Change In Urine Albumin-creatinine Ratio Research Articles

Effect of spironolactone wash-out on albuminuria after long-term treatment in individuals with type 2 diabetes and high risk of kidney disease-An observational follow-up of the PRIORITY study.

This study aimed to explore the effect of discontinuation of long-term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study. An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re-examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin-creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow-up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium. No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI -12, 55; p = 0.28) nor the placebo (5%; 95% CI -13, 26; p = 0.63) group at follow-up. No difference in UACR between the groups was observed at follow-up (relative difference in geometric mean: 11%, 95% CI -26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05). UACR did not change after discontinuation of long-term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys.

#2500 Renal perfusion and SGLT2i

Abstract Background and Aims Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) have revolutionized treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), improving cardiovascular and renal endpoints. This improvement could be due to a decrease in renal perfusion (RP), attenuating glomerular hyperfiltration thus leading to kidney protection. This has been demonstrated in patients with type 1 diabetes and in animal studies, but not in patients with DM2 and it has never before been investigated in patients with CKD. Our aim was to examine the effects of the SGLT2i empagliflozin on RP in patients with DM2, DM2 and CKD and non-diabetic CKD, respectively. Methods We conducted three randomized, double-blind placebo controlled cross-over studies, including patients with: Participants were randomized to four weeks' treatment with empagliflozin 10 mg or matching placebo and were, after a washout period of at least two weeks, crossed over to four weeks of the opposite treatment. At the end of each treatment period we measured RP using 82Rb-PET/CT and standardized GFR using 99mTc-DTPA-clearence. We also measured 24-hour ambulatory blood pressure (BP), urinary albumin/creatinine ratio (UACR) and Hb1Ac. Results A total of 49 patients completed the studies, 16 in the DM2-group, 17 in the DM2-CKD-group and 16 in the CKD-group. In the combined study-population empagliflozin reduced RP compared to placebo by 4% (geometric mean ratio: 0.96, 95% CI: 0.94; 0.99, p = 0.0171). This change was most pronounced in the DM2-CKD-group, with a reduction of 6% (geometric mean ratio: 0.94, 95% CI: 0.91; 0.97), p &amp;lt; 0.001). There was a decrease of 4% in the DM2-group and 1% in the CKD-group, though these changes were not statistically significant (p = 0.29 and 0.72, respectively, see Fig. 1). In the 29 patients with a UACR &amp;gt; 30 mg/g, empagliflozin treatment led to a significant decrease in UACR in the combined study-population (geometric mean ratio: 0.61, 95% CI: 0.46; 0.80, p = 0.001), again primarily driven by a decrease in the DM2-CKD-group (geometric mean ratio: 0.51, 95% CI: 0.31; 0.85, p = 0.014), with non-significant decreases in the remaining groups. Empagliflozin decreased standardized GFR and BP in the combined population as well as in all sub-groups, while we found no change in Hb1Ac. For further details, see Table 1. Conclusion Short-term empagliflozin treatment reduces RP, GFR, BP and albumin excretion. Relative changes in RP and UACR were most pronounced in patients with concomitant DM2 and CKD, whereas changes in BP and GFR were seen in all groups.

Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial.

Key Points The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD.Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo.Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. Background Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia. Methods In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60. Results Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups. Conclusions Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo. Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363.

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: The FINE-ONE trial

AimsDespite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. MethodsFINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months’ duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200–< 5000 mg/g (≥ 22.6–< 565 mg/mmol) and eGFR of ≥ 25–< 90 ml/min/1.73 m2. ResultsThe primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. ConclusionsFINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years.Trial registration:ClinicalTrials.gov NCT05901831.

Additive effects of dapagliflozin and finerenone on albuminuria in non-diabetic CKD: an open-label randomized clinical trial.

