One lithium level >1.0 mmol/L causes an acute decline in eGFR: findings from a retrospective analysis of a monitoring database

Objectives Lithium is a mainstay of bipolar disorder treatment, however, there are still differences in opinion on the effects of lithium use on renal function. The aim of this analysis was to determine if there is an association between short-term exposure to various elevated lithium levels and estimated-glomerular filtration rate (eGFR) at ≤3 months, 6 months (±3 months) and 1 year (±3 months) follow-up. Setting Norfolk-wide (UK) lithium register and database. Participants 699 patients from the Norfolk database. Primary outcome measures eGFR change from baseline at ≤3 months, 6 months (±3 months) and 1 year (±3 months) after exposure to a lithium level within these ranges: 0.81–1.0 mmol/L (group 2), 1.01–1.2 mmol/L (group 3) and 1.21–2.0 mmol/L (group 4). The reference group was patients whose lithium levels never exceeded 0.8 mmol/L. Results Compared to the reference group, groups 3 and 4 showed a significant decrease in eGFR in the first 3 months after exposure (p=0.047 and p=0.040). At 6 months (±3 months) postexposure group 4 still showed a decline in eGFR, however, this result was not significant (p=0.298). Conclusions These results show for the first time that a single incident of a lithium level >1.0 mmol/L is associated with a significant decrease in eGFR in the following 3 months when compared to patients whose lithium levels never exceeded 0.8 mmol/L. It is still not known whether the kidneys can recover this lost function and the impact that more than a single exposure to a level within these ranges can have on renal function. These results suggest that lithium level monitoring should be undertaken at least every 3 months, in line with current UK guidelines and not be reduced further until the impact of more than one exposure to these lithium levels has been fully established

The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection

Background The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. Results Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. Conclusions These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions

Rapid selection of P323L in the SARS-CoV-2 polymerase (NSP12) in humans and non-human primate models and confers a large plaque phenotype

The mutational landscape of SARS-CoV-2 varies at both the dominant viral genome sequence and minor genomic variant population. An early change associated with transmissibility was the D614G substitution in the spike protein. This appeared to be accompanied by a P323L substitution in the viral polymerase (NSP12), but this latter change was not under strong selective pressure. Investigation of P323L/D614G changes in the human population showed rapid emergence during the containment phase and early surge phase of wave 1 in the UK. This rapid substitution was from minor genomic variants to become part of the dominant viral genome sequence. A rapid emergence of 323L but not 614G was observed in a non-human primate model of COVID-19 using a starting virus with P323 and D614 in the dominant genome sequence and 323L and 614G in the minor variant population. In cell culture, a recombinant virus with 323L in NSP12 had a larger plaque size than the same recombinant virus with P323. These data suggest that it may be possible to predict the emergence of a new variant based on tracking the distribution and frequency of minor variant genomes at a population level, rather than just focusing on providing information on the dominant viral genome sequence e.g., consensus level reporting. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions