Cognitive decline related to chronic kidney disease as an exclusion factor from kidney transplantation: results from an international survey.

Background and hypothesis: There seems to be a lack of consensus on the necessity and the modality of psychological and specifically cognitive assessment of candidates for kidney transplantation. Both points are often delegated to individual hospitals/centres, whereas international guidelines are inconsistent. We think it is essential to investigate professionals' opinions to advance towards a consistent clinical practice. Methods: This paper presents the results of an international survey among clinical professionals, mainly nephrologists from the CONNECT (Cognitive decline in Nephro-Neurology: European Cooperative Target) network and beyond (i.e. from personal contacts of CONNECT members). The survey investigated their opinions about the question of whether cognitive decline in patients with chronic kidney disease may affect their eligibility for kidney transplantation. Results: Our results show that most clinicians working with patients affected by chronic kidney disease think that cognitive decline may challenge their eligibility for transplantation despite data that suggest that, in some patients, cognitive problems improve after kidney transplantation. Conclusion: We conclude that three needs emerge as particularly pressing: defining agreed-on standards for a multifaceted and multifactorial assessment (i.e. including both clinical/medical and psychosocial factors) of candidates with chronic kidney disease to kidney transplantation; further investigating empirically the causal connection between chronic kidney disease and cognition; and further investigating empirically the possible partial reversibility of cognitive decline after kidney transplantation.

Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data.

OBJECTIVE: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice. DESIGN: Cohort study emulating a comparative effectiveness trial (target trial). SETTING: Linked primary care, hospital, and death data in England, 2015-21. PARTICIPANTS: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin. MAIN OUTCOME MEASURES: Primary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures. RESULTS: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43). CONCLUSIONS: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints.

Identification of patients undergoing chronic kidney replacement therapy in primary and secondary care data: validation study based on OpenSAFELY and UK Renal Registry.

Objective: To validate primary and secondary care codes in electronic health records to identify people receiving chronic kidney replacement therapy based on gold standard registry data. Design: Validation study using data from OpenSAFELY and the UK Renal Registry, with the approval of NHS England. Setting: Primary and secondary care electronic health records from people registered at 45% of general practices in England on 1 January 2020, linked to data from the UK Renal Registry (UKRR) within the OpenSAFELY-TPP platform, part of the NHS England OpenSAFELY covid-19 service. Participants: 38 745 prevalent patients (recorded as receiving kidney replacement therapy on 1 January 2020 in UKRR data, or primary or secondary care data) and 10 730 incident patients (starting kidney replacement therapy during 2020), from a population of 19 million people alive and registered with a general practice in England on 1 January 2020. Main outcome measures: Sensitivity and positive predictive values of primary and secondary care code lists for identifying prevalent and incident kidney replacement therapy cohorts compared with the gold standard UKRR data on chronic kidney replacement therapy. Agreement across the data sources overall, and by treatment modality (transplantation or dialysis) and personal characteristics. Results: Primary and secondary care code lists were sensitive for identifying the UKRR prevalent cohort (91.2% (95% confidence interval (CI) 90.8% to 91.6%) and 92.0% (91.6% to 92.4%), respectively), but not the incident cohort (52.3% (50.3% to 54.3%) and 67.9% (66.1% to 69.7%)). Positive predictive values were low (77.7% (77.2% to 78.2%) for primary care data and 64.7% (64.1% to 65.3%) for secondary care data), particularly for chronic dialysis (53.7% (52.9% to 54.5%) for primary care data and 49.1% (48.0% to 50.2%) for secondary care data). Sensitivity decreased with age and index of multiple deprivation in primary care data, but the opposite was true in secondary care data. Agreement was lower in children, with 30% (295/980) featuring in all three datasets. Half (1165/2315) of the incident patients receiving dialysis in UKRR data had a kidney replacement therapy code in the primary care data within three months of the start date of the kidney replacement therapy. No codes existed whose exclusion would substantially improve the positive predictive value without a decrease in sensitivity. Conclusions: Codes used in primary and secondary care data failed to identify a small proportion of prevalent patients receiving kidney replacement therapy. Codes also identified many patients who were not recipients of chronic kidney replacement therapy in UKRR data, particularly dialysis codes. Linkage with UKRR kidney replacement therapy data facilitated more accurate identification of incident and prevalent kidney replacement therapy cohorts for research into this vulnerable population. Poor coding has implications for any patient care (including eligibility for vaccination, resourcing, and health policy responses in future pandemics) that relies on accurate reporting of kidney replacement therapy in primary and secondary care data.

