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A global rise in the prevalence of patients with chronic kidney disease (CKD) with end-stage kidney disease (ESKD) has led to a considerable and increasing burden to health systems, patients, and society. Sodium–glucose cotransporter 2 (SGLT2) inhibitors are proven to reduce incidence of cardio-renal outcomes, including onset of ESKD. Recent post hoc analyses of SGLT2 inhibitor trials extrapolate substantial delays in the average time to ESKD over a patient's lifetime. In this article, we explore the possible real-world effects of such a delay by considering the available evidence reporting outcomes following onset of ESKD. From the patient perspective, a delay in reaching ESKD could substantially improve health-related quality of life and result in additional life years without the need for kidney replacement therapies, a target relevant to all CKD subpopulations. Furthermore, should a patient initiate dialysis at an older age as a result of CKD progression, the time spent in receipt of dialysis, and therefore associated healthcare costs, may also be reduced. A delay in progression may also lead to changes in the management of ESKD, such as increased election of conservative care in preference to dialysis, particularly in elderly populations. For younger patients with CKD, those who reach ESKD while employed face considerable work impairment and productivity loss, as may families and care partners of working age. Therefore, a delay to the onset of ESKD will reduce the proportion of their working lives affected by productivity losses or unemployment due to medical reasons. In conclusion, optimised treatment of CKD may lead to a shift in treatment options, but proper and timely implementation is essential for the realisation of improved outcomes. [ABSTRACT FROM AUTHOR]

This article explores the gap between knowledge and implementation in kidney care, emphasizing the need to translate evidence-based treatments into daily practice more quickly. It discusses the global issue of undiagnosed and untreated kidney disease, highlighting the importance of early diagnosis and optimal care to prevent complications. The text addresses barriers at various levels and calls for policies and improvements in healthcare systems to address these gaps. It emphasizes the importance of collaborative care models, involving various stakeholders, and the need for innovation and patient empowerment to achieve health equity. [Extracted from the article]

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages, it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay. [ABSTRACT FROM AUTHOR]

The article discusses the global burden of kidney disease and the gaps in kidney care, particularly in low- and middle-income countries. It highlights the high death rates and economic burden associated with chronic kidney disease (CKD) and the disparities in prevention, early detection, diagnosis, and treatment. The text emphasizes the importance of integrating kidney care into national non-communicable disease strategies and strengthening health systems. It also discusses the challenges in managing CKD, including the need for regulation and monitoring of drug manufacturing, the importance of real-world data, and strategies to improve CKD management. The article addresses the cost and availability of medication for individuals with kidney disease, highlighting the paradoxical situation in high-income countries and the catastrophic health expenditure in low- and middle-income countries. It calls for pharmaceutical companies to ensure diverse participation in research studies and fair pricing of effective drugs. The article also emphasizes the need to focus on children with kidney diseases and suggests strategies to improve kidney disease care, including the use of polypills and digital technologies. It concludes with a call to action to address barriers and disparities in access to diagnosis and treatment and to ensure equitable kidney care worldwide. [Extracted from the article]

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay. [ABSTRACT FROM AUTHOR]

Background: The sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown. Objective: We performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex. Design: Prospective randomized placebo-controlled trial. Participants: A total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes. Intervention: Dapagliflozin 10 mg versus placebo once daily. Main Measures: Primary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality. Key Results: Median follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope. Conclusions: Dapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit. Trial Registry: clinicaltrials.gov NIH Trial Registry Number: NCT03036150 [ABSTRACT FROM AUTHOR]

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition because in the early stages, it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay. [ABSTRACT FROM AUTHOR]

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly efective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is ofen silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay. [ABSTRACT FROM AUTHOR]

Background The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial enrolled patients with estimated glomerular filtration rate 25–75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio >200 mg/g. The Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial enrolled patients with type 2 diabetes, a higher range of kidney function and no albuminuria criterion. The study objective was to estimate the cost-effectiveness of dapagliflozin in a broad chronic kidney disease population based on these two trials in the UK, Spain, Italy and Japan. Methods We adapted a published Markov model based on the DAPA-CKD trial but to a broader population, irrespective of urine albumin-to-creatinine ratio, using patient-level data from the DAPA-CKD and DECLARE-TIMI 58 trials. We sourced cost and utility inputs from literature and the DAPA-CKD trial. The analysis considered healthcare system perspectives over a lifetime horizon. Results Treatment with dapagliflozin was predicted to attenuate disease progression and extend projected life expectancy by 0.64 years (12.5 versus 11.9 years, undiscounted) in the UK, with similar estimates in other settings. Clinical benefits translated to mean quality-adjusted life year (QALY; discounted) gains between 0.45 and 0.68 years across countries. Incremental cost-effectiveness ratios in the UK, Spain, Italy and Japan ($10 676/QALY, $14 479/QALY, $7771/QALY and $13 723/QALY, respectively) were cost-effective at country-specific willingness-to-pay thresholds. Subgroup analyses suggest dapagliflozin is cost-effective irrespective of urinary albumin-to-creatine ratio and type 2 diabetes status. Conclusion Treatment with dapagliflozin may be cost-effective for patients across a wider spectrum of estimated glomerular filtration rates and albuminuria than previously demonstrated, with or without type 2 diabetes, in the UK, Spanish, Italian and Japanese healthcare systems. [ABSTRACT FROM AUTHOR]

Background A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. Methods Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes. Results Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211–0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33–0.76], 0.62 [0.45–0.85], and 0.64 [0.49–-0.83], respectively; p -interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p -interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p -interaction = 0.63), and all-cause mortality (p -interaction p  = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively). Conclusions The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety. [ABSTRACT FROM AUTHOR]

Introduction: Peritoneal dialysis (PD) guidelines recommend a 14‐day break‐in period after catheter placement, yet this period could be shortened with new insertion techniques. Methods: We conducted a prospective cohort study to compare percutaneous vs. surgical catheter insertion in a newly established PD program. The break‐in period was intentionally shortened to <24 h to start PD almost immediately. Results: We included 223 subjects who underwent percutaneous (34%) or surgical (66%) catheter placement. Compared to the surgical group, the percutaneous group had a higher proportion of early dialysis initiation within 24 h (97% vs. 8%, p < 0.001), similar successful initiation rates (87% vs. 92%, p = 0.34), and shorter lengths of stay (12 [9–18] vs. 18 [14–22] days, p < 0.001). Percutaneous insertion increased the likelihood of successful PD initiation within 24 h (OR 74, 95% CI 31–182), without increasing major complications. Conclusion: Percutaneous placement could represent a cost‐effective and efficient technique to shorten break‐in periods. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532. [ABSTRACT FROM AUTHOR]

Introduction: Expanded hemodialysis (HDx) is expected to provide enhanced permeability of medium-sized molecules, selective solute retention, and better internal retrofiltration. The primary objective of this study was to compare the efficiency for removal of β2-microglobulin with 3 different extracorporeal therapies (ETs): high-flux hemodialysis (HF), online hemodiafiltration (OL-HDF), and HDx. The secondary objective was to evaluate the efficiency of removal of other uremic toxins, including urea, phosphate, CRP, IL-6, IL-10, TNF-⍺, indoxyl sulfate, and p-cresol. Methods: This single-center, randomized, and cross-over study was performed. Patients were randomized to determine the initial modality of treatment, each period lasted 4 weeks and between one modality and another, there was a washout period of 1 week. Reduction ratios (RRs) of different-size molecules and albumin were calculated for the different ET. Results: Twenty-two patients were included, β2-microglobulin RR was greater during both OL-HDF and HDx as compared to HF (RR 62% vs. 73% vs. 27%, respectively, p = <0.0001), and there was no significant difference between HDx and OL-HDF (p = 0.09). A decrease in serum phosphate levels was observed in the HDx and OL-HDF periods, contrary to an increase in HF (−0.79 mg/dL vs. −1.02 mg/dL vs. + 0.11 mg/dL, respectively, p = <0.0001). There was no difference in RRs of other molecules (BUN, CRP, IL-6, IL-10, TNF-⍺, indoxyl sulfate, and p-Cresol). There was no decrease in serum albumin in any ET. Conclusion: HDx provides enhanced removal of β2-microglobulin and phosphate as compared to HF, and similar efficacy as with OL-HDF. HDx should be considered an alternative to chronic convective therapies. [ABSTRACT FROM AUTHOR]

