scholarly journals A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores

2021 ◽  
Vol 12 ◽  
pp. 204201882097419
Author(s):  
Nienke M. A. Idzerda ◽  
Sok Cin Tye ◽  
Dick de Zeeuw ◽  
Hiddo J. L. Heerspink
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Serum Creatinine ◽  
Risk Score ◽  
Drug Response ◽  
Drug Effects ◽  
Risk Scores ◽  
Renal Outcome ◽  
Response Score

Background: Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes. Methods: The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months’ treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease. Results: The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) −5 to 12], whereas the observed risk change was −28.8% (95% CI −42.0 to −11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of −12.4% (95% CI −17 to −7), which underestimated the observed risk change −21.8% (95% CI −34 to −6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [−24.0% (95% CI −30 to −17) and −22.6% (95% CI −23 to −16) for ESRD and the composite renal outcome, respectively]. Conclusion: A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies.

scholarly journals Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

Diabetologia ◽  
2021 ◽  
Author(s):  
David Z. I. Cherney ◽  
◽  
Bernard Charbonnel ◽  
Francesco Cosentino ◽  
Samuel Dagogo-Jack ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Kidney Disease ◽  
Serum Creatinine ◽  
Renal Dialysis ◽  
Composite Endpoint ◽  
Composite Outcome ◽  
The Impact

Abstract Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT01986881 Graphical abstract

P0775A RETROSPECTIVE OBSERVATIONAL COHORT STUDY TO ASSESS THE PREVALENCE OF CHRONIC KIDNEY DISEASE AMONG TYPE 2 DIABETES MELLITUS PATIENTS IN ONTARIO, CANADA

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Wally Rapattoni ◽  
David Zante ◽  
Sha Kang ◽  
Ali Tehrani ◽  
Varun Myageri ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Cohort Study ◽  
Kidney Disease ◽  
Serum Creatinine ◽  
Real World ◽  
Burden Of Illness ◽  
Total Prevalence ◽  
Capture Recapture

Abstract Background and Aims The CREDENCE trial with canagliflozin demonstrated definitive evidence of renal benefits to slow the progression of end stage renal disease (ESRD) in type 2 diabetes (T2D) patients with chronic kidney disease (CKD). This real-world study was undertaken to better understand the prevalence of CKD among T2D patients in Ontario using the CREDENCE trial criteria. Ontario is the largest province, accounting for 38.8% of Canada’s population in 20191. Patients were identified in the following cohorts: T2D-CKD, T2D-CKD+cardiovascular disease (CVD), T2D-CKD+stroke, and T2D-CKD+CVD or stroke. Method This population-based retrospective cohort study was conducted in partnership with IQVIA and the Institute for Clinical Evaluative Sciences (ICES). The ICES data repository contains publicly funded administrative health service records for the Ontario population eligible for universal health coverage since 1986. Patients’ eligibility for this study was aligned with enrolment criteria in the CREDENCE trial. Patients were ≥30 years of age at index and were identified as having both T2D and CKD. Diabetes patients were identified using the validated Ontario Diabetes Database (ODD), patients <19 years of age when first diagnosed with diabetes were excluded due to suspected type 1 diabetes (T1D). Additionally, patients with a T1D diagnosis at any time-point were excluded. CKD patients were identified through diagnosis/billing codes or estimated glomerular filtration rate(eGFR)<90 ml/min/1.73ml2 derived from serum creatinine laboratory values. Diagnosis/billing codes are expected to have poor sensitivity2,3 when used as the sole method to identify CKD. To account for anticipated missing information in each dataset, the capture-recapture method was used to obtain a more accurate estimate for the total prevalence. Capture-recapture accounts for incomplete ascertainment of administrative datasets by using the overlap between the datasets to derive an estimate of the total population4,5 (Figure 1). This method was used in Manitoba to estimate the total CKD population, using administrative and laboratory datasets4. Therefore, each cohort (T2D-CKD, T2D-CKD+CVD, T2D-CKD+stroke, and T2D-CKD+CVD or stroke) has utilized each of the following four methods to identify CKD patients: diagnosis/billing codes, eGFR, diagnosis/billing codes or eGFR, and capture-recapture method. Yearly point prevalence of CKD among T2D patients is reported for the five fiscal years (FY) between 2011/12 and 2015/16. Results The prevalence of T2D patients ≥30 years of age in Ontario has increased from 959,850 in FY2011/12 to 1,169,759 in FY2015/16 (Figure 2). The prevalence of CKD among T2D patients ≥30 years of age in Ontario has increased across all methods from FY2011/12 to FY2015/16: from 21% to 28% based on diagnosis/billing codes, 47% to 63% based on eGFR, 55% to 70% based on diagnosis/billing codes or eGFR, and 76% to 84% based on capture-recapture. Similarly, prevalence of T2D-CKD+CVD, T2D-CKD+stroke, and T2D-CKD+CVD or stroke has increased in most cases (Figure 3). Conclusion CKD is a common comorbidity amongst T2D patients ≥30 years of age. The study provides estimates of the prevalence of CKD in four cohorts of T2D patients with defined co-morbidities and shows that the use of diagnosis/billing codes alone may underestimate the prevalence of CKD in T2D patients. Furthermore, this real-world analysis highlights a significant, increasing prevalence of CKD among T2D patients ≥30 years of age in Ontario with all methods. On-going research aims to assess the burden of illness of patients with both T2D and CKD who are incident to T2D-related outcomes (CKD or CVD related death, kidney transplant, kidney dialysis, doubling of serum creatinine).

