Changes In Urinary Albumin-to-creatinine Ratio Research Articles

Markers of Kidney Injury, Inflammation, and Fibrosis Associated With Ertugliflozin in Patients With CKD and Diabetes

IntroductionSodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD).MethodsParticipants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks.ResultsErtugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed.ConclusionIn conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function.

Combined changes in albuminuria and kidney function and subsequent risk for kidney failure in type 2 diabetes

IntroductionChanges in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether...

Change in Urine Albumin-to-Creatinine Ratio and Risk of Diabetic Peripheral Neuropathy in Type 2 Diabetes: A Retrospective Cohort Study.

PurposeThis study aimed to assess association between change in urine albumin-to-creatinine ratio (UACR) and the risk of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus.Patients and MethodsA retrospective study was performed, which included 185 individuals with type 2 diabetes. At baseline, and at two-year follow-up, we collected basic data, recorded symptoms and signs of DPN, measured biochemical indicators, composite motor nerve conduction velocity (composite MCV), and composite sensory nerve conduction velocity (composite SCV).ResultsChanges of composite SCV, MCV and TCSS among different changes in UACR in patients without DPN and with DPN were not significantly different. An increase in UACR ≥30% (OR 3.059, 95%; CI: 1.012–9.249) suggested a risk for new-onset DPN. Based on ROC curve analysis, the areas under the curve were 0.654 ± 0.066 for change of UACR levels in non-DPN patients.ConclusionChange in UACR and NCV was not related in patients without DPN and with DPN; change in UACR ≥30% suggested a risk for new-onset DPN.

Dose-Response Mixed Models for Repeated Measures \u2013 a New Method for Assessment of Dose-Response

PurposeIn this paper we investigated a new method for dose-response analysis of longitudinal data in terms of precision and accuracy using simulations.MethodsThe new method, called Dose-Response Mixed Models for Repeated Measures (DR-MMRM), combines conventional Mixed Models for Repeated Measures (MMRM) and dose-response modeling. Conventional MMRM can be applied for highly variable repeated measure data and is a way to estimate the drug effect at each visit and dose, however without any assumptions regarding the dose-response shape. Dose-response modeling, on the other hand, utilizes information across dose arms and describes the drug effect as a function of dose. Drug development in chronic kidney disease (CKD) is complicated by many factors, primarily by the slow progression of the disease and lack of predictive biomarkers. Recently, new approaches and biomarkers are being explored to improve efficiency in CKD drug development. Proteinuria, i.e. urinary albumin-to-creatinine ratio (UACR) is increasingly used in dose finding trials in patients with CKD. We use proteinuria to illustrate the benefits of DR-MMRM.ResultsThe DR-MMRM had higher precision than conventional MMRM and less bias than a dose-response model on UACR change from baseline to end-of-study (DR-EOS).ConclusionsDR-MMRM is a promising method for dose-response analysis.

Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker

Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin–angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (−1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

Propagermanium administration for patients with type 2 diabetes and nephropathy: A randomized pilot trial.

SummaryAimsWe assessed the potential efficacy and safety of propagermanium (PG), an organic compound that inhibits the C–C chemokine receptor type 2, administration in patients with type 2 diabetes and nephropathy. Furthermore, we assessed the feasibility of future studies.Materials and methodsWe recruited patients from nine medical institutions in Japan for this randomized, open‐label, parallel two‐arm pilot trial. Inclusion criteria were diagnosis of type 2 diabetes, age 30‐75 years, dipstick proteinuria of ≥1+ or urinary albumin‐to‐creatinine ratio (UACR) of ≥30 mg/g and estimated glomerular filtration rate of ≥30 mL/min/1.73 m2. Patients were randomly assigned (1:2) using a minimization algorithm to either continuing usual care or concomitant administration of 30 mg PG per day for 12 months. The primary outcome was the change in UACR from baseline to 12 months. We also collected safety information for all patients who received at least one dose of PG.ResultsWe enrolled 29 patients, 10 were assigned to continue usual care and 19 to receive PG. Changes in UACR by PG in addition to the usual care were 25.0% (95% CI −20.4%, 96.5%, P = .33). No severe adverse events or renal events were observed during the study.ConclusionAlthough the treatment with PG was generally well tolerated, the dosage of 30 mg/d for 12 months did not reduce albuminuria when used in addition to usual care in patients with type 2 diabetes and nephropathy. Efficacy of PG should be verified in future definitive trials.

