Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

Prevalence of secondary care multimorbidity in mid-life and its association with premature mortality in a large longitudinal cohort study.

OBJECTIVES: Multimorbidity is the coexistence of two or more health conditions in an individual. Multimorbidity in younger adults is increasingly recognised as an important challenge. We assessed the prevalence of secondary care multimorbidity in mid-life and its association with premature mortality over 15 years of follow-up, in the Aberdeen Children of the 1950s (ACONF) cohort. METHOD: A prospective cohort study using linked electronic health and mortality records. Scottish ACONF participants were linked to their Scottish Morbidity Record hospital episode data and mortality records. Multimorbidity was defined as two or more conditions and was assessed using healthcare records in 2001 when the participants were aged between 45 and 51 years. The association between multimorbidity and mortality over 15 years of follow-up (to ages 60-66 years) was assessed using Cox proportional hazards regression. There was also adjustment for key covariates: age, gender, social class at birth, intelligence at age 7, secondary school type, educational attainment, alcohol, smoking, body mass index and adult social class. RESULTS: Of 9625 participants (51% males), 3% had multimorbidity. The death rate per 1000 person-years was 28.4 (95% CI 23.2 to 34.8) in those with multimorbidity and 5.7 (95% CI 5.3 to 6.1) in those without. In relation to the reference group of those with no multimorbidity, those with multimorbidity had a mortality HR of 4.5 (95% CI 3.4 to 6.0) over 15 years and this association remained when fully adjusted for the covariates (HR 2.5 (95% CI 1.5 to 4.0)). CONCLUSION: Multimorbidity prevalence was 3% in mid-life when measured using secondary care administrative data. Multimorbidity in mid-life was associated with premature mortality.

Impact of educational attainment on the association between social class at birth and multimorbidity in middle age in the Aberdeen Children of the 1950s cohort study.

OBJECTIVE: Multimorbidity (the coexistence of two or more health conditions) is increasingly prevalent. No long-term cohort study has examined the impact of contemporaneously measured birth social class along with educational attainment on adult self-reported multimorbidity. We investigated the impact of educational attainment on the relationship between social class at birth and adult self-reported multimorbidity in the Aberdeen Children of the 1950s (ACONF) cohort. METHODS: A prospective cohort study using the ACONF cohort. ACONF included 12 150 individuals born in Aberdeen, Scotland 1950-1956. In 2001, 7184 (64%) responded to a questionnaire providing information including self-reported morbidity and educational attainment. The exposure was father's social class at birth from birth records and the outcome was self-reported multimorbidity.Logistic regression assessed the association between social class and multimorbidity with adjustment for gender, then by educational attainment and finally by childhood cognition and secondary school type. ORs and 95% CIs were presented. RESULTS: Of 7184 individuals (mean age 48, 52% female), 5.4% reported multimorbidity. Birth social class was associated with adult multimorbidity. For example, the OR of multimorbidity adjusted by gender was 0.62 (95% CI 0.39 to 1.00) in the highest social class group (I/II) in relation to the reference group (III (manual)) and was 1.85 (95% CI 1.19 to 2.88) in the lowest social class group. This was partially attenuated in all social class categories by educational attainment, for example, the OR was 0.74 (95% CI 0.45 to 1.21) in group I/II following adjustment. CONCLUSION: Lower social class at birth was associated with developing multimorbidity in middle age. This was partially mediated by educational attainment and future research should consider identifying the other explanatory variables. The results are relevant to researchers and to those aiming to reduce the impact of multimorbidity.

Acute kidney injury in the UK: a replication cohort study of the variation across three regional populations.

OBJECTIVES: A rapid growth in the reported rates of acute kidney injury (AKI) has led to calls for greater attention and greater resources for improving care. However, the reported incidence of AKI also varies more than tenfold between previous studies. Some of this variation is likely to stem from methodological heterogeneity. This study explores the extent of cross-population variation in AKI incidence after minimising heterogeneity. DESIGN: Population-based cohort study analysing data from electronic health records from three regions in the UK through shared analysis code and harmonised methodology. SETTING: Three populations from Scotland, Wales and England covering three time periods: Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012. PARTICIPANTS: All residents in each region, aged 15 years or older. MAIN OUTCOME MEASURES: Population incidence of AKI and AKI phenotype (severity, recovery, recurrence). Determined using shared biochemistry-based AKI episode code and standardised by age and sex. RESULTS: Respectively, crude AKI rates (per 10 000/year) were 131, 138, 139, 151 and 124 (p=0.095), and after standardisation for age and sex: 147, 151, 146, 146 and 142 (p=0.257) for Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012. The pattern of variation in crude rates was robust to any modifications of the AKI definition. Across all populations and time periods, AKI rates increased substantially with age from ~20 to ~550 per 10 000/year among those aged <40 and ≥70 years. CONCLUSION: When harmonised methods are used and age and sex differences are accounted for, a similar high burden of AKI is consistently observed across different populations and time periods (~150 per 10 000/year). There are particularly high rates of AKI among older people. Policy-makers should be careful not draw simplistic assumptions about variation in AKI rates based on comparisons that are not rigorous in methodological terms.

