A validated LC-MS/MS method for the simultaneous quantification of iothalamate and hippuran in serum and urine for non-radioactive kidney function assessment.

A novel liquid chromatography-tandem mass spectrometry method is described for the quantitative determination of the kidney function markers iothalamate and hippuran in human serum and urine. It is based on protein precipitation with methanol followed by dilution of the supernatant for serum and simple dilution for urine. The polar analytes are chromatographically separated by a 6.5-min gradient on a low-ligand density reversed-phase column; detection is performed by electrospray ionization tandem mass spectrometry in the positive ion mode against stable-isotope labeled internal standards. The results of a thorough method validation show that iothalamate and hippuran can be simultaneously quantified in the concentration ranges 0.500-30.0 ng/mL and 10.0-5000 ng/mL for serum and urine, respectively, with values for CV and absolute bias not exceeding 10 %, and with sufficient stability in all relevant matrices and solvents. The method was successfully applied for the analysis of serum and urine samples of multiple individuals who received both iothalamate and hippuran.

Canagliflozin and iron metabolism in the CREDENCE trial.

BACKGROUND AND HYPOTHESIS: Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency. METHODS: We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT < 20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively. RESULTS: Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared to placebo, increased TIBC by 2.1% (95%CI 0.4-3.8; p = 0.014) and decreased ferritin by 11.5% (95%CI 7.1-15.7; p < 0.001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2-8.5; p < 0.001) and 6.7 g/L (95% CI 5.2- 8.2; p < 0.001) in patients with and without iron deficiency, respectively (p-interaction = 0.38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (HR 0.70, 95%CI 0.56-0.87) was consistent regardless of iron deficiency (p-interaction 0.83), as were effects on other cardiovascular and mortality outcomes (all p-interactions ≥ 0.10). CONCLUSIONS: Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with T2D and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.

A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease.

Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD ,estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks treatment with standard of care plus subcutaneous cotadutide up-titrated to100, 300, or 600 µg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once-weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m2, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 µg (-43.9% [95%confidence interval -54.7 to -30.6]) and 600 µg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 µg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.

Screening for chronic kidney disease: change of perspective and novel developments.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is a serious health issue because of its rising global prevalence and its complications, such as kidney failure and cardiovascular disease (CVD). CKD is mainly diagnosed late or undiagnosed, delaying or missing the initiation of preventive interventions. Screening can prevent or delay progressive kidney function decline and CVD. This article reviews diagnostic tests and risk prediction developments for patients with CKD, highlights key evidence for targeted screening, and provides new insights into population-wide screening. RECENT FINDINGS: Large cohort studies and clinical trial data established the strong association of albuminuria with CKD outcomes, supporting the role of albuminuria as target of CKD screening and treatment. Significant advances in both risk prediction of CKD and CVD in CKD patients and treatment options provided new evidence for the relevance and implications of CKD screening. Guidelines recommend targeted screening in high-risk patients, but evidence suggests limited adherence to guideline recommendations. More recently, population-wide screening has been investigated as another approach, showing potential effectiveness and cost-effectiveness. SUMMARY: There is increasing evidence for the methods, implications, and effectiveness of CKD screening. Implementing and optimizing screening strategies requires enhanced awareness and understanding of the possibilities for CKD screening within different healthcare systems.

A randomized, open-label, clinical trial examined the effects of canagliflozin on albuminuria and eGFR decline using an individual pre-intervention eGFR slope.

