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1.
Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression.
Neuen, BL, Tighiouart, H, Heerspink, HJL, Vonesh, EF, Chaudhari, J, Miao, S, Chan, TM, Fervenza, FC, Floege, J, Goicoechea, M, et al
Journal of the American Society of Nephrology : JASN. 2022;(2):291-303
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Abstract
BACKGROUND Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.
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The safety outcomes of sodium-glucose cotransporter 2 inhibitors in patients with different renal function: A systematic review and meta-analysis.
Bai, Y, Jin, J, Zhou, W, Zhang, S, Xu, J
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(5):1365-1374
Abstract
AIMS: We aimed to assess whether the safety outcomes exerted by sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with different renal function at baseline. DATA SYNTHESIS We searched randomized controlled trials comparing SGLT2 inhibitors with placebo in participants simultaneously involving the entire range of estimated glomerular filtration rate (eGFR) levels at baseline in one study. According to eGFR, we divided the population into two subgroups with eGFR <60 ml/min/1.73 m2 and eGFR≥60 ml/min/1.73 m2. Data from the CANVAS program, CREDENCE, EMPA-REG OUTCOME, DECLARE-TIMI 58, DAPA-HF, and EMPA-REG RENAL were included. SGLT2 inhibitors significantly reduced the risk of all serious adverse events (HR 0.91 [95% CI 0.87 to 0.95], p < 0.001) and acute kidney injury (HR 0.74 [95% CI 0.64 to 0.85], p < 0.001). Except for high risk of genital infection, SGLT2 inhibitors did not increase the risk of amputation, fracture, hyperkalemia, hypoglycemia, volume depletion, or urinary tract infection. Further analyses showed that these safety outcomes were similar between subgroups (p-interaction > 0.05). For osmotic diuresis, SGLT2 inhibitors significantly increased the risk by 75% (p = 0.036), and subgroup analyses showed that this effect was completely attributed to the increase in patients with eGFR ≥60 ml/min/1.73 m2 (p-interaction<0.001). CONCLUSION The indication of no risk of osmotic diuresis in patients with eGFR<60 ml/min/1.73 m2 and the consistency of other safety outcomes across different baseline renal function may allow additional individuals to safely use SGLT2 inhibitors.
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Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study.
Lin, FJ, Wang, CC, Hsu, CN, Yang, CY, Wang, CY, Ou, HT
Cardiovascular diabetology. 2021;(1):203
Abstract
BACKGROUND To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2). METHODS Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics. RESULTS There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37-0.69), 0.51 (0.37-0.70), and 0.47 (0.31-0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups. CONCLUSIONS This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.
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Incretin based therapies and SGLT-2 inhibitors in kidney transplant recipients with diabetes: A systematic review and meta-analysis.
Oikonomaki, D, Dounousi, E, Duni, A, Roumeliotis, S, Liakopoulos, V
Diabetes research and clinical practice. 2021;:108604
Abstract
AIMS: We aimed to conduct a systematic review and meta-analysis regarding the use of incretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists as well as sodium-glucose co-transporter-2 (SGLT2) inhibitorsin persons with posttransplantation diabetes mellitus (PTDM) so as to assess both their efficacy and safety. METHODS We searched for publications on Kidney/Renal Transplantation and DPP-4 inhibitors, GLP-1-receptor agonists and SGLT-2 inhibitors and included every study using these antidiabetics. A p-value < 0.05 was considered statistical significant. RESULTS Sixteen studies and 310 individuals with a mean age of 55.98 ± 8.81 years were included in the analysis. Participants received DPP-4 inhibitors in 8 studies, SGLT-2 inhibitors in 6 studies and GLP-1 receptor agonists in 2 studies, with a mean follow-up of 22.03 ± 14.95 weeks. Hemoglobin A1c (HbA1c) reduction was demonstrated in 10 studies (mean +/- standard deviation (MD) = - 0.38%, I2 = 45%). MD of HbA1c was -0.3741 and -0.4596 mg/dl for DPP-4 inhibitors and SGLT-2 inhibitors respectively. Nine studies demonstrated differences in fasting plasma glucose (FPG) (MD = - 25,76) and 5 studies in post-prandial glucose (PPG) (MD = - 6.61) before and following treatment. Most studies did not show adverse effects on the glomerular filtration rate (GFR) and hepatic function. CONCLUSIONS DPP-4 inhibitors and SGLT2 inhibitors appear both efficacious and safe in renal transplant recipients. More high-quality studies are required to guide therapeutic choices for PTDM.