Dapagliflozin and finerenone reduce albuminuria and slow CKD progression, but additive effects remain unstudied. We compared their individual and combined efficacy and safety in patients with non-diabetic CKD. In an open-label, randomized clinical trial, we included patients aged 18-80 on maximal tolerated ACE inhibitor or angiotensin receptor blocker with eGFR 25-45mL/min/1,73m2 and albuminuria 150-2000mg/g. Participants received either finerenone 20mg/day or dapagliflozin 10mg/day for four weeks, followed by combination therapy for four weeks. Data were collected at baseline, 4 and 8 weeks. Twenty patients (10 per group) with a mean mGFR of 34mL/min/1,73 m2 and a mean urine albumin creatinine ratio (UACR) of 469mg/g were included. Finerenone alone or in addition to dapagliflozin resulted in -24% (95% CI, -36% to -11%) and -34% (95% CI, -47% to -18%) change in UACR, respectively. Dapagliflozin alone or in addition to finerenone resulted in -8% (95% CI, -22 to 9%) and -10% (95% CI, -28% to 12%) change in UACR, respectively. Overall, UACR change after 8 weeks was -36% (95% CI, -46% to -24%). After 8 weeks, systolic blood pressure and mGFR were reduced by 10mmHg (95% CI, 6-13mmHg) and 7mL/min/1,73 m2 (95% CI, 5-8mL/min/1,73 m2). Adverse effects were minimal. The combination of finerenone and dapagliflozin was safe and significantly reduced albuminuria. The effect of combination therapy was at least equal to the calculated, combined effect of each of the drugs, suggesting an additive effect on albuminuria. Larger studies assessing long-term effects and safety are warranted.

Albuminuria-lowering effect of adding semaglutide on top of empagliflozin in individuals with type 2 diabetes: A randomized and placebo-controlled study.

To investigate whether combined treatment with empagliflozin (a sodium-glucose cotransporter-2 inhibitor) and semaglutide (a glucagon-like peptide-1 receptor agonist) can reduce urinary albumin-creatinine ratio (UACR) compared to treatment with empagliflozin alone in individuals with type 2 diabetes (T2D) and albuminuria. We conducted a randomized, placebo-controlled, double-blind, parallel study including 60 individuals with T2D and albuminuria. All participants initiated open-label empagliflozin 25 mg once daily, on top of renin-angiotensin system inhibition, in a run-in period of 26 weeks. Subsequently, participants were randomized to semaglutide or placebo 1 mg once weekly for 26 weeks. The primary endpoint was change in UACR. Secondary endpoints were change in: (i) measured glomerular filtration rate (GFR); (ii) 24-hour systolic blood pressure; (iii) glycated haemoglobin (HbA1c) level; (iv) body weight; and (v) plasma renin and aldosterone levels. Addition of semaglutide to empagliflozin provided no additional change in UACR from randomization to end-of-treatment. The mean (95% confidence interval) difference in UACR was -22 (-44; 10)% (P = 0.15) between treatment groups. Neither GFR, 24-hour blood pressure, body weight, nor plasma renin activity was changed with semaglutide. HbA1c (-8 [-13; -3] mmol/mol; P = 0.003) and plasma aldosterone (-30 [-50; -3] pmol/L; P = 0.035) were reduced with semaglutide compared to placebo. Semaglutide added to empagliflozin did not change UACR, measured GFR, 24-hour systolic blood pressure, body weight or plasma renin levels in individuals with T2D and albuminuria. Semaglutide improved glycaemic control and plasma aldosterone levels compared to placebo.

884-P: Decentralized N=1 Study—A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin

Background: The SGLT2 inhibitor dapagliflozin reduces kidney function decline and urine albumin:creatinine ratio (UACR) on a population level. However, there is marked heterogeneity in the efficacy among individual patients. We conducted a decentralized (i.e. at home) N=1 trial to assess the effect of dapagliflozin in individual patients and the feasibility of remote data collection. Methods: Twenty patients with type 2 diabetes, UACR &amp;gt;20 mg/g and eGFR &amp;gt;30 mL/min/1.73m2 entered the randomized placebo-controlled double-blind N=1 trial. Patients were randomly assigned to two periods of 1-week treatment with dapagliflozin 10 mg/day and two periods of 1-week treatment with placebo in random order with 1-week wash-out periods in between. Patients collected and sent their own data with automatic uploading to an online platform and sent early morning urines 5 times/week to the laboratory for albumin and creatinine assessment. Primary outcome was UACR change from baseline (mixed effects model). The study had 80% power to detect a correlation in UACR change between first and second dapagliflozin period of 0.6. Results: Patients had a mean eGFR of 70.2 mL/min/1.73m2 and median UACR of 94.7 mg/g. During the study, dapagliflozin compared to placebo reduced albuminuria by 15.1% (95%CI 3.3 - 28.2; p=0.013). There was a marked variation in the change from baseline in UACR during dapagliflozin treatment periods (range first and second exposure -26.9 to -4.7% and -30.5 to -5.8%, respectively). The individual change in UACR during the first and second exposure correlated in the dapagliflozin periods (r=0.50; p=0.026) but not in the placebo periods (r=0.09; p=0.69). Of all scheduled urine collections (N=816), only 5 collections (0.61%) were not delivered in the laboratory. Conclusion: The individual UACR response to dapagliflozin varies among individual patients and is consistent upon re-exposure. Remote data collection was very reliable with nearly any missed urine collection. Disclosure J.Beernink: None. G.D.Laverman: Advisory Panel; AstraZeneca, Vifor Pharma Management Ltd., Boehringer Ingelheim Inc., Astellas Pharma Inc., Lilly, Other Relationship; Sanofi, AstraZeneca. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck &amp; Co., Inc., Janssen Research &amp; Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.Jongs: Speaker's Bureau; AstraZeneca.

#4441 KIDNEY DISEASE OUTCOMES WITH SEMAGLUTIDE VERSUS PLACEBO ACROSS BASELINE KDIGO RISK CATEGORIES: A POST HOC ANALYSIS OF SUSTAIN 6

Abstract Background and Aims The Kidney Disease: Improving Global Outcomes (KDIGO) risk categories classify risk of progression of chronic kidney disease (CKD) and cardiovascular (CV) complications based on estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (UACR). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended by the KDIGO 2022 Clinical Practice Guidelines for Diabetes and CKD in patients with type 2 diabetes (T2D) and CKD who need better glycaemic control or CV risk reduction. In patients with T2D, once-weekly (OW) semaglutide, a GLP-1RA, reduces albuminuria and may preserve eGFR compared with placebo, irrespective of baseline eGFR or UACR. The aim of this analysis was to assess the treatment effects on kidney outcomes of OW semaglutide by KDIGO risk category at baseline compared with placebo. Method In a post hoc analysis from the SUSTAIN 6 trial (NCT01720446), randomised patients with T2D (N = 3,297) treated with OW semaglutide (0.5 and 1.0 mg) or placebo were stratified by baseline KDIGO risk category (low, moderate, high, and very high). The median follow-up time was 2.1 years. The treatment effect on the adjudicated endpoint of time to first new or worsening nephropathy (a composite of macroalbuminuria onset, doubling of serum creatinine and eGFR &amp;lt;45 mL/min/1.73 m2, need for kidney replacement therapy, or death due to kidney disease) across KDIGO categories was analysed using Cox regression. Analyses of treatment for eGFR slope and change in UACR (log-transformed) across KDIGO categories were performed using random slope modelling and mixed models adjusted for baseline UACR and assessed at 104 weeks. Results Participants with baseline eGFR and UACR values (N = 3,238) were stratified in to the low (n = 1,596 [49%]; 60% male; mean 64 years), moderate (n = 831 [26%]; 62% male; mean 65 years), high (n = 445 [14%]; 62% male; mean 66 years) and very high (n = 366 [11%]; 59% male; mean 67 years) KDIGO risk categories. Regardless of treatment group, participants in the moderate-, high- and very high-risk groups were more likely to experience the new or worsening nephropathy endpoint vs participants in the low-risk group at end of trial (hazard ratios [95% confidence intervals] 15.7 [8.0;35.7], 15.7 [7.7;36.6] and 23.9 [11.5;55.9], respectively). The treatment effect of OW semaglutide vs placebo was comparable in the low-, moderate-, high- and very high-risk categories (n = 785, 433, 227 and 171 for semaglutide and n = 811, 398, 218 and 195 for placebo, respectively) for new or worsening nephropathy (pinteraction = 0.28), eGFR slope (pinteraction = 0.44) and change in UACR (pinteraction = 0.84; Figure). Conclusion Participants in the higher risk groups had substantially greater hazards of adverse kidney outcomes compared with participants in the low-risk group, as predicted by KDIGO risk category classification. The treatment effect of OW semaglutide vs placebo on risk of new or worsening nephropathy, eGFR slope and change in UACR was consistent across KDIGO risk categories. The ongoing FLOW kidney outcomes trial has a population with T2D and CKD that corresponds to the high- and very high-risk KDIGO categories, and it will provide primary outcome data on potential kidney-protective effects of OW semaglutide; results are anticipated in 2024.

