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.

Prolonged Duration of Renal Recovery Following ANCA-Associated Glomerulonephritis.

BACKGROUND: As renal biopsies are not routinely repeated to monitor treatment response in anti-neutrophil cytoplasm antibody (ANCA)-associated glomerulonephritis, serum creatinine (SC) and proteinuria assessed by urine protein:creatinine ratio (UPCR) measurements are relied upon to provide a non-invasive estimate of disease activity within the kidney. However, sparse information exists about the time to achieve maximal improvement in these parameters, which has important implications for treatment decisions and disease-scoring systems. METHODS: We analysed patients with ANCA-associated glomerulonephritis and renal impairment from cohorts in the United Kingdom and Ireland, with the primary objective of determining actuarial time to nadir SC and UPCR. Time to disappearance of haematuria was analysed as a secondary objective. RESULTS: Ninety-four patients fulfilled our selection criteria, with 94 (100%) and 66 (70%) having reached their nadir SC and UPCR respectively during the follow-up period. Nadir SC was achieved after a median of 88 days (95% CI 74-102), UPCR at 346 days (95% CI 205-487). Those of Indo-Asian ethnic origin reached their nadir SC faster (34 days) than other ethnicities (p < 0.01). There were no significant differences in time to nadir SC or UPCR on the basis of gender, clinical diagnosis, ANCA positivity or renal biopsy findings. CONCLUSION: In this retrospective study, nadir creatinine and proteinuria occur later than other signs of clinical remission, suggesting that ongoing renal recovery continues for a significant time after diagnosis. It may benefit disease-scoring systems to take into account SC levels beyond the initial assessment.

Population-level detection of early loss of kidney function: 7-year follow-up of a young adult cohort at risk of Mesoamerican nephropathy.

BACKGROUND: Mesoamerican nephropathy is a leading contributor to premature mortality in Central America. Efforts to identify the cause are hampered by difficulties in distinguishing associations with potential initiating factors from common exposures thought to exacerbate the progression of all forms of established chronic kidney disease (CKD). We explored evidence of disease onset or departure from the healthy estimated glomerular filtration rate distribution [departure from ∼eGFR(healthy)] in an at-risk population. METHODS: Two community-based cohorts (adults aged 18-30 years, n = 351 and 420) from 11 rural communities in Northwest Nicaragua were followed up over 7 and 3 years respectively. We examined associations with both (i) incident CKD and (ii) the time point of departure from ∼eGFR(healthy), using a hidden Markov model. RESULTS: CKD occurred in men only (male incidence rate: 0.7%/year). Fifty-three (out of 1878 visits, 2.7%) and 8 (out of 1067 visits, 0.8%) episodes of probable departure from ∼eGFR(healthy) occurred in men and women, respectively. Cumulative time in sugarcane work and symptoms of excess occupational sun exposure were associated with incident CKD. The same exposures were associated with probability of departure from ∼eGFR(healthy) in time-updated analyses along with measured and self-reported weight loss, nausea, vomiting and cramps, as well as non-steroidal anti-inflammatory drug use. CONCLUSIONS: CKD burden in this population is high and risk factors for established disease are occupational. Additionally, a syndrome suggesting an alternative exposure is associated with evidence of disease onset supporting a possible separate unknown initiating factor for which further investigation is needed. Interventions to reduce the impact of occupational risks should be pursued meanwhile.

"Epigenome-wide methylation profile of chronic kidney disease-derived arterial DNA uncovers novel pathways in disease-associated cardiovascular pathology."

Chronic kidney disease (CKD) related cardiovascular disease (CVD) is characterized by vascular remodelling with well-established structural and functional changes in the vascular wall such as arterial stiffness, matrix deposition, and calcification. These phenotypic changes resemble pathology seen in ageing, and are likely to be mediated by sustained alterations in gene expression, which may be caused by epigenetic changes such as tissue-specific DNA methylation. We aimed to investigate tissue specific changes in DNA methylation that occur in CKD-related CVD. Genome-wide DNA methylation changes were examined in bisulphite converted genomic DNA isolated from the vascular media of CKD and healthy arteries. Methylation-specific PCR was used to validate the array data, and the association between DNA methylation and gene and protein expression was examined. The DNA methylation age was compared to the chronological age in both cases and controls. Three hundred and nineteen differentially methylated regions (DMR) were identified spread across the genome. Pathway analysis revealed that DMRs associated with genes were involved in embryonic and vascular development, and signalling pathways such as TGFß and FGF. Expression of top differentially methylated gene HOXA5 showed a significant negative correlation with DNA methylation. Interestingly, DNA methylation age and chronological age were highly correlated, but there was no evidence of accelerated age-related DNA methylation in the arteries of CKD patients. In conclusion, we demonstrated that differential DNA methylation in the arterial tissue of CKD patients represents a potential mediator of arterial pathology and may be used to uncover novel pathways in the genesis of CKD-associated complications.

SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay.

The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive.

Novel Signs and Their Clinical Utility in Diagnosing Complex Regional Pain Syndrome (CRPS): A Prospective Observational Cohort Study.

OBJECTIVES: Delays in diagnosis occur with complex regional pain syndrome (CRPS). We define and prospectively demonstrate that novel bedside tests measuring body perception disruption can identify patients with CRPS postfracture. METHODS: The objectives of our study were to define and validate 4 bedside tests, to identify the prevalence of positive tests in patients with CRPS and other chronic pain conditions, and to assess the clinical utility (sensitivity, specificity, positive predictive value, negative predictive value) for identifying CRPS within a Fracture cohort. This was a single UK teaching hospital prospective cohort study with 313 recruits from pain-free volunteers and patients with chronic pain conditions.Four novel tests were Finger Perception (FP), Hand Laterality identification (HL), Astereognosis (AS), and Body Scheme (BS) report. Five questionnaires (Brief Pain Inventory, Upper Extremity Functional Index, Lower Extremity Functional Index, Neglect-like Symptom Questionnaire, Hospital Anxiety and Depression Score) assessed the multidimensional pain experience. RESULTS: FP and BS were the best performing tests. Prospective monitoring of fracture patients showed that out of 7 fracture patients (total n=47) who had both finger misperception and abnormal BS report at initial testing, 3 developed persistent pain with 1 having a formal diagnosis of CRPS. DISCUSSION: Novel signs are reliable, easy to perform, and present in chronic pain patients. FP and BS have significant clinical utility in predicting persistent pain in a fracture group thereby allowing targeted early intervention.