Drug stewardship in chronic kidney disease to achieve effective and safe medication use.

People living with chronic kidney disease (CKD) often experience multimorbidity and require polypharmacy. Kidney dysfunction can also alter the pharmacokinetics and pharmacodynamics of medications, which can modify their risks and benefits; the extent of these changes is not well understood for all situations or medications. The principle of drug stewardship is aimed at maximizing medication safety and effectiveness in a population of patients through a variety of processes including medication reconciliation, medication selection, dose adjustment, monitoring for effectiveness and safety, and discontinuation (deprescribing) when no longer necessary. This Review is aimed at serving as a resource for achieving optimal drug stewardship for patients with CKD. We describe special considerations for medication use during pregnancy and lactation, during acute illness and in patients with cancer, as well as guidance for the responsible use of over-the-counter drugs, herbal remedies, supplements and sick-day rules. We also highlight inequities in medication access worldwide and suggest policies to improve access to quality and essential medications for all persons with CKD. Further strategies to promote drug stewardship include patient education and engagement, the use of digital health tools, shared decision-making and collaboration within interdisciplinary teams. Throughout, we position the person with CKD at the centre of all drug stewardship efforts.

Absolute and Relative Risks of Kidney and Urological Complications in Patients With Inflammatory Bowel Disease.

INTRODUCTION: The burden of kidney and urological complications in patients with inflammatory bowel disease (IBD) remains poorly characterized. METHODS: We analyzed association between developing IBD (as a time-varying exposure) and relative risks of receiving diagnoses of chronic kidney disease (CKD), acute kidney injury (AKI), or kidney stones, and experiencing a clinically-relevant decline in estimated glomerular filtration rate (eGFR) (CKD progression; composite of kidney failure or an eGFR decline ≥30%) in 1,682,795 individuals seeking healthcare in Stockholm, Sweden, during 2006-2018. We quantified 5- and 10-year absolute risks of these complications in a parallel matched cohort of IBD cases and random controls matched (1:5) on sex, age, and eGFR. RESULTS: During median 9 years, 10,117 participants developed IBD. Incident IBD was associated with higher risks of kidney-related complications compared with non-IBD periods: hazard ratio (HR) (95% confidence interval) was 1.24 (1.10-1.40) for receiving a CKD diagnosis and 1.11 (1.00-1.24) for CKD progression. For absolute risks, 11.8% IBD cases had a CKD event within 10-year. Of these, 6.4% received a CKD diagnosis, and 7.9% reached CKD progression. The risks of AKI (HR 1.97 [1.70-2.29]; 10-year absolute risk 3.6%) and kidney stones (HR 1.69 [1.48-1.93]; 10-year absolute risk 5.6%) were also elevated. Risks were similar in Crohn's disease and ulcerative colitis. DISCUSSION: More than 10% of patients with IBD developed CKD within 10-year from diagnosis, with many not being identified through diagnostic codes. This, together with their elevated AKI and kidney stone risks, highlights the need of established protocols for kidney function monitoring and referral to nephrological/urological care for patients with IBD.

Sevelamer Use and Mortality in People with Chronic Kidney Disease Stages 4 and 5 Not on Dialysis.

Rationale and objective: Data suggest that non-calcium-based binders, and specifically sevelamer, may lead to lower rates of death when compared with calcium-based binders in end-stage renal disease (ESRD) patients. However, the association between sevelamer use and mortality for those with non-dialysis-dependent chronic kidney disease (NDD-CKD) patients has been uncertain. Study design: Our research is presented in a prospective cohort study. Setting and participants: A total of 966 participants with NDD-CKD stages 4-5 were enrolled in the PECERA study from 12 centers in Spain. Exposure: The participants were treated with sevelamer. Outcome: This study yielded all-cause and cardiovascular mortality outcomes. Analytical approach: We conducted an association analysis between mortality and sevelamer use with time-dependent Cox proportional hazards models. Results: After a median follow-up of 29 months (IQR: 13-36 months), death occurred in 181 participants (19%), with cardiovascular (n = 95, 53%) being the leading cause of death. In a multivariable model, the adjusted hazard ratios (HRs) for patients under sevelamer treatment were 0.44 (95% CI, 0.22 to 0.88) and 0.37 (95% CI, 0.18 to 0.75) for all-cause and cardiovascular mortality, respectively, compared with those of untreated patients. Limitations: Some limitations include potential confusion via indication bias; causal statements about these associations cannot be made due to the observational nature of this study. Conclusions: In this prospective NDD-CKD cohort study, the administration of sevelamer was independently associated with lower all-cause and cardiovascular mortality, suggesting that non-calcium-based phosphate binders might be the first-line therapy for phosphate lowering in this population. Further interventional studies clarifying the risks and benefits of phosphate binders in NDD-CKD are warranted.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

The Kidney Failure Risk Equation: Evaluation of Novel Input Variables including eGFR Estimated Using the CKD-EPI 2021 Equation in 59 Cohorts.