494-P: Effects of a Novel Xanthine Oxidase Inhibitor, TMX-049, on Urinary Albumin Excretion in Patients with Type 2 Diabetes and Albuminuria

Background: TMX-049 is a novel xanthine oxidase (XO) inhibitor that reduced both liver and kidney XO activity and decreased albuminuria in a type 2 diabetes (T2D) rat model. This 12-week, placebo-controlled, double-blind study (ClinicalTrials.gov: NCT03449199) was designed to assess effects of TMX-049 40 or 200 mg (T40 or T200) compared to placebo (P) on urinary albumin to creatinine ratio (UACR) in participants with T2D and albuminuria despite treatment with an angiotensin inhibitor. Methods: Eligible participants had T2D, HbA1c ≤ 11%, UACR 200-3000 mg/g, CKD-EPI eGFR ≥ 30 ml/min/1.73 m2 and serum uric acid (sUA) 4-10 mg/dL and were randomized to P (n=42), T40 (n=44) or T200 (n=44). The primary efficacy analysis utilized change from Baseline to Week 12 (or the last observation) in log-transformed UACR in an analysis of covariance (ANCOVA) model. Results: Reductions in UACR from Baseline to Week 12 were P: 9%, T40: 14%, T200: 41%; the difference in change was statistically significant vs. P in the T200 group (p=0.031) but not in the T40 group (p=0.795). The reduction with T200 relative to P was 35% (95% CI: 4-56%). Mean changes in sUA were T40: -2.4 mg/dL and T200: -3.2 mg/dL (p&amp;lt;0.001 vs. placebo for both comparisons). A correlation between sUA and UACR change was not apparent in either the T40 or the T200 group. Both TMX-049 doses were generally well tolerated but 2 participants in the T200 group had episodes of gout. The proportion with any AE (P: 45%, T40: 43%, T200: 39%) or any serious AE (P: 10%, T40: 9%, T200: 5%) was similar in the P, T40 and T200 groups. No serious treatment related cutaneous, liver or renal adverse events were reported in either TMX-049 dose groups. Conclusions: Once daily dosing of T40 or T200 was well tolerated in this 12-week study of participants with T2D and albuminuria. Although both doses reduced sUA, albuminuria reduction was only observed with T200. Reduced DKD progression may be achievable with TMX-049, a dual hepatic and renal XO inhibitor. Disclosure G. Bakris: Consultant; Self; Alnylam, Merck &amp; Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. H. Mikami: Employee; Self; Teijin Pharma Limited. M. Hirata: Employee; Self; Teijin Pharma Limited. M. Cressman: Employee; Self; Covance, LabCorp. Funding Teijin America, Inc.

Abstract P182: Diet Quality and Longitudinal Change in Kidney Function: Findings From the Hispanic Community Health Study/Study of Latinos (hchs/sol)

Introduction: Recent studies suggest an association between healthy diet and incident chronic kidney disease (CKD), but these included few Hispanics/Latinos. We examined the relationship of diet quality with change in kidney function in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Given the bidirectional relationship between CKD and cardiovascular disease (CVD), we assessed prevalent CVD as a potential effect modifier. Methods: Data from HCHS/SOL Visits 1 (2008-2011) and 2 (2014-2017) were used. The Alternative Healthy Eating Index (AHEI-2010), a measure of diet quality, was calculated from two 24-hour dietary recalls administered at Visit 1 and analyzed as quintiles (lowest to highest quality). Kidney function was assessed using CKD-EPI creat glomerular filtration rate estimating equation (eGFR), and urine albumin-to-creatinine ratio (UACR). Annualized change was computed as the difference in eGFR or UACR between visits divided by follow-up time in years. CVD was defined at Visit 1 as self-reported coronary heart disease, cerebrovascular events, peripheral artery disease or heart failure. Of 16415 HCHS/SOL participants, data from 9336 and 9209 persons with complete information on dietary intake, and change in eGFR and UACR, respectively, were analyzed using linear regression. Interaction between AHEI-2010 and CVD was explored. Analyses accounted for complex sampling design. Results: Average age was 41 years, 52% were women, and 22% had prevalent CVD. On average, eGFR declined by 0.67 mL/min/1.73 m 2 / year, and UACR increased by 2.0 mg/g/year. A significant interaction between diet quality and CVD was seen (p &lt; 0.01). Lower AHEI-2010 quintiles were associated with greater decline in eGFR in a dose-response manner in persons without CVD (P-trend &lt;0.01, Table). The association between diet quality and eGFR was stronger in those with CVD. AHEI-2010 was not associated with change in UACR. Conclusion: These findings have important implications for CKD prevention, especially for those with CVD.

