Increased serum hepcidin contributes to the anemia of chronic kidney disease in a murine model.
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ABSTRACT:
SUBMITTER: Hanudel MR
PROVIDER: S-EPMC5394962 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
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Increased serum hepcidin contributes to the anemia of chronic kidney disease in a murine model.
Hanudel Mark R MR Rappaport Maxime M Gabayan Victoria V Jung Grace G Salusky Isidro B IB Nemeth Elizabeta E Ganz Tomas T Zaritsky Joshua J
Haematologica 20161124 3
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Project description:Malaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. Iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liver-derived hormone hepcidin. We examined the regulation of hepcidin during malarial infection in mice using the rodent parasite Plasmodium berghei K173. Mice infected with Plasmodium berghei K173 develop a severe anemia and die after 18 to 22 days without cerebral malaria. During the early phase of blood-stage infection (days 1 to 5), a strong inflammatory signature was associated with an increased production of hepcidin. Between days 7 and 18, while infection progressed, red blood cell count, hemoglobin and hematocrit dramatically decreased. In the late phase of malarial infection, hepcidin production was reduced concomitantly to an increase in the messenger RNA expression of the hepcidin suppressor erythroferrone in the bone marrow and the spleen. Compared with wild-type mice, Erfe-/- mice failed to adequately suppress hepcidin expression after infection with Plasmodium berghei K173. Importantly, the sustained production of hepcidin allowed by erythroferrone ablation was associated with decreased parasitemia, providing further evidence that transient iron restriction could be beneficial in the treatment of malaria.
| S-EPMC5210233 | biostudies-other
Project description:Leptin is an adipokine that regulates various metabolism, but its association with secondary hyperparathyroidism (SHPT), a clinical manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD), remains obscure. Parathyroidectomy (PTX) is recommended for severe SHPT patients. Here, the associations between circulating leptin and clinical characteristics in CKD patients were investigated. Effects of PTX on leptin production were analyzed in vivo and in vitro. Controls and CKD patients had approximate serum leptin levels in that a larger proportion of CKD patients with body mass index (BMI) <23 kg/m(2). Serum leptin was related to anemia, albumin, and bone metabolism disorders in CKD patients. Lower intact parathyroid hormone (PTH) was related with higher leptin in PTX patients group. Severe SHPT inhibited uremia-enhanced leptin production in 3T3-L1 adipocytes, which was attenuated after PTX. High levels of PTH were found to reduce Akt phosphorylation and leptin production in vitro but high levels of calcium and phosphorus were not. Successful PTX was found to improve anemia and malnutrition in severe SHPT patients, and this was correlated with increased circulating leptin levels via up-regulated Akt signaling in adipocytes. These findings indicated the therapeutic potential of leptin and related target pathway for improving survival and quality of life in CKD.
| S-EPMC4910047 | biostudies-literature
Project description:BackgroundAnemia is highly prevalent in chronic kidney disease (CKD). Elevated hepcidin concentrations are an important mediator of disordered iron metabolism, a key mechanism underlying anemia of CKD. Vitamin D was recently shown to reduce serum hepcidin concentrations in healthy individuals. We examined whether treatment with calcitriol reduces serum hepcidin in individuals with CKD.MethodsA total of 40 participants with stage 3 or 4 CKD (eGFR 15-60 ml/min/1.73m2) were randomized to receive either oral calcitriol 0.5 mcg daily or identically-matched placebo for 6 weeks. The primary outcome variable was change in serum hepcidin concentrations. Secondary outcomes variables included the change in iron parameters, calcium, phosphorus, intact parathyroid hormone and hemoglobin concentrations. Study samples were drawn at baseline, 3 days, 1 week, 4 weeks and 6 weeks after randomization. Repeated measures analysis was used to examine differences in outcome variables over time in the two groups.ResultsThere were no significant differences in the baseline characteristics between the placebo and calcitriol arms. Over 6 weeks of follow-up there were no significant differences in the change in serum hepcidin, iron parameters, or hemoglobin between the two groups. Serum calcium and phosphorus significantly increased and PTH significantly decreased after 6 weeks in calcitriol group whereas these analytes did not change in the placebo group.ConclusionCalcitriol did not reduce serum hepcidin concentrations among individuals with mild to moderate CKD. Future studies are needed to assess if nutritional forms of vitamin D affect hepcidin concentrations in CKD.Trial registrationClinicalTrials.gov Identifier: NCT01988116 . Registered: November 4, 2013.
| S-EPMC5807766 | biostudies-literature
Project description:Using the nonaccelerated murine nephrotoxic nephritis (NTN) as a model of chronic kidney disease (CKD) could provide an easily inducible model that enables a rapid test of treatments. Originally, the NTN model was developed as an acute model of glomerulonephritis, but in this study we evaluate the model as a CKD model and compare CD1 and C57BL/6 female and male mice. CD1 mice have previously showed an increased susceptibility to CKD in other CKD models. NTN was induced by injecting nephrotoxic serum (NTS) and evaluated by CKD parameters including albuminuria, glomerular filtration rate (GFR), mesangial expansion, and renal fibrosis. Both strains showed significant albuminuria on days 2-3 which remained significant until the last time point on days 36-37 supporting dysfunctional filtration also observed by a significantly declined GFR on days 5-6, 15-17, and 34-37. Both strains showed early progressive mesangial expansion and significant renal fibrosis within three weeks suggesting CKD development. CD1 and C57BL/6 females showed a similar disease progression, but female mice seemed more susceptible to NTS compared to male mice. The presence of albuminuria, GFR decline, mesangial expansion, and fibrosis showed that the NTN model is a relevant CKD model both in C57BL/6 and in CD1 mice.