SIGNIFICANCE STATEMENT: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict 2- and 5-year risk of kidney failure in populations with eGFR <60 ml/min per 1.73 m 2 . However, the CKD-EPI 2021 creatinine equation for eGFR is now recommended for use but has not been fully tested in the context of KFRE. In 59 cohorts comprising 312,424 patients with CKD, the authors assessed the predictive performance and calibration associated with the use of the CKD-EPI 2021 equation and whether additional variables and accounting for the competing risk of death improves the KFRE's performance. The KFRE generally performed well using the CKD-EPI 2021 eGFR in populations with eGFR <45 ml/min per 1.73 m 2 and was not improved by adding the 2-year prior eGFR slope and cardiovascular comorbidities. BACKGROUND: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict kidney failure risk in people with GFR <60 ml/min per 1.73 m 2 . METHODS: Using 59 cohorts with 312,424 patients with CKD, we tested several modifications to the KFRE for their potential to improve the KFRE: using the CKD-EPI 2021 creatinine equation for eGFR, substituting 1-year average ACR for single-measure ACR and 1-year average eGFR in participants with high eGFR variability, and adding 2-year prior eGFR slope and cardiovascular comorbidities. We also assessed calibration of the KFRE in subgroups of eGFR and age before and after accounting for the competing risk of death. RESULTS: The KFRE remained accurate and well calibrated overall using the CKD-EPI 2021 eGFR equation. The other modifications did not improve KFRE performance. In subgroups of eGFR 45-59 ml/min per 1.73 m 2 and in older adults using the 5-year time horizon, the KFRE demonstrated systematic underprediction and overprediction, respectively. We developed and tested a new model with a spline term in eGFR and incorporating the competing risk of mortality, resulting in more accurate calibration in those specific subgroups but not overall. CONCLUSIONS: The original KFRE is generally accurate for eGFR <45 ml/min per 1.73 m 2 when using the CKD-EPI 2021 equation. Incorporating competing risk methodology and splines for eGFR may improve calibration in low-risk settings with longer time horizons. Including historical averages, eGFR slopes, or a competing risk design did not meaningfully alter KFRE performance in most circumstances.

Intradialytic parenteral nutrition for patients on hemodialysis: when, how and to whom?

Hemodialysis is associated with high morbidity and mortality rates as well as low quality of life. Altered nutritional status and protein-energy wasting are important indicators of these risks. Maintaining optimal nutritional status in patients with hemodialysis is a critical but sometimes overlooked aspect of care. Nutritional support strategies usually begin with dietary counseling and oral nutritional supplements. Patients may not comply with this advice or oral nutritional supplements, however , or compliance may be affected by other complications of progressive chronic kidney disease. Intradialytic parenteral nutrition (IDPN) may be a possibility in these cases, but lack of knowledge on practical aspects of IDPN delivery are seldom discussed and may represent a barrier. In this review, we, as a consensus panel of clinicians experienced with IDPN, survey existing literature and summarize our views on when to use IDPN, which patients may be best suited for IDPN, and how to effectively deliver and monitor this strategy for nutritional support.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Estimated Glomerular Filtration Rate and the Risk of Inflammatory Bowel Disease in Adults: A Swedish Population-Based Study.

BACKGROUND: Kidney complications are common in patients with long-standing inflammatory bowel disease (IBD). Whether kidney complications, defined as low estimated glomerular filtration rate (eGFR), may predispose to later IBD is unknown. METHODS: We analyzed the association between eGFR and the risk of being subsequently diagnosed with IBD among 1 612 160 adults from Stockholm. The exposure was categories of eGFR, with 90 to 104 mL/min/1.73 m2 as the reference. Cox regression models were used to investigate the association between eGFR, IBD, and IBD subtypes. Subgroup analyses included age strata, sex, education, and comorbidities. To explore the possibility of detection bias or reverse causation, we estimated IBD hazard ratios (HRs) after excluding cases and individuals censored during early years of follow-up. RESULTS: During a median of 9 years of follow-up, we detected 9663 cases of IBD (3299 Crohn's disease, 5072 ulcerative colitis, 1292 IBD unclassified). Lower eGFR levels were associated with higher IBD risk (for eGFR 30-59 mL/min/1.73 m2: adjusted HR, 1.15; 95% confidence interval [CI], 1.01-1.33; and for eGFR <30 mL/min/1.73 m2: adjusted HR, 1.65; 95% CI, 1.16-2.37). This association was stronger in magnitude for Crohn's disease (for eGFR 30-59 mL/min/1.73 m2: HR, 1.33, 95% CI, 1.04-1.72; and for eGFR <30 mL/min/1.73 m2: HR, 2.25; 95% CI, 1.26-3.99). Results were consistent across strata of age, comorbidities, and attained education but suggested the association between eGFR and IBD to be stronger in women (P for interaction <.05). Results attenuated but were robust to exclusion of early IBD cases. CONCLUSIONS: We observed an association between reduced eGFR and the risk of developing IBD, which was stronger in magnitude for Crohn's disease.