scholarly journals LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

2019 ◽  
Vol 30 (4) ◽  
pp. 546-562 ◽  
Author(s):  
Quan Hong ◽  
Lu Zhang ◽  
Jia Fu ◽  
Divya A. Verghese ◽  
Kinsuk Chauhan ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renal Outcome ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Genetic Ablation ◽  
Glomerular Endothelial Cells

BackgroundGlomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear.MethodsWe analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.ResultsLRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.ConclusionsThese findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

scholarly journals Impact of overlapping risks of type 2 diabetes and obesity on coronavirus disease severity in the United States

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wataru Ando ◽  
Takeshi Horii ◽  
Takayuki Uematsu ◽  
Hideaki Hanaki ◽  
Koichiro Atsuda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Critical Care ◽  
Risk Score ◽  
The United States ◽  
Risk Scores ◽  
Research Database ◽  
Male Sex ◽  
The Impact ◽  
Diabetes And Obesity

AbstractThe impact of overlapping risk factors on coronavirus disease (COVID-19) severity is unclear. To evaluate the impact of type 2 diabetes (T2D) and obesity on COVID-19 severity, we conducted a cohort study with 28,095 anonymized COVID-19 patients using data from the COVID-19 Research Database from January 1, 2020 to November 30, 2020. The mean age was 50.8 ± 17.5 years, and 11,802 (42%) patients were male. Data on age, race, sex, T2D complications, antidiabetic medication prescription, and body mass index ≥ 30 kg/m2 (obesity) were analysed using Cox proportional hazard models, with hospitalization risk and critical care within 30 days of COVID-19 diagnosis as the main outcomes. The risk scores were 0–4 for age ≥ 65 years, male sex, T2D, and obesity. Among the participants, 11,294 (61.9%) had obesity, and 4445 (15.8%) had T2D. T2D, obesity, and male sex were significantly associated with COVID-19 hospitalization risk. Regarding hospitalization risk scores, compared with those for hospitalization risk score 0 and critical care risk score 0, hazard ratios [95% confidence intervals] were 19.034 [10.470–34.600] and 55.803 [12.761–244.015] (P < 0.001) (P < 0.001), respectively, for risk score 4. Complications from diabetes and obesity increased hospitalization and critical care risks for COVID-19 patients.

scholarly journals How to Assess Diabetic Kidney Disease Progression? From Albuminuria to GFR

2021 ◽  
Vol 10 (11) ◽  
pp. 2505
Author(s):  
Clara García-Carro ◽  
Ander Vergara ◽  
Sheila Bermejo ◽  
María A. Azancot ◽  
Ana I. Sánchez-Fructuoso ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
New Drugs ◽  
Renal Outcome ◽  
Renal Protection ◽  
Diabetic Kidney ◽  
Cardiovascular Outcome Trials ◽  
Advanced Stages

Diabetic kidney disease (DKD) is one of the most relevant complications of type 2 diabetes and dramatically increases the cardiovascular risk in these patients. Currently, DKD is severely infra-diagnosed, or its diagnosis is usually made at advanced stages of the disease. During the last decade, new drugs have demonstrated a beneficial effect in terms of cardiovascular and renal protection in type 2 diabetes, supporting the crucial role of an early DKD diagnosis to permit the use of new available therapeutic strategies. Moreover, cardiovascular and renal outcome trials, developed to study these new drugs, are based on diverse cardiovascular and renal simple and composite endpoints, which makes difficult their interpretation and the comparison between them. In this article, DKD diagnosis is reviewed, focusing on albuminuria and the recommendations for glomerular filtration rate measurement. Furthermore, cardiovascular and renal endpoints used in classical and recent cardiovascular outcome trials are assessed in a pragmatic way.

