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Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial.
Scirica, BM, Bohula, EA, Dwyer, JP, Qamar, A, Inzucchi, SE, McGuire, DK, Keech, AC, Smith, SR, Murphy, SA, Im, K, et al
Circulation. 2019;(3):366-375
Abstract
BACKGROUND Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). METHODS CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. RESULTS At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001). CONCLUSIONS Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.
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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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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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A prospective study to compare the measured glomerular filtration rate compared to estimated glomerular filtration rate in patients undergoing definitive chemoradiation, with platinum agents for various malignancies.
Rudresh, AH, Asati, V, Lakshmaiah, KC, Lokanatha, D, Babu, S, Rajeev, LK, Lokesh, KN, Babu, G
Journal of cancer research and therapeutics. 2019;(Supplement):S56-S59
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CONTEXT Renal function assessment is of paramount importance before using the platinum agents especially cisplatin. Glomerular filtration rate (GFR) estimation by diethyl-triamine-penta-acetic acid (DTPA) scan (measured GFR [mGFR]) is considered gold standard. AIMS The aim of this study is to know if we can replace the mGFR with the GFR estimation with Cockcroft-Gault formula (eGFR) in patients undergoing chemoradiation. SETTINGS AND DESIGN This is a prospective, descriptive study. SUBJECTS AND METHODS Patients who are planned for definitive chemoradiation will be eligible for the study. Renal function will be measured DTPA scan and Cockcroft-Gault (CG) formula. Subgroup analysis based on the weight, age, and sex will be done. STATISTICAL ANALYSIS USED Demographic and renal function parameters were analyzed using summary measures. To test the significance of the difference between mGFR and cGFR, a paired t-test will be used; to look for an association between various estimates of renal function, the Pearson's correlation coefficient will be calculated using a two-tailed test. RESULTS Median mGFR of patients was 82.7 (range: 65-125 ml/min, standard deviation [SD] =14.0 ml/min) while the median eGFR as per the CG formula was 83.9 ml/min (range: 37-137 ml/min, SD = 24.4 ml/min). The median mGFR was only 1.2 ml/min lesser when measures by the CG formula with no significance difference between them (P = 0.66, 95% confidence interval: -4.5-6.3). CONCLUSIONS We concluded that in resource-limited setting eGFR using CG formula can replace mGFR, especially in patients with age <60 years. Although weight did not showed a significant difference by two methods, a study with large sample is needed to confirm the result.
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Denosumab Improves Glomerular Filtration Rate in Osteoporotic Patients With Normal Kidney Function by Lowering Serum Phosphorus.
Miyaoka, D, Inaba, M, Imanishi, Y, Hayashi, N, Ohara, M, Nagata, Y, Kurajoh, M, Yamada, S, Mori, K, Emoto, M
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(11):2028-2035
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Higher serum phosphorus (Pi) increases the risk for chronic kidney disease (CKD). It was reported that a single administration of denosumab or zoledronate significantly suppressed serum Pi levels as well as those of bone resorption markers in serum. Also, previous evidences suggest a link between bone anti-resorptive therapy and vasoprotective/renoprotective effects through mechanisms that remain unexplored. The aim of this study is to assess the renoprotective effect of denosumab and involvement of denosumab-induced reduction in serum Pi in osteoporotic patients. Osteoporotic patients (n = 73) without overt proteinuria in dipstick test results were treated with denosumab (60 mg) every 6 months during the study period (24 months). Estimated glomerular filtration rate based on serum cystatin C (eGFRcys) was used as a filtration marker and tartrate-resistant acid phosphatase-5b (TRACP-5b) as a bone resorption marker. For analysis of non-CKD patients (n = 56), those with eGFRcys <60 mL/min/1.73 m2 were excluded. A single injection of denosumab suppressed serum Pi as well as TRACP-5b during the first 6 months, whereas age-related decline in eGFRcys was significantly reversed, with an increase of 2.75 ± 1.2 mL/min/1.73 m2 after 24 months noted. Multivariate analysis showed that serum Pi reduction following the initial denosumab injection was positively associated with serum TRACP-5b suppression during that same period (β = 0.241, p = 0.049). In addition, a positive association of serum Pi suppression, but not of corrected calcium or TRACP-5b, with eGFRcys increase after 24 months (β = 0.321, p = 0.014) was found after adjustments for gender, age, BMI, antihypertensive drug use, albumin, and eGFRcys. The same was observed in osteoporotic cases restricted to non-CKD patients. In conclusion, serum Pi reduction resulting from phosphorus load decrement from bone induced by denosumab is a determinant for eGFRcys increase. Early introduction of bone antiresorptive therapy can retain glomerular filtration in osteoporosis cases, including non-CKD patients. © 2019 American Society for Bone and Mineral Research.
