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Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycemia and reduce insulin requirements in type 1 (T1D) and type 2 (T2D) diabetes. While SGLT2 inhibitors lower cardiovascular disease (CVD) and end-stage kidney disease (ESKD) risk in T2D, no dedicated cardiorenal outcome trials in T1D have been done to date. Using validated risk prediction models, this study evaluated the effect of SGLT2 inhibition on estimated CVD and ESKD risk in a T1D cohort., Methods: Demographics, medical history, and biomarkers were extracted from 1,473 participants with T1D enrolled in the Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT)-1 and -2 trials. Data at baseline, 24-, 52- and 56-weeks (four weeks post-drug cessation) were used to estimate 10-year CVD and five-year ESKD risk using the Steno T1 Risk Engine (SRE) and Scottish Diabetes Research Network (SDRN) risk prediction models. Risk reduction was determined based on relative change in risk from baseline between participants receiving dapagliflozin (pooled 5 and 10 mg) vs. placebo. Subgroup analyses were conducted by age, sex, diabetes duration, CVD risk and chronic kidney disease (CKD) status at baseline., Results: The relative change in 10-year estimated CVD risk (SRE: -6.50% [-8.04, -4.95%] & SDRN: -6.77% [-8.40, -5.13%]; all P<0.001) and five-year ESKD risk (SRE: -4.48% [-7.68, -1.28%]; P=0.006) were lower at the end of 24 weeks of dapagliflozin treatment compared to placebo. Further, the greatest relative change in 5-year ESKD risk was observed at week 56 (SRE: -12.84% [-16.65, -9.03%]; P<0.001), in conjunction with an expected rise in estimated glomerular filtration rate post-drug washout. Subgroup analysis revealed larger relative lowering in 10-year CVD risk in those with CKD compared to those without (SRE: -11.3% vs -5.9%, & SDRN: -11.9% vs -6.1%, respectively; all Pinteraction<0.02)., Conclusion: Dapagliflozin improves estimated CVD and ESKD risk in T1D participants, emphasizing the need for cardiorenal outcome trials in people living with T1D., (Copyright © 2025 by the American Society of Nephrology.)

People with chronic kidney disease (CKD) are at a high risk of heart disease and end-stage kidney disease. This review describes how new medications, such as glucagon-like peptide-1 receptor agonists (GLP1RA), aldosterone synthase inhibitors (ASi), soluble guanylate cyclase (sGC) and endothelin receptor antagonists (ERA), can lower heart-kidney risk in people with CKD. GLP1RA are already recommended for managing blood sugar in people with CKD and type 2 diabetes and have been shown to lower the risk of developing end-stage kidney disease. GLP1RA will likely soon be included in clinical guidelines, but further research is needed to understand how these medications protect the kidneys. ASi are another new medication that lower the protein found in urine. Larger trials are being done to see how well these medications work in slowing CKD. Lastly, both sGC agonists and ERAs have been shown to relax blood vessels to improve blood flow in the kidney, and reduce the amount of protein found in urine, both of which are critical to protecting kidneys. Larger clinical trials are being done to see if these medications prevent CKD from getting worse. In summary, this review describes the new and promising treatments for CKD. These therapies hold the potential to slow kidney disease and improve the wellbeing of patients. Further research of these new treatments is important for improving CKD care., Abstract: Despite recent advancements in the treatment of chronic kidney disease (CKD), identifying novel therapies beyond guideline-directed therapies that reduce residual cardiorenal risk remains imperative. In this review, we highlight the clinical evidence supporting emerging therapies for CKD, including glucagon-like peptide-1 receptor agonists (GLP1RA) and other incretin-based therapies, aldosterone synthase inhibitors (ASI), endothelin receptor antagonists (ERA), soluble guanylate cyclase (sGC) agonists and anti-inflammatory drugs. Long-acting GLP1RA are already recommended for glycemic control in patients with CKD and type 2 diabetes and the large, dedicated kidney outcome trial FLOW was recently stopped early for efficacy. Emerging clinical trial evidence supports the concept that ASI also provide additional benefit on top of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which remain a cornerstone of CKD treatment. Next, we consider the use of sGC agonists, which target nitric oxide bioavailability and thereby reduce albuminuria. Finally, we explore the therapeutic potential of ERA, which act through hemodynamic and anti-fibrotic mechanisms, thereby addressing a common final pathway in the development of CKD. Accordingly, our review highlights the changing therapeutic landscape for CKD with promising agents to further prevent the progression of kidney disease., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Aims: To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D)., Methods: Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D., Results: In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip., Conclusion: The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DZIC has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. BAP has received speaker honoraria from Novo