#3318 PHASE II DOSE-SELECTION, RANDOMISED DOUBLE-BLIND TRIAL OF THE ASI, BI 690517, ALONE AND IN COMBINATION WITH EMPA IN PEOPLE WITH CKD

Abstract Background and Aims Elevated aldosterone levels are associated with chronic kidney disease (CKD) progression and adverse kidney and cardiovascular disease outcomes. Therapy with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) improves clinical outcomes, yet elevated aldosterone levels often persist. BI 690517 is a first-in-class, selective aldosterone synthase inhibitor (ASi) that may reduce deleterious mineralocorticoid receptor-dependent and -independent actions of aldosterone. Coadministration of BI 690517 with a sodium–glucose cotransporter-2 inhibitor could mitigate the risk of hyperkalaemia. This study is investigating the efficacy and safety of three doses of BI 690517, alone and in combination with empagliflozin (EMPA), on top of an ACEi or ARB, for treatment of CKD with or without type 2 diabetes. Method A randomised, double-blind, placebo-controlled, parallel-dose Phase II trial (NCT05182840) in adults with or without type 2 diabetes who had an estimated glomerular filtration rate (eGFR) ≥30 and &amp;lt;90 mL/min/1.73 m2, urine albumin:creatinine ratio (UACR) ≥200 and &amp;lt;5000 mg/g, and serum potassium ≤4.8 mmol/L on stable background therapy with an ACEi or ARB. After an 8-week run-in period to assigned background therapy (EMPA 10 mg or matched placebo randomised 1:1), participants were randomised 1:1:1:1 to BI 690517 (low, medium or high dose) or matched placebo for 14 weeks. Primary outcome was the change in UACR measured in a first morning void (UACRFMV) from baseline to Week 14. Secondary outcomes were the proportion of participants with ≥15 and 30% decreases in UACRFMV. Safety outcomes and changes in eGFR and serum potassium were also evaluated. Results Recruitment is complete, with 1719 participants from 168 sites in 29 countries screened. In total, 714 were randomised and entered the run-in period (last randomisation on 30 December 2022). The trial is currently ongoing; data on baseline characteristics will become available and shared. Conclusion This study will provide key data on the potential synergistic kidney-protective effects and safety of combination therapy with BI 690517 plus EMPA, as well as data on monotherapy, for CKD with or without type 2 diabetes. Findings will inform BI 690517 dose selection for further clinical trial development.

#3000 EFFICACY AND SAFETY OF COTADUTIDE, A DUAL GLP1-GLUCAGON RECEPTOR AGONIST, IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND T2DM

Abstract Background and Aims Cotadutide is a dual GLP1-glucagon receptor agonist under development for NASH and CKD with T2DM. Incretin-based therapies have been shown to promote improvements in albuminuria while the addition of glucagon has been suggested to provide hepatic benefits; the renal benefits of dual GLP1-glucagon receptor agonism are unknown but kidney and liver are the organs with highest expression of glucagon receptor. We sought to evaluate the efficacy and safety of cotadutide in patients with CKD and T2DM. Method In this randomised, double-blind, phase 2b study, patients with T2DM and CKD on insulin and/or oral therapy including ≥ 40% treated with SGLT-2i (HbA1c ≥ 6.5 and ≤ 10.5%), eGFR ≥ 20 and &amp;lt; 90 ml/min/1.73m2 and BMI ≥ 25 (23 in Japan) kg/m2 were treated for 26 weeks. Participants were randomised (n = 45 per arm) to receive once-daily SC cotadutide titrated up to 100, 300 or 600 µg, or placebo. The primary endpoint was percentage change in UACR (log-transformed) at 14 weeks. Secondary endpoints evaluated urinary albumin creatinine ratio (UACR) at 26 weeks, safety and tolerability. Changes in renal function was evaluated as an exploratory endpoint. Results A total of 248 Participants were randomised. Approximately 47% were on SGLT-2i and 97% were on ACE inhibitors or ARBs at baseline. The primary endpoint was met. Dose dependent reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 µg of cotadutide, -39.9% (95% CI -52,5, -23.9) and -46.0% (95% CI -57.1, -32.1) vs placebo (P &amp;lt;0.001). In patients on background SGLT2i therapy, similar reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 µg of cotadutide, - 31.2% (95% CI – 51.9, -1.5) and - 48.7% (95% CI -64.1, - 26.6) vs placebo (P = 0.01 and &amp;lt;0.001 respectively). There was no observed change in eGFR early in dosing. At 26 weeks, an increase in eGFR (+5.5 ml/min/1.73m2) was observed with 600 µg of cotadutide (p = 0.028). A statistically significant, modest reduction in serum uric acid was observed as an exploratory endpoint at 26 weeks in the 100 and 600 µg arms (- 0.54 mg/dL, p = 0.03 and 0.76 mg/dL, p = 0.001 respectively) but not the 300 µg arm (- 0.32 mg/dL, p = 0.17). No significant changes in urine KIM-1 were observed. A significant increase in pulse rate was observed (+4.8 bpm), alongside a numerical reduction in systolic BP (-8.3 mmHg) at 600 µg on office-based measures. SAEs were balanced across all arms and there were fewer AE-related discontinuations at 100 and 300 ug versus placebo, but more discontinuations at 600 µg. Conclusion In patients with CKD with T2DM, cotadutide promoted clinically important effects on UACR on top of standard of care with an acceptable tolerability profile. The results suggest cotadutide has potential to provide benefit to patients with CKD and T2DM. Larger studies will be required to evaluate this.

Endothelin and the role of venous capacitance in fluid retention with endothelin antagonists -- a mathematical modeling analysis

Background and objectives: Selective endothelin-1 (ET1) receptor A (ETA) antagonists have been evaluated for the treatment of chronic kidney disease and cancer. However, the investigation has been challenged due to the increased safety concern of fluid retention, which can increase the risk of heart failure. The mechanisms responsible for the fluid retention remain incompletely understood, in part because of the complexity of the endothelin system. The objective of this study was to incorporate the physiology of ET1, its receptors ETA and ETB, and their mechanisms of action into an existing model of cardiorenal function, and to investigate physiological mechanisms that may explain fluid retention observed with endothelin receptor antagonists. Methodology: Processes of ET1 production from BigET-1, distribution between peripheral compartments (kidney/lung) and blood, binding to ETA/ETB, and clearance were modeled. Parameters were estimated by fitting to experimental studies of ET-1 kinetics following ET-1 or BigET-1 infusion. A minimal set of physiological effects of ET1-bound ETA and ETB were estimated by fitting published experimental data of ET1 infusion with and without ETA or ETB antagonism in healthy subjects. The model was then used to simulate changes in eGFR, mean arterial pressure (MAP), urinary albumin creatinine ratio (UACR), and hematocrit with the ETA antagonist atrasentan in the RADAR clinical trial. Results and Conclusions: The model describes ET-1 kinetics well, and reproduces responses to ET1 infusion in healthy subjects, including changes in GFR, renal blood flow, renal vascular resistance, urinary sodium/water excretion, and mean arterial pressure. It was also able to differentiate the response to ETA and ETB antagonism. The determined minimal set of necessary mechanisms were: systemic, afferent, and efferent vasoconstriction and proximal tubule sodium retention through ETB; efferent dilatation and reduced collecting duct sodium and water reabsorption through ETB. While these mechanisms described the response in healthy subjects well and reproduced the reduction in MAP with atrasentan in the RADAR study, the the model initially underpredicted the change in UACR and predicted hematocrit would decrease, when in fact the study showed an increase, reflecting fluid retention and increased blood volume. We hypothesized that the changes in MAP and blood volume in opposite directions in RADAR indicate increased venous capacitance with ETA antagonism due to venodilation. Adding this single mechanistic effect (i.e. ET-1 induced vasoconstriction) into the model allowed it to fully reproduce the MAP, UACR, and hematocrit response in RADAR. In addition, simulations with the model illustrate the mechanisms by which venodilation can alter starling forces, leading to redistribution of fluid, a vasopressin response, and fluid retention with ETA antagonism. AstraZeneca Pharmaceuticals This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Efficacy of Direct Renin Inhibitors in Slowing Down the Progression of Diabetic Kidney Disease: A Meta-Analysis.

Albuminuria is a risk factor for chronic kidney disease and cardiovascular events in diabetic people. The pathogenic processes in these circumstances have been documented to be significantly influenced by enhanced renin-angiotensin system activity. The current meta-analysis was carried out to assess the efficacy of direct renin inhibitors in preventing the progression of diabetic kidney disease. This meta-analysis was conducted as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched the relevant medical literature through PubMed, Cochrane library and EMBASE. The primary efficacy outcome was a percentage change in urine albumin-creatinine ratio (UACR) (in mg/g) level. Other primary efficacy outcomes included remission from microalbuminuria to normal albuminuria and progression from microalbuminuria to macroalbuminuria. Four randomized control studies were identified and included in the current meta-analysis involving 9,609 participants. The use of direct renin inhibitors was superior in reducing mean UACR compared to angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. The pooled mean difference in UACR between direct renin inhibitors and the control group was 9.42% (95% CI: -15.70 to -3.15: p-value=0.003). The odds of progression from microalbuminuria to normal albuminuria are 1.26 times higher in patients receiving direct renin inhibitors compared to patients in the control group (OR: 1.26, 95% CI: 1.08-1.46, p-value=0.002). The odds of remission from microalbuminuria to macroalbuminuria were 20% lower in patients receiving direct renin inhibitors compared to patients in the control group (OR: 0.80, 95% CI: 0.69-0.93, p-value=0.003). The use of aliskiren is associated with a significant reduction in UACR, increased remission from microalbuminuria to normal albuminuria and decreased progression from microalbuminuria to macroalbuminuria.

Chlorthalidone and Advanced Chronic Kidney Disease.

Chlorthalidone and Advanced Chronic Kidney Disease.

Endothelin Receptor Antagonists for Kidney Protection: Lessons from the SONAR Trial.

Endothelin Receptor Antagonists for Kidney Protection: Lessons from the SONAR Trial.

Association of Metals and Metalloids With Urinary Albumin/Creatinine Ratio: Evidence From a Cross-Sectional Study Among Elderly in Beijing.