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Benefits of resistant starch type 2 for patients with end-stage renal disease under maintenance hemodialysis: a systematic review and meta-analysis.
Jia, L, Dong, X, Li, X, Jia, R, Zhang, HL
International journal of medical sciences. 2021;(3):811-820
Abstract
Background: Resistant starch type 2 (RS2) has been documented to regulate gut microbiota and to improve the clinical outcomes of several diseases. However, whether RS2 may benefit patients with end-stage renal disease under maintenance hemodialysis (MHD) remains unknown. Methods: We conducted a systemic review and meta-analysis of randomized controlled trials (RCTs). Adult patients receiving MHD were treated with RS2 (CRD42020160332). The primary outcomes were changes of uremic toxins, and the secondary outcomes were changes of inflammatory indicators, albumin and phosphorus. Results: After screening 65 records, five RCTs (n = 179) were included. A significant decrease of blood urea nitrogen (weighted mean difference (WMD) = -6.91, 95% CI: -11.87 to -1.95, I2 = 0%, P = 0.006), serum creatinine (WMD = -1.11, 95% CI: -2.18 to -0.05, I2 = 44%, P = 0.04) and interleukin (IL)-6 in blood (standard mean difference (SMD) = -1.08, 95% CI: -1.64 to -0.53, I2 = 35%, P = 0.0001) was revealed in the RS2 group. Analyses of blood levels of uric acid, p-cresyl sulfate, indoxyl sulfate, high sensitive C-reaction protein, albumin and phosphorus yielded no significant difference. Conclusions: Our results suggest that RS2 may improve the residual renal function of patients under MHD and mitigate a proinflammatory response.
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Effects of ACEIs and ARBs on the Residual Renal Function in Peritoneal Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials.
Ding, L, Yang, J, Li, L, Yang, Y
BioMed research international. 2020;:6762029
Abstract
BACKGROUND In peritoneal dialysis (PD) patients, whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could protect residual renal function is still controversial. To assess the effects of ACEIs and ARBs on the residual renal function and cardiovascular (CV) events in peritoneal dialysis patients, we performed a meta-analysis of randomized controlled trials. MATERIALS AND METHODS We searched PubMed, EMBASE, the Cochrane Library, the CNKI database, and the Wanfang database for relevant articles from database inception to November 30, 2019. Randomized controlled trials were included. The primary outcome was the decline in the residual renal function (RRF). RESULTS Thirteen trials with 625 participants were included in the meta-analysis. The average residual GFR declined by 1.79 ml/min per 1.73 m2 in the ACEI/ARB group versus 1.44 ml/min per 1.73 m2 in the placebo or active control group at 3 mo. The average residual GFR declined by 2.02 versus 2.06, 2.16 versus 2.72, and -0.04 versus 2.74 ml/min per 1.73 m2 in the placebo or active control group at 6 months (mo), 12 mo, and 24 mo, respectively. The decline in residual GFR showed a significant difference between the ACEI/ARB group and the placebo or active control group at 12 mo (MD = -0.64 ml/min per 1.73 m2; 95% CI: -0.97~-0.32; I 2 = 44%; P < 0.0001). No significant difference was observed in Kt/V, urinary protein excretion, weekly creatinine clearance, CV events, or serum potassium levels. CONCLUSIONS In the present study, we found that the use of ACEIs and ARBs, especially long-term treatment, decreased the decline of RRF in patients on PD. ACEIs and ARBs do not cause an additional risk of side effects.
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Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes.
Tofte, N, Vogelzangs, N, Mook-Kanamori, D, Brahimaj, A, Nano, J, Ahmadizar, F, van Dijk, KW, Frimodt-Møller, M, Arts, I, Beulens, JWJ, et al
The Journal of clinical endocrinology and metabolism. 2020;(7)
Abstract
CONTEXT There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. OBJECTIVE To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). DESIGN 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. MAIN OUTCOME MEASURES Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. RESULTS In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. CONCLUSIONS This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.
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Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium.
Inker, LA, Grams, ME, Levey, AS, Coresh, J, Cirillo, M, Collins, JF, Gansevoort, RT, Gutierrez, OM, Hamano, T, Heine, GH, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2019;(2):206-217
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Abstract
RATIONALE & OBJECTIVE Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. STUDY DESIGN Cross-sectional individual participant-level analyses in a global consortium. SETTING & STUDY POPULATIONS 17 CKD and 38 general population and high-risk cohorts. SELECTION CRITERIA FOR STUDIES Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. DATA EXTRACTION Data were obtained and analyzed between July 2015 and January 2018. ANALYTICAL APPROACH We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. RESULTS The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g). LIMITATIONS Variations in study era, health care delivery system, typical diet, and laboratory assays. CONCLUSIONS Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.