Background The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial assessed dapagliflozin versus placebo, in addition to standard therapy, in patients with chronic kidney disease (CKD) and albuminuria, and was terminated prematurely due to overwhelming efficacy. The study objective was to model the long-term clinical outcomes of DAPA-CKD beyond the trial follow-up. Methods A Markov model extrapolated event incidence per 1000 patients and CKD progression rates for patients receiving dapagliflozin or placebo over a 10-year time horizon. We derived treatment-specific CKD stage transition matrices using DAPA-CKD trial data. We extrapolated relevant efficacy endpoints using parametric survival equations for all-cause mortality and generalized estimating equations for recurrent events. Results When extrapolated over a 10-year period, patients randomized to dapagliflozin spent more time in CKD stages 1–3 and less in stages 4–5 than placebo [0.65 (95% CrI 0.41, 0.90) and –0.23 (95% CrI -0.45, 0.00) years per patient, respectively]. Dapagliflozin prevented an estimated 83 deaths and 51 patients initiating kidney replacement therapy per 1000 patients over 10 years. Predicted rates of hospitalized heart failure and abrupt declines in kidney function were reduced (19 and 39 estimated events per 1000 patients, respectively). Conclusions Adding dapagliflozin to standard therapeutic management of CKD is expected to have long-term cardiorenal benefit beyond what has been demonstrated in the DAPA-CKD trial, with patients predicted to live longer with fewer complications. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether the benefits of dapagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) in the Dapagliflozin And Prevention of Adverse Outcomes in CKD trial (DAPA-CKD) varied by background glucose-lowering therapy (GLT). RESEARCH DESIGN AND METHODS: We randomized 4,304 adults (including 2,906 with type 2 diabetes) with a baseline estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of 200–5,000 mg/g to dapagliflozin 10 mg or placebo once daily (NCT03036150). The primary end point was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular cause of death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. In this prespecified analysis, we investigated the effects of dapagliflozin on these and other outcomes according to baseline GLT class or number of GLTs. RESULTS: The effects of dapagliflozin on the primary composite outcome were consistent across GLT classes and according to the number of GLTs (all interaction P > 0.08). Similarly, we found consistent benefit of dapagliflozin compared with placebo on the secondary end points regardless of background GLT class or number of GLTs. The same applied to the rate of decline in the eGFR rate and safety end points. Dapagliflozin reduced the initiation of insulin therapy during follow-up compared with placebo (hazard ratio 0.72; 95% CI 0.54–0.96; P = 0.025). CONCLUSIONS: Dapagliflozin reduced kidney and cardiovascular events in patients with type 2 diabetes and CKD across baseline GLT class or classes in combination. [ABSTRACT FROM AUTHOR]

Background: Acute hospitalizations are common in patients with chronic kidney disease (CKD) and often lead to decreases in health-related quality of life and increased care costs.Objective: To determine the effects of dapagliflozin on first hospitalizations and all (first and subsequent) hospitalizations and to explore effects on cause-specific hospitalizations.Design: Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT03036150).Setting: 386 ambulatory practice sites in 21 countries from 2 February 2017 through 12 June 2020.Participants: Adults with an estimated glomerular filtration rate of 25 to 75 mL/min/1.73 m2 and a urinary albumin-creatinine ratio of 200 to 5000 mg/g, with and without type 2 diabetes.Intervention: Dapagliflozin, 10 mg once daily, or matching placebo (1:1 ratio).Measurements: The effects of dapagliflozin on first hospitalizations for any cause, all hospitalizations, and cause-specific (first and recurrent) hospitalizations were determined. The reported system organ class was used to evaluate reasons for admission. Hospitalizations were analyzed using Cox proportional hazards regression models (first hospitalization), the Lin-Wei-Yang-Ying method (all hospitalizations or death), and negative binomial models (cause-specific hospitalizations).Results: The study included 4304 patients (mean age, 61.8 years; 33.1% women). During a median follow-up of 2.4 years, 2072 hospitalizations were reported among 1224 (28.4%) participants. Compared with placebo, dapagliflozin reduced risk for a first hospitalization (hazard ratio, 0.84 [95% CI, 0.75 to 0.94]) and all hospitalizations or death (rate ratio, 0.79 [CI, 0.70 to 0.89]). There was no evidence that the effects of dapagliflozin on first and all hospitalizations varied by baseline presence of type 2 diabetes (P for interaction = 0.60 for each). Compared with placebo, dapagliflozin reduced the rate of admissions due to cardiac disorders, renal and urinary disorders, metabolism and nutrition disorders, and neoplasms.Limitations: This was a post hoc analysis and should be viewed as hypothesis-generating. Hospitalizations and causes were reported by site investigators and were not centrally adjudicated.Conclusion: Dapagliflozin reduced the risk for hospitalization for any cause in patients with CKD with and without type 2 diabetes.Primary Funding Source: AstraZeneca. [ABSTRACT FROM AUTHOR]

Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management. Chronic kidney disease (CKD) has a high clinical, economic, and societal burden and it affects approximately 8-16% of the global population. The progressive nature of CKD may lead to complications, co-morbidities, and mortality, costing healthcare systems millions and consuming a large proportion of healthcare resources. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, has been demonstrated to slow CKD progression and reduce cardio-renal complications, as demonstrated in the DAPA-CKD trial. With the emergence of dapagliflozin as a treatment for CKD, it is important for clinicians and healthcare providers to understand how effective treatment can positively affect short-term healthcare service delivery and associated costs. This medical care cost offset modelling analysis considers a scalable population of 100,000 patients in 31 countries/regions worldwide. The analysis estimates treatment with dapagliflozin plus standard therapy to be offset by a 33% reduction in costs associated with key cardio-renal outcomes, translating to an average $264 million in cost offsets per 100,000 treated patients. This modelling analysis of pivotal trial data shows dapagliflozin could have considerable benefits to healthcare systems worldwide that are under strain from the rising burden of CKD. [ABSTRACT FROM AUTHOR]