Association between atherosclerotic cardiovascular diseases risk and renal outcome in patients with type 2 diabetes mellitus

2020 ◽  
Author(s):  
Honghong Ren ◽  
Lijun Zhao ◽  
Yutong Zou ◽  
Yiting Wang ◽  
Junlin Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cardiovascular Diseases ◽  
Risk Score ◽  
Hazard Analysis ◽  
Renal Outcome ◽  
Ckd Stage ◽  
Ascvd Risk

Abstract Background Chronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and ASCVD risk is unclear. Methods This retrospective study enrolled 218 adult patients with type 2 diabetes mellitus and biopsy-proven DKD, and without known cardiovascular diseases. These patients were followed up at least 1 year. Baseline characteristics were obtained and the 10-year ASCVD risk score was calculated using the Pooled Cohort Equation (PCE). Renal outcome was defined as progression to end-stage renal disease (ESRD). The association between ASCVD risk and renal function and outcome was further analyzed with logistic regression and Cox proportional hazard analysis. Results Among all patients, the median 10-year ASCVD risk score was 14.1%. The median of ASCVD risk score in CKD stage 1, 2, 3, and 4 was 10.9%, 12.3%, 16.5%, and 14.8%, respectively (P = 0.268). Compared with patients with lower ASCVD risk(༜14.1%), those with higher ASCVD risk had lower eGFR, higher systolic blood pressure, and more severe renal interstitial inflammation. High ASCVD risk(> 14.1%) was an independent indicator of renal dysfunction in multivariable-adjusted logistic analysis(odds ratio [OR], 3.997; 95% confidence interval [CI], 1.385–11.530;P = 0.010). However, univariate and multivariate COX proportional hazard analysis showed the 10-year ASCVD risk score failed to be an independent risk factor for ESRD in patients with type 2 diabetes mellitus. Conclusions PCE can estimate ASCVD risk in patients with DKD, and DKD patients even in CKD stage 1 had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Higher ASCVD risk indicated severe renal insufficiency, while no prognostic value of ASVCD risk for renal outcome was observed, which implied macroangiopathy and microangiopathy in patients with DKD were related, but relatively independent.

scholarly journals Serum and urinary SOD3 in patients with type 2 diabetes: comparison with early chronic kidney disease patients and association with development of diabetic nephropathy

2019 ◽  
Vol 316 (1) ◽  
pp. F32-F41 ◽  
Author(s):  
Chia-Wen Kuo ◽  
Hsiao-Ling Chen ◽  
Min-Yu Tu ◽  
Chuan-Mu Chen
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Serum Creatinine ◽  
Urinary Albumin ◽  
Renal Diseases ◽  
Heparin Binding ◽  
Patients With Diabetes

Extracellular superoxide dismutase 3 (SOD3), one member of the antioxidant defense system and a superoxide scavenger, has been noted to be downregulated in the kidneys of diabetic mice and is characterized by a heparin-binding domain that can anchor the protein to the endothelium and extracellular matrix. The association of the serum and urinary SOD3 levels with diabetic nephropathy in different stages has never been evaluated. It remains unclear how urinary SOD3 changes in different renal diseases. We recruited 98 Taiwanese patients with type 2 diabetes and 10 patients with early chronic kidney disease (CKD) into this study. Biochemical analyses were performed, including evaluation of the serum SOD3, urinary SOD3, urinary albumin, urinary vascular endothelial growth factor (VEGF), and urinary angiotensinogen (ANG). The Kruskal-Wallis rank sum test was used to compare various parameters among the three groups of patients: early CKD, diabetes alone, and diabetes with CKD. Results showed that lower serum and urinary SOD3 levels were observed in the group of patients with diabetes alone. Higher serum and urinary SOD3 levels were observed in the group of patients with diabetes and CKD, which had higher albuminuria and serum creatinine levels. The serum SOD3 levels were significantly positively correlated with renal function, according to the serum creatinine level. The urinary levels of SOD3 were significantly correlated with other urinary biomarkers such as urinary ANG and VEGF. Furthermore, albuminuria can positively predict the serum SOD3 level for the ratio of urinary albumin to urinary creatinine (ACR) >1,190.769 mg/g and the urinary SOD3 level for ACR ≥300 mg/g.

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