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Exercise therapy improves eGFR, and reduces blood pressure and BMI in non-dialysis CKD patients: evidence from a meta-analysis.
Zhang, L, Wang, Y, Xiong, L, Luo, Y, Huang, Z, Yi, B
BMC nephrology. 2019;(1):398
Abstract
BACKGROUND Patients with chronic kidney disease (CKD) have a high prevalence of cardiovascular diseases, which often lead to physical inactivity that correlates with CKD exacerbation. The benefits of regular exercise to cardiovascular health have been well established in healthy population and highly suggestive in patients with CKD. To further strengthen the evidence base for the management of CKD, this meta-analysis was performed to systematically evaluate the effects of exercise therapy on renal function, blood pressure, blood lipid and body mass index (BMI) in non-dialysis CKD patients. METHODS This meta-analysis was conducted following a previous protocol. Randomized controlled trials (RCTs) examining the effects of exercise therapy in non-dialysis CKD patients were searched in Pubmed, Embase, Cochrane Library, and three major Chinese biomedical databases (CNKI, WANGFANG and VIP) from their start date to October 30th, 2018. The Cochrane systematic review methods were applied for quality assessment and data extraction, and Revman version 5.3 was used for systematic review and meta-analysis. RESULTS 13 RCTs, representing 421 patients with non-dialysis CKD, were included in this meta-analysis. Compared to the controls, exercise therapy brought an increase in eGFR (MD = 2.62, 95% CI:0.42 to 4.82, P = 0.02, I2 = 22%), and decreases in systolic blood pressure (SBP) (MD = -5.61, 95% CI:-8.99 to - 2.23, P = 0.001, I2 = 44%), diastolic blood pressure (DBP) (MD = -2.87, 95% CI:-3.65 to - 2.08, P < 0.00001, I2 = 16%) and BMI (MD = -1.32, 95% CI:-2.39 to - 0.25, P = 0.02, I2 = 0%) in non-dialysis CKD patients. Exercise therapy of short-term (< 3 months) decreased triglyceride (TG) level (P = 0.0006). However, exercise therapy did not significantly affect serum creatinine (SCr), total cholesterol (TC), high density lipoprotein (HDL) or low density lipoprotein (LDL) in non-dialysis CKD patients. CONCLUSION Exercise therapy could benefit non-dialysis CKD patients by increasing eGFR while reducing SBP, DBP and BMI. Additionally, short-term intervention of exercise could decrease TG.
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Effect of SGLT2 inhibitor on renal function in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.
Feng, C, Wu, M, Chen, Z, Yu, X, Nie, Z, Zhao, Y, Bao, B
International urology and nephrology. 2019;(4):655-669
Abstract
OBJECTIVE This study summarizes the evidence from randomized controlled trials (RCTs) to assess the effects of SGLT2 inhibitors on renal function and albuminuria in patients with type 2 diabetes. MATERIALS/METHODS We searched PubMed, Web of Science, Cochrane Library and EMBASE for reports published up to March 2018 and included RCTs reporting estimated glomerular filtration rate (eGFR) and/or urine albumin/creatinine ratio (UACR) changes. Data extraction and assessment of research quality based on Cochrane risk biasing tools. Data were calculated to represent the standardized mean difference (SMD) for each study, and the SMDs with 95% confidence intervals (CIs) were pooled using a random effects model. RESULTS Fifty-one studies were included that evaluated eGFR levels, and 17 studies were included that evaluated UACR levels. A meta-analysis showed that SGLT2 inhibitors had no significant effect on eGFR levels (SMD - 0.02, 95% CI - 0.06, 0.03, p = 0.45), and eGFR reduction was observed in the subsets of the duration of the trial 12 < duration ≤ 26 weeks (SMD - 0.08, 95% CI - 0.13, - 0.02, p = 0.005) and mean baseline eGFR < 60 ml/min per 1.73 square meters (SMD - 0.22, 95% CI - 0.37, - 0.07, p = 0.004). We found that SGLT2 inhibitors reduced UACR levels in patients with type 2 diabetes (SMD - 0.11, 95% CI - 0.17, - 0.05, p = 0.0001). Compared with monotherapy, the combination with other hypoglycemic agents can reduce albuminuria levels (SMD - 0.13, 95% CI - 0.19, - 0.06, p < 0.0001). CONCLUSIONS The effect of SGLT2 inhibitor on eGFR in patients with T2DM was not statistically significant, but it was effective in reducing albuminuria levels.