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Fotheringham J.,Sheffield Kidney Institute | Fotheringham J.,University of Sheffield | Weatherley N.,Sheffield Kidney Institute | Kawar B.,Sheffield Kidney Institute | And 3 more authors.
Kidney International | Year: 2014

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m 2 or more versus the normal of 18.5-25 kg/m 2) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m 2, height 1.76 m, and BMI 22 or 45 kg/m 2 had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research. © 2014 International Society of Nephrology.

Borthwick E.M.,Regional Nephrology Unit
Cochrane database of systematic reviews (Online) | Year: 2013

Severe sepsis and septic shock are leading causes of death in the intensive care unit (ICU). This is despite advances in the management of patients with severe sepsis and septic shock including early recognition, source control, timely and appropriate administration of antimicrobial agents, and goal directed haemodynamic, ventilatory and metabolic therapies. High-volume haemofiltration (HVHF) is a blood purification technique which may improve outcomes in critically ill patients with severe sepsis or septic shock. The technique of HVHF has evolved from renal replacement therapies used to treat acute kidney injury (AKI) in critically ill patients in the ICU. This review assessed whether HVHF improves clinical outcome in adult critically ill patients with sepsis in an ICU setting. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 7); MEDLINE (1990 to August 2011), EMBASE (1990 to August 2011); LILACS (1982 to August 2011), Web of Science (1990 to August 2011), CINAHL (1982 to August 2011) and specific websites. We included randomized controlled trials (RCTs) and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to standard or usual dialysis therapy; and RCTs and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to no similar dialysis therapy. The studies involved adults in critical care units. Three review authors independently extracted data and assessed trial quality. We sought additional information as required from trialists. We included three randomized trials involving 64 participants. Due to the small number of studies and participants, it was not possible to combine data or perform sub-group analyses. One trial reported ICU and 28-day mortality, one trial reported hospital mortality and in the third, the number of deaths stated did not match the quoted mortality rates. No trials reported length of stay in ICU or hospital and one reported organ dysfunction. No adverse events were reported. Overall, the included studies had a low risk of bias. There were no adverse effects of HVHF reported.There is insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and or septic shock except as interventions being investigated in the setting of a randomized clinical trial. These trials should be large, multi-centred and have clinically relevant outcome measures. Financial implications should also be assessed.

Magee B.A.,Northern Ireland Histocompatibility and Immunogenetics Laboratory | Martin J.,Northern Ireland Histocompatibility and Immunogenetics Laboratory | Cole M.P.,Northern Ireland Histocompatibility and Immunogenetics Laboratory | Morris K.G.,Northern Ireland Blood Transfusion Service | Courtney A.E.,Regional Nephrology Unit
Transplantation | Year: 2012

BACKGROUND: HLA sensitization in potential renal transplant recipients hinders opportunities of receiving suitable organs. To alleviate this, we sought to determine if supplying closely HLA Class I matched leukodepleted blood would minimize sensitization. METHODS: Patients received HLA selected or random units of packed red cells. Selected units were sourced from blood donors included in the British Bone Marrow Registry and had no HLA-A and HLA-B mismatches where available, or alternatively, no HLA antigens with more than five immunogenic triplet mismatches as determined by the HLAMatchmaker algorithm. Posttransfusion antibody screening confirmed development of de novo Class I and Class II HLA-specific IgG antibody(s) or increases in preexisting antibody levels of at least 20%. RESULTS: Thirty-seven and 31 patients received HLA selected (mean, 2.5 units) and random (mean, 3.4 units) blood, respectively. A total of 20 of 37 (54.1%) patients receiving selected units and 10 of 31 (32.3%) patients receiving random units were previously sensitized. No patient receiving HLA selected units demonstrated any change in antibody levels. In patients who received random units, 7 of 31 demonstrated changes in antibody levels with three developing de novo HLA-specific antibodies and four an increase in panel reactive antibody (PRA) of at least 20% (P=0.002). CONCLUSIONS: The risk of developing HLA-specific antibody is significantly reduced in renal patients awaiting transplantation when transfused with HLA selected units of blood compared with random units. With planning, access to HLA typed blood is achievable as many blood transfusion centers recruit donors for stem cell donor registries. Copyright © 2012 Lippincott Williams &Wilkins.

Paul R.,Ards Hospital | Minay J.,Belfast City Hospital | Cardwell C.,Queens University of Belfast | Fogarty D.,Regional Nephrology Unit | Kelly C.,Belfast City Hospital
Journal of Psychopharmacology | Year: 2010

There is conflicting evidence concerning lithium's effect on renal function. The aim is to clarify whether lithium affects kidney function and at what stage of treatment any effect may occur. Systematic review identified 23 studies split into three groups on which meta-analysis was performed to identify the following: A) lithium's effect on renal function in cross-sectional case-control studies, B) studies of renal function before and after commencement on lithium, C) studies of longer term effect in those already established on lithium therapy. Group A showed a statistically significant increase of 5.7 μmol/L in creatinine in the study population compared with controls. Group B showed a non-statistically significant rise in creatinine (2.9 μmol/L) after a mean follow-up of 86 months. Group C showed a statistically significant increase in creatinine of 7.0 μmol/L over a mean duration of 64 months. An increase in creatinine of an average of 1.6 μmol/L/year on lithium was also identified in this group. Any lithium-associated increase in serum creatinine is quantitatively small and of questionable clinical significance. However, routine renal function monitoring of patients on lithium is essential. © The Author(s), 2010.

Swan E.J.,Queens University of Belfast | Maxwell A.P.,Queens University of Belfast | Maxwell A.P.,Regional Nephrology Unit | Mcknight A.J.,Queens University of Belfast
Diabetic Medicine | Year: 2015

Aims: Epigenetic modifications, such as DNA methylation, can influence the risk of developing kidney disease. We studied methylation profiles in genes related to mitochondrial function to assess whether differences in these epigenetic features were associated with diabetic kidney disease in people with Type 1 diabetes. Methods: A case-control association study was undertaken (n = 196 individuals with diabetic kidney disease vs. n = 246 individuals without renal disease). Participants were White and diagnosed with Type 1 diabetes before 31 years of age. Genes that encode mitochondrial proteins (n = 780) were downloaded from mitoproteome.org. DNA methylation profiles from blood-derived DNA were generated using the Illumina Infinium HumanMethylation450 (262 samples) and Illumina Infinium HumanMethylation27 (192 samples) arrays. Beta values (β) were calculated and quality control was conducted, including evaluating blind duplicate DNA samples. Results: Fifty-four Cytosine-phosphate-Guanine probes across 51 unique genes were significantly associated (P ≤ 10-8) with diabetic kidney disease across both the 450K and the 27K methylation arrays. A subanalysis, employing the 450K array, identified 755 Cytosine-phosphate-Guanine probes in 374 genes that were significantly associated (P ≤ 10-8) with end-stage renal disease. Forty-six of the top-ranked variants for diabetic kidney disease were also identified as being differentially methylated in individuals with end-stage renal disease. The largest change in methylation (Δβ = 0.2) was observed for cg03169527 in the TAMM41 gene, chromosome 3p25.2. Three genes, PMPCB, TSFM and AUH, were observed with differential methylation at multiple Cytosine-phosphate-Guanine sites each (P < 10-12). Conclusions: Differential methylation in genes that influence mitochondrial function are associated with kidney disease in individuals with Type 1 diabetes. What's new?: Mitochondrial dysfunction has been identified in diabetic kidney disease, but relatively large-scale genetic and epigenetic studies focused on mitochondria have not yet been described. We report a novel case-control analysis of DNA methylation in 442 individuals, with Type 1 diabetes, for 780 mitochondrial proteins. Stringent quality control was applied and different chemistry employed for two different methylation arrays. Fifty-one genes demonstrated genome-wide significance (P ≤ 10-8) for association with diabetic kidney disease, 46 of which were also supported by subgroup analysis for end-stage renal disease. Genetic and epigenetic risk variants in mitochondrial related genes are associated with kidney disease in individuals with Type 1 diabetes. © 2015 Diabetes UK.

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