The Heritability of Kidney Function Using an Older Australian Twin Population

Introduction: Twin studies are unique population models which estimate observed rather than inferred genetic components of complex traits. Nonmonogenic chronic kidney disease (CKD) is a complex disease process with strong genetic and environmental influences, amenable to twin studies. We aimed to assess the heritability of CKD using twin analysis and modeling within Older Australian Twin Study (OATS) data. Methods: OATS had 109 dizygotic (DZ) and 126 monozygotic (MZ) twin pairs with paired serum creatinine levels. Heritability of kidney function as estimated glomerular filtration rate (eGFR CKD Epidemiology Collaboration [CKD-EPI]) was modeled using the ACE model to estimate additive heritability (A), common (C), and unique (E) environmental factors. Intratwin pair analysis using mixed effects logistic regression allowed analysis of variation in eGFR from established CKD risk factors. Results: The median age was 69.71 (interquartile range 78.4–83.0) years, with 65% female, and a mean CKD-EPI of 82.8 ml/min (SD 6.7). The unadjusted ACE model determined kidney function to be 33% genetically determined (A), 18% shared genetic-environmental (C), and 49% because of unique environment (E). This remained unchanged when adjusted for age, hypertension, and sex. Hypertension was associated with eGFR; however, intertwin variance in hypertension did not explain variance in eGFR. Two or more hypertension medications were associated with decreased eGFR (P = 0.009). Conclusion: This study estimates observed heritability at 33%, notably higher than inferred heritability in genome-wide association study (GWAS) (7.1%–18%). Epigenetics and other genomic phenomena may explain this heritability gap. Difference in antihypertension medications explains part of unique environmental exposures, though discordance in hypertension and diabetes does not

Buccal, intranasal or intravenous lorazepam for the treatment of acute convulsions in children in Malawi: An open randomized trial

IntroductionAcute convulsions in children are a common emergency worldwide. Benzodiazepines are the recommended first line treatment. Intravenous lorazepam is inexpensive, long acting and the first line drug in resource-rich settings. However, comparable efficacy by other routes of administration is unknown. We wished to compare the efficacy of lorazepam by the buccal, intranasal or intravenous route in the treatment of acute seizures in Malawian children.MethodsA prospective, open-label, randomised, non-inferiority trial was performed in children aged 2months to 14years presenting to the Queen Elizabeth Central Hospital in Blantyre, Malawi with acute seizures lasting longer than 5min. Children were randomly assigned to receive lorazepam, 0.1mg/kg, by the buccal, intranasal or intravenous route. The primary endpoint was seizure cessation within 10min of drug administration.ResultsThere were 761 seizures analysed, with 252 patients in the buccal, 245 in the intranasal and 264 in the intravenous groups. Intravenous lorazepam stopped seizures within 10min in 83%, intranasal lorazepam in 57% (RR 2.46, CI 1.82–3.34), and the buccal route in 46% (RR 3.14, CI 2.35–4.20; p=0.001) of children. There were no significant cardio-respiratory events and no difference in mortality or neurological deficits. The study was halted after an interim analysis showed that the primary endpoint had exceeded the protocol-stopping rule.ConclusionsIntravenous lorazepam effectively treats most childhood seizures in this setting. Intranasal and buccal routes are less effective but may be useful in pre-hospital care or when intravenous access cannot be obtained. Further studies comparing intranasal lorazepam to other benzodiazepines, or alternative doses by a non-intravenous route are warranted

Association of polygenic scores with chronic kidney disease phenotypes in a longitudinal study of older adults

Risk of chronic kidney disease (CKD) is influenced by environmental and genetic factors and increases sharply in individuals 70 years and older. Polygenic scores (PGS) for kidney disease-related traits have shown promise but require validation in well-characterized cohorts. Here, we assessed the performance of recently developed PGSs for CKD-related traits in a longitudinal cohort of healthy older individuals enrolled in the Australian ASPREE randomized controlled trial of daily low-dose aspirin with CKD risk at baseline and longitudinally. Among 11,813 genotyped participants aged 70 years or more with baseline eGFR measures, we tested associations between PGSs and measured eGFR at baseline, clinical phenotype of CKD, and longitudinal rate of eGFR decline spanning up to six years of follow-up per participant. A PGS for eGFR was associated with baseline eGFR, with a significant decrease of 3.9 mL/min/1.73m2 (95% confidence interval -4.17 to -3.68) per standard deviation (SD) increase of the PGS. This PGS, as well as a PGS for CKD stage 3 were both associated with higher risk of baseline CKD stage 3 in cross-sectional analysis (Odds Ratio 1.75 per SD, 95% confidence interval 1.66-1.85, and Odds Ratio 1.51 per SD, 95% confidence interval 1.43-1.59, respectively). Longitudinally, two separate PGSs for eGFR slope were associated with significant kidney function decline during follow-up. Thus, our study demonstrates that kidney function has a considerable genetic component in older adults, and that new PGSs for kidney disease-related phenotypes may have potential utility for CKD risk prediction in advanced age

Assessing household wealth in health studies in developing countries: a comparison of participatory wealth ranking and survey techniques from rural South Africa