BackgroundEnvironmental exposure to toxic elements contributes to the pathogenesis of chronic kidney disease (CKD). Few studies focus on the association of urinary metals and metalloids concentrations with the urinary albumin/creatinine ratio (UACR) among elderly, especially in areas and seasons with severe air pollution.ObjectiveWe aimed to evaluate the associations of urinary metals and metalloids concentration with UACR, which is an early and sensitive indicator of CKD.MethodWe conducted a cross-sectional study among 275 elderly people in Beijing from November to December 2016, which has experienced the most severe air pollution in China. We measured 15 urinary metals and metalloids concentration and estimated their association with UACR using a generalized linear model (GLM). Bayesian kernel machine regression (BKMR) and quantile g-computation (qgcomp) models were also conducted to evaluate the combined effect of metal and metalloid mixtures concentration.ResultsOf the 275 elderly people included in the analysis, we found that higher urinary Cu concentration was positively associated with UACR using GLM (β = 0.36, 95% CI: 0.25, 0.46). Using the BKMR model, we found that the change in UACR was positively associated with a change in urinary Cu concentration from its 25th to 75th percentile value with all other metals and metalloids concentration fixed at their 25th, 50th, or 75th percentile levels. Urinary Cu concentration had the most significant positive contribution (59.15%) in the qgcomp model. Our finding was largely robust in three mixture modeling approaches: GLM, qgcomp, and BKMR.ConclusionThis finding suggests that urinary Cu concentration was strongly positively associated with UACR. Further analyses in cohort studies are required to corroborate this finding.

Trial in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase IIa CROSSWALK-c Trial Evaluating the Efficacy of Crovalimab As Adjunct Treatment in the Prevention of Vaso-Occlusive Episodes (VOEs) in Patients with Sickle Cell Disease (SCD)

BackgroundSCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β- globin gene, with either homozygous inheritance, or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. This point mutation results in the production of hemoglobin S, which polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. In addition to VOEs, patients with SCD may experience severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. The current treatment strategy for patients with SCD includes hydroxyurea, along with newer treatments such as L-glutamine, crizanlizumab, and voxelotor. However, despite the availability of these treatments, considerable morbidity and mortality among patients with SCD represents a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crisis, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. Crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety in a Phase I/II study (Röth et al. Blood 2020), in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder.Study Design and MethodsCROSSWALK-c (NCT number pending) is a placebo-controlled, randomized, double-blind, Phase IIa study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0), and presenting with ≥ 2 to ≤ 10 VOEs are eligible for this study. Patients on concurrent SCD-directed therapies are also eligible. Vaccination against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumonia are required for enrollment. Patients with a history of hematopoietic stem cell transplant are excluded from the study. Eligible patients will be randomized 1:1 to the crovalimab or placebo treatment arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be administered on Day 1 Week 1, followed by four weekly SC doses on Day 2 Week 1, and then on Weeks 2-4. Maintenance dosing will be administered from Week 5, followed by once every 4 weeks thereafter, for 48 weeks. All patients will receive study treatment according to a weight-based tiered dosing schedule. The primary objective is to evaluate the efficacy of crovalimab compared with placebo, based on the annualized rate of medical facility VOEs. Secondary efficacy objectives include the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin-creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetics, immunogenicity, and exploratory biomarker objectives will also be evaluated. [Display omitted] DisclosuresCallaghan: Agios Pharmaceuticals: Current Employment; Roche/Genentech: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy, Speakers Bureau; Forma: Consultancy; Hema Biologics: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; BioMarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Chiesi: Consultancy; Kedrion: Consultancy; Pfizer: Consultancy. Ataga: Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: CSL Behring: Other: Endpoint adjudicator ; Forma: Consultancy; Novo Nordisk: Consultancy; Chiesi: Consultancy; Bluebird Bio: Other: Endpoint adjudicator ; Novartis: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy. Balachandran: F. Hoffmann-La Roche Ltd: Current Employment. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Perretti: F. Hoffmann-La Roche Ltd: Current Employment. Ramos: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Bartolucci: Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; INNOVHEM: Other: Co-founder; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Hemanext: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy.

Changes in GFR and Albuminuria in Routine Clinical Practice and the Risk of Kidney Disease Progression

Changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used separately as alternative kidney disease outcomes in randomized trials. We tested the hypothesis that combined changes in UACR and eGFR predict advanced kidney disease better than either alone. Observational cohort study. 91,319 primary care patients assembled from the Clinical Practice Research Datalink in the United Kingdom between 2000 and2015. Changes in UACR and eGFR (categorized as≥30% increase, stable, or≥30% decrease), alone and in combination, over a 3-year period. The primary outcome was advanced CKD (sustained eGFR<30 mL/min/1.73 m2); secondary outcomes included kidney failure, cardiovascular disease, and all-cause mortality. Multivariable Cox regression with bias from missing values assessed using multiple imputation; discrimination statistics compared across exposure groups. 91,319 individuals were studied, with amean eGFR of 72.6 mL/min/1.73 m2 and medianUACR of 9.7 mg/g; 70,957 (77.7%) had diabetes. During a median follow-up of 2.9 years, 2,541 people progressed to advanced CKD. Compared with stable values, hazard ratios for a≥30% increase in UACR and≥30% decrease in eGFR were 1.78 (95% CI, 1.59-1.98) and 7.53 (95% CI, 6.70-8.45), respectively, for the outcome of advanced CKD. Compared with stable values of both, the hazard ratio for the combination of an increase in UACR and a decrease in eGFR was 15.15 (95% CI, 12.43-18.46) for the outcome of advanced CKD. The combination of changes in UACR and eGFR predicted kidney outcomes better than either alone. Selection bias, relatively small proportion of individuals without diabetes, and very few kidney failure events. In a large-scale general population, the combination of an increase in UACR and a decrease in eGFR was strongly associated with the risk of advanced CKD. Further assessment of combined changes in UACR and eGFR as an alternative outcome for kidney failure in trials of CKD progression is warranted.

Association of Diet Quality Indices with Longitudinal Changes in Kidney Function in U.S. Hispanics/Latinos: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Recent studies suggest an association between diet quality and incident CKD. However, Hispanics/Latinos were under-represented in these studies. We examined the relationship of diet quality with change in kidney function in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Individuals who participated in HCHS/SOL visits 1 (2008-2011) and 2 (2014-2017) were analyzed (n=9921). We used Alternate Healthy Eating Index 2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), and Mediterranean Diet (MeDS) scores as measures of dietary quality. Scores were calculated from two 24-hour dietary recalls administered at visit 1 and categorized into quartiles of each dietary score (higher quartiles correspond to a healthier diet). Kidney function was assessed at both visits using eGFR and urine albumin-creatinine ratio (UACR). Annualized change was computed as the difference in eGFR or UACR between visits divided by follow-up time in years. Weighted linear-regression models were used to examine the association between quartiles of each dietary quality index and annualized change in eGFR and UACR, adjusted for potential confounders. At visit 1, the mean (SD) age of participants was 41 (0.28) years, and 56% were female. The baseline mean eGFR was 107.1 ml/min per 1.73 m2, and baseline median UACR was 6.1 mg/g. On average, eGFR declined by 0.65 ml/min per 1.73 m2 per year, and UACR increased by 0.79 mg/g per year over a 6-year period. Lower AHEI-2010 quartiles were associated with eGFR decline in a dose-response manner (P trend=0.02). Higher AHEI-2010 quartiles showed a trend toward lower annualized change in UACR, but the result did not reach significance. Neither MeDS nor DASH scores were associated with eGFR decline or change in UACR. Unhealthy diet, assessed at baseline by AHEI-2010, was associated with kidney-function decline over 6 years. Improving the quality of foods and nutrients according to the AHEI-2010 may help maintain kidney function in the Hispanic/Latino community.

Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial

Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks:-38.6% (90% CI,-60.9% to-3.6%),-39.4% (90% CI,-61.8% to-3.8%), and-49.3% (90% CI,-68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. This study was supported by AstraZeneca. Registered at ClinicalTrials.gov with study number NCT03118739.

Effect of high-dose mineralocorticoid receptor antagonist eplerenone on urinary albumin excretion in patients with type 2 diabetes and high cardiovascular risk: Data from the MIRAD trial

AimAs mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints—namely, change in urinary albumin–creatinine ratio (UACR) and 24-h ambulatory blood pressure—in the MIRAD trial. MethodsThis was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100–200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events. ResultsA total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13–22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: −51% to −12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (−3 mmHg; 95% CI: −6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m2, and 12 (± 9%) had an eGFR of 41–59 mL/min/1.73 m2. No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed. ConclusionThe addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.