Demonstrating drug efficacy in slowing kidney disease progression requires large clinical trials when targeting participants with an early stage of chronic kidney disease (CKD). In this randomized, parallel-group, open-labeled trial (CANPIONE study), we assessed the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin using the individual's change in estimated glomerular filtration rate (eGFR) slope before (pre-intervention slope) and during treatment (chronic slope). We randomly assigned (1:1) participants with type 2 diabetes, urinary albumin-to-creatinine ratio (UACR) of 50 to under 300 mg/g, and an eGFR of at least 45 ml/min/1.73m2 to receive canagliflozin or guideline-recommended treatment except for SGLT2 inhibitors (control). The first and second primary outcomes were the geometric mean percentage change from baseline in UACR and the change in eGFR slope, respectively. Of 98 randomized participants, 96 received at least one study treatment. The least-squares mean change from baseline in log-transformed geometric mean UACR was significantly greater in the canagliflozin group than the control group (between group-difference, -30.8% (95% confidence interval -42.6 to -16.8). The between-group difference (canagliflozin group - control group) of change in eGFR slope (chronic - pre-intervention) was 4.4 (1.6 to 7.3) ml/min/1.73 m2 per year, which was more pronounced in participants with faster eGFR decline. In summary, canagliflozin reduced albuminuria and the participant-specific natural course of eGFR decline in participants with type 2 diabetes and microalbuminuria. Thus, the CANPIONE study suggests that the within-individual change in eGFR slope may be a novel approach to determine the kidney protective potential of new therapies in early stages of CKD.

Cardiovascular, Kidney and Safety Outcomes with GLP-1 Receptor Agonists Alone and in Combination with SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors both improve cardiovascular and kidney outcomes in persons with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. Methods: We searched MEDLINE and Embase databases from inception until July 12, 2024 for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events ([MACE] nonfatal myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50 % reduction in estimated glomerular filtration rate (eGFR ), kidney failure or death due to kidney failure, and annualized rate of decline in eGFR (eGFR slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on PROSPERO (CRD42024565765). Results: We identified three trials with 1,743/17,072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of MACE by 21% (HR 0.79, 95% CI 0.71-0.87), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR 0.77, 95% CI 0.54-1.09 and HR 0.79, 95% CI 0.71-0.87, respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR 0.58, 95% CI 0.36-0.93 and HR 0.73, 95% CI 0.63-0.85; P-heterogeneity=0.26). Effects on the composite kidney outcome (RR 0.79, 95% CI 0.66-0.95 ) and eGFR slope (0.78 mL/min/1.73m2/year, 95% CI 0.57-0.98) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively). Conclusions: In persons with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.

Protocol and rationale for a randomized controlled SGLT2 inhibitor trial in pediatric and young adult populations with chronic kidney disease: DOUBLE PRO-TECT Alport.

BACKGROUND AND HYPOTHESIS: Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium-glucose-co-transporter-2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKD). Whether benefits extend to children, teenagers, and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2-inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years. METHODS AND RATIONALE: DOUBLE PRO-TECT Alport is a multicenter, randomized, double-blind, placebo-controlled trial (RCT). Participants (aged 10 to 39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (> 3 months) maximum tolerated dose of a renin-angiotensin-system-inhibitor (RASi) and must have a Urinary Albumin to Creatinine Ratio (UACR) of >300 mg/g (pediatric) or >500 mg/g (adult).Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day -to- matched placebo. Most participants are expected to be children with a normal glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to Week 48) and key secondary (eGFR change from baseline to Week 52) efficacy outcomes will be analyzed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation. CONCLUSION: DOUBLE PRO-TECT Alport will assess whether SGLT2-inhibitors can safely reduce change from baseline in UACR as a marker for progression of CKD in young patients living with AS.

Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD.

BACKGROUND: Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with chronic kidney disease (CKD). Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post-hoc analysis of the ZENITH-CKD trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone, and in combination with the SGLT2 inhibitor dapagliflozin. METHODS: In ZENITH-CKD, 508 patients with CKD (estimated glomerular filtration rate ≥ 20 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio of 150-5000 mg/g) were randomized to treatment with placebo, dapagliflozin 10 mg plus placebo, zibotentan (0.25, 1.5 or 5 mg) plus dapagliflozin 10 mg and zibotentan 5 mg plus placebo. We evaluated correlations between changes in fluid retention markers and bioimpedance-measured extracellular fluid (ECF) in response to zibotentan treatment. We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention, and the relationship between zibotentan plasma exposure and fluid retention. RESULTS: After 3 weeks of treatment with zibotentan 0.25, 1.5 or 5 mg plus dapagliflozin 10 mg, changes in body weight (ß=0.36 [95%CI 0.26,0.45]) per kg, B-type natriuretic peptide (ß=0.38 [95%CI 0.22, 0.54]) per doubling, and hemoglobin (ß=-0.29 [95%CI -0.48, -0.10]) per g/dL were independently associated with changes in ECF. Higher doses of zibotentan were associated with significantly higher risk of fluid retention compared to dapagliflozin alone (zibotentan 5 mg HR 8.50 (95%CI 3.40, 21.30). The hazard ratio attenuated when zibotentan was combined with dapagliflozin (HR zibotentan/dapagliflozin 5/10 mg 3.09 [95%CI 1.08, 8.80], zibotentan/dapagliflozin 1.5/10 mg 2.70 [95%CI 1.44, 5.07] and zibotentan/dapagliflozin 0.25/10 mg HR 1.21 [95%CI 0.50, 2.91]). The risk of fluid retention was higher with higher zibotentan exposure and lower eGFR. CONCLUSIONS: High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.

