseases during which hypoxia occurs as an unavoidable consequence in renal tubular cells. Two major fibrotic factors, hypoxia and transforming growth factor-β (TGF-β), upregulate the production of plasminogen activator inhibitor-1 (PAI-1), a fibrosis enhancer. Most recently, we reported that GC increases PAI-1 production in human proximal tubular epithelial cells (HPTEC). However, the detailed interactions that occur between these PAI-1 inducers in HPTEC remain to be clarified. Confluent HPTECs were treated with GC and/or TGF-β for 24 h under normoxia or hypoxia. The mRNA and protein amounts of PAI-1 and GC receptor (GR) were determined by TaqMan quantitative PCR and immunoassays, respectively. GC and hypoxia response element (GRE and HRE) activities were measured by transient transfection of GRE- and HRE-luciferase expression vector. Hypoxia had no influence on dexamethasone (DXA)-enhanced GRE activity, as DXA had no influence on hypoxia-enhanced HRE activity. Hypoxia induced PAI-1 expression. TGF-β increased basal and hypoxia-stimulated PAI-1 production. Hydrocortisone (HC) and DXA increased hypoxia- or TGF-β-stimulated production of PAI-1 mRNA and protein. Moreover, DXA enhanced hypoxia plus TGF-β-stimulated PAI-1 production. The PAI-1-increasing effect of HC under hypoxia was abolished completely by RU-486, a specific inhibitor of the GR, and largely by PP2, a specific inhibitor of the Src family of protein tyrosine kinases. Glucocorticoid induces hypoxia- and hypoxia plus TGF-β-stimulated PAI-1 production via the GR and tyrosine kinase pathways. These actions of GC may partially explain the renal fibrotic changes seen in progressive inflammatory kidney diseases during GC treatment.

Macrophages Expressing Heme Oxygenase-1 Improve Renal Function in Ischemia/Reperfusion Injury

Acute kidney injury has a high mortality and lacks specific therapies, with ischemia/reperfusion injury (IRI) being the predominant cause. Macrophages (M phi) have been used successfully in cell therapy to deliver targeted therapeutic genes in models of inflammatory kidney disease. Heme oxygenase-1 (HO-1) catalyzes heme breakdown and has important cytoprotective functions. We hypothesized that administration of M phi modified to overexpress HO-1 would protect from renal IRI. Using an adenoviral construct (Ad-HO-1), HO-1 was overexpressed in primary bone marrow-derived M phi (BMDM). In vitro Ad-HO-1 M phi showed an anti-inflammatory phenotype with increased phagocytosis of apoptotic cells (ACs) and increased interleukin (IL)-10 but reduced TNF-alpha and nitric oxide (NO) following lipopolysaccharide/interferon-gamma (IFN gamma) stimulation compared to control transduced or unmodified M phi. In vivo, intravenously (IV) injected M phi homed preferentially to the post-IRI kidney compared to uninjured control following experimental IRI. At 24 hours postinjury, despite equivalent levels of tubular necrosis, apoptosis, and capillary density between groups, the injection of Ad-HO-1 M phi resulted in preserved renal function (serum creatinine reduced by 46%), and reduced microvascular platelet deposition. These data demonstrate that genetically modified M phi improve the outcomes in IRI when administered after the establishment of structural injury, raising the prospect of targeted cell therapy to support the function of the acutely injured kidney.

Docosahexaenoic Acid-Enriched Fish Oil Attenuates Kidney Disease and Prolongs Median and Maximal Life Span of Autoimmune Lupus-Prone Mice

The therapeutic efficacy of individual components of fish oils (FOs) in various human inflammatory diseases still remains unresolved, possibly due to low levels of n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or lower ratio of DHA to EPA. Because FO enriched with DHA (FO-DHA) or EPA (FO-EPA) has become available recently, we investigated their efficacy on survival and inflammatory kidney disease in a well-established animal model of human systemic lupus erythematosus. Results show for the first time that FO-DHA dramatically extends both the median (658 d) and maximal (848 d) life span of (NZB x NZW)F1 (B x W) mice. In contrast, FO-EPA fed mice had a median and maximal life span of approximately 384 and 500 d, respectively. Investigations into possible survival mechanisms revealed that FO-DHA (versus FO-EPA) lowers serum anti-dsDNA Abs, IgG deposition in kidneys, and proteinuria. Further, FO-DHA lowered LPS-mediated increases in serum IL-18 levels and caspase-1-dependent cleavage of pro-IL-18 to mature IL-18 in kidneys. Moreover, FO-DHA suppressed LPS-mediated PI3K, Akt, and NF-kappaB activations in kidney. These data indicate that DHA, but not EPA, is the most potent n-3 fatty acid that suppresses glomerulonephritis and extends life span of systemic lupus erythematosus-prone short-lived B x W mice, possibly via inhibition of IL-18 induction and IL-18-dependent signaling.