BACKGROUND: Accurate tools for assessing household wealth are essential for many health studies in developing countries. Household survey and participatory wealth ranking (PWR) are two approaches to generate data for this purpose. METHODS: A household survey and PWR were conducted among eight villages in rural South Africa. We developed three indicators of household wealth using the data. One indicator used PWR data only, one used principal components analysis to combine data from the survey, while the final indicator used survey data combined in a manner informed by the PWR. We assessed internal consistency of the indices and assessed their level of agreement in ranking household wealth. RESULTS: Food security, asset ownership, housing quality and employment were important indicators of household wealth. PWR, consisting of three independent rankings of 9671 households, showed a high level of internal consistency (intraclass correlation coefficient 0.81, 95% CI 0.79-0.82). Data on 1429 households were available from all three techniques. There was moderate agreement in ranking households into wealth tertiles between the two indicators based on survey data (spearman rho = 0.69, kappa = 0.43), but only limited agreement between these techniques and the PWR data (spearman rho = 0.38 and 0.31, kappa = 0.20 and 0.17). CONCLUSION: Both PWR and household survey can provide a rapid assessment of household wealth. Each technique had strengths and weaknesses. Reasons for differences might include data inaccuracies or limitations in the methods by which information was weighted. Alternatively, the techniques may measure different things. More research is needed to increase the validity of measures of socioeconomic position used in health studies in developing countries

Monogenic and polygenic concepts in chronic kidney disease (CKD)

Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily autosomal dominant inheritance patterns account for 10% of adult and 50% of paediatric kidney diseases. However, kidney function is also a complex trait with polygenic architecture, where genetic factors interact with environment and lifestyle factors. Family studies suggest that kidney function has significant heritability at 35–69%, capturing complexities of the genome with shared environmental factors. Genome-wide association studies estimate the single nucleotide polymorphism-based heritability of kidney function between 7.1 and 20.3%. These heritability estimates, measuring the extent to which genetic variation contributes to CKD risk, indicate a strong genetic contribution. Polygenic Risk Scores have recently been developed for chronic kidney disease and kidney function, and validated in large populations. Polygenic Risk Scores show correlation with kidney function but lack the specificity to predict individual-level changes in kidney function. Certain kidney diseases, such as membranous nephropathy and IgA nephropathy that have significant genetic components, may benefit most from polygenic risk scores for improved risk stratification. Genetic studies of kidney function also provide a potential avenue for the development of more targeted therapies and interventions. Understanding the development and validation of genomic scores is required to guide their implementation and identify the most appropriate potential implications in clinical practice. In this review, we provide an overview of the heritability of kidney function traits in population studies, explore both monogenic and polygenic concepts in kidney disease, with a focus on recently developed polygenic risk scores in kidney function and chronic kidney disease, and review specific diseases which are most amenable to incorporation of genomic scores. Graphical abstract: [Figure not available: see fulltext.]

Comparison of previous and present World Health Organization clinical staging criteria in HIV-infected Malawian children.

In many settings, HIV infected children are looked after with limited access to CD4 cell count or viral load. The decision to initiate antiretroviral therapy (ART) is made clinically, based on the WHO paediatric staging criteria, which were revised in 2006. Results of using new and old criteria were compared. Of 694 children, 626 (90.2%) fulfilled criteria to start ART when applying the new WHO staging guidelines, whereas 330 (47.6%) children were eligible for ART when using the old WHO criteria. This signifies a marked rise in the number of paediatric patients qualifying for ART on clinical grounds

Explaining continued high HIV prevalence in South Africa: socioeconomic factors, HIV incidence and sexual behaviour change among a rural cohort, 2001-2004.

OBJECTIVES: To estimate HIV incidence and explore evidence for changing sexual behaviour over time among men and women belonging to different socioeconomic groups in rural South Africa. DESIGN AND METHODS: A cohort study conducted between 2001 and 2004; 3881 individuals aged 14-35 years enumerated in eight villages were eligible. At least three household visits were made to contact each eligible respondent at both timepoints. Sexual behaviour data were collected in structured, respondent-focused interviews. HIV serostatus was assessed using an oral fluid enzyme-linked immunosorbent assay at each timepoint. RESULTS: Data on sexual behaviour were available from 1967 individuals at both timepoints. A total of 1286 HIV-negative individuals at baseline contributed to the analysis of incidence. HIV incidence was 2.2/100 person-years among men and 4.9/100 person-years in women, among whom it was highest in the least educated group. Median age at first sex was lower among later birth cohorts. A higher number of previously sexually active individuals reported having multiple partners in the past year in 2004 than 2001. Condom use with non-spousal partners increased from 2001 to 2004. Migrant men more often reported multiple partners. Migrant and more educated individuals of both sexes and women from wealthier households reported higher levels of condom use. DISCUSSION: HIV incidence is high in rural South Africa, particularly among women of low education. Some risky sexual behaviours (early sexual debut, having multiple sexual partners) are becoming more common over time. Condom use is increasing. Existing HIV prevention strategies have only been partly effective in generating population-level behavioural change