Nordisk, Insulet, Abbott, Medronic and Sanofi; has received research grant support from Novo Nordisk and BMO Bank of Montreal; and serves as an advisor to Sanofi, Novo Nordisk, Nephris, and Vertex. AA holds the Keenan Chair in Medicine at St. Michael’s Hospital and University of Toronto, and has received research support from Boehringer Ingelheim. VSS is supported by the Department of Medicine Eliot Phillipson Clinician Scientist Training Program and a Banting and Best Diabetes Centre Postdoctoral fellowship at the University of Toronto. VSS has received conference and travel support from Merck Canada. LK, YL and LEL do not have any disclosures relevant to this paper to report., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Pancreatitis, panniculitis, and polyarthritis (PPP) syndrome presents a unique challenge in diagnosis and management because of its rarity and heterogeneous initial presentation. This manuscript presents a case series of two patients with PPP syndrome, shedding light on the diagnostic process and care for this uncommon condition. PPP syndrome is characterized by the simultaneous occurrence of pancreatitis or pseudocysts alongside polyarthritis and panniculitis. While its exact pathophysiology remains obscure, pancreatic inflammation is assumed to trigger the hematogenous dissemination of pancreatic enzymes, leading to fat necrosis and subsequent panniculitis, as well as chondronecrosis and/or osteonecrosis causing polyarthritis. Despite its recognition in medical literature since the late 1980s, PPP syndrome remains poorly understood, with only a limited number of cases reported globally. Its rarity and varied initial manifestations often result in misdiagnosis, causing delays in appropriate treatment. The presented case series highlights key clinical features and diagnostic clues of PPP syndrome. Both patients exhibited initial symptoms of inflammatory polyarthritis, accompanied by characteristic findings of "ghost cells" on skin biopsy. Additionally, radiographic and laboratory evidence revealed pancreatic changes consistent with this syndrome. This case series underscores the importance of multidisciplinary collaboration in managing PPP syndrome. Early recognition and accurate diagnosis are pivotal in initiating prompt and effective therapeutic interventions, thereby improving patient outcomes and minimizing long-term sequelae., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kugathasan et al.)

Introduction: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA)., Methods: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework., Results: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab., Conclusion: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

The coexistence of cardiovascular disease (CVD) and diabetic kidney disease (DKD) is common in people with type 1 diabetes (T1D) and is strongly associated with an increased risk of morbidity and mortality. Hence, it is imperative to explore robust tools that can accurately reflect the development and progression of cardiorenal complications. Several cardiovascular and kidney biomarkers have been identified to detect at-risk individuals with T1D. The primary aim of this review is to highlight biomarkers of injury, inflammation, or renal hemodynamic changes that may influence T1D susceptibility to CVD and DKD. We will also examine the impact of approved pharmacotherapies for type 2 diabetes, including renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on candidate biomarkers for cardiorenal complications in people with T1D and discuss how these changes may potentially mediate kidney and cardiovascular protection. Identifying predictive and prognostic biomarkers for DKD and CVD may highlight potential drug targets to attenuate cardiorenal disease progression, implement novel risk stratification measures in clinical trials, and improve the assessment, diagnosis, and treatment of at-risk individuals with T1D., Competing Interests: Declaration of competing interest DZIC has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk and received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. PB reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli-Lilly, LG Chemistry, Sanofi, Novo-Nordisk, and Horizon Pharma, and on the advisory boards and/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo-Nordisk, Lilly and XORTX. PB also serves as DMC chair for Bayer. AA holds the Keenan Chair in Medicine at St. Michael's Hospital and University of Toronto. VSS has received conference and travel support from Merck Canada. LK, KLT, CX, and AA do not have any disclosures relevant to this paper to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Optimizing energy use in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter 2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of 25 mg empagliflozin orally once per day in 40 normotensive normoalbuminuric young adults with T1D. A consecutive 2-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and posttreatment visits. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways: aminoacyl-tRNA; valine, leucine, and isoleucine; arginine; and phenylalanine, tyrosine, and tryptophan. In acute hyperglycemia, empagliflozin significantly attenuated the increases in aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism., (© 2024 by the American Diabetes Association.)