Ambient heat exposure and kidney function in patients with chronic kidney disease: a post-hoc analysis of the DAPA-CKD trial.

BACKGROUND: Higher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis. METHODS: DAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73 m2. In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS: Climate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m2; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days' heat index of more than 30°C was associated with a -0·6% (95% CI -0·9% to -0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m2 located in a very hot versus a temperate environment. INTERPRETATION: Higher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression. FUNDING: None.

Associations of early childhood body mass index trajectories with body composition and cardiometabolic markers at age 10 years: the Ethiopian infant anthropometry and body composition (iABC) birth cohort study.

BACKGROUND: Variability in body mass index (BMI) (kg/m2) trajectories is associated with body composition and cardiometabolic markers in early childhood, but it is unknown how these associations track to later childhood. OBJECTIVES: We aimed to assess associations of BMI trajectories from 0 to 5 y with body composition and cardiometabolic markers at 10 y. METHODS: In the Ethiopian infant anthropometry and body composition (iABC) birth cohort, we previously identified 4 distinct BMI trajectories from 0 to 5 y: stable low BMI (19.2%), normal BMI (48.8%), rapid growth to high BMI (17.9%), and slow growth to high BMI (14.1%). At 10 y, we obtained data from 320 children on anthropometry, body composition, abdominal subcutaneous and visceral fat, and cardiometabolic markers. Associations of BMI trajectories and 10-y outcomes were analyzed using multiple linear regression. RESULTS: Compared with children with the normal BMI trajectory, those with rapid growth to high BMI had 1.7 cm (95% CI: 0.1, 3.3) larger waist circumference and those with slow growth to high had 0.63 kg/m2 (95% CI: 0.09, 1.17) greater fat mass index and 0.19 cm (95% CI: 0.02, 0.37) greater abdominal subcutaneous fat, whereas those with stable low BMI had -0.28 kg/m2 (95% CI: -0.59, 0.03) lower fat-free mass at 10 y. Although the confidence bands were wide and included the null value, children with rapid growth to high BMI trajectory had 48.6% (95% CI: -1.4, 123.8) higher C-peptide concentration and those with slow growth to high BMI had 29.8% (95% CI: -0.8, 69.8) higher insulin and 30.3% (95% CI: -1.1, 71.6) higher homeostasis model assessment of insulin resistance, whereas those with rapid growth to high BMI had -0.23 mmol/L (95% CI: -0.47, 0.02) lower total cholesterol concentration. The trajectories were not associated with abdominal visceral fat, blood pressure, glucose, and other lipids at 10 y. CONCLUSIONS: Children with rapid and slow growth to high BMI trajectories before 5 y tend to show higher measures of adiposity and higher concentrations of markers related to glucose metabolism at 10 y. CLINICAL TRIAL REGISTRY: ISRCTN46718296 (https://www.isrctn.com/ISRCTN46718296).

Ambient heat and acute kidney injury: case-crossover analysis of 1 354 675 automated e-alert episodes linked to high-resolution climate data.

BACKGROUND: As global temperatures continue to rise, the effects of ambient heat on acute kidney injury (AKI) are of growing concern. We used a novel nationwide electronic alert (e-alert) system to detect increases in AKI risk associated with high temperatures. METHODS: We used a case-crossover design to link 1 354 675 AKI episodes occurring in England between April and September in years 2017-2021 to daily maximum temperature data at postcode sector level. AKI episode data were obtained from the UK Renal Registry. There were no further inclusion or exclusion criteria. Conditional logistic regression employing distributed lag non-linear models was used to assess odds of AKI episode on case days compared with day-of-week matched control days. Effects during heatwaves were also assessed using heat-episode analysis. FINDINGS: There were strongly increased odds of AKI episode associated with high temperatures, with odds ratio (OR) 1·623 (95% CI 1·319-1·997) on a day of temperature 32°C compared with one of 17°C, the effects being strongest on a lag of 1 day. There was an OR of 1·020 (1·019-1·020) per 1°C increase in temperature above 17°C. The odds of a heat-related AKI episode were similar between AKI stages 1 and 2, but considerably lower for stage 3 events. A 7-day heatwave in July 2021 was associated with a 28·6% increase in AKI counts (95% CI 26·5-30·7). INTERPRETATION: Heat-related AKI is a growing public health challenge. As even small changes in renal function can affect patient outcomes, susceptible individuals should be advised to take preventive measures whenever hot weather is forecast. Use of an e-alert system allows effects in milder cases that do not require secondary care to also be detected. FUNDING: National Institute for Health and Care Research (NIHR).