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25–75 mL/min/1.73 m2, and a urine albumin‐to‐creatinine ratio of 300–5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin‐1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma‐concentration time curve from zero to infinity (AUC0−inf) 41.3 ng·h/mL) or slow (atrasentan AUC0−inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45–0.81) and 1.35 (95% CI: 0.84–2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95–4.03, P‐interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37–12.7, P‐interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between‐patient variability in atrasentan plasma exposure and long‐term efficacy and safety. [ABSTRACT FROM AUTHOR]

Purpose: Free calcium is the gold standard for diagnosis of calcium disorders, although calcium assessment is routinely performed by albumin-adjusted calcium. Our objective was to develop a novel-specific correction equation for free calcium employing serum total calcium and other analytes. Methods: Retrospective single-center cohort study. A new equation for free calcium assessment was formulated from data of hospitalized patients (n = 3481, measurements = 7157) and tested in a validation cohort (n = 3218, measurements = 6911). All measurements were performed simultaneously from the same blood draw. Results: Total CO2 and phosphate, in addition to albumin, were the principal factors associated to calcium misdiagnosis. A novel laboratory-specific prediction equation was developed: free calcium (mmol/L) = 0.541 + (total calcium [mmol/L] *0.441) – (serum albumin [g/L] *0.0067) – (serum phosphate [mmol/L] *0.0425) – (CO2 [mmol/L] *0.003). This new equation substantially improved adjusted R2 to 0.67 (95% CI 0.78–0.82, p < 0.001; Kendall's c-tau: 0.28, p < 0.001). Bland–Altman plots of estimated free calcium and free calcium showed a mean difference of − 0.0006 mmol/L (LOA + 0.126 to − 0.124). In validation cohort, the AUC–ROC curves for hypercalcemia and hypocalcemia diagnosis deploying the new equation were 0.88 (95% CI 0.86–0.89, p < 0.001) and 0.98 (95% CI 0.97–99, p < 0.001), respectively, which were superior to historical formulas for calcium. In univariate models, eGFR was associated with Ca-status misdiagnosis, yet this association disappeared when analysis was adjusted to phosphate and CO2. Conclusions: The novel equation proposed for prediction of free calcium could be useful when free calcium is not available. The conventional formulas misclassify many patients, in particular when phosphate or bicarbonate disturbances are present. [ABSTRACT FROM AUTHOR]

Background Despite renin–angiotensin–aldosterone system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease trial (DAPA-CKD) was to assess efficacy and safety of dapagliflozin in a small subgroup of participants with FSGS confirmed by kidney biopsy. Methods In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200–5000 mg/g (22.6–565 mg/mol) were randomized to dapagliflozin 10 mg once daily or placebo as an adjunct to standard care and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment). Results Of 104 participants with biopsy-confirmed FSGS, 45 were randomized to dapagliflozin and 59 to placebo. Mean (standard deviation) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73 m2 and median (interquartile range) UACR 1248 (749–2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomized to dapagliflozin and placebo, respectively [hazard ratio 0.62, 95% confidence interval (95% CI) 0.17, 2.17]. Dapagliflozin led to a larger acute reduction (standard error) in eGFR compared with placebo (−4.5, 95% CI −5.9 to −3.1 versus −0.9, −2.1 to 0.4 mL/min/1.73 m2/2 weeks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were −1.9 (−3.0, −0.9) and −4.0 (−4.9, −3.0) mL/min/1.73 m2/year, respectively (difference 2.0, 95% CI 0.6 to 3.5, mL/min/1.73 m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin. Conclusions Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared with placebo, although this difference was not statistically significant. [ABSTRACT FROM AUTHOR]

Introduction: The protein‐energy wasting (PEW) syndrome is a common complication in hemodialysis (HD) patients associated to morbidity and mortality. Our objective was to assess the prevalence of PEW and its association with erythropoietin resistance index (ERI) score, body composition by impedance, health‐related quality of life, and muscle strength. Methods: In this cross‐sectional, observational, multicenter study, we included data from 191 HD patients from three HD clinics located in Mexico City, Mexico. Clinical and biochemistry variables, body composition, handgrip strength, and the KDQOL‐SF36 questionnaire were collected for each patient. Findings: Prevalence of PEW was 22% (n = 41/191), with a higher frequency in those with diabetes mellitus (59% vs. 49%, p = 0.04). Subjects with PEW had lower hemoglobin levels (9.5 + 1.6 g/dl vs. 10.3 + 1.7 g/dl; p = 0.005) and higher ERI scores (19.2 ± 11.2 vs. 15.6 ± 8.2; p = 0.04) compared with the non‐PEW group. In analysis of body composition, PEW was associated to higher overhydration status (42.2 vs. 24.9 OH/kg; p = 0.009), higher extracellular water (263 ± 40 vs. 246 ± 32 ml/kg; p = 0.019), lower lean tissue index (12.2 ± 3.2 vs. 14.1 ± 3.7 ml/m2; p = 0.021), and lower fat tissue index (9.6 ± 5.7 vs. 12.3 ± 6.2 ml/m2; p = 0.043). Handgrip strength was lower in PEW patients (22.5 vs. 28.1 kg; p = 0.002). Finally, no significant differences were observed between groups in quality‐of‐life assessment. Discussion: In this study, PEW was associated to poor responsiveness to erythropoiesis‐stimulating agents, lower muscle strength, and higher overhydration status due to the increase in extracellular water which replaced the loss of tissue. Nevertheless, quality‐of‐life assessment was not different in patients with PEW compared with those without this complication. [ABSTRACT FROM AUTHOR]

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Aims/hypothesis: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories. Methods: DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25–75 ml min−1 [1.73 m]−2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200–5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories. Results: Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories. Conclusion/interpretations: The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity. Trial registration: ClinicalTrials.gov NCT03036150. Funding: The study was funded by AstraZeneca. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of dapagliflozin in patients with chronic kidney disease (CKD) and albuminuria, with and without type 2 diabetes, stratified by the Quételet (body mass) index (BMI). Methods: We randomized 4304 adult patients with an estimated glomerular filtration rate (eGFR) of 25‐75 ml/min/1.73m2 and urinary albumin‐to‐creatinine ratio of 200‐5000 mg/g to dapagliflozin 10 mg/day or placebo. The primary outcome was a composite of sustained decline in eGFR of 50% or more, kidney failure, or death from kidney or cardiovascular causes. Secondary outcomes included kidney composite endpoint (primary composite endpoint without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure/ cardiovascular death), and all‐cause mortality. We categorized participants according to World Health Organization BMI criteria: lean/ideal (<25 kg/m2), overweight (25‐< 30 kg/m2), grade 1 obesity (30‐<35 kg/m2), and grade 2/3 obesity (≥35 kg/m2). Results: Of 4296 (99.8%) randomized participants, 888 (20.7%), 1491 (34.7%), 1136 (26.4%), and 781 (18.2%) were categorized as lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity, respectively. Median follow‐up was 2.4 years. Benefits of dapagliflozin were observed independent of baseline BMI for primary and secondary endpoints. Hazard ratios (95% CI) for dapagliflozin versus placebo for the primary composite endpoint were 0.60 (0.43, 0.85), 0.55 (0.40, 0.75), 0.71 (0.49, 1.04), and 0.57 (0.37, 0.87) among participants in the lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity groups (interaction P =.72). Conclusion: Among participants with CKD and albuminuria, with or without type 2 diabetes, kidney and cardiovascular benefits of dapagliflozin were evident and consistent across the BMI spectrum. [ABSTRACT FROM AUTHOR]

Background. Acute kidney injury (AKI) is a common complication of COVID-19. Several etiologies have been identified, including pigment deposition likely associated with myopathic damage. Nevertheless, the relationship between longitudinal creatine-kinase trends and renal outcomes is uncertain. Aim. To correlate longitudinal changes in serum creatine-kinase levels with hospital-acquired AKI (beyond 48 h of hospital admission) in severe COVID-19 patients. Methods. This is a retrospective cohort study, and creatine-kinase levels were assessed over time in 1551 hospitalized patients with normal renal function at the time of hospital admission. Results. In subjects who developed hospital-acquired AKI (n = 126, 8.1%), the serum creatine-kinase concentration before AKI onset was not different when compared to patients without AKI (slope of log creatine-kinase/day = −0.09 [95% CI −0.17 to +0.19] vs. +0.03 [95% CI −0.1 to +0.1]). After AKI diagnosis, serum creatine-kinase levels showed a significantly ascendent slope (slope of log creatine-kinase/day after AKI diagnosis = +0.14; 95% CI + 0.05 to +0.3). The AKI evolution was the main factor associated with the creatine-kinase trend. Subjects with persistent AKI (n = 40, 32%) had rising creatine-kinase levels during hospitalization (slope of log creatine-kinase/day = +0.30 95% CI + 0.19 to +0.51). A rising creatine-kinase trend (n = 114, 8%) was associated with a 1.89-fold higher risk of in-hospital death (95% CI 1.14 to 3.16). Nevertheless, this association disappeared after adjusting AKI evolution and LDH baseline levels. Conclusion. In severe COVID-19 patients, a slight increase in creatine-kinase levels was observed after AKI occurrence but not before. Our results show that, at least for the appearance of hospital-acquired AKI, the CK rise does not meet the temporality criterion of causality regarding the occurrence of AKI. Rising creatine-kinase trends were associated with a higher risk of mortality, but this association was modified by AKI evolution and inflammation. There is a limited efficiency for AKI prognosis in the serial follow-up of CK levels in severe COVID-19 patients with normal renal function. [ABSTRACT FROM AUTHOR]

Aim: To assess the risk of major adverse cardiovascular events (MACE) of canagliflozin in Hispanic patients with type 2 diabetes (T2D) and high cardiovascular risk or nephropathy with varying levels of kidney function. Materials and Methods: This post hoc analysis included integrated, pooled data from the CANVAS Program and CREDENCE trial. The effects of canagliflozin versus placebo on major adverse cardiovascular events (MACE; i.e. cardiovascular death, non‐fatal myocardial infarction, and non‐fatal stroke) were assessed in subgroups by baseline estimated glomerular filtration rate (eGFR; <45, 45‐60, and >60 mL/min/1.73 m2) overall and in the Hispanic cohort. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models, with subgroup by treatment interaction terms added to test for heterogeneity. Results: A total of 14 543 participants were included; 3029 (20.8%) self‐identified as Hispanic. In the overall population, canagliflozin reduced the risk of MACE compared with placebo (HR, 0.83; 95% CI, 0.75, 0.92), with no heterogeneity observed across eGFR subgroups (interaction P =.22). In the Hispanic cohort, canagliflozin also reduced the risk of MACE (HR, 0.71; 95% CI, 0.55, 0.92), with no heterogeneity by baseline eGFR (interaction P =.25), including among the Hispanic participants at highest risk with a baseline eGFR of less than 45 mL/min/1.73 m2. Conclusion: Canagliflozin reduced the risk of MACE overall, and among Hispanic participants with T2D and high cardiovascular risk or nephropathy in the CANVAS Program and CREDENCE trial, without heterogeneity by baseline eGFR. [ABSTRACT FROM AUTHOR]

Introduction: Acute kidney injury (AKI) is common in coronavirus disease 2019 (COVID-19). It is unknown if hospital-acquired AKI (HA-AKI) and community-acquired AKI (CA-AKI) convey a distinct prognosis. Methods: The study aim was to evaluate the incidence and risk factors associated with both CA-AKI and HA-AKI. Consecutive patients hospitalized at a reference center for COVID-19 were included in this prospective cohort study. Results: We registered 349 (30%) AKI episodes in 1,170 hospitalized patients, 224 (19%) corresponded to CA-AKI, and 125 (11%) to HA-AKI. Compared to patients with HA-AKI, subjects with CA-AKI were older (61 years [IQR 49–70] vs. 50 years [IQR 43–61]), had more comorbidities (hypertension [44 vs. 26%], CKD [10 vs. 3%]), higher Charlson Comorbidity Index (2 points [IQR 1–4] vs. 1 point [IQR 0–2]), and presented to the emergency department with more severe disease. Mortality rates were not different between CA-AKI and HA-AKI (119 [53%] vs. 63 [50%], p = 0.66). In multivariate analysis, CA-AKI was strongly associated to a history of CKD (OR 4.17, 95% CI 1.53–11.3), hypertension (OR 1.55, 95% CI 1.01–2.36), Charlson Comorbidity Index (OR 1.16, 95% CI 1.02–1.32), and SOFA score (OR 2.19, 95% CI 1.87–2.57). HA-AKI was associated with the requirement for mechanical ventilation (OR 68.2, 95% CI 37.1–126), elevated troponin I (OR 1.95, 95% CI 1.01–3.83), and glucose levels at admission (OR 1.05, 95% CI 1.02–1.08). Discussion/Conclusions: CA-AKI and HA-AKI portend an adverse prognosis in CO-VID-19. Nevertheless, CA-AKI was associated with a higher comorbidity burden (including CKD and hypertension), while HA-AKI occurred in younger patients by the time severe multiorgan disease developed. [ABSTRACT FROM AUTHOR]

Objective: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.Research Design and Methods: We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.Results: Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.Conclusions: Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status. [ABSTRACT FROM AUTHOR]

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long‐term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time‐to‐event models were used to quantify the association between plasma exposure and long‐term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28–0.85) for kidney events and 1.13 (95% CI: 1.03–2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population. [ABSTRACT FROM AUTHOR]

