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Background and Hypothesis: Young adults starting kidney replacement therapy (KRT) during childhood and reaching their 18th birthday (i.e. adult survivors of childhood KRT) form a challenging population of interest to nephrologists treating adults, as during this period there will be a transition to adult renal centres. Nonetheless, few studies have focused on the epidemiology of KRT in this group. We aimed to provide an update on these patients' characteristics, treatment history, graft and patient survival, to report their 5-year prognosis, and expected remaining lifetime., Methods: Data on KRT patients reaching their 18th birthday in 2008-2019 were collected from 21 European countries/regions providing individual patient data to the European Renal Association (ERA) Registry. Patient characteristics and treatment trajectories were examined before and after turning 18 years. Kaplan-Meier and Cox proportional hazards regression were used for patient and graft survival analyses., Results: In total, 2944 patients were included. The proportion of adult survivors initiating KRT at a very young age (0-4 years), and undergoing pre-emptive kidney transplantation increased. Unadjusted 5-year patient survival was 96.9% (95% CI: 96.2-97.5). Dialysis patients had a higher risk of death than kidney transplant recipients (adjusted hazard ratio 5.44 (95% CI: 3.34-8.86)). Between ages 18 and 23 years, about 21% of the adult survivors lost their kidney transplant and 34% of the dialysis patients continued this treatment. Compared with the general population, life expectancy for eighteen-year-old kidney transplant and dialysis patients was 17 and 40 years shorter, respectively., Conclusion: Life expectancy of 18-year-old kidney transplant recipients was lower compared with the general population. Yet, having a functioning kidney graft at age 18 years resulted in better outcomes than being on dialysis. Nevertheless, between ages 18 and 23 years, about one-fifth of the kidney grafts failed and one-third of the patients remained on dialysis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

In the SARS-CoV-2 lineage, RNA elements essential for its viral life cycle, including genome replication and gene expression, have been identified. Still, the precise structures and functions of these RNA regions in coronaviruses remain poorly understood. This lack of knowledge points out the need for further research to better understand these crucial aspects of viral biology and, in time, prepare for future outbreaks. In this research, the in silico analysis of the cis RNA structures that act in the alpha-, beta-, gamma-, and deltacoronavirus genera has provided a detailed view of the presence and adaptation of the structures of these elements in coronaviruses. The results emphasize the importance of these cis elements in viral biology and their variability between different viral variants. Some coronavirus variants in some groups, depending on the cis element (stem-loop1 and -2; pseudoknot stem-loop1 and -2, and s2m), exhibited functional adaptation. Additionally, the conformation flexibility of the s2m element in the SARS variants was determined, suggesting a coevolution of this element in this viral group. The variability in secondary structures suggests genomic adaptations that may be related to replication processes, genetic regulation, as well as the specific pathogenicity of each variant. The results suggest that RNA structures in coronaviruses can adapt and evolve toward different viral variants, which has important implications for viral adaptation, pathogenicity, and future therapeutic strategies.

Introduction: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury., Methods: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls., Results: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse., Conclusions: Podocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

The incidence of antibiotics and transcriptional regulation of ARGs in isolated bacteria from wastewater needs to be explored. By HPLC, in samples of untreated wastewater, ampicillin (49.74 ± 5.70 µg/mL), chloramphenicol (0.60 ± 0.03 µg/mL), tylosin (72.95 ± 2.03 µg/mL), and oxytetracycline (0.22 ± 0.01 µg/mL) was determined. Through metagenomic analysis identified 58 bacterial species belonging to 9 phyla and at least 14 species have shown resistance to a variety of antibiotics. Twenty-two bacterial isolates were proved to be resistant to fifteen antibiotics of new generation and used in medical research to combat infectious diseases. Fourteen strains were shown to harbor plasmids in size ranges of 2-5 Kb, 6-10 Kb and plasmids with size greater than 10 Kb. By quantitative PCR it was possible to identify genes sul, qnr, cat1, aadA1, and sat-1 gene were shown to be present in gDNA samples from treated and untreated samples of wastewater and by relative expression analysis, differential expression of cat1, ermB, act, and tetA genes was demonstrated in strains that showed identity with Escherichia coli, Bacteroides fragilis, and Salmonella thyphi, and that were stressed with different concentrations of antibiotics. The presence of ARGs in untreated water samples, as well as in bacterial isolates, was indicative that in these habitats there are microorganisms that can resist β-lactams, aminoglycosides, tetracyclines, sulfonamides, and quinolones., (© 2023. The Author(s).)

Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Purohit, Piani, Ordoñez, de Lucas-Collantes, Bauer and Cara-Fuentes.)

Introduction: Minimal change disease (MCD) is considered a podocyte disorder triggered by unknown circulating factors. Here, we hypothesized that the endothelial cell (EC) is also involved in MCD., Methods: We studied 45 children with idiopathic nephrotic syndrome (44 had steroid sensitive nephrotic syndrome [SSNS], and 12 had biopsy-proven MCD), 21 adults with MCD, and 38 healthy controls (30 children, 8 adults). In circulation, we measured products of endothelial glycocalyx (EG) degradation (syndecan-1, heparan sulfate [HS] fragments), HS proteoglycan cleaving enzymes (matrix metalloprotease-2 [MMP-2], heparanase activity), and markers of endothelial activation (von Willebrand factor [vWF], thrombomodulin) by enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. In human kidney tissue, we assessed glomerular EC (GEnC) activation by immunofluorescence of caveolin-1 ( n = 11 MCD, n = 5 controls). In vitro , we cultured immortalized human GEnC with sera from control subjects and patients with MCD/SSNS sera in relapse ( n = 5 per group) and performed Western blotting of thrombomodulin of cell lysates as surrogate marker of endothelial activation., Results: In circulation, median concentrations of all endothelial markers were higher in patients with active disease compared with controls and remained high in some patients during remission. In the MCD glomerulus, caveolin-1 expression was higher, in an endothelial-specific pattern, compared with controls. In cultured human GEnC, sera from children with MCD/SSNS in relapse increased thrombomodulin expression compared with control sera., Conclusion: Our data show that alterations involving the systemic and glomerular endothelium are nearly universal in patients with MCD and SSNS, and that GEnC can be directly activated by circulating factors present in the MCD/SSNS sera during relapse., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

This corrects the article DOI: 10.1038/pr.2017.95.

Growth retardation is a major manifestation of chronic kidney disease (CKD) in pediatric patients. The involvement of the various pathogenic factors is difficult to evaluate in clinical studies. Here, we present an experimental model of adenine-induced CKD for the study of growth failure. Three groups (n = 10) of weaning female rats were studied: normal diet (control), 0.5% adenine diet (AD), and normal diet pair fed with AD (PF). After 21 days, serum urea nitrogen, creatinine, parathyroid hormone (PTH), weight and length gains, femur osseous front advance as an index of longitudinal growth rate, growth plate histomorphometry, chondrocyte proliferative activity, bone structure, aorta calcifications, and kidney histology were analyzed. Results are means ± SE. AD rats developed renal failure (serum urea nitrogen: 70 ± 6 mg/dl and creatinine: 0.6 ± 0.1 mg/dl) and secondary hyperparathyroidism (PTH: 480 ± 31 pg/ml). Growth retardation of AD rats was demonstrated by lower weight (AD rats: 63.3 ± 4.8 g, control rats: 112.6 ± 4.7 g, and PF rats: 60.0 ± 3.8 g) and length (AD rats: 7.2 ± 0.2 cm, control rats: 11.1 ± 0.3 cm, and PF rats: 8.1 ± 0.3 cm) gains as well as lower osseous front advances (AD rats: 141 ± 13 μm/day, control rats: 293 ± 16 μm/day, and PF rats: 251 ± 10 μm/day). The processes of chondrocyte maturation and proliferation were impaired in AD rats, as shown by lower growth plate terminal chondrocyte height (21.7 ± 2.3 vs. 26.2 ± 1.9 and 23.9 ± 1.3 μm in control and PF rats) and proliferative activity index (AD rats: 30 ± 2%, control rats: 38 ± 2%, and PF rats: 42 ± 3%). The bone primary spongiosa structure of AD rats was markedly disorganized. In conclusion, adenine-induced CKD in young rats is associated with growth retardation and disturbed endochondral ossification. This animal protocol may be a useful new experimental model to study growth in CKD., (Copyright © 2015 the American Physiological Society.)