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

BACKGROUND: 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 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 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 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). 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.

A comparison of the epidemiology of kidney replacement therapy between Europe and the United States: 2021 data of the ERA Registry and the USRDS.

BACKGROUND AND HYPOTHESIS: This paper compares the most recent data on the incidence and prevalence of kidney replacement therapy (KRT), kidney transplantation rates, and mortality on KRT from Europe to those from the United States (US), including comparisons of treatment modalities (haemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KTx)). METHODS: Data were derived from the annual reports of the European Renal Association (ERA) Registry and the United States Renal Data System (USRDS). The European data include information from national and regional renal registries providing the ERA Registry with individual patient data. Additional analyses were performed to present results for all participating European countries together. RESULTS: In 2021, the KRT incidence in the US (409.7 per million population (pmp)) was almost 3-fold higher than in Europe (144.4 pmp). Despite the substantial difference in KRT incidence, approximately the same proportion of patients initiated HD (Europe: 82%, US: 84%), PD (14%; 13% respectively), or underwent pre-emptive KTx (4%; 3% respectively). The KRT prevalence in the US (2436.1 pmp) was 2-fold higher than in Europe (1187.8 pmp). Within Europe, approximately half of all prevalent patients were living with a functioning graft (47%), while in the US, this was one third (32%). The number of kidney transplantations performed was almost twice as high in the US (77.0 pmp) compared to Europe (41.6 pmp). The mortality of patients receiving KRT was 1.6-fold higher in the US (157.3 per 1000 patient years) compared to Europe (98.7 per 1000 patient years). CONCLUSIONS: The US had a much higher KRT incidence, prevalence, and mortality compared to Europe, and despite a higher kidney transplantation rate, a lower proportion of prevalent patients with a functioning graft.

Vaccination for Patients Receiving Dialysis.

Vaccinating patients receiving dialysis may prevent morbidity and mortality in this vulnerable population. The National Forum of End-Stage Renal Disease Networks (the Forum) published a revised vaccination toolkit in 2021 to update evidence and recommendations on vaccination for patients receiving dialysis. Significant changes in the last 10 years include more data supporting the use of a high-dose influenza vaccine, the introduction of the Heplisav-B vaccine for hepatitis B, and changes in pneumococcal vaccines, including the approval of the PCV15 and PCV20 to replace the PCV13 and PPSV23 vaccines. Additional key items include the introduction of vaccines against severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19), and a new vaccine to prevent respiratory syncytial virus disease. Historically, influenza and pneumococcal vaccinations were routinely administered by dialysis facilities, and because of possible risks of hematogenous spread of hepatitis B, dialysis providers often have detailed hepatitis B vaccine protocols. In March 2021, COVID-19 vaccines were made available for dialysis facilities to administer, although with the end of the public health emergency, vaccine policies by dialysis facilities against COVID-19 remains uncertain. The respiratory syncytial virus vaccine was authorized in 2023, and how dialysis facilities will approach this vaccine also remains uncertain. This review summarizes the Forum's vaccination toolkit and discusses the role of the dialysis facility in vaccinating patients to reduce the risk of severe infections.

Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe: findings from the ERA Registry.

BACKGROUND AND HYPOTHESIS: Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death. METHODS: We used data from the European Renal Association (ERA) Registry on 69 854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence, and survival. RESULTS: The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidence of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium, and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had five-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death (adjusted hazard ratio: 1.8 [95% confidence interval: 1.6-1.9]) compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%). CONCLUSION: The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest and increasing for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach.

Mendelian randomization studies on coronary artery disease: a systematic review and meta-analysis.