Association of Longitudinal Trajectory of Albuminuria in Young Adulthood With Myocardial Structure and Function in Later Life

Albuminuria, as measured by single urine albumin-to-creatinine ratio (UACR) levels, is associated with cardiac remodeling and adverse clinical outcomes. The longitudinal patterns of change in UACR through young adulthood and their associations with myocardial structure and function later in life remain unclear. To describe the trajectory of albuminuria as measured by UACR across a 20-year span and evaluate the association of albuminuria trajectory with echocardiographic indices of structure and function in middle age. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort of black and white participants aged 18 to 30 years at baseline (March 1985 to June 1986) were evaluated over 30 years. Participants underwent evaluations at 4 urban US sites. Data were collected from March 1985 to May 2016, and data were analyzed from September 2018 to April 2019. Trajectories of UACR from the year 10 examination to the year 30 examination as determined by latent class modeling. Echocardiographic indices of myocardial structure, systolic function, and diastolic function at the year 30 examination. Of the 2647 included participants, 1441 (54.4%) were white, 1206 (45.6%) were black, and the mean (SD) age was 35.2 (3.6) years. A total of 5 trajectory groups of UACR were identified, including 1718 participants (64.9%) in the low-stable group, 682 (25.8%) in the moderate-stable group, 116 (4.4%) in the high-stable group, 88 (3.3%) in the moderate-increasing group, and 43 (1.6%) in the high-increasing group. Apart from the high-increasing cohort, the remaining 4 groups had median baseline UACR levels less than 30 mg/g. Male sex, current smoking, diabetes, and elevated blood pressure were more common in the moderate-increasing and high-increasing UACR groups. After adjustment for clinical variables and baseline UACR levels, there were significant differences in left ventricular (LV) mass by trajectory group (mean [SE] LV mass: high-increasing, 98.4 [3.4] g/m2; moderate-increasing, 91.7 [2.2] g/m2; high-stable, 86.0 [2.1] g/m2; moderate-stable, 82.3 [0.8] g/m2; low-stable, 78.6 [0.5] g/m2; P < .001). Significant differences by trajectory group were also noted in LV longitudinal strain, e' tissue velocities, and estimated LV filling pressures, even after adjustment for clinical variables and baseline UACR level. The association of trajectory group with indices of myocardial structure and function remained significant after adjustment for clinical variables and cumulative UACR from the year 10 to year 25 examinations. There are distinct patterns of change in albuminuria among young adults over a 20-year span, and these trajectory groups cannot be identified by baseline UACR level alone. Dynamic changes in albuminuria are independently associated with adverse alterations to cardiac structure, LV systolic function, and LV diastolic function.

MON-300 EFFICACY AND SAFETY OF CANAGLIFLOZIN, A SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR, IN DIABETIC KIDNEY DISEASE: A RANDOMIZED OPEN-LABEL PROSPECTIVE TRIAL

Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to have, renoprotective effects based on the possible mechanism that SGLT2 inhibitors reduce hyperfiltration by blocking proximal tubule sodium reabsorption and activating tubuloglomerular feedback (TGF) and may decrease inflammatory, fibrotic, and hyperplastic response of proximal tubular cells by blocking glucose reabsorption into proximal tubular cells. Although SGLT2 inhibition is associated with an acute reduction in estimated glomerular filtration rate (eGFR) by about 4-6 mL/min per 1.73m2, eGFR typically has a tendency to return to baseline and remains stable thereafter. Furthermore, a 30 to 40% reduction in albuminuria was found. However, the effects of SGLT2 inhibition are unclear with regard to other kidney related biomarkers, such as those associated with tubulointerstitial damage. In the present study, we aimed to examine precisely the renoprotective effects of the SGLT2 inhibitor canagliflozin by measuring albuminuria, tubulointerstitial biomarkers, eGFR, and other metabolic parameters in patients with diabetic kidney disease (DKD) who are treated with renin-angiotensin system (RAS) inhibitors. In this prospective, open-label, parallel-group study, Japanese diabetes patients were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) and RAS inhibitors for 8 weeks; these drugs were continued during the study. A total of 44 patients were randomly assigned to the canagliflozin group (n = 22) or the control group (n = 22). Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory and vital parameters, and adverse events. Both groups included 22 patients in the analysis. Mean change in UACR was -221 g/gCr and 81 mg/gCr in the canagliflozin and control groups, respectively (P=0.004). Percent reduction in UACR was significantly greater in the canagliflozin group than in the control group (-49 ± 26% vs. 24 ± 47 %; P<0.0001). Urinary liver-type fatty acid binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in eGFR at the end of the study was 0.7 and -3.4 mL/min/1.73m2 in the canagliflozin and control group, respectively (P=0.024). A significant decrease in body mass index (BMI), systolic, diastolic blood pressure (BP), and mean arterial pressure was observed in the canagliflozin group. In addition, canagliflozin was associated with a significant increase in hemoglobin concentrations and hematocrit levels. Canagliflozin treatment leads to a reduction in albuminuria, urinary L-FABP, NAG, and β2-microglobulin levels in patients with DKD, regardless of simultaneous RAS inhibition. Furthermore, after 52 weeks, canagliflozin, in contrast to the control treatment, significantly reduced HbA1c and was associated with reductions in body weight, BPs, and liver transaminase levels in patients with DKD. The effect of canagliflozin on UACR appeared to be, in large part, beyond the effects on glycemic control. These findings suggest that canagliflozin may be an appropriate treatment option for patients with DKD.

Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers.

The sodium glucose co‐transporter‐2 inhibitor dapagliflozin has been shown to decrease urinary albumin‐to‐creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non‐response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non‐responders. At 24 weeks, the UACR‐adjusted mean change from baseline was −71.2% and 25.9% in responders and non‐responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non‐responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long‐term renal and cardiovascular outcomes remains to be determined.

Proteinuria and Renal Dysfunction after Intravitreal Injection of Bevacizumab in Patients with Diabetic Nephropathy: A Prospective Observational Study.

Background: Proliferative diabetic retinopathy (PDR) is one of the most important microvascular complications among the patients with diabetes. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agent enacts a key role in PDR. Some studies have dealt with the systemic exposure to these agents after intravitreal administration. However, renal dysfunction following this therapy has scarcely been reported. Hence, this study aimed to determine the effect of intravitreal bevacizumab treatment on the deterioration of renal function and proteinuria. Materials and Methods: This present prospective observational study was performed on 40 patients with diabetic nephropathy and PDR and/or significant diabetic macular edema as the candidates for receiving intravitreal injection of bevacizumab. To evaluate renal function, changes in the urinary albumin-to-creatinine ratio (UACR), serum creatinine (SCr), and estimated glomerular filtration rate (eGFR) one month after injection were measured. Also, changes in systolic and diastolic blood pressures (BPs), plasma VEGF level, platelet, white blood cell (WBC) counts, and hemoglobin (Hb) level were measured at the baseline and one month after treatment. Results: The mean age of the patients was 60.3 ± 9.2 years, and 33 patients were female. The decrease in the plasma VEGF level and platelet count, as well as the increase in diastolic BP, and Hb level were significant. However, systolic BP and WBC count remained unchanged. There were no significant changes in UACR, SCr, and eGFR after the injection as compared to baseline (P>0.05). Conclusion: Our study indicated that intravitreal bevacizumab injection was not associated with renal dysfunction and proteinuria in patients with diabetic nephropathy. Nevertheless, diastolic BP and Hb level could increase after one month.