Over the last decade the discovery of fibroblast growth factor 23 (FGF23) and the progressive and ongoing clarification of its role in phosphate and mineral metabolism have led to expansion of the diagnostic spectrum of primary hypophosphatemic syndromes. This article focuses on the impairment of growth in these syndromes. Growth retardation is a common, but not constant, feature and it presents with large variability. As a result of the very low prevalence of other forms of primary hypophosphatemic syndromes, the description of longitudinal growth and the pathogenesis of its impairment have been mostly studied in X-linked hypophosphatemia (XLH) patients and in Hyp mice, the animal model of this disease. In general, children with XLH have short stature with greater shortness of lower limbs than trunk. Treatment with phosphate supplements and 1α vitamin D derivatives heals active lesions of rickets, but does not normalize growth of XLH patients. Patients might benefit from recombinant human growth hormone (rhGH) therapy, which may accelerate the growth rate without increasing body disproportion or correcting hypophosphatemia. These clinical data as well as research findings obtained in Hyp mice suggest that the pathogenesis of defective growth in XLH and other hypophosphatemic syndromes is not entirely dependent on the mineralization disorder and point to other effects of hypophosphatemia itself or FGF23 on the metabolism of bone and growth plate.

Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped (n = 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg x kg(-1) x day(-1) during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (+/-SD) being 67.07 +/- 10.44 and 81.56 +/- 12.70 microm/day, respectively. GH treatment did not accelerate growth rate. The tibial growth plate of KD rats had marked morphological alterations: lower heights of growth cartilage (228.26 +/- 23.58 microm), hypertrophic zone (123.68 +/- 13.49 microm), and terminal chondrocytes (20.8 +/- 2.39 microm) than normokalemic CPF (264.21 +/- 21.77, 153.18 +/- 15.80, and 24.21 +/- 5.86 microm). GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.

Rapamycin is a potent immunosuppressant with antitumoral properties widely used in the field of renal transplantation. To test the hypothesis that the antiproliferative and antiangiogenic activity of rapamycin interferes with the normal structure and function of growth plate and impairs longitudinal growth, 4-week-old male rats (n = 10/group) receiving 2 mg/kg per day of intraperitoneal rapamycin (RAPA) or vehicle (C) for 14 days were compared. Rapamycin markedly decreased bone longitudinal growth rate (94 +/- 3 vs. 182 +/- 3 microm/day), body weight gain (60.2 +/- 1.4 vs. 113.6 +/- 1.9 g), food intake (227.8 +/- 2.6 vs. 287.5 +/- 3.4 g), and food efficiency (0.26 +/- 0.00 vs. 0.40 +/- 0.01 g/g). Signs of altered cartilage formation such as reduced chondrocyte proliferation (bromodeoxiuridine-labeled cells 32.9 +/- 1.4 vs. 45.2 +/- 1.1%), disturbed maturation and hypertrophy (height of terminal chondrocytes 26 +/- 0 vs. 29 +/- 0 microm), and decreased cartilage resorption (18.7 +/- 0.5 vs. 31.0 +/- 0.8 tartrate-resistant phosphatase alkaline reactive cells per 100 terminal chondrocytes), together with morphological evidence of altered vascular invasion, were seen in the growth plate of RAPA animals. This study indicates that rapamycin can severely impair body growth in fast-growing rats and distort growth-plate structure and dynamics. These undesirable effects must be kept in mind when rapamycin is administered to children.

The primary goal of this study was to determine if the ability to undergo catch-up growth following a transient injury is preserved in an experimental model of moderate chronic renal failure (CRF) and the effect of growth hormone (GH) administration on such phenomenon. Young rats were subtotally nephrectomized (days 0 and 4) (Nx). From days 11 to 13, food intake was restricted in subgroups of Nx and control (C) rats (NxR and CR). After refeeding, subgroups of NxR and CR rats received GH from days 14 to 20 (NxRGH and CRGH). Rats were killed on days 14 (C, CR, Nx, NxR), 17 and 21 (C, CR, CRGH, Nx, NxR, NxRGH), and 36 (C, CR, Nx, NxR). Longitudinal growth rate was measured by osseous front advance in the proximal tibiae. With refeeding, growth rate of CR, NxR, and NXrGH rats became significantly greater than that of C, indicating catch-up growth. This occurred later and with lower growth rate in NxR than in CR rats, whereas the characteristics of catch-up growth in CR and NxRGH animals were similar. Changes in growth rate were associated with modifications in the morphology and proliferative activity of growth cartilage. We conclude that catch-up growth occurs in renal insufficiency but follows a different pattern from that observed with normal renal function. GH treatment normalizes the pattern of catch-up growth in CRF. Changes in growth velocity are associated to modifications in the structure and dynamics of growth cartilage.