Removing race from the CKD-EPI equation and its impact on prognosis in a predominantly White European population.

BACKGROUND: While American nephrology societies recommend using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation without a Black race coefficient, it is unknown how this would impact disease distribution, prognosis and kidney failure risk prediction in predominantly White non-US populations. METHODS: We studied 1.6 million Stockholm adults with serum/plasma creatinine measurements between 2007 and 2019. We calculated changes in eGFR and reclassification across KDIGO GFR categories when changing from the 2009 to 2021 CKD-EPI equation; estimated associations between eGFR and the clinical outcomes kidney failure with replacement therapy (KFRT), (cardiovascular) mortality and major adverse cardiovascular events using Cox regression; and investigated prognostic accuracy (discrimination and calibration) of both equations within the Kidney Failure Risk Equation. RESULTS: Compared with the 2009 equation, the 2021 equation yielded a higher eGFR by a median [interquartile range (IQR)] of 3.9 (2.9-4.8) mL/min/1.73 m2, which was larger at older age and for men. Consequently, 9.9% of the total population and 36.2% of the population with CKD G3a-G5 was reclassified to a higher eGFR category. Reclassified individuals exhibited a lower risk of KFRT, but higher risks of all-cause/cardiovascular death and major adverse cardiovascular events, compared with non-reclassified participants of similar eGFR. eGFR by both equations strongly predicted study outcomes, with equal discrimination and calibration for the Kidney Failure Risk Equation. CONCLUSIONS: Implementing the 2021 CKD-EPI equation in predominantly White European populations would raise eGFR by a modest amount (larger at older age and in men) and shift a major proportion of CKD patients to a higher eGFR category. eGFR by both equations strongly predicted outcomes.

Sex Differences in the Recognition, Monitoring, and Management of CKD in Health Care: An Observational Cohort Study.

INTRODUCTION: Reported sex differences in the etiology, population prevalence, progression rates, and health outcomes of people with CKD may be explained by differences in health care. METHODS: We evaluated sex as the variable of interest in a health care-based study of adults (n=227,847) with at least one outpatient eGFR<60 ml/min per 1.73 m2 measurement denoting probable CKD in Stockholm from 2009 to 2017. We calculated the odds ratios for diagnosis of CKD and provision of RASi and statins at inclusion, and hazard ratios for CKD diagnosis, visiting a nephrologist, or monitoring creatinine and albuminuria during follow-up. RESULTS: We identified 227,847 subjects, of whom 126,289 were women (55%). At inclusion, women had lower odds of having received a diagnostic code for CKD and were less likely to have received RASi and statins, despite having guideline-recommended indications. In time-to-event analyses, women were less likely to have received a CKD diagnosis (HR, 0.43; 95% CI, 0.42 to 0.45) and visited a nephrologist (HR, 0.46; 95% CI, 0.43 to 0.48) regardless of disease severity, presence of albuminuria, or criteria for referral. Women were also less likely to undergo monitoring of creatinine or albuminuria, including those with diabetes or hypertension. These differences remained after adjustment for comorbidities, albuminuria, and highest educational achievement, and among subjects with confirmed CKD at retesting. Although in absolute terms all nephrology-care indicators gradually improved over time, the observed sex gap persisted. CONCLUSIONS: There were profound sex differences in the detection, recognition, monitoring, referrals, and management of CKD. The disparity was also observed in people at high risk and among those who had guideline-recommended indications. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2022_10_11_JASN2022030373.mp3.

Comprehensive comparison of stroke risk score performance: a systematic review and meta-analysis among 6 267 728 patients with atrial fibrillation.