Hip fracture incidence and mortality in chronic kidney disease: the GLOMMS-II record linkage cohort study.

BACKGROUND: Individuals on renal replacement therapy (RRT) have increased fracture risk, but risk in less advanced chronic kidney disease (CKD) is unclear. OBJECTIVE: To investigate CKD associations with hip fracture incidence and mortality. DESIGN: Record linkage cohort study Grampian Laboratory Outcomes Mortality and Morbidity Study II. SETTING: Single health region in Scotland. PARTICIPANTS: All individuals (≥15 years) with sustained CKD stages 3-5 and those on RRT, and a 20% random sample of those with normal renal function, in the resident population in 2003. OUTCOME MEASURES: Outcomes were (1) incident hip fracture measured with (A) admissions or (B) deaths, with at least 5.5 years follow-up and (2) post-hip fracture mortality. Unadjusted and adjusted, incident rate ratios (IRRs) and mortality rate ratios were calculated using Poisson regression. RESULTS: Of 39 630 individuals identified in 2003 (41% males, mean age 63.3 years), 19 537 had CKD stages 3-5, 345 were on RRT and 19 748 had normal estimated glomerular filtration rate (eGFR). Hip fracture incidence, measured by admissions, was increased in CKD stages 3-5 (compared with normal eGFR), both overall (adjusted IRR 1.49 (95% CI 1.24 to 1.79)) and for individual CKD stages 3a, 3b and 4. Hip fracture incidence, measured using deaths, was increased in those with CKD stages 3b and 4. Post-hip fracture mortality was only increased in CKD stage 4. There was only a small number of individuals and events for CKD stage 5, resulting in insufficient statistical power. CONCLUSION: Hip fracture incidence was higher in CKD stages 3-5 compared with normal eGFR. Post-hip fracture mortality was only increased in CKD stage 4. Reducing hip fracture incidence in CKD through regular fall and fracture risk review should reduce overall deaths after hip fracture in the population.

Long-term prognosis after acute kidney injury (AKI): what is the role of baseline kidney function and recovery? A systematic review.

OBJECTIVES: To summarise the evidence from studies of acute kidney injury (AKI) with regard to the effect of pre-AKI renal function and post-AKI renal function recovery on long-term mortality and renal outcomes, and to assess whether these factors should be taken into account in future prognostic studies. DESIGN/SETTING: A systematic review of observational studies listed in Medline and EMBASE from 1990 to October 2012. PARTICIPANTS: All AKI studies in adults with data on baseline kidney function to identify AKI; with outcomes either stratified by pre-AKI and/or post-AKI kidney function, or described by the timing of the outcomes. OUTCOMES: Long-term mortality and worsening chronic kidney disease (CKD). RESULTS: Of 7385 citations, few studies met inclusion criteria, reported baseline kidney function and stratified by pre-AKI or post-AKI function. For mortality outcomes, three studies compared patients by pre-AKI renal function and six by post-AKI function. For CKD outcomes, two studies compared patients by pre-AKI function and two by post-AKI function. The presence of CKD pre-AKI (compared with AKI alone) was associated with doubling of mortality and a fourfold to fivefold increase in CKD outcomes. Non-recovery of kidney function was associated with greater mortality and CKD outcomes in some studies, but findings were inconsistent varying with study design. Two studies also reported that risk of poor outcome reduced over time post-AKI. Meta-analysis was precluded by variations in definitions for AKI, CKD and recovery. CONCLUSIONS: The long-term prognosis after AKI varies depending on cause and clinical setting, but it may also, in part, be explained by underlying pre-AKI and post-AKI renal function rather than the AKI episode itself. While carefully considered in clinical practice, few studies address these factors and with inconsistent study design. Future AKI studies should report pre-AKI and post-AKI function consistently as additional factors that may modify AKI prognosis.