| S-EPMC5859794 | biostudies-literature
Project description:BACKGROUND:Few studies have examined the relationship between cardiac function and geometry and serum hepcidin levels in patients with chronic kidney disease (CKD). We aimed to identify the relationship between cardiac function and geometry and serum hepcidin levels. METHODS:We reviewed data of 1,897 patients in a large-scale multicenter prospective Korean study. Logistic regression analysis was used to identify the relationship between cardiac function and geometry and serum hepcidin levels. RESULTS:The mean relative wall thickness (RWT) and left ventricular mass index (LVMI) were 0.38 and 42.0 g/m2.7, respectively. The mean ejection fraction (EF) and early diastolic mitral inflow to annulus velocity ratio (E/e') were 64.1% and 9.9, respectively. Although EF and E/e' were not associated with high serum hepcidin, RWT and LVMI were significantly associated with high serum hepcidin levels in univariate logistic regression analysis. In multivariate logistic regression analysis after adjusting for variables related to anemia, bone mineral metabolism, comorbidities, and inflammation, however, only each 0.1-unit increase in RWT was associated with increased odds of high serum hepcidin (odds ratio, 1.989; 95% confidence interval, 1.358-2.916; P < 0.001). In the subgroup analysis, the independent relationship between RWT and high serum hepcidin level was valid only in women and patients with low transferrin saturation (TSAT). CONCLUSION:Although the relationship was not cause-and-effect, increased RWT was independently associated with high serum hepcidin, particularly in women and patients with low TSAT. The relationship between cardiac geometry and serum hepcidin in CKD patients needs to be confirmed in future studies.
| S-EPMC6942131 | biostudies-literature
Project description:IntroductionDespite the pivotal role of hepcidin in the development of anemia among the patients with chronic kidney disease (CKD), the association between serum hepcidin levels and CKD progression has been never investigated. We here hypothesized that elevation in serum hepcidin levels might be associated with the risk of incident end-stage kidney disease (ESKD) among the patients with pre-dialysis CKD.MethodsA total of 2,109 patients with pre-dialysis CKD at stages 1 to pre-dialysis 5 were categorized into the quartiles by serum hepcidin levels. The study outcome was incident ESKD. The median duration of follow-up was 7.9 years.ResultsThe analysis of the baseline characteristics revealed that unfavorable clinical features were in general associated with higher serum hepcidin levels. The cumulative incidence of ESKD was significantly differed by serum hepcidin levels, with the highest incidence in the 4th quartile (p < 0.001, by log-rank test). Cox regression analysis demonstrated that, compared to the 1st quartile, the risk of incident ESKD is significantly increased in the 4th quartile (adjusted hazard ratio 1.372, 95% confidence interval 1.070-1.759). Penalized spline curve analysis illustrated a linear, positive correlation between serum hepcidin levels and the risk of incident ESKD. Subgroup analyses revealed that the association is significantly more prominent in the patients with advanced CKD (i.e., estimated glomerular filtration rate <45 mL/min/1.73 m2).ConclusionElevation in serum hepcidin levels is significantly associated with the risk of incident ESKD among the patients with pre-dialysis CKD.
| S-EPMC11631166 | biostudies-literature
Project description:ObjectivesTrefoil factor 3 (TFF3) is a small peptide that plays an important role in mucosal protection, cell proliferation, and cell migration. The aberrant expression of TFF3 is correlated with gastrointestinal inflammation, solid tumors, and other clinical diseases. The objective of this study was to identify the distribution characteristics of serum TFF3 in common clinical diseases.Materials and methodsA large prospective randomized study of 1,072 Chinese patients was performed using an enzyme-linked immunosorbent assay (ELISA) to examine the serum TFF3 concentrations in patients with different diseases. A matched case-control study was conducted on patients with chronic kidney disease (CKD) stages 1-5. Immunohistochemistry (IHC) was performed using renal tissues to determine the relationship between the severity of CKD and the serum and urine concentrations of TFF3 peptides.ResultsThe mean serum concentrations of TFF3 in patients with CKD, metastatic and secondary carcinoma (MC) and acute gastroenteritis (AG) (200.9 ng/ml, 95.7 ng/ml and 71.7 ng/ml, respectively) were significantly higher than those in patients with other common clinical diseases. A positive correlation tendency was observed between the serum TFF3 concentrations and the severity of CKD. The mean serum TFF3 values for CKD stages 1-5 were 23.6 ng/ml, 29.9 ng/ml, 54.9 ng/ml, 85.0 ng/ml and 176.6 ng/ml, respectively. The same trend was observed in the urine TFF3 concentrations and the CKD stages. The creatinine(Cr)-corrected concentrations of TFF3 in urine were 367.1 ng/mg·Cr, 910.6 ng/mg·Cr, 1,149.0 ng/mg·Cr, 1,610.0 ng/mg·Cr and 3,475.0 ng/mg·Cr for CKD stages 1-5, respectively. IHC revealed that TFF3 expression was concentrated in tubular epithelial cells.ConclusionsThe influence of kidney injuries must be fully considered when performing clinical TFF3 research. Further studies on TFF3 in CKD will contribute to our understanding of its pathological roles and mechanisms in other diseases.