AIMS: Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations and updates, assess their methodological quality, and calculate pooled estimates of the predictive performance. METHODS AND RESULTS: We searched PubMed and Web of Science for studies developing, validating, or updating risk scores for IS in AF patients. Methodological quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). To assess discrimination, pooled c-statistics were calculated using random-effects meta-analysis. We identified 19 scores, which were validated and updated once or more in 70 and 40 studies, respectively, including 329 validations and 76 updates-nearly all on the CHA2DS2-VASc and CHADS2. Pooled c-statistics were calculated among 6 267 728 patients and 359 373 events of IS. For the CHA2DS2-VASc and CHADS2, pooled c-statistics were 0.644 [95% confidence interval (CI) 0.635-0.653] and 0.658 (0.644-0.672), respectively. Better discriminatory abilities were found in the newer risk scores, with the modified-CHADS2 demonstrating the best discrimination [c-statistic 0.715 (0.674-0.754)]. Updates were found for the CHA2DS2-VASc and CHADS2 only, showing improved discrimination. Calibration was reasonable but available for only 17 studies. The PROBAST indicated a risk of methodological bias in all studies. CONCLUSION: Nineteen risk scores and 76 updates are available to predict IS in patients with AF. The guideline-endorsed CHA2DS2-VASc shows inferior discriminative abilities compared with newer scores. Additional external validations and data on calibration are required before considering the newer scores in clinical practice. CLINICAL TRIAL REGISTRATION: ID CRD4202161247 (PROSPERO).

Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes.

OBJECTIVE: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. RESEARCH DESIGN AND METHODS: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; ≥60 or <60 mL/min/1.73 m2) to predict a composite of ≥40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. RESULTS: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting ≥40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. CONCLUSIONS: Novel prediction equations for a decline of ≥40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR.

Use of nephrotoxic medications in adults with chronic kidney disease in Swedish and US routine care.

Background: To characterize the use of nephrotoxic medications in patients with chronic kidney disease (CKD) Stages G3-5 in routine care. Methods: We studied cohorts of adults with confirmed CKD G3-5 undergoing routine care from 1 January 2016 through 31 December 2018 in two health systems [Stockholm CREAtinine Measurements (SCREAM), Stockholm, Sweden (N = 57 880) and Geisinger, PA, USA (N = 16 255)]. We evaluated the proportion of patients receiving nephrotoxic medications within 1 year overall and by baseline kidney function, ranked main contributors and examined the association between receipt of nephrotoxic medication and age, sex, CKD G-stages comorbidities and provider awareness of the patient's CKD using multivariable logistic regression. Results: During a 1-year period, 20% (SCREAM) and 17% (Geisinger) of patients with CKD received at least one nephrotoxic medication. Among the top nephrotoxic medications identified in both cohorts were non-steroidal anti-inflammatory drugs (given to 11% and 9% of patients in SCREAM and Geisinger, respectively), antivirals (2.5% and 2.0%) and immunosuppressants (2.7% and 1.5%). Bisphosphonate use was common in SCREAM (3.3%) and fenofibrates in Geisinger (3.6%). Patients <65 years of age, women and those with CKD G3 were at higher risk of receiving nephrotoxic medications in both cohorts. Notably, provider awareness of a patient's CKD was associated with lower odds of nephrotoxic medication use {odds ratios [OR] 0.85[95% confidence interval (CI) 0.80-0.90] in SCREAM and OR 0.80 [95% CI 0.72-0.89] in Geisinger}. Conclusions: One in five patients with CKD received nephrotoxic medications in two distinct health systems. Strategies to increase physician's awareness of patients' CKD and knowledge of drug nephrotoxicity may reduce prescribing nephrotoxic medications and prevent iatrogenic kidney injury.

GLP-1 receptor agonist versus DPP-4 inhibitor and kidney and cardiovascular outcomes in clinical practice in type-2 diabetes.

Whether glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce detrimental kidney outcomes is uncertain. In secondary analyses, trials have shown consistent reductions in macroalbuminuria, but inconclusive results about kidney function decline. To help clarify this, we conducted a cohort study to compare kidney and cardiovascular outcomes in individuals who started GLP1-RA or dipeptidyl peptidase-4 inhibitors (DPP4i) (reduces degradation of endogenous GLP1). The primary outcome was a composite of sustained doubling of creatinine, kidney failure or kidney death. The secondary outcomes were three-point major adverse cardiovascular events (MACE) and its individual components. Propensity score weighted Cox regression was used to balance 53 confounders. A total of 19,766 individuals were included, of whom 5,699 initiated GLP1-RA, and were followed for a median 2.9 years. Mean age was 63 years, 26.2% had atherosclerotic cardiovascular disease and 16.0% had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m2. The adjusted hazard ratio for GLP1-RA vs. DPP4i was 0.72 (95% confidence interval 0.53-0.98) for the composite kidney outcome and 0.85 (0.73-0.99) for MACE, with absolute five-year risk reductions of 0.8% (0.1%-1.5%) and 1.6% (0.2%-2.9%), respectively. Hazard ratios were 0.79 (0.60-1.05) for cardiovascular death, 0.86 (0.68-1.09) for myocardial infarction and 0.74 (0.59-0.93) for stroke. Results were consistent within subgroups, including age, sex, eGFR and baseline metformin use. Thus, in our analysis of patients from routine clinical practice, the use of GLP1-RA was associated with a lower risk of kidney outcomes compared with DPP4i. Reductions in both kidney outcomes and MACE were similar in magnitude to those reported in large cardiovascular outcome trials.

