Browsing by Subject "Kidneys"

Now showing 1 - 7 of 7
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    Open Access
    Computational analysis of candidate disease genes and variants for salt-sensitive hypertension in indigenous Southern Africans
    (Public Library of Science, 2010) Tiffin, Nicki; Meintjes, Ayton; Ramesar, Rajkumar; Bajic, Vladimir B.; Rayner, Brian
    Multiple factors underlie susceptibility to essential hypertension, including a significant genetic and ethnic component, and environmental effects. Blood pressure response of hypertensive individuals to salt is heterogeneous, but salt sensitivity appears more prevalent in people of indigenous African origin. The underlying genetics of salt-sensitive hypertension, however, are poorly understood. In this study, computational methods including text- and data-mining have been used to select and prioritize candidate aetiological genes for salt-sensitive hypertension. Additionally, we have compared allele frequencies and copy number variation for single nucleotide polymorphisms in candidate genes between indigenous Southern African and Caucasian populations, with the aim of identifying candidate genes with significant variability between the population groups: identifying genetic variability between population groups can exploit ethnic differences in disease prevalence to aid with prioritisation of good candidate genes. Our top-ranking candidate genes include parathyroid hormone precursor ( PTH ) and type-1angiotensin II receptor ( AGTR1 ). We propose that the candidate genes identified in this study warrant further investigation as potential aetiological genes for salt-sensitive hypertension.
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    Open Access
    Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1
    (Public Library of Science, 2013) Marakalala, Mohlopheni J; Vautier, Simon; Potrykus, Joanna; Walker, Louise A; Shepardson, Kelly M; Hopke, Alex; Mora-Montes, Hector M; Kerrigan, Ann; Netea, Mihai G; Murray, Graeme I
    Author Summary Dectin-1 is a pattern recognition receptor recognising the fungal cell-wall component, β-glucan, and plays an essential role in controlling C. albicans infections in both mouse and man. Candida albicans is part of the normal human microflora, yet is capable of causing superficial mucosal infections as well as life-threatening invasive diseases, particularly in patients whose immune function is compromised. Here we found that the contribution of Dectin-1 is limited to specific strains of C. albicans ; effects which are due to the differential adaptation of these pathogens during infection. Importantly, C. albicans strains showed variations in both the composition and nature of their cell walls, and it was these differences which influenced the role of Dectin-1. Crucially, we found that we could alter the fungal cell wall, and subsequent interactions with the host, using antifungal drugs. These findings have substantial implications for our understanding of the factors contributing to human susceptibility to infections with C. albicans , but also treatment strategies.
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    Genetic variation at selected SNPs in the leptin gene and association of alleles with markers of kidney disease in a Xhosa population of South Africa
    (Public Library of Science, 2010) Okpechi, Ikechi G; Rayner, Brian L; van der Merwe, Lize; Mayosi, Bongani M; Adeyemo, Adebowale; Tiffin, Nicki; Ramesar, Rajkumar
    BACKGROUND: Chronic kidney disease (CKD) is a significant public health problem that leads to end-stage renal disease (ESRD) with as many as 2 million people predicted to need therapy worldwide by 2010. Obesity is a risk factor for CKD and leptin, the obesity hormone, correlates with body fat mass and markers of renal function. A number of clinical and experimental studies have suggested a link between serum leptin and kidney disease. We hypothesised that variants in the leptin gene ( LEP ) may be associated with markers of CKD in indigenous black Africans. METHODOLOGY/PRINCIPAL FINDINGS: Black South Africans of Xhosa (distinct cultural Bantu-speaking population) descent were recruited for the study and four common polymorphisms of the LEP (rs7799039, rs791620, rs2167270 and STS-U43653 [ENSSNP5824596]) were analysed for genotype and haplotype association with urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), Serum creatinine (Scr) and serum leptin level. In one of the four single nucleotide polymorphisms (SNPs) we examined, an association with the renal phenotypes was observed. Hypertensive subjects with the T allele (CT genotype) of the ENSSNP5824596 SNP had a significantly higher eGFR (p = 0.0141), and significantly lower Scr (p = 0.0137). This was confirmed by haplotype analysis. Also, the haplotype GAAC had a modest effect on urine albumin-to-creatinine ratio in normotensive subjects (p = 0.0482). Conclusions/Significance These results suggest that genetic variations of the LEP may be associated with phenotypes that are markers of CKD in black Africans.
