Current classification for acute kidney injury (AKI) in critically ill patients with sepsis relies only on its severity-measured by maximum creatinine which overlooks inherent complexities and ...longitudinal evaluation of this heterogenous syndrome. The role of classification of AKI based on early creatinine trajectories is unclear.
This retrospective study identified patients with Sepsis-3 who developed AKI within 48-h of intensive care unit admission using Medical Information Mart for Intensive Care-IV database. We used latent class mixed modelling to identify early creatinine trajectory-based classes of AKI in critically ill patients with sepsis. Our primary outcome was development of acute kidney disease (AKD). Secondary outcomes were composite of AKD or all-cause in-hospital mortality by day 7, and AKD or all-cause in-hospital mortality by hospital discharge. We used multivariable regression to assess impact of creatinine trajectory-based classification on outcomes, and eICU database for external validation.
Among 4197 patients with AKI in critically ill patients with sepsis, we identified eight creatinine trajectory-based classes with distinct characteristics. Compared to the class with transient AKI, the class that showed severe AKI with mild improvement but persistence had highest adjusted risks for developing AKD (OR 5.16; 95% CI 2.87-9.24) and composite 7-day outcome (HR 4.51; 95% CI 2.69-7.56). The class that demonstrated late mild AKI with persistence and worsening had highest risks for developing composite hospital discharge outcome (HR 2.04; 95% CI 1.41-2.94). These associations were similar on external validation.
These 8 classes of AKI in critically ill patients with sepsis, stratified by early creatinine trajectories, were good predictors for key outcomes in patients with AKI in critically ill patients with sepsis independent of their AKI staging.
Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including ...proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
Display omitted
•TREM2-deficient microglia undergo increased autophagy in an AD mouse model•Microglia in humans with AD-risk-associated TREM2 alleles display marked autophagy•TREM2 deficiency impairs microglial mTOR activation and metabolism•Cyclocreatine improves microglia metabolism and pathology in TREM2-deficient AD mice
The Alzheimer’s disease risk factor TREM2 regulates microglial function through modulation of cellular biosynthetic metabolism.
Rationale: CRCs are known to be key determinants of patient outcomes in T2D; however, the burden of undiagnosed CRCs in unselected T2D population remains unclear, particularly in low-to-middle income ...countries (LMICs) . ‘Take CaRe of Me’ (TCOM) programme aims to determine the global burden and treatment patterns of CRCs in people with T2D without prior history of cardiovascular (CV) and renal disease.
Methods: TCOM programme records data in a cloud based repository after being reported by primary care physicians on albuminuria, eGFR, CV risk, echocardiography and treatment patterns in adults with T2D and no CRCs at index visit for early identification of CRCs. We present a descriptive analysis (up to Dec 2021) of baseline cardiorenal factors from 6 LMICs.
Results: We recruited 11335 adults (mean ±SD age, 54.8±11.4 yrs; 57.9% women, mean T2D duration, 9.8±8.0 yrs) . Mean HbA1c was 8.3±2.2% (65.8% with HbA1c >7%) . Individuals with moderate-to-high renal risk (per urine albumin-creatinine ratio) ranged from 24.8% (Mexico) to 45.1% (Philippines) and with high/very high CV risk (per ESC 2019) ranged from 31.6% (Philippines) to 45.0% (Egypt) (Table) .
Discussion: There is high burden of unrecognized CRCs in T2D in real-world setting, with >35% having moderate-to-high renal and high/very high CV risks. Our results point at the unmet need for early diagnosis, risk factor management and use of cardiorenoprotective glucose lowering drugs.
Disclosure
K.Khunti: Consultant; Abbott, Amgen Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Napp Pharmaceuticals Limited, Novartis AG, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.I.Silva: Employee; AstraZeneca. F.Surmont: Employee; AstraZeneca. H.Vasnawala: None. E.Vazquez-mendez: None. P.Fenici: Employee; AstraZeneca. S.Goncalves: None. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Joshi: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Dr. Reddy’s Laboratories Ltd., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Consultant; Biocon, Glenmark Pharmaceuticals, Sanofi, USV Private Limited. M.N.Kosiborod: Advisory Panel; Amgen Inc., Applied Therapeutics, Bayer AG, Eli Lilly and Company, ESPERION Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Pharmacosmos A/S, Sanofi, Vifor Pharma Management Ltd., Consultant; Alnylam Pharmaceuticals, Inc., Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. C.S.Lam: Other Relationship; Prosciento Inc, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Abbott, Actelion, Amgen, AnaCardio , Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cytokinetics, Darma., EchoNous, Impulse Dynamics, Ionis Pharma, Janssen R&D, Medscape/WebM, Us2.ai. A.Nicolucci: Board Member; AstraZeneca, Research Support; Novo Nordisk, PIKDARE S.p.A., Sanofi, Shionogi & Co., Ltd., Swedish Orphan Biovitrum AB, Speaker's Bureau; Eli Lilly and Company. L.Ramirez: Employee; AstraZeneca.
Funding
TCoM study was funded by AstraZeneca International
In their study, the authors aimed to prove association of positive FB after diagnosis of acute kidney injury (AKI) and an increased risk of mortality during intensive care unit (ICU) stay. In this ...study, patients with end-stage kidney disease requiring dialysis, an ICU length of stay <72 h or received RRT in the first 72 h were excluded. Declaration of competing interest There are no conflict of interest for the authors.
Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. ...However, its long-term effects on kidney and cardiovascular outcomes are unknown.
In this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m
of body-surface area, and diabetic retinopathy, or they had a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of 25 to less than 75 ml per minute per 1.73 m
. All the patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval CI, 0.73 to 0.93; P = 0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P = 0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively).
In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.).
Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter ...2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m
of body-surface area and albuminuria (ratio of albumin mg to creatinine g, >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m
), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.
The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval CI, 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.
In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. ...Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.
A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.
Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).
Background Glomerular filtration rate estimation equations use demographic variables to account for predicted differences in creatinine generation rate. In contrast, assessment of albuminuria from ...urine albumin-creatinine ratio (ACR) does not account for these demographic variables, potentially distorting albuminuria prevalence estimates and clinical decision making. Study Design Polynomial regression was used to derive an age-, sex-, and race-based equation for estimation of urine creatinine excretion rate, suitable for use in automated estimated albumin excretion rate (eAER) reporting. Setting & Participants The MDRD (Modification of Diet in Renal Disease) Study cohort (N = 1,693) was used for equation derivation. Validation populations were the CRIC (Chronic Renal Insufficiency Cohort; N = 3,645) and the DCCT (Diabetes Control and Complications Trial; N = 1,179). Index Test eAER, calculated by multiplying ACR by estimated creatinine excretion rate, and ACR. Reference Test Measured albumin excretion rate (mAER) from timed 24-hour urine collection. Results eAER estimated mAER more accurately than ACR; the percentages of CRIC participants with eAER within 15% and 30% of mAER were 33% and 60%, respectively, versus 24% and 39% for ACR. Equivalent proportions in DCCT were 52% and 86% versus 15% and 38%. The median bias of ACR was −20.1% and −37.5% in CRIC and DCCT, respectively, whereas that of eAER was +3.8% and −9.7%. Performance of eAER also was more consistent across age and sex categories than ACR. Limitations Single timed urine specimens used for mAER, ACR, and eAER. Conclusions Automated eAER reporting potentially is a useful approach to improve the accuracy and consistency of clinical albuminuria assessment.
Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This ...study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis.
This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate eGFR ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499.
Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 41% of 179 patients vs 40 23% of 178 patients; odds ratio 2·65; 95% CI 1·64–4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one <1% patient in the voclosporin group and five 3% patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.
Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis.
Aurinia Pharmaceuticals.
PDF