Albuminuria Testing in Hypertension and Diabetes: An Individual-Participant Data Meta-Analysis in a Global Consortium.

[Figure: see text].

Stopping mineralocorticoid receptor antagonists after hyperkalaemia: trial emulation in data from routine care.

AIMS: Whether to continue or stop mineralocorticoid receptor antagonists (MRA) after an episode of hyperkalaemia is a challenge in clinical practice. While stopping MRA may prevent recurrent hyperkalaemias, it deprives patients of their cardioprotection. We here assessed the association between stopping vs. continuing MRA therapy after hyperkalaemia and the subsequent risks of adverse health events. METHODS AND RESULTS: Observational study from the Stockholm CREAtinine Measurements (SCREAM) project 2006-2018. We identified patients initiating MRA and surviving a first-detected episode of hyperkalaemia (plasma potassium >5.0 mmol/L). Using target trial emulation methods, we assessed the association between stopping vs. continuing MRA within 6 months after hyperkalaemia and subsequent outcomes. The primary outcome was the composite of hospital admission with heart failure, stroke, myocardial infarction, or death. The secondary outcome was occurrence of another hyperkalaemia event. Among 39 518 patients initiating MRA, we identified 7366 who developed hyperkalaemia. Median age was 76 years, 45% were women and 69% had a history of heart failure. Following hyperkalaemia, 2222 (30%) discontinued treatment. Compared with continuing MRA, stopping therapy was associated with a lower 2-year risk of recurrent hyperkalaemia [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.72-0.79], but a higher risk of the primary outcome (HR 1.10, 95% CI 1.06-1.14). Similar results were observed in patients with heart failure, after censoring when treatment decision was changed, and across pre-specified subgroups. CONCLUSIONS: Stopping MRA after an episode of hyperkalaemia was associated with reduced risk for recurrent hyperkalaemia, but higher risk of death or cardiovascular events. Recurrent hyperkalaemia was common in either strategy.

Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection.

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.

Muscle Mass Assessed by Computed Tomography at the Third Lumbar Vertebra Predicts Patient Survival in Chronic Kidney Disease

OBJECTIVE: Muscle mass is a key element for the evaluation of nutritional disturbances in patients with chronic kidney disease (CKD). Low muscle mass is associated with increased morbidity and mortality. The assessment of muscle mass by computed tomography at the third lumbar vertebra region (CTMM-L3) is an accurate method not subject to errors from fluctuation in the hydration status. Therefore, we aimed at investigating whether CTMM-L3 was able to predict mortality in nondialyzed CKD 3-5 patients. METHODS: This is a prospective observational cohort study. We evaluated 223 nondialyzed CKD patients (60.3 ± 10.6 years; 64% men; 50% diabetics; glomerular filtration rate 20.7 ± 9.6 mLmin1.73 m2). Muscle mass was measured by CTMM-L3 using the Slice-O-Matic software and analyzed according to percentile adjusted by gender. Nutritional parameters, laboratory data, and comorbidities were evaluated, and mortality was followed up for 4 years. RESULTS: During the study period, 63 patients died, and the main cause of death was cardiovascular disease. Patients who died were older, had lower hemoglobin and albumin, as well as lower muscle markers. CTMM-L3 below the 25th percentile was associated with higher mortality according to the Kaplan-Meier curve (P = .017) and in Cox regression analysis (crude hazard ratio, 1.87 [95% confidence interval, 1.11-3.16]), also when adjusting for potential confounders (hazard ratio 1.83 [95% confidence interval 1.02-3.30]). CONCLUSION: Low muscle mass measured by computed tomography at the third lumbar vertebra region is an independent predictor of increased mortality in nondialyzed CKD patients.

Validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function.

AIMS: The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function. METHODS AND RESULTS: Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30-60 mL/min/1.73 m2), and advanced CKD (eGFR <30 mL/min/1.73 m2). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS2 score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration. CONCLUSION: In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients.