Investigating the potential causes of Mesoamerican Nephropathy (MeN)

Mesoamerican Nephropathy (MeN) has emerged as a major public health concern in Central America. MeN is not associated with traditional chronic kidney disease (CKD) risk factors, and the cause remains unknown. Our aim was to bring together evidence for and against potential causes of MeN. We used biosamples collected from 350 initially apparently healthy men and women aged 18-30 years from a population at risk of MeN to: (i) explore potential early biomarkers of kidney dysfunction, and (ii) quantify associations between possible nephrotoxins and change in renal function over a 2-year follow-up period. We quantified a range of serum and urinary markers of renal injury. Twelve metals and metalloids were analysed by inductively-coupled plasma-mass spectrometry. Twelve pesticides, their metabolites and two mycotoxins were analysed by liquid chromatography coupled to mass spectrometry. Differences in the creatinine-corrected urinary and serum concentrations of the measured exposures were examined between participants in different kidney function decline groups. Furthermore, the effect of heat and elevated fructose individually and in combination was assessed in vitro. The levels of urinary RBP, NGAL and serum UA were significantly elevated in the established kidney dysfunction group but did not help identify those with a normal baseline but declining function. Elevated levels of aluminium and total arsenic were observed across the population but no differences were identified between the different groups. Finally, in vitro experiments showed that heat stress suppressed the mRNA expression of MCP-1 but caused an early increase in expression of fibrogenic genes. Elevated fructose led to early mRNA increase in MCP-1, KIM-1, TGF-β, COLA1 and KIM-1 secretion. However, a number of these molecules were suppressed after longer term exposure. These findings provide evidence against the xenobiotic hypothesis investigated in this thesis as the primary cause(s) of MeN in Nicaragua. Future research priorities include examining alternative toxins not included in the present study and identification of more accurate biomarkers for the early detection of MeN

Thiamine pyrophosphokinase deficiency causes a Leigh disease like phenotype in a sibling pair: Identification through whole exome sequencing and management strategies

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical cours

Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy.

Background Epidemic levels of CKD of undetermined cause, termed Mesoamerican nephropathy in Central America, have been found in low- and middle-income countries. We investigated the natural history of, and factors associated with, loss of kidney function in a population at high risk for this disease.Methods We conducted a 2-year prospective, longitudinal study with follow-up every 6 months in nine rural communities in northwestern Nicaragua and included all men (n=263) and a random sample of women (n=87) ages 18-30 years old without self-reported CKD, diabetes, or hypertension. We used growth mixture modeling to identify subgroups of eGFR trajectory and weighted multinomial logistic regression to examine associations with proposed risk factors.Results Among men, we identified three subpopulations of eGFR trajectory (mean baseline eGFR; mean eGFR change over follow-up): 81% remained stable (116 ml/min per 1.73 m2; -0.6 ml/min per 1.73 m2 per year), 9.5% experienced rapid decline despite normal baseline function (112 ml/min per 1.73 m2; -18.2 ml/min per 1.73 m2 per year), and 9.5% had baseline dysfunction (58 ml/min per 1.73 m2; -3.8 ml/min per 1.73 m2 per year). Among women: 96.6% remained stable (121 ml/min per 1.73 m2; -0.6 ml/min per 1.73 m2 per year), and 3.4% experienced rapid decline (132 ml/min per 1.73 m2; -14.6 ml/min per 1.73 m2 per year; n=3 women). Among men, outdoor and agricultural work and lack of shade availability during work breaks, reported at baseline, were associated with rapid decline.Conclusions Although Mesoamerican nephropathy is associated with agricultural work, other factors may also contribute to this disease

Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy.

OBJECTIVES: There is an epidemic of Mesoamerican nephropathy (MeN) in Central America, where sugarcane production is prominent. Numerous causes are proposed, but to date limited evidence supports any one hypothesis. A nested case-control study using biosamples from a rural, community-based follow-up study of 350 young adults from Northwest Nicaragua at risk of MeN was conducted with the aim of characterising the associations between urinary concentrations of metals, pesticides and mycotoxins from samples collected in the first 6 months and decline in kidney function over 2 years. METHODS: Urine samples collected at baseline (pre-sugarcane harvest) and the first 6 month follow-up (post-sugarcane harvest) visit were tested. Twelve metals and metalloids (aluminium, total arsenic, cadmium, chromium, cobalt, copper, lead, manganese, mercury, selenium, silicon and strontium) were analysed by inductively coupled plasma-mass spectrometry. Twelve pesticides or their metabolites (2,4-dichlorophenoxyacetic acid, 3-phenoxybenzoic acid, 4-fluoro-3-phenoxybenzoic acid, chloro-3,3,3-trifluoro-1-propen-1-yl-2,2-dimethylcyclopropanecarboxylic acid, cis/trans 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, ethylenethiourea, glyphosate, 4-chloro-2-methylphenoxy acetic acid, 3-hydroxy-pyrimetanil, 5-hydroxytiabendazole, hydroxy-tebuconazole and 3,5,6-trichloro-2-pyridinol) and two mycotoxins (ochratoxin A (OTA) and citrinin (CIT)) were analysed by liquid chromatography coupled-mass spectrometry. Differences in the creatinine-corrected urinary concentrations of the measured exposures between outcome groups (participants with stable vs declining kidney function) were examined. RESULTS: Elevated levels of aluminium and total arsenic as well as metabolites of several pesticides were detected across the population. No differences were identified between the declining and stable groups in the levels of metals or pesticides tested. OTA and CIT were below the limit of detection. CONCLUSIONS: The tested metals, metalloids, pesticides and mycotoxins were not associated with loss of kidney function in participants at-risk of MeN

Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy

Background Epidemic levels of CKD of undetermined cause, termed Mesoamerican nephropathy in Central America, have been found in low- and middle-income countries. We investigated the natural history of, and factors associated with, loss of kidney function in a population at high risk for this disease.Methods We conducted a 2-year prospective, longitudinal study with follow-up every 6 months in nine rural communities in northwestern Nicaragua and included all men (n=263) and a random sample of women (n=87) ages 18-30 years old without self-reported CKD, diabetes, or hypertension. We used growth mixture modeling to identify subgroups of eGFR trajectory and weighted multinomial logistic regression to examine associations with proposed risk factors.Results Among men, we identified three subpopulations of eGFR trajectory (mean baseline eGFR; mean eGFR change over follow-up): 81% remained stable (116 ml/min per 1.73 m2; -0.6 ml/min per 1.73 m2 per year), 9.5% experienced rapid decline despite normal baseline function (112 ml/min per 1.73 m2; -18.2 ml/min per 1.73 m2 per year), and 9.5% had baseline dysfunction (58 ml/min per 1.73 m2; -3.8 ml/min per 1.73 m2 per year). Among women: 96.6% remained stable (121 ml/min per 1.73 m2; -0.6 ml/min per 1.73 m2 per year), and 3.4% experienced rapid decline (132 ml/min per 1.73 m2; -14.6 ml/min per 1.73 m2 per year; n=3 women). Among men, outdoor and agricultural work and lack of shade availability during work breaks, reported at baseline, were associated with rapid decline.Conclusions Although Mesoamerican nephropathy is associated with agricultural work, other factors may also contribute to this disease

HEALTHCARE PROFESSIONALS’ EXPERIENCE OF HR MANAGEMENT DURING BREXIT - A CASE STUDY OF RECRUITMENT AND RETENTION WITHIN THE NHS AFTER THE REFERENDUM TO LEAVE THE EUROPEAN UNION (BREXIT)

Purpose: The aim of this Thesis is to explore how EU nationals employed in the NHS experience uncertainty during Brexit and how they have perceived HR support with particular reference to recruitment and retention. Theory: The present study draws on Discourse Theory in that it explores the impact of the Brexit discourse on EU-born employees’ experiences. Moreover, to highlight the importance of HR support in times of uncertainty, interview material was collected about relevant aspects and conceptualisation in relation to Perceived Organizational Support Theory, Isomorphism and Decoupling. This is to gain in-depth knowledge of employees’ experiences and perceptions. Method: A qualitative interview study that wishes to understand the impact of the Brexit discourse on NHS employees and their perception of HR support post-Brexit. Primary and secondary data were used in order to answer the research question. Primary data came from semi-structured telephone interviews with EU healthcare professionals currently employed in the NHS. Additionally, secondary data was offered by newspaper articles, official documents published by the UK Government notably the White Paper on Brexit, and documents, information emails sent by the NHS to their employees. The various data sources were analysed with the help of thematic coding. Result: The Brexit discourse has had an impact on NHS healthcare professionals, who are concerned about the potential consequences of the UK leaving the EU. Various concerns regarding taxes, rights to stay, citizenship, family members were articulated by interviewees. However, NHS employees are seemingly not worried about losing their jobs, since the NHS and its HR department seem to have been successful in reassuring employees that their skills are required and that they are needed. The NHS employees have therefore experienced organisational support. Notably, the NHS HR department was the first national institution to introduce a settlement scheme, something that has increased employees’ commitment and contributed to their wish to stay in the UK. Thus, HR has played a significant role in managing employees 3 uncertainty by taking a proactive role and providing central support so that employees are willing to stay. This is a considerable achievement during uncertain times when EU nationals are reportedly coming to the UK in smaller numbers and leaving the UK in larger numbers than before Brexit