BACKGROUND: Coronary artery disease (CAD) remains one of the leading causes of mortality worldwide. We aimed to summarize what is currently known with regard to causal modifiable risk factors associated with CAD in populations of diverse ancestries through conducting a systematic review and meta-analysis of Mendelian randomization (MR) studies on CAD. METHODS: The databases Embase, Medline, Cochrane Library and Web of Science were searched on the 19th and 20th of December 2022 for MR studies with CAD as a primary outcome; keywords of the search strategy included "coronary artery disease" and "mendelian randomization". Studies were included if they were published in the English language, included only human participants, employed Mendelian randomization as the primary methodology and studied CAD as the outcome of interest. The exclusion criteria resulted in the removal of studies that did not align with the predefined inclusion criteria, as well as studies which were systematic reviews themselves, and used the same exposure and outcome source as another study. An ancestry-specific meta-analysis was subsequently conducted on studies which investigated either body mass index, lipid traits, blood pressure or type 2 diabetes as an exposure variable. Assessment of publication bias and sensitivity analyses was conducted for risk of bias assessment in the included studies. RESULTS: A total of 1781 studies were identified through the database searches after de-duplication was performed, with 47 studies included in the quantitative synthesis after eligibility screening. Approximately 80% of all included study participants for MR studies on CAD were of European descent irrespective of the exposure of interest, while no study included individuals of African ancestry. We found no evidence of differences in terms of direction of causation between ancestry groups; however, the strength of the respective relationships between each exposure and CAD were different, with this finding most evident when blood pressure was the exposure of interest. CONCLUSIONS: Findings from this review suggest that patterns regarding the causational relationship between modifiable risk factors and CAD do not differ in terms of direction when compared across diverse ancestry populations. Differences in the observed strengths of the respective relationships however are indicative of the value of increasing representation in non-European populations, as novel genetic pathways or functional SNPs relating to CAD may be uncovered through a more global analysis. SYSTEMATIC REVIEW REGISTRATION: The protocol for this systematic review was registered to the International Prospective Register of Systematic Reviews (PROSPERO) and is publicly available online (CRD42021272726).

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.

Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients.

There is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood-brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects.

Advances in the management of chronic kidney disease.

Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure.

Kidney Function Measures and Mortality: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Individuals with a low estimated glomerular filtration rate (eGFR) are at a high risk of death. However, the causes underpinning this association are largely uncertain. This study aimed to assess the causal relationship of low eGFR with all-cause and cause-specific mortality. STUDY DESIGN: Retrospective cohort study incorporating Mendelian randomization (MR). SETTING & PARTICIPANTS: Individual-level data from 436,214 White participants (54.3% female; aged 56.8±8.0 years) included in the UK Biobank. EXPOSURES: eGFR estimated using cystatin C (eGFRcyst). OUTCOMES: The outcomes of interest included all-cause mortality, cardiovascular mortality, cancer mortality, infection mortality, and other-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards analysis for the conventional observational analyses; linear and nonlinear MR analyses implemented using genetic allele scores as instrumental variables representing kidney function to estimate the effect of kidney function on the survival outcomes. RESULTS: During a median follow-up of 12.1 years, there were 30,489 deaths, 6,098 of which were attributed to cardiovascular events, 15,538 to cancer, 1,516 to infection, and 7,227 to other events. In the conventional observational analysis, eGFRcyst exhibited a nonlinear association with all the outcomes. MR analysis suggested that a genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (HR, 1.43; 95% CI, 1.18-1.75) across the entire measurement range (every 10-mL/min/1.73m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR, 1.07; 95% CI, 0.98-1.17) or any types of noncardiovascular mortality were detected. LIMITATIONS: Potential misclassification of the actual cause of death, a nonrepresentative sample, and potential error in the interpretation of the magnitude of associations generated in MR analyses. CONCLUSIONS: These findings suggest a potential causal association between low eGFR and cardiovascular mortality in the general population, but no causal relationship with all-cause mortality or noncardiovascular mortality was observed. Further studies in other populations are warranted to confirm these findings. PLAIN-LANGUAGE SUMMARY: This study investigated the existence of a causal relationship between lower kidney function and death of different causes. Using data from 436,214 people in the United Kingdom, we applied conventional statistical analyses and those incorporating genetic data to implement Mendelian randomization, an approach that estimates causal associations. The observational analysis showed a nonlinear association between kidney function and various types of mortality outcomes. However, Mendelian randomization analysis suggested a linear increase in the risk of cardiovascular mortality with lower kidney function, but no causal link between the level of kidney function and all-cause or noncardiovascular mortality was identified. Managing kidney health may help reduce cardiovascular mortality, but caution is needed in interpreting the magnitudes of these results. Further validation in other populations and in those with advanced kidney failure is needed.