Aim: Severe hypocalcaemia following parathyroidectomy for secondary or tertiary hyperparathyroidism (SHPT/THPT) is scarcely studied. We aimed to describe and identify risk factors for early and persistent hypocalcaemia after parathyroidectomy. Methods: Retrospective pair‐matched cohort study. We assessed 87 dialysis patients with SHPT (n = 73) or THPT (n = 14) paired with 146 subjects with primary hyperparathyroidism (PHPT) who underwent parathyroidectomy and were followed for 12 months. Early severe hypocalcaemia was defined as a free Ca ≤0.8 mmol/L [3.2 mg/dl] or corrected Ca ≤1.87 mmol/L [7.5 mg/dl] within 48 h. After parathyroidectomy and persistent hypocalcaemia, as an elemental Ca intake >3.0 g/day to achieve corrected Ca >2 mmol/L [8.0 mg/dl]. Results: Early severe hypocalcaemia occurred in 77% (67/87) versus 6.8% (10/146) of subjects with SHPT/THPT and PHPT, respectively (p <.001). In SHPT/THPT cases, persistent hypocalcaemia occurred in 77% (49/64) and 64% (35/54) after 6 and 12 months of parathyroidectomy, respectively. In PHPT cases, persistent hypocalcaemia occurred in 6.8% (10/146) after 4–12 months of parathyroidectomy. Preoperative serum alkaline phosphatase (ALP) was the only risk factor associated to early severe hypocalcaemia (OR 7.3, 95% C.I. 1.7–10.9, p =.006) and persistent hypocalcaemia (OR 7.1, 95% C.I: 2.1–14.2, p =.011). Subjects with persistently low intact parathormone (iPTH) (<5.3 pmol/L [50 ng/ml]), suggestive of adynamic bone disease) showed higher Ca increases and less oral calcium requirements compared to those who progressively increased iPTH after parathyroidectomy. Conclusion: Early and persistent hypocalcaemia after parathyroidectomy in severe HPT were a common event associated directly to preoperative ALP levels. Subjects with persistently low postoperative iPTH normalized serum Ca more frequently after 1 year of follow up. SUMMARY AT A GLANCE: The authors present an analysis of biochemical findings related to hyperparathyroidism (HPT) comparing primary HPT with secondary/tertiary HPT. Early and persistent hypocalcaemia after parathyroidectomy in severe HPT were a common event associated directly to preoperative ALP levels. Subjects with persistently low postoperative iPTH tend to attain normal serum calcium levels more frequently after 1 year. [ABSTRACT FROM AUTHOR]

Introduction: Patients with acute respiratory distress syndrome (ARDS) secondary to COVID-19 frequently develop severe acute kidney injury (AKI). Although continuous renal replacement therapy is the standard of care for critically ill patients, prolonged intermittent renal replacement therapy (PIRRT) may be a feasible option. We aimed to describe the tolerability and security of PIRRT treatments in COVID-19 patients with ARDS who required mechanical ventilation and developed severe AKI. Methods: We prospectively analyzed patients who underwent PIRRT treatments at a COVID-19 reference hospital in Mexico City. Intradialytic hypotension was defined as a systolic blood pressure decrease of ≥20 mm Hg or an increase of 100% in vasopressor dose. Results: We identified 136 AKI cases (60.7%) in 224 patients admitted to the intensive care unit. Among them, 21 (15%) underwent PIRRT (130 sessions) due to stage 3 AKI. The median age of the cohort was 49 (range 36–73) years, 17 (81%) were male, 7 (33%) had diabetes, and the median time between symptoms onset and PIRRT initiation was 12 (interquartile range [IQR] 7–14) days. The median of PIRRT procedures for each patient was 5 (IQR 4–9) sessions. In 108 (83%) PIRRT sessions, the total ultrafiltration goal was achieved. In 84 (65%) PIRRT procedures, there was a median increase in norepinephrine dose of +0.031 mcg/kg/min during PIRRT (IQR 0.00 to +0.07). Intradialytic hypotensive events occurred in 56 (43%) procedures. Fifteen (12%) PIRRT treatments were discontinued due to severe hypotension. Vasopressor treatment at PIRRT session onset (OR 6.2, 95% CI 1.4–28.0, p: 0.02) and a pre-PIRRT lactate ≥3.0 mmol/L (OR 4.63, 95% CI 1.3–12.8, p: 0.003) were independently and significantly associated with the risk of hypotension during PIRRT. During follow-up, 11 patients (52%) recovered from AKI and respiratory failure and 9 (43%) died. Several adaptations to our PIRRT protocol during the COVID-19 outbreak are presented. Conclusions: PIRRT was feasible in the majority of COVID-19 patients with ARDS and severe AKI, despite frequent transitory intradialytic hypotensive episodes. PIRRT may represent an acceptable alternative of renal replacement therapy during the COVID-19 outbreak. [ABSTRACT FROM AUTHOR]

