Significance of Elevated Blood Metal Ion Levels in Patients with Metal-on-Metal Prostheses: An Evaluation of Oxidative Stress Markers

It is widely known that cobalt and chromium ions can enhance the production of reactive oxygen species, known to be damaging to cells by disturbing their redox status and then generating oxidative stress. The aim of the present study was to determine if increased metal ion levels induce a state of oxidative stress in patients with metal-on-metal (MM) hip arthroplasty. Results indicated that there was no significant difference in the concentration of oxidative stress markers (total antioxidants, peroxides, and nitrated proteins) in the patients with MM bearings compared to patients without prostheses. The activity antioxidant enzymes was stable (catalase and glutathione peroxidase) or slightly decreased (superoxide dismutase and heme oxygenase-1) over time. This work is the first to determine the biological effects of metal ions released from MM hip implants with regards to mid-term systemic oxidative stress and showed that the increased levels of Co and Cr ions are not associated with significant oxidative stress damage in the plasma of patients with these implants

Ions released from metal-on-metal hip implants: «in vitro» and «in vivo» investigations

Studies have shown that Co and Cr particles and ions can enter the bloodstream and accumulate in tissues and organs of patients after metal-on-metal (MM) total hip arthroplasty (THA). These ions can generate reactive oxygen species (ROS) that can be deleterious for cells. We first assessed the biological effects of Cr(VI), Co(II), and Cr(III) by testing their effect on antioxidant enzymes (SODs, CAT, GPx, HO-1) that represent a primary defense system against ROS. We demonstrated that Cr(VI) induced the protein expression (translation) of antioxidant enzymes, whereas it had no effect on the mRNA expression (transcription). Co(II) induced the expression of both protein and mRNA of HO-1 only. Cr(III) had no effect on the activity of these enzymes. We then suggested that a difference in molecular structure may be at the origin of their differential effects and showed that Cr(III) can form precipitable complexes, whereas Co(II) and Cr(VI) cannot form complexes in the same experimental conditions. These Cr(III) complexes, formed in simulated-physiological fluids, were constituted by an organic phase (amino acids, phosphate) tangled with an inorganic phase (Cr, Ca, Na). Interestingly, these Cr(III) complexes interacted only with albumin in presence of fetal bovine serum, whereas they interacted with 8 different human serum proteins in presence of human serum. The interaction of Cr(III) complexes with serum proteins affect their internalization by macrophages, complexes formed with human serum being more easily internalized than those bound to bovine proteins. Lastly, results suggested that the levels of Co and Cr ions in patients with MM THA are not sufficient to induce significant oxidative stress in the blood of these patients, bringing optimism over concern for the long term biological effects of Co and Cr ions released from metal-metal bearings. In conclusion, this thesis gives very valuable information on the biological effects of Cr and Co ions and gives insight iDe nombreuses études ont montré que les particules et ions métalliques (Cr(III), Co(II) et Cr(VI)) générés par l'usure de prothèses de hanche métalliques (PHM) se retrouvent dans le flux sanguin des patients et s'accumulent également dans leurs tissus et leurs organes. Ces ions peuvent génèrer des radicaux libres qui peuvent à leur tour être nocifs pour la cellule. Nous avons déterminé les effets de ces ions sur les enzymes antioxidantes (SODs, CAT, GPx, HO-1) qui représentent la première ligne de défense cellulaire contre les radicaux libres. Nos travaux ont révélé que le Cr(VI) induit l'expression de ces protéines (traduction) mais non l'expression de leur ARNm (transcription). Le Co(II) induit l'expression de la proteine et de l'ARNm de HO-1 seulement alors que le Cr(III) n'a aucun effet sur l'expression de ces enzymes. Nous avons par la suite suggéré, que la structure moléculaire de ces ions pouvait avoir une influence sur leurs différents effets. Les résultats ont montré que le Cr(III) formait des complexes constitués d'une partie organique (acides aminés et phosphates) et d'une partie inorganique (Cr, calcium et sodium), alors que ni le Co(II), ni le Cr(VI) ne formaient de complexes dans les mêmes conditions expérimentales. En présence de sérum bovin fétal, les complexes de Cr(III) pouvent se lier seulement à l'albumine, alors qu'en présence de sérum humain, ces mêmes complexes intéragissent avec 8 protéines de nature differente. Cette intéraction avec les protéines humaines semble augmenter l'internalisation des complexes par les macrophages. Finalement, les résultats démontrent que la concentration d'ions Co et Cr présents dans le sang de patients portant une PHM est insuffisante pour induire un stress oxydant et apportent un souffle optimiste sur les effets à long terme des ions métalliques chez les patients. Dans son ensemble ce projet apporte de nouveaux éléments de connaissances sur les effets biologi

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10(−8)) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41–6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10(–9)). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR

Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract (Nature Genetics, (2019), 51, 1, (117-127), 10.1038/s41588-018-0281-y)

In the version of this article initially published, affiliation 38 incorrectly read “ICNU-Nephrology and Urology Department, Barcelona, Spain”; “Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain” is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article

Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

In the version of this article initially published, affiliation 38 incorrectly read ICNU-Nephrology and Urology Department, Barcelona, Spain ; Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article

The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome

Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract (Nature Genetics, (2019), 51, 1, (117-127), 10.1038/s41588-018-0281-y)

In the version of this article initially published, affiliation 38 incorrectly read “ICNU-Nephrology and Urology Department, Barcelona, Spain”; “Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain” is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome