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The mitochondrial DNA depletion syndromes: mitochondrial DNA polymerase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Enlarging experience with mutations in POLG1 suggests that there is a spectrum of clinical phenotypes with presentations from the neonatal period to late adulthood [23]. Severe encephalopathy and hepatic failure represent one extreme. At the other end, are patients with autosomal dominant progressive external ophthalmoplegia (adPEO, MIM 157640) and multiple mitochondrial DNA deletions. Others with multiple deletions have adult-onset cerebellar ataxia. Other dominant kindreds have Parkinson syndrome and premature ovarian failure. Patients with mutations in RRM1B had severe hypotonia, nephrocalcinosis and renal tubulopathy, hyporegenerative anemia, and congenital defects [18].
Novel psychoactive substances and inhalants
Published in Ilana B. Crome, Richard Williams, Roger Bloor, Xenofon Sgouros, Substance Misuse and Young People, 2019
Exposure to spray paints and glue sniffing has been associated with various renal disorders (Lauwerys et al., 1985; Meadows and Verghese, 1996) and case reports suggest that chronic renal diseases are common among children and adolescents who abuse inhalants (Lorenc, 2003; Olgar et al., 2008). Renal disorders include distal renal tubular acidosis, glomerulonephritis, tubulopathy, Goodpasture’s syndrome, and other nephritic changes (Nathan and Toseland, 1979; Lauwerys et al., 1985; Meadows and Verghese, 1996; Lorenc, 2003). Toluene is regarded as particularly nephrotoxic, but it may be more likely that renal abnormalities occur due to a combination of intoxicants in the toluene products. There are also reports that chloroform (Lock, 1989), methylene chloride (Miller, 1985), and trichloroethylene (Kimbrough et al., 1985) may also contribute to renal damage.
Rodent Autosomal Dominant Polycystic Kidney Disease Models
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sara J. Holditch, Raphael A. Nemenoff, Katharina Hopp
Another transgenic PKD2 model, expressing human PKD2 cloned from a BAC, PKD2-Y,147 also presented with renal abnormalities albeit much milder than reported in the Tg(CAG-PKD2)#Hwl model. PKD2-Y mice aged to greater than 12 mo develop tubulopathy with microscopic cysts and proteinuria, and exhibit a disorganized renal cortex. Interestingly, genomic analysis of PKD2-Y revealed polyploidy, mitotic instability, and centrosome overduplication, suggesting PC2 plays a role in centrosome duplication and/or the M-phase of cellular division.148
Safety of current antiviral drugs for chronic hepatitis B
Published in Expert Opinion on Drug Safety, 2022
Chiara Masetti, Nicola Pugliese, Alessio Aghemo, Mauro Viganò
Several studies have analyzed markers of early tubular damage during antiviral treatment. In a French study by Brayette et al. [32], markers of subclinical proximal tubulopathy (SPT) were collected in 196 patients, divided into three groups; naïve, ETV, or TDF-treated. After 24 months, the prevalence of SPT was not significantly different in the three groups, even if incidence of SPT tends to be higher in the TDF group compared to the naïve group (p = 0.05). Tien et al. followed a cohort of 146 naïve or NUC-treated consecutive patients for a median period of 29 months. Proximal tubular handling of phosphate (defined as tubular maximum reabsorption of phosphate/glomerular filtration rate, TmPO4/GFR) was similar in patients treated with TDF compared to naïve patients or those treated with ETV: however, after 18 months of treatment, TDF patients showed an increased risk of proximal tubular dysfunction compared to patients treated with ETV (48.5% vs. 12.5%, respectively) [33]. Similarly, in the MENTE study, which compared 280 subjects either naïve or treated with NUCs, patients treated with TDF showed a significantly higher rate of tubular damage compared to the ETV group, defined as RBP/creatinine excretion (25% vs. 7%, p < 0.001) [34].
Electron microscopic findings can support multiple etiologies of nephrotoxicity in renal tubules
Published in Ultrastructural Pathology, 2020
Ping L. Zhang, Timothy Pancioli, Wei Li, Hassan D. Kanaan
The use of EM in identifying the renal tubular injury is somewhat limited. Classic use of EM for tubular injury includes identifying immune complex deposits along the tubular basement membranes in extensive lupus nephritis, which provides us with a supportive evidence of lupus nephritis.3 Tubular cilia metaplasia as a reactive change in proximal tubules following acute tubular injury reported by others and us may be another example of supportive evidence.17 By contrast, the powdering type of deposits in monoclonal light deposition disease can be considered diagnostic evidence for the entity, since this finding is characteristic enough to serve as independent/unique feature of such disease identity. Similarly, the identification of cytoplasmic crystals in monoclonal proximal tubulopathy may be considered as diagnostic evidence as well.18,19 Renal tubules appear to be a main target for drug-induced nephrotoxicity, either acute tubular injury (so-called acute tubular necrosis) or acute interstitial nephritis. Some drugs may lead to some EM findings while others may cause either of the tubular injury without a trace of ultrastructural identity. The goal of this current series case reports was to illustrate variants of drug-induced tubular injury identifiable by EM to highlight potential clues for reaching correct diagnosis in daily renal pathology practice. The nephrotoxic medications presented here include variants of aminoglycodes, vancomycin, and Vedolizumab20–23 and their ultrastructural findings causing renal injury are illustrated in details.
An evaluation of elvitegravir plus cobicistat plus tenofovir alafenamide plus emtricitabine as a single-tablet regimen for the treatment of HIV in children and adolescents
Published in Expert Opinion on Pharmacotherapy, 2019
Vania Giacomet, Maria V. Cossu, Amedeo F. Capetti, GianVincenzo Zuccotti, Giuliano Rizzardini
Kidneys: Tenofovir tends to accumulate in the renal proximal tubular cells, causing various degrees or nephrotoxicity; TAF reaches inferior concentrations than TDF in the kidneys and causes less damage; however, its long-term effects still need to be described [20]. E/C/F/TAF has mainly been studied against TDF-containing regimens in this regard [12,13], showing an advantage in terms of eGFR (-6.4 vs -11.2 mL/min in naïve and +1.2 vs -3.7 in treatment-experienced adults) and less proteinuria. Likewise, in naïve adolescents starting E/C/F/TAF median serum creatinine levels increased by 6.2 µmol/L by week 48 [13]. When studied against efavirez-emtricitabine-tenofovir alafenamide in treatment-experienced adults over 48 weeks, however, serum creatinine increased more in the E/C/F/TAF arm (+9.2 vs +1.77 µmol/L), probably due to the inhibition by cobicistat on creatinine tubular secretion [2]. In treatment-naïve adolescents, proximal renal tubulopathy was not reported over 48 weeks’ treatment [14]. In treatment-experienced adults with stable renal impairment, switching to E/C/F/TAF was not associated with non-significant variations from baseline in eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using serum creatinine or cystatin C in a 48-week follow-up (-1.8 and 1.6 mL/min, respectively) [18], stabilizing thereafter. A post hoc analysis in patients with baseline eGFR by the Cockroft-Gault equation below 50 mL/min (n = 80) at week 48 reported similar findings [18].