Proteinuria and Renal Dysfunction after Intravitreal Injection of Bevacizumab in Patients with Diabetic Nephropathy: A Prospective Observational Study

Background: Proliferative diabetic retinopathy (PDR) is one of the most important microvascular complications among the patients with diabetes. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agent enacts a key role in PDR. Some studies have dealt with the systemic exposure to these agents after intravitreal administration. However, renal dysfunction following this therapy has scarcely been reported. Hence, this study aimed to determine the effect of intravitreal bevacizumab treatment on the deterioration of renal function and proteinuria.&#x0D; Materials and Methods: This present prospective observational study was performed on 40 patients with diabetic nephropathy and PDR and/or significant diabetic macular edema as the candidates for receiving intravitreal injection of bevacizumab. To evaluate renal function, changes in the urinary albumin-to-creatinine ratio (UACR), serum creatinine (SCr), and estimated glomerular filtration rate (eGFR) one month after injection were measured. Also, changes in systolic and diastolic blood pressures (BPs), plasma VEGF level, platelet, white blood cell (WBC) counts, and hemoglobin (Hb) level were measured at the baseline and one month after treatment.&#x0D; Results: The mean age of the patients was 60.3 ± 9.2 years, and 33 patients were female. The decrease in the plasma VEGF level and platelet count, as well as the increase in diastolic BP, and Hb level were significant. However, systolic BP and WBC count remained unchanged. There were no significant changes in UACR, SCr, and eGFR after the injection as compared to baseline (P&gt;0.05).&#x0D; Conclusion: Our study indicated that intravitreal bevacizumab injection was not associated with renal dysfunction and proteinuria in patients with diabetic nephropathy. Nevertheless, diastolic BP and Hb level could increase after one month. [GMJ.2018;In press:e1299]

Proteinuria and Renal Dysfunction after Intravitreal Injection of Bevacizumab in Patients with Diabetic Nephropathy: A Prospective Observational Study

Background: Proliferative diabetic retinopathy (PDR) is one of the most important microvascular complications among the patients with diabetes. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agent enacts a key role in PDR. Some studies have dealt with the systemic exposure to these agents after intravitreal administration. However, renal dysfunction following this therapy has scarcely been reported. Hence, this study aimed to determine the effect of intravitreal bevacizumab treatment on the deterioration of renal function and proteinuria.Materials and Methods: This present prospective observational study was performed on 40 patients with diabetic nephropathy and PDR and/or significant diabetic macular edema as the candidates for receiving intravitreal injection of bevacizumab. To evaluate renal function, changes in the urinary albumin-to-creatinine ratio (UACR), serum creatinine (SCr), and estimated glomerular filtration rate (eGFR) one month after injection were measured. Also, changes in systolic and diastolic blood pressures (BPs), plasma VEGF level, platelet, white blood cell (WBC) counts, and hemoglobin (Hb) level were measured at the baseline and one month after treatment.Results: The mean age of the patients was 60.3 ± 9.2 years, and 33 patients were female. The decrease in the plasma VEGF level and platelet count, as well as the increase in diastolic BP, and Hb level were significant. However, systolic BP and WBC count remained unchanged. There were no significant changes in UACR, SCr, and eGFR after the injection as compared to baseline (P&gt;0.05).Conclusion: Our study indicated that intravitreal bevacizumab injection was not associated with renal dysfunction and proteinuria in patients with diabetic nephropathy. Nevertheless, diastolic BP and Hb level could increase after one month. [GMJ.2018;In press:e1299]

Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial

The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10-20 μg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was -1·69% (95% CI -11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, -21·10% (-42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and -39·18% (-68·53 to -9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741-1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. Sanofi.

Lixisenatide and Renal Outcomes in Patients with Type 2 Diabetes—A Post-Hoc Analysis of the ELIXA Trial