Effect of semaglutide on kidney function across different levels of baseline HbA1c, blood pressure, body weight and albuminuria in SUSTAIN 6 and PIONEER 6.

BACKGROUND AND HYPOTHESIS: This post-hoc analysis explored the semaglutide effects on eGFR slope by baseline glycemic control, blood pressure (BP), body mass index (BMI), and albuminuria status in people with type 2 diabetes and high cardiovascular risk. METHODS: Pooled SUSTAIN 6 and PIONEER 6 data were analyzed for change in estimated glomerular filtration (eGFR) slope by baseline HbA1c (<8%/≥8%; <64 mmol/mol/≥64 mmol/mol), systolic BP (<140/90 mmHg/≥140/90 mmHg), and BMI (<30 kg/m2/≥30 kg/m2). SUSTAIN 6 data were analyzed by baseline urinary albumin: creatinine ratio (UACR; <30/30 - 300/>300 mg/g). RESULTS: The estimated absolute treatment differences (ETD) overall in eGFR slope [95% confidence intervals] favored semaglutide versus placebo in the pooled analysis (0.59 [0.29;0.89] mL/min/1.73m2/year) and in SUSTAIN 6 (0.60 [0.24;0.96] mL/min/1.73m2/year); the absolute benefit was consistent across all HbA1c, BP, BMI, and UACR subgroups (all p-interaction > 0.5). CONCLUSION: A clinically meaningful reduction in risk of chronic kidney disease progression was observed with semaglutide versus placebo regardless of HbA1c, BP, BMI, and UACR levels.

Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials.

BACKGROUND: SGLT2 inhibitors and GLP-1 receptor agonists both improve cardiovascular and kidney outcomes in patients with type 2 diabetes. We sought to evaluate whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists. METHODS: We conducted a collaborative meta-analysis of trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium, restricted to participants with diabetes. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis. The two main cardiovascular outcomes assessed included major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and hospitalisation for heart failure or cardiovascular death. The main kidney outcomes assessed were chronic kidney disease progression (≥40% decline in estimated glomerular filtration rate [eGFR], kidney failure [eGFR <15 mL/min/1·73 m2, chronic dialysis, or kidney transplantation], or death due to kidney failure), and the rate of change in eGFR over time. Safety outcomes were also assessed. FINDINGS: Across 12 randomised, double-blind, placebo-controlled trials, 3065 (4·2%) of 73 238 participants with diabetes were using GLP-1 receptor agonists at baseline. SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR] 0·81, 95% CI 0·63-1·03 vs 0·90, 0·86-0·94; p-heterogeneity=0·31). Effects on hospitalisation for heart failure or cardiovascular death (0·76, 0·57-1·01 vs 0·78, 0·74-0·82; p-heterogeneity=0·90) and chronic kidney disease progression (0·65, 0·46-0·94 vs 0·67, 0·62-0·72; p-heterogeneity=0·81) were also consistent regardless of GLP-1 receptor agonist use, as was the effect on the chronic rate of change in eGFR over time (heterogeneity=0·92). Fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk 0·87, 95% CI 0·79-0·96 vs 0·91, 0·89-0·93; p-heterogeneity=0·41). INTERPRETATION: The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of the background use of GLP-1 receptor agonists. These findings suggest independent effects of these evidence-based therapies and support clinical practice guidelines recommending the use of these agents in combination to improve cardiovascular and kidney metabolic outcomes. FUNDING: National Health and Medical Research Council of Australia and the Ramaciotti Foundation.