Background: The use of induction therapy (IT) agents in the early post-heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx)., Methods: We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient-important outcomes, and another on patients' values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post-operative use of Thymoglobulin or Basiliximab., Results: The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post-operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab., Conclusion: This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Introduction: We evaluated the effect of relative changes in combined tacrolimus and sirolimus (drug) levels, following sirolimus initiation, on outcomes in ambulatory heart transplantation (HTx) recipients., Methods: We performed a retrospective analysis of HTx recipients who received tacrolimus, followed by sirolimus initiation, any time after HTx. We calculated the relative change in combined drug levels 1-month post-sirolimus initiation, relative to tacrolimus levels pre-initiation, and categorized patients into decreased (≥15% decrease), stable (<15% decrease to <15% increase), or increased (≥15% increase) groups. We compared, across the three groups, changes in post-initiation estimated glomerular filtration rate (eGFR) and left ventricular ejection fraction (LVEF) using one-way ANOVA and Šidák's post-hoc analysis, as well as the individual and composite outcomes of new donor specific antibodies (DSA), acute cellular rejection (ACR), and all-cause mortality using Fisher's exact test., Results: Amongst 99 HTx recipients included, the median age was 53 years, time to sirolimus initiation was 1.5 years post-HTx, and pre-sirolimus eGFR was 52 mL/min/1.73 m 2 . Nine patients had decreased, 15 stable, and 75 increased, relative combined drug levels. Relative change in eGFR was significantly higher in patients with decreased levels compared to patients with increased levels at 6 months post-initiation (P < .05), but this was not sustained at 12 months. There were no differences in LVEF change or in individual and composite risks for developing DSA, ACR, and all-cause mortality at 12 months across the groups., Conclusion: Post-sirolimus initiation, a relative decrease in combined drug levels, compared to increased levels, was associated with temporarily improved renal function., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Studies evaluating the effectiveness of care based on patients' risk of adverse outcomes (risk-guided care) use a variety of study designs. In this scoping review, using examples, we review characteristics of relevant studies and present key design features to optimize the trustworthiness of results., Study Design and Setting: We searched five online databases for studies evaluating the effect of risk-guided care among adults on clinical outcomes, process, or cost. Pairs of reviewers independently performed screening and data abstraction. We descriptively summarized the study design and characteristics., Results: Among 14,561 hits, we identified 116 eligible studies. Study designs included randomized controlled trials (RCTs), post hoc analysis of RCTs, and retrospective or prospective cohort studies. Challenges and sources of bias in the design included limited performance of predictive models, contamination, inadequacy to address the credibility of subgroup effects, absence of differences in care across risk strata, reporting only process measures as opposed to clinical outcomes, and failure to report benefits and harms., Conclusion: To assess the benefit of risk-guided care, RCTs provide the most trustworthy evidence. Observational studies offer an alternative but are hampered by confounding and other limitations. Reaching valid conclusions when testing risk-guided care requires addressing the challenges identified in our review., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Aims: We evaluated the performance of creatinine-based equations that are currently used to estimate glomerular filtration rate (GFR) in people with type 2 diabetes compared to measured GFR using gold-standard methods., Methods: In this post-hoc analysis, 32 participants underwent repeated measurement of GFR by inulin clearance (mGFR). GFR was estimated by serum creatinine using the MDRD (eGFR MDRD ) and CKD-EPI (eGFR CKD-EPI ) equations four times over the course of one month. Performance was evaluated using measurements of bias (mean difference), precision (SD), and inaccuracy (proportion of eGFR that differed by >20 % of mGFR). Treatment and time effects on bias were evaluated using linear mixed effects models., Results: At baseline, participants (38 % female) were age 60 ± 8 years, had diabetes duration of 9 ± 7 years, HbA1c 56 ± 9 mmol/mol (7.2 ± 0.8 %), and BMI 31.0 ± 6.2 kg/m 2 . Mean mGFR was 113 ± 24, mean eGFR MDRD was 93 ± 12, and mean eGFR CKD-EPI was 94 ± 9 mL/min/1.73 m 2 . When 128 observations (32 participants measured 4 times) were evaluated, both equations substantially underestimated mGFR. For eGFR MDRD , mean bias was -21.5 mL/min/1.73 m 2 , precision was 22.7 mL/min/1.73 m 2 , and 46 % of observations differed by >20 %. Results were similar for eGFR CKD-EPI . No time or treatment effects on bias were observed., Conclusions: In adults with type 2 diabetes and preserved renal function, eGFR equations underestimated mGFR, lacked precision and accuracy, and performance was lower at higher ranges of mGFR. Current eGFR equations by serum creatinine are inaccurate in adults with type 2 diabetes with preserved renal function, highlighting the necessity to develop new methods to measure kidney function at earlier stages of diabetic kidney disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JAL has received speaker honoraria and/or consulting fees from Novo Nordisk, Boehringer Ingelheim, Merck, Eli Lilly, Prometric, and AstraZenca, and grant support from Merck, Novo Nordisk, and Sanofi. PB has received consulting fees and/or research support from Bayer, Bristol-Myers Squibb and Horizon Pharma. PB has received speaking honorarium from Boehringer Ingelheim-Eli. P.B. is on the scientific advisory board for XORTX. DZIC has received speaker honoraria from Janssen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Merck and has received research grant support from AstraZeneca, Merck, and Boehringer Ingelheim. BAP has received speaker honoraria from Medtronic, Johnson & Johnson, Roche, GlaxoSmithKline Canada, Novo Nordisk, and Sanofi; has received research grant support from Medtronic and Boehringer Ingelheim; and serves as a consultant for NeuroMetrix., (Copyright © 2023. Published by Elsevier Inc.)

Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton's tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Introduction: Hypertension is a well-established risk factor for cardiovascular (CV) events in patients with chronic kidney disease (CKD), heart failure, obesity, and diabetes. Despite the usual prescribed antihypertensive therapies, many patients fail to achieve the recommended blood pressure (BP) targets., Areas Covered: This review summarizes the clinical BP-lowering data presented in major CV and kidney outcome trials for sodium-glucose cotransporter-2 (SGLT2) inhibitors, as well as smaller dedicated BP trials in high-risk individuals with and without diabetes. We have also highlighted potential mechanisms that may contribute to the antihypertensive effects of SGLT2 inhibitors, including natriuresis and hemodynamic changes, a loop diuretic-like effect, and alterations in vascular physiology., Expert Opinion: The antihypertensive properties of SGLT2 inhibitors are generally modest but may be larger in certain patient populations. SGLT2 inhibitors may have an additional role as an adjunctive BP-lowering therapy in patients with hypertension at high risk of CV disease or kidney disease.

Background: Coronavirus disease 2019 (COVID-19) has resulted in a reduction in patients seeking timely consultation for illnesses that are not related to COVID-19. Previously, we reported a decline in the number of emergency department (ED) visits and hospitalizations for acute decompensated heart failure (ADHF) during the 2020 COVID-19 pandemic vs that in 2019. We aimed to determine the consequences of these early trends on ADHF-patient morbidity and mortality., Methods: We compared consecutive patients presenting with ADHF to 3 academic medical centres in Toronto, Canada from March 1-September 28, 2020, vs those from the same time period in 2019. We used multivariate logistic regression models to evaluate whether the odds of hospitalization after presenting to the ED, recurrent ED visits or readmission within 30 days, and in-hospital all-cause mortality differed by timeframe., Results: We observed that, during the COVID-19 pandemic, a lower total number of patients presented to the hospital with ADHF, vs that in 2019. Despite this difference, the probability of being admitted to the hospital did not differ for patients seen in 2020 vs 2019. Among ADHF patients admitted to the hospital, however, we observed a significantly higher proportion being admitted to the intensive care unit, and a relative 66% increase in in-hospital mortality during the 2020 COVID-19 era, compared to that in 2019., Conclusions: Our findings suggest that improved messaging may be needed for patients living with chronic health conditions, including HF, during the pandemic, to educate and encourage them to present to hospital services when in need., (© 2022 The Authors.)