Limited data exist on long-term effects of GLP-1 receptor agonists on kidney function and albuminuria in T2D. In ELIXA, a study of cardiovascular safety of lixisenatide (Lixi) over a median follow-up of 25 months in 6068 patients (pts) with T2D and an acute coronary event ≥180 days before screening, slower progression of urinary albumin-to-creatinine ratio (UACR) was seen with Lixi vs. placebo (Pbo). In a mixed-effect model with repeated measures for comparisons between treatment (Tx) groups of changes in UACR, the interaction between Tx and baseline (BL) UACR categories was significant (p&amp;lt;0.01). We assessed change in estimated glomerular filtration rate (eGFR, per the 4-variable modification of diet in renal disease formula) and UACR by BL albuminuria status. eGFR was not significantly different for Lixi vs. Pbo overall or by BL albuminuria status. UACR percent change from BL was lower for Lixi vs. Pbo in pts with micro- or macroalbuminuria (Table). In a Cox proportional hazards model adjusted for BL and on-trial HbA1c, Lixi was associated with 23% lower risk for first macroalbuminuria event in pts without BL macroalbuminuria (HR 0.77; 95% CI: 0.62, 0.96; p=0.0174). In conclusion, in pts with T2D and a recent acute coronary event, Lixi reduced UACR progression in pts with BL micro- or macroalbuminuria and was associated with lower incidence of macroalbuminuria beyond glycemic control. Disclosure M.A. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Tonneijck: Consultant; Spouse/Partner; Eli Lilly and Company. Y. Huang: Consultant; Self; Sanofi. M. Liu: Employee; Self; Sanofi. A. Saremi: Employee; Self; Sanofi US. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Consultant; Self; Janssen Research &amp; Development, Fresenius SE &amp; Co. KGaA. Advisory Panel; Self; Merck &amp; Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. D.H. van Raalte: Advisory Panel; Self; Sanofi. Research Support; Self; Sanofi, Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH, Merck &amp; Co., Inc., Novo Nordisk Inc.. Research Support; Self; AstraZeneca.

Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial.

To evaluate the renoprotective effects of canagliflozin, we assessed the albuminuria-lowering effect in Japanese type 2 diabetes patients with chronic kidney disease (CKD). In this prospective, open-label, parallel-group study, type 2 diabetes patients with CKD were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory parameters, and adverse events. Both groups included 20 patients in the analysis. Mean changes in UACR was -83 (-266 to -31) mg/gCr and 27 (-11 to 131) mg/gCr, in the canagliflozin and control groups, respectively ( p = 0.004). Urinary liver-type free acid binding protein, N-acetyl-β-d-glucosaminidase, and β2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in estimated glomerular filtration rate at the end of the study was 0.7 and -3.4 mL/min/1.73 m2 in the canagliflozin and control group, respectively ( p = 0.024). Canagliflozin treatment led to improvement of glycaemic control and reduction in body weight, blood pressure, and liver transaminase. There were no adverse events associated with canagliflozin. Canagliflozin was associated with slower progression of kidney disease and reduction in albuminuria and tubulointerstitial markers in diabetes patients with CKD.

Change in Albuminuria and Risk of Renal and Cardiovascular Outcomes: Natural Variation Should Be Taken into Account

IntroductionChanges in urinary albumin-to-creatinine ratio (UACR) may affect the risk of advanced chronic kidney disease (CKD). How much the association changes after taking account for natural variation in UACR and the length of time taken to observe changes in UACR is unknown.MethodsEnglish Clinical Practice Research Datalink records (2000−2015) with linkage to secondary care and death certification were used to identify prospective cohorts with at least 2 measures of UACR within 1, 2, and 3 years. Adjusted Cox regression assessed the separate relevance of the baseline UACR and the UACR change to the risk of developing stages 4 to 5 CKD and end-stage renal disease (ESRD). Associations were compared before and after accounting for the effects of the natural variation in UACR (i.e., regression to the mean).ResultsA total of 212,810 individuals had baseline UACR measurements; 22% had a UACR ≥3.4 mg/mmol, and 3% had UACR ≥33.9 mg/mmol. During a median 4-year follow-up, 5976 developed stage 4 to 5 CKD, and 1076 developed ESRD. There were strong associations between baseline UACR and stage 4 to 5 CKD or ESRD risk, which doubled in strength after accounting for regression to the mean. Over 3 years, the hazard ratios (95% confidence intervals) for stage 4 to 5 CKD, relative to stable UACR, were 0.62 (0.50−0.77) for at least a halving of UACR and 2.68 (2.29−3.14) for at least a doubling of UACR. Associations were weaker for shorter exposure windows (and for cardiovascular disease or death), but strengthened after allowing for regression to the mean.ConclusionBaseline values and subsequent medium-term increases in albuminuria are both associated with substantially increased risk of developing advanced CKD. Standard analyses, not allowing for natural variation in UACR, may underestimate these associations.