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    Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients
    (Public Library of Science, 2013) Young-Gqamana, Brandy; Brignol, Nastry; Chang, Hui-Hwa; Khanna, Richie; Soska, Rebecca; Fuller, Maria; Sitaraman, Sheela A; Germain, Dominique P; Giugliani, Roberto; Hughes, Derralynn A
    Fabry disease (FD) results from mutations in the gene ( GLA ) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb 3 ). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb 3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb 3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb 3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb 3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb 3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.
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    Polymorphisms in the non-muscle myosin heavy chain gene (MYH9) are associated with lower glomerular filtration rate in mixed ancestry diabetic subjects from South Africa
    (Public Library of Science, 2012) Matsha, Tandi Edith; Masconi, Katya; Yako, Yandiswa Yolanda; Hassan, Mogamat Shafick; Macharia, Muiriri; Erasmus, Rajiv Timothy; Kengne, Andre Pascal
    Objective: Though single nucleotide polymorphisms (SNPs) in the non-muscle myosin gene (MYH9) have been reported to explain most of the excess risk of nondiabetic chronic kidney disease (CKD), in African-Americans, some studies have also shown associations with diabetic end-stage renal disease. We investigated the association of MYH9 SNPs with renal traits in a mixed-ancestry South African population prone to diabetes. Research Design and METHODS: Three SNPs known to be associated with CKD (rs4821480, rs5756152 and rs12107) were genotyped using Taqman assay in 716 adults (198 with diabetes) from the Bellville-South community, Cape Town. Glomerular filtration rate was estimated (eGFR) and urinary albumin/creatinine ratio (ACR) assessed. Multivariable regressions were used to relate the SNPs with renal traits. RESULTS: Mean age was 53.6 years, with the expected differences observed in characteristics by diabetic status. Significant associations were found between rs575152 and serum creatinine, and eGFR in the total population, and in diabetic participants (all p≤0.003), but not in non-diabetics (all p≥0.16), with significant interactions by diabetes status (interaction-p≤0.009). The association with ACR was borderline in diabetic participants (p = 0.05) and non-significant in non-diabetics (p = 0.85), with significant interaction (interaction p = 0.02). rs12107 was associated with fasting-, 2-hour glucose and HbA1c in diabetic participants only (interaction-p≤0.003), but not with renal traits. CONCLUSION: MYH9 SNPs were associated with renal traits only in diabetic participants in this population. Our findings and other studies suggest that MYH9 may have a broader genetic risk effect on kidney diseases.
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    Risk models to predict chronic kidney disease and its progression: a systematic review
    (Public Library of Science, 2012) Echouffo-Tcheugui, Justin B; Kengne, Andre P
    A systematic review of risk prediction models conducted by Justin Echouffo-Tcheugui and Andre Kengne examines the evidence base for prediction of chronic kidney disease risk and its progression, and suitability of such models for clinical use.
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    Use of the 'Accountability for Reasonableness' Approach to Improve Fairness in Accessing Dialysis in a Middle-Income Country
    (Public Library of Science, 2016) Moosa, Mohammed Rafique; Maree, Jonathan David; Chirehwa, Maxwell T; Benatar, Solomon R
    Universal access to renal replacement therapy is beyond the economic capability of most low and middle-income countries due to large patient numbers and the high recurrent cost of treating end stage kidney disease. In countries where limited access is available, no systems exist that allow for optimal use of the scarce dialysis facilities. We previously reported that using national guidelines to select patients for renal replacement therapy resulted in biased allocation. We reengineered selection guidelines using the 'Accountability for Reasonableness' (procedural fairness) framework in collaboration with relevant stakeholders, applying these in a novel way to categorize and prioritize patients in a unique hierarchical fashion. The guidelines were primarily premised on patients being transplantable. We examined whether the revised guidelines enhanced fairness of dialysis resource allocation. This is a descriptive study of 1101 end stage kidney failure patients presenting to a tertiary renal unit in a middle-income country, evaluated for dialysis treatment over a seven-year period. The Assessment Committee used the accountability for reasonableness-based guidelines to allocate patients to one of three assessment groups. Category 1 patients were guaranteed renal replacement therapy, Category 3 patients were palliated, and Category 2 were offered treatment if resources allowed. Only 25.2% of all end stage kidney disease patients assessed were accepted for renal replacement treatment. The majority of patients (48%) were allocated to Category 2. Of 134 Category 1 patients, 98% were accepted for treatment while 438 (99.5%) Category 3 patients were excluded. Compared with those palliated, patients accepted for dialysis treatment were almost 10 years younger, employed, married with children and not diabetic. Compared with our previous selection process our current method of priority setting based on procedural fairness arguably resulted in more equitable allocation of treatment but, more importantly, it is a model that is morally, legally and ethically more defensible.