Clinical trial designs to assess treatment effects on glomerular filtration rate decline.

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPA-REG Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end of treatment (chronic slope in a standard randomized trial design) with GFR change calculated from randomization to end of wash out, or GFR change from treatment-specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73 m2/year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73 m2/year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73 m2/year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73 m2/year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

Selonsertib in Patients with Diabetic Kidney Disease: A Phase 2b Randomized Active Run-In Clinical Trial.

BACKGROUND: Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease. METHODS: We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min/1.73 m2 with UACR 150 to 5000 mg/g on maximum tolerated dose of ACE inhibitor or ARB. To account for an acute selonsertib-related decrease in eGFRcr, patients entered a 4-week selonsertib run-in period to establish treatment-specific baseline eGFRcr. Patients were randomized 1:1 to selonsertib 18 mg or matching placebo once daily. We followed all participants up until the last randomized participant completed 48 weeks follow-up. The primary efficacy outcome was the difference in eGFRcr slopes from treatment-specific baselines to week 84, evaluated at a prespecified two-sided P = 0.30. We also evaluated kidney clinical events (eGFRcr ≥40% decline from pre-run-in baseline, kidney failure, or death due to kidney disease) and adverse events. RESULTS: In total, 310 patients were randomized (selonsertib n=154, placebo n=156; 68% male, mean age 65 years, mean baseline eGFRcr 35 ml/min/1.73 m2). Mean difference between selonsertib and placebo eGFRcr slopes at week 84 was 1.20 ml/min/1.73 m2/year (95% CI, -0.41 to 2.81; P = 0.14). Kidney clinical events occurred in 17% (26/154) of patients randomized to selonsertib and 12% (19/156) of those randomized to placebo (difference 4.7%; 95% CI, -6.3% to 15.9%). The most common investigator-reported adverse event was acute kidney injury (selonsertib 11.0/100 and placebo 5.9/100 patient-years). CONCLUSIONS: Selonsertib attenuated the decline in eGFRcr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported acute kidney injury.

Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease.

Introduction: Inflammation is a significant contributor to cardiorenal morbidity and mortality in diabetic kidney disease (DKD). The pathophysiological mechanisms linking systemic, subacute inflammation and local, kidney injury-initiated immune maladaptation is partially understood. Methods: Here, we explored the expression of proinflammatory cytokines in patients with DKD; investigated mouse models of type 1 and type 2 diabetes (T2D); evaluated glomerular signaling in vitro; performed post hoc analyses of systemic and urinary markers of inflammation; and initiated a phase 2b clinical study (FRONTIER-1; NCT04170543). Results: Transcriptomic profiling of kidney biopsies from patients with DKD revealed significant glomerular upregulation of interleukin-33 (IL-33). Inhibition of IL-33 signaling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model (T2D/DKD). On a cellular level, inhibiting IL-33 improved glomerular endothelial health by decreasing cellular inflammation and reducing release of proinflammatory cytokines. Therefore, FRONTIER-1 was designed to test the safety and efficacy of the IL-33-targeted monoclonal antibody tozorakimab in patients with DKD. So far, 578 patients are enrolled in FRONTIER-1. The baseline inflammation status of participants (N > 146) was assessed in blood and urine. Comparison to independent reference cohorts (N > 200) validated the distribution of urinary tumor necrosis factor receptor 1 (TNFR1) and C-C motif chemokine ligand 2 (CCL2). Treatment with dapagliflozin for 6 weeks did not alter these biomarkers significantly. Conclusion: We show that blocking the IL-33 pathway may mitigate glomerular endothelial inflammation in DKD. The findings from the FRONTIER-1 study will provide valuable insights into the therapeutic potential of IL-33 inhibition in DKD.