Impact of Dapagliflozin Therapy on Renal Protection and Kidney Morphology in Patients With Uncontrolled Type 2 Diabetes Mellitus.

BackgroundWe examined whether the sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin can improve urine albumin-to-creatinine ratio (UACR) associated with a reduction in body weight or body fat in patients with type 2 diabetes mellitus (T2DM).MethodsWe prospectively recruited T2DM patients having inadequate glycemic control (hemoglobin A1c (HbA1c) > 7.0%) not on SGLT2i therapy. We treated the patients with add-on dapagliflozin treatment or intensification of non-SGLT2 inhibitor therapies for 6 months. We measured UACR, urine N-acetyl-β-glucosaminidase (uNAG), and body composition including total body fat mass (TBFM) as assessed by bioelectrical impedance analysis. We also investigated changes in length and radiation attenuation properties of the kidneys and abdominal fat area using computed tomography.ResultsWe enrolled 62 patients with a mean HbA1c of 8.0%. The HbA1c and fasting blood glucose were significantly decreased in both the dapagliflozin-group and non-SGLT2i-group, with no significant difference between the two groups. Dapagliflozin treatment, but not non-SGLT2i treatment, significantly decreased UACR and uNAG. The changes in UACR and uNAG were significantly greater in the dapagliflozin group compared with the non-SGLT2i group. Dapagliflozin treatment, but not non-SGLT2i treatment, significantly decreased the body weight, TBFM, and abdominal fat area and significantly increased kidney length and radiation attenuation. The percentage change in UACR was significantly correlated with changes in TBFM, but not with body weight. By multivariate logistic regression analysis, dapagliflozin treatment was significantly associated with the improvement of UACR.ConclusionsAdd-on treatment with dapagliflozin exhibited significant renoprotective effects, with improvement of UACR and uNAG and increased kidney length and radiation attenuation in patients with uncontrolled T2DM.

Effects of Olmesartan and Azilsartan on Albuminuria and the Intrarenal Renin-Angiotensin System

Olmesartan and azilsartan decrease blood pressure more effectively than other angiotensin receptor blockers (ARBs). ARBs additionally decrease the urinary albumin to creatinine ratio (UACR), a urinary albumin marker, and urinary angiotensinogen (u-AGT), an intrarenal renin-angiotensin system activity marker. We examined the effects of these ARBs on blood pressure, UACR, and u-AGT in patients with uncontrolled hypertension.Patients with uncontrolled hypertension treated with conventional ARBs, excluding olmesartan and azilsartan, for over 8 weeks were enrolled. We randomly switched patients from their prior ARBs to either olmesartan or azilsartan, and followed them for 24 weeks.Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic blood pressure (cSBP) significantly decreased at 24 weeks. UACR and u-AGT also decreased at 24 weeks in both groups. There were no significant differences in SBP, DBP, cSBP, UACR, or u-AGT between the groups. Therefore, we combined both groups for further analyses. After combining, SBP (160.5 ± 16.4 to 139.6 ± 15.6 mm Hg, P < 0.0001), DBP (88.4 ± 13.7 to 80.7 ± 13.2 mm Hg, P = 0.008), cSBP (167.4 ± 20.8 to 146.6 ± 24.6 mm Hg, P < 0.0001), UACR (13.8 to 9.0 mg/g Cre, P = 0.0096), and u-AGT (4.13 to 2.32 μg/g Cre, P = 0.0074) significantly decreased at 24 weeks. Patients with microalbuminuria (UACR ≥ 30 mg/g Cre) had significantly greater ΔUACR (-39.4 vs 0.27, P = 0.0024) and Δu-AGT (-11.9 vs -0.61, P = 0.0235) than patients without microalbuminuria. The changes in u-AGT were significantly associated with changes in UACR (r = 0.411, P = 0.046); however, there was no significant relationship between the changes in u-AGT and those in SBP or DBP.Olmesartan and azilsartan decreased blood pressure, UACR, and u-AGT more than the other ARBs, and exerted depressor and renoprotective effects.