Genome-wide association studies on coronary artery disease: A systematic review and implications for populations of different ancestries.

BACKGROUND: Cardiovascular diseases are some of the leading causes of death worldwide, with coronary artery disease leading as one of the primary causes of mortality in both the developing and developed worlds. Despite its prevalence, there is a disproportionately small number of studies conducted in populations of non-European ancestry, with the limited sample sizes of such studies further restricting the power and generalizability of respective findings. This research aimed at understanding the differences in the genetic architecture of coronary artery disease (CAD) in populations of diverse ancestries in order to contribute towards the understanding of the pathophysiology of coronary artery disease. METHODS: We performed a systematic review on the 6th of October, 2022 summarizing genome-wide association studies on coronary artery disease, while employing the GWAS Catalog as an independent database to support the search. We developed a framework to assess the methodological quality of each study. We extracted and grouped associated single nucleotide polymorphisms and genes according to ancestry groups of participants. RESULTS: We identified 3100 studies, of which, 36 relevant studies were included in this research. Three of the studies that were included were not listed in the GWAS Catalog, highlighting the value of conducting an independent search alongside established databases in order to ensure the full research landscape has been captured. 743,919 CAD case participants from 25 different countries were analysed, with 61% of the studies identified in this research conducted in populations of European ancestry. No studies investigated populations of Africans living in continental Africa or admixed American ancestry groups besides African-Americans, while limited sample sizes were included of population groups besides Europeans and East Asians. This observed disproportionate population representation highlights the gaps in the literature, which limits our ability to understand coronary artery disease as a global disease. 71 genetic loci were identified to be associated with coronary artery disease in more than one article, with ancestry-specific genetic loci identified in each respective population group which were not detected in studies of other ancestries. CONCLUSIONS: Although the replication and validation of these variants are still warranted, these finding are indicative of the value of including diverse ancestry populations in GWAS reference panels, as a more comprehensive understanding of the genetic architecture and pathophysiology of CAD can be achieved.

Comparative effectiveness of sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in patients on kidney replacement therapy: observational study using the OpenSAFELY-UKRR and SRR databases.

Background: Due to limited inclusion of patients on kidney replacement therapy (KRT) in clinical trials, the effectiveness of coronavirus disease 2019 (COVID-19) therapies in this population remains unclear. We sought to address this by comparing the effectiveness of sotrovimab against molnupiravir, two commonly used treatments for non-hospitalised KRT patients with COVID-19 in the UK. Methods: With the approval of National Health Service England, we used routine clinical data from 24 million patients in England within the OpenSAFELY-TPP platform linked to the UK Renal Registry (UKRR) to identify patients on KRT. A Cox proportional hazards model was used to estimate hazard ratios (HRs) of sotrovimab versus molnupiravir with regards to COVID-19-related hospitalisations or deaths in the subsequent 28 days. We also conducted a complementary analysis using data from the Scottish Renal Registry (SRR). Results: Among the 2367 kidney patients treated with sotrovimab (n = 1852) or molnupiravir (n = 515) between 16 December 2021 and 1 August 2022 in England, 38 cases (1.6%) of COVID-19-related hospitalisations/deaths were observed. Sotrovimab was associated with substantially lower outcome risk than molnupiravir {adjusted HR 0.35 [95% confidence interval (CI) 0.17-0.71]; P = .004}, with results remaining robust in multiple sensitivity analyses. In the SRR cohort, sotrovimab showed a trend toward lower outcome risk than molnupiravir [HR 0.39 (95% CI 0.13-1.21); P = .106]. In both datasets, sotrovimab had no evidence of an association with other hospitalisation/death compared with molnupiravir (HRs ranged from 0.73 to 1.29; P > .05). Conclusions: In routine care of non-hospitalised patients with COVID-19 on KRT, sotrovimab was associated with a lower risk of severe COVID-19 outcomes compared with molnupiravir during Omicron waves.