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The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients.

ABSTRACT: Iron is essential for most living organisms but iron excess can be toxic. Cellular and systemic iron balance is therefore tightly controlled. Iron homeostasis is dysregulated in chronic kidney disease (CKD) and contributes to the anemia that is prevalent in this patient population. Iron supplementation is one cornerstone of anemia management in CKD patients, but has not been rigorously studied in large prospective randomized controlled trials. This review highlights important advances from genetic studies and animal models that have provided key insights into the molecular mechanisms governing iron homeostasis and its disturbance in CKD, and summarizes how these findings may yield advances in the care of this patient population.

SUBMITTER: Zumbrennen-Bullough K

PROVIDER: S-EPMC3910345 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients.

Zumbrennen-Bullough Kimberly K Babitt Jodie L JL

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20131113 2

Iron is essential for most living organisms but iron excess can be toxic. Cellular and systemic iron balance is therefore tightly controlled. Iron homeostasis is dysregulated in chronic kidney disease (CKD) and contributes to the anemia that is prevalent in this patient population. Iron supplementation is one cornerstone of anemia management in CKD patients, but has not been rigorously studied in large prospective randomized controlled trials. This review highlights important advances from genet ...[more]

PMID: 24235084

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Project description:BackgroundIntravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients.MethodsThis real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators' discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions.ResultsThe probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg.ConclusionsThe >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study.Trial registrationClinicalTrials.gov NCT02546154 , 10 September 2015.

Project description:Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

Dataset Information

The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients.

Publications

The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients.

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