Prevalence and Load of the Campylobacter Genus in Infants and Associated Household Contacts in Rural Eastern Ethiopia: a Longitudinal Study from the Campylobacter Genomics and Environmental Enteric Dysfunction (CAGED) Project

In our previous cross-sectional study, multiple species of Campylobacter were detected (88%) in stool samples from children (12 to 14 months of age) in rural eastern Ethiopia. This study assessed the temporal fecal carriage of Campylobacter in infants and identified putative reservoirs associated with these infections in infants from the same region. The prevalence and load of Campylobacter were determined using genus-specific real-time PCR. Stool samples from 106 infants (n = 1,073) were collected monthly from birth until 376 days of age (DOA). Human stool samples (mothers and siblings), livestock feces (cattle, chickens, goats, and sheep), and environmental samples (soil and drinking water) from the 106 households were collected twice per household (n = 1,644). Campylobacter was most prevalent in livestock feces (goats, 99%; sheep, 98%; cattle, 99%; chickens, 93%), followed by human stool samples (siblings, 91%; mothers, 83%; infants, 64%) and environmental samples (soil, 58%; drinking water, 43%). The prevalence of Campylobacter in infant stool samples significantly increased with age, from 30% at 27 DOA to 89% at 360 DOA (1% increase/day in the odds of being colonized) (P < 0.001). The Campylobacter load increased linearly (P < 0.001) with age from 2.95 logs at 25 DOA to 4.13 logs at 360 DOA. Within a household, the Campylobacter load in infant stool samples was positively correlated with the load in mother stool samples (r2 = 0.18) and soil collected inside the house (r2 = 0.36), which were in turn both correlated with Campylobacter loads in chicken and cattle feces (0.60 < r2 < 0.63) (P < 0.01). In conclusion, a high proportion of infants are infected with Campylobacter in eastern Ethiopia, and contact with the mother and contaminated soil may be associated with early infections. IMPORTANCE A high Campylobacter prevalence during early childhood has been associated with environmental enteric dysfunction (EED) and stunting, especially in low-resource settings. Our previous study demonstrated that Campylobacter was frequently found (88%) in children from eastern Ethiopia; however, little is known about potential Campylobacter reservoirs and transmission pathways leading to infection of infants by Campylobacter during early growth. In the longitudinal study presented here, Campylobacter was frequently detected in infants within the 106 surveyed households from eastern Ethiopia, and the prevalence was age dependent. Furthermore, preliminary analyses highlighted the potential role of the mother, soil, and livestock in the transmission of Campylobacter to the infant. Further work will explore the species and genetic composition of Campylobacter in infants and putative reservoirs using PCR and whole-genome and metagenomic sequencing. The findings from these studies can lead to the development of interventions to minimize the risk of transmission of Campylobacter to infants and, potentially, EED and stunting.fals

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Individuals with rare kidney diseases account for 5–10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. Methods: People aged 0–96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan–Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1\ub773 m2 or more to first eGFR of less than 30 mL/min per 1\ub773 m2 (the therapeutic trial window). Findings: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9\ub76 years (IQR 5\ub79–16\ub77). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2\ub781 million UK patients with all-cause chronic kidney disease (28% vs 1%; p&lt;0\ub70001), but better survival rates (standardised mortality ratio 0\ub742 [95% CI 0\ub732–0\ub752]; p&lt;0\ub70001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. Interpretation: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3–5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. Funding: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity

Characterization of the macrophage transcriptome in glomerulonephritis-susceptible and -resistant rat strains

Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. WKY rats show marked susceptibility to CRGN, while Lewis rats are resistant. Glomerular injury and crescent formation are macrophage-dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterised Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change, <1% False Discovery Rate) for basal and LPS-stimulated macrophages. Moreover, we identified 8 genes with differentially expressed alternatively spliced isoforms, by using an in depth analysis at probe-level that allowed us to discard false positives due to polymorphisms between the two rat strains. Pathway analysis identified several common linked pathways, enriched for differentially expressed genes, which affect macrophage activation. In summary, our results identify distinct macrophage transcriptome profiles between two rat strains that differ in susceptibility to glomerulonephritis, provide novel positional candidates for Crgn3-7, and define groups of genes that play a significant role in differential regulation of macrophage activity

Quantifying association of early proteinuria and estimated glomerular filtration rate changes with long-term kidney failure in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis using the United Kingdom RaDaR Registry

\ua9 2025 International Society of Nephrology. Introduction: C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare disorders that frequently result in kidney failure over the long-term. Presently, there are no disease-specific treatments approved for these disorders, although there is much interest in the therapeutic potential of complement inhibition. However, the limited duration and necessarily small size of controlled trials means there is a need to quantify how well short-term changes in estimated glomerular filtration rate (eGFR) and proteinuria predict the clinically important outcome of kidney failure. Methods: We address this using longitudinal data from the UK Registry of Rare Kidney Diseases (RaDaR) involving retrospective and prospective data collection with linkage to hospital laboratories via automated feeds of 371 patients. Analyses of kidney survival were conducted using Kaplan–Meier and Cox regression with eGFR slope estimated using linear mixed models. Results: In a median of 11.0 (inter quartile range 7.4-15.1) years follow-up, 148 patients (40%) reached kidney failure. There was no significant difference in progression to kidney failure between C3G and IC-MPGN groups. Baseline urine protein-creatinine ratio (UPCR), although high, was not associated with kidney failure in either group. Two-year eGFR slope had a modest association with kidney failure. In contrast, both 20%‒50% and 50 mg/mmol reductions in UPCR between 0-12 months were associated with lower kidney failure risk in both groups. Notably, those with a UPCR under 100 mg/mmol at 12 months had a substantially lower risk of kidney failure (hazard ratio 0.10 (95% confidence interval 0.03-0.30). Conclusions: Overall, proteinuria a short time after diagnosis is strongly associated with long-term outcomes and a UPCR under 100 mg/mmol at one year is associated with a substantially lower kidney failure risk

Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility

Crescentic glomerulonephritis is an important cause of human kidney failure for which the underlying molecular basis is largely unknown. In previous studies, we mapped several susceptibility loci, Crgn1-Crgn7, for crescentic glomerulonephritis in the Wistar Kyoto (WKY) rat. Here we show by combined congenic, linkage and microarray studies that the activator protein-1 (AP-1) transcription factor JunD is a major determinant of macrophage activity and is associated with glomerulonephritis susceptibility. Introgression of Crgn2 from the nonsusceptible Lewis strain onto the WKY background leads to significant reductions in crescent formation, macrophage infiltration, Fc receptor-mediated macrophage activation and cytokine production. Haplotype analysis restricted the Crgn2 linkage interval to a 430-kb interval containing Jund, which is markedly overexpressed in WKY macrophages and glomeruli. Jund knockdown in rat and human primary macrophages led to significantly reduced macrophage activity and cytokine secretion, indicating conservation of JunD function in macrophage activation in rats and humans and suggesting in vivo inhibition of Jund as a possible new therapeutic strategy for diseases characterized by inflammation and macrophage activation