| S-EPMC3840008 | biostudies-literature
Project description:AimsErythropoiesis-stimulating agents used to treat anaemia in patients with chronic kidney disease (CKD) have been associated with cardiovascular adverse events. Hepcidin production, controlled by bone morphogenic protein 6 (BMP6), regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anaemia in CKD patients. To investigate alternative therapies to erythropoiesis-stimulating agents for CKD patients, monoclonal antibodies, LY3113593 and LY2928057, targeting BMP6 and ferroportin respectively, were tested in CKD patients.MethodsPreclinical in vitro/vivo data and clinical data in healthy subjects and CKD patients were used to illustrate the translation of pharmacological properties of LY3113593 and LY2928057, highlighting the novelty of targeting these nodes within the hepcidin-ferroportin pathway.ResultsLY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower haemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (mean [90% confidence interval]) 1.98 [1.46-2.68] and 1.36 [1.22-1.51] fold-relative to baseline following LY2928057 600 mg and LY311593 150 mg respectively in CKD patients. LY3113593 specifically blocked BMP6 binding to its receptor and produced increases in iron and transferrin saturation and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in haemoglobin and reduction in ferritin (compared to placebo).ConclusionLY3113593 and LY2928057 pharmacological effects (serum iron and ferritin) were translated from preclinical-to-clinical development. Such interventions may lead to new CKD anaemia treatments.
| S-EPMC6475730 | biostudies-literature
Project description:Clinical studies suggest that non-alcoholic steatohepatitis (NASH) is an independent risk factor for chronic kidney disease (CKD), but causality and mechanisms linking these two major diseases are lacking. To assess whether NASH can induce CKD, we have characterized kidney function, histological features, transcriptomic and lipidomic profiles in a well-validated murine NASH model. Mice with NASH progressively developed significant podocyte foot process effacement, proteinuria, glomerulosclerosis, tubular epithelial cell injury, lipid accumulation, and interstitial fibrosis. The progression of kidney fibrosis paralleled the severity of the histologic NASH-activity score. Significantly, we confirmed the causal link between NASH and CKD by orthotopic liver transplantation, which attenuated proteinuria, kidney dysfunction, and fibrosis compared with control sham operated mice. Transcriptomic analysis of mouse kidney cortices revealed differentially expressed genes that were highly enriched in mitochondrial dysfunction, lipid metabolic process, and insulin signaling pathways in NASH-induced CKD. Lipidomic analysis of kidney cortices further revealed that phospholipids and sphingolipids were the most significantly changed lipid species. Notably, we found similar kidney histological changes in human NASH and CKD. Thus, our results confirm a causative role of NASH in the development of CKD, reveal potential pathophysiologic mechanisms of NASH-induced kidney injury, and established a valuable model to study the pathogenesis of NASH-associated CKD. This is an important feature of fatty liver disease that has been largely overlooked but has clinical and prognostic importance.
| S-EPMC10922588 | biostudies-literature
Project description:BackgroundWe hypothesized that phosphorus has an effect on anemia in both normal kidney function and early chronic kidney disease (CKD). We sought to determine whether higher phosphorus levels are associated with anemia in a large diverse population without CKD and early CKD.MethodsThis study is a historical population-based study within the Kaiser Permanente Southern California health system (1 January 1998 to 31 December 2013) among individuals aged 18 years and older with estimated glomerular filtration rate >30 mL/min/1.73 m(2) and measurements of serum phosphorus, creatinine and hemoglobin. Individuals were excluded if they had secondary causes of anemia. Odds ratio (OR) estimated for moderate anemia defined as hemoglobin <11 g/dL for both sexes. Mild anemia was defined as <12 g/dL (females) and <13 g/dL (males).ResultsAmong 155 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia. Serum phosphorus levels ≥3.5 mg/dL were associated with both mild and moderate anemia. Moderate anemia OR (95% confidence interval) was 1.16 (1.04-1.29) for every 0.5 mg/dL phosphorus increase and 1.26 (1.07-1.48) in the highest versus middle phosphorus tertile. Additional independent anemia risk factors, including female sex, Asian race, diabetes, low albumin and low iron saturation, were observed, but did not alter the anemia-phosphorus association.ConclusionsHigher phosphorus levels were associated with a greater likelihood for anemia in a population with early CKD and normal kidney function. Phosphorus may be a biomarker for anemia and may affect aspects of hematopoiesis.
| S-EPMC4805130 | biostudies-literature