Background Patients undergoing haemodialysis (HD) are often discouraged from eating fruits and vegetables because of fears of hyperkalaemia and undernutrition, yet evidence to support these claims is scarce. We here explore the association between adherence to a healthy plant-based diet with serum potassium, surrogates of nutritional status and attainment of energy/protein intake targets in HD patients. Methods We performed an observational single-centre study of stable patients undergoing HD with repeated dietary assessment every 3 months. Patients were provided with personalized nutritional counselling according to current guidelines. The diet was evaluated by 3-day food records and characterized by a healthy plant-based diet score (HPDS), which scores positively the intake of plant foods and negatively animal foods and sugar. The malnutrition inflammation score (MIS) and serum potassium were also assessed at each visit. We used mixed-effects models to evaluate the association of the HPDS with markers of nutritional status, serum potassium levels and attainment of energy/protein intake targets. Results After applying inclusion and exclusion criteria, a total of 150 patients contributing to 470 trimestral observations were included. Their mean age was 42 years [standard deviation (SD) 18] and 59% were women. In multivariable models, a higher HPDS was not associated with serum potassium levels or odds of hyperkalaemia {potassium >5.5 mEq/L; odds ratio [OR] 1.00 [95% confidence interval (CI) 0.94–1.07] per HPDS unit higher}. Patients with a higher HPDS did not differ in terms of energy intake [OR for consuming <30 kcal/kg day 1.05 (95% CI 0.97–1.13)] but were at risk of low protein intake [OR for consuming <1.1 g of protein/kg/day 1.11 (95% CI 1.04–1.19)]. A higher HPDS was associated with a lower MIS, indicating better nutritional status. Conclusions In patients undergoing HD, adherence to a healthy plant-based diet was not associated with serum potassium, hyperkalaemia or differences in energy intake. Although these patients were less likely to reach daily protein intake targets, they appeared to associate with better nutritional status over time. [ABSTRACT FROM AUTHOR]

Aims  Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death. Methods and results  DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n  = 2152) or placebo (n  = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P  = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo. Conclusion  In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether atrasentan plasma exposure explains between‐patient variability in urinary albumin‐to‐creatinine ratio (UACR) response, a surrogate for kidney protection, and B‐type natriuretic peptide (BNP) response, a surrogate for fluid expansion. Methods: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run‐in period. Individual area under the concentration‐time‐curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. Results: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th‐97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was −36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th‐97.5th P: −76.2% to 44.5%; BNP, 2.5th‐97.5th P: −71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P <.01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P <.01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). Conclusion: Atrasentan plasma exposure varied among individual patients and partially explained between‐patient variability in efficacy and safety response. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the prevalence of thyroid dysfunction in a cohort of healthy individuals in Mexico City, as well as to investigate the potential associations of these results with their estimated iodine intake (EII) as reflected by their 24-hour urinary iodine excretion (24-h UIE). Methods: From the SALMEX cohort, 683 adults provided an appropriate 24-h urine sample. Thyroid function tests and thyroid antibody concentrations were determined in the participants' sera. We analyzed discrepancies between the commonly used urinary parameters to determine the iodine intake status and the performance of thyroglobulin (Tg) as a biomarker of its status in the adult population. Results: The prevalence of dysthyroidism was high, being similar to other studies. Subclinical hypothyroidism was detected in 5.0% of individuals, clinical hypothyroidism in 1.8% of individuals, and sub-clinical hyperthyroidism in 2.8% of individuals. The median EII was 285 μg/d (IQR 215.0–369.0); 94% of individuals had EII >150 µg/d recommended daily allowance (RDA) in adults. The urinary iodine concentration (UIC) and the UIE had relative biases in their averages of 34.4%. The Tg median was 7.21 ng/mL. The prevalence of increased Tg was 6.15%. There was no correlation between Tg and EII (r= 0.019, p= 0.606). Conclusions: Thyroid dysfunction was highly prevalent in this population. Our cohort revealed a slight discrepancy between dysthyroidism manifestations and iodine intake markers; the latter represent a population with adequate iodine intake. Further studies are necessary to clearly define the prevalence of thyroid dysfunction as well as the iodine nutritional status in Mexico. [ABSTRACT FROM AUTHOR]

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Aims: Renin‐angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium‐glucose co‐transporter‐2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. Materials and methods: We evaluated the effects of dapagliflozin 10 mg/day over 12–24 weeks across 13 placebo‐controlled studies in patients with T2D with a urinary albumin‐to‐creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. Results: Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo‐adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. Conclusions: Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline. [ABSTRACT FROM AUTHOR]

Background Recent cardiovascular outcome trials have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. Methods DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2–4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin–angiotensin system inhibitor at enrolment. Results After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). Conclusion DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes. [ABSTRACT FROM AUTHOR]