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Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial.
Clegg, LE, Penland, RC, Bachina, S, Boulton, DW, Thuresson, M, Heerspink, HJL, Gustavson, S, Sjöström, CD, Ruggles, JA, Hernandez, AF, et al
Cardiovascular diabetology. 2019;(1):138
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. METHODS In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. RESULTS In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m2/year). CONCLUSIONS This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.
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Plasma dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP): reference intervals in Caucasian adults and diabetic kidney disease biomarker potential.
Griffin, TP, Islam, MN, Wall, D, Ferguson, J, Griffin, DG, Griffin, MD, O'Shea, PM
Scientific reports. 2019;(1):18452
Abstract
Recent studies suggest a possible association between dephosphorylated-uncarboxylated MGP (dp-ucMGP) and glomerular filtration rate (GFR). This study aimed to establish normative data in an adult Caucasian population and to explore the potential utility of dp-ucMGP in patients with diabetes mellitus (DM) with and without diabetic kidney disease (DKD). Healthy volunteers (HVs) (cross-sectional study) and participants with DM (prospective cohort study) were recruited. Plasma dp-ucMGP was measured using the IDS®-iSYS Ina Ktif (dp-ucMGP) assay. Of the HVs recruited (n = 208), 67(32.2%) were excluded leaving a reference population of 141(67.8%) metabolically healthy participants with normal kidney function. Plasma dp-ucMGP RIs were <300-532 pmol/L. There were 100 eligible participants with DKD and 92 with DM without DKD. For the identification of participants with DKD, the area under the receiver operating characteristic curve (AUC) for dp-ucMGP was 0.842 (95%CI:0.799-0.880; p < 0.001). Plasma dp-ucMGP demonstrated similar ability to urine albumin:creatinine ratio (uACR) to detect participants with DM and renal function decline. Among patients with DM, there was a negative correlation between natural log (LN) dp-ucMGP and eGFR (r = -0.7041; p < 0.001) and rate of change in renal function [%change (r = -0.4509; p < 0.001)] and a positive correlation between LN dp-ucMGP and LN uACR (r = 0.3392; p < 0.001). These results suggest the potential for plasma dp-ucMGP with well-defined RIs to identify adults at high risk for vascular disease in the context of progressive DKD.
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Long-Term Effects of Intensive Low-Salt Diet Education on Deterioration of Glomerular Filtration Rate among Non-Diabetic Hypertensive Patients with Chronic Kidney Disease.
Ahn, SY, Kim, DK, Park, JH, Shin, SJ, Lee, SH, Choi, BS, Lim, CS, Lee, A, Jung, H, Chin, HJ
Kidney & blood pressure research. 2019;(5):1101-1114
Abstract
BACKGROUND Diet modification, especially a decrease in salt intake, might be an important non-pharmacological strategy to improve chronic kidney disease (CKD) prognosis. OBJECTIVES We conducted a prospective cohort study to investigate whether an intensive low-salt diet education program effectively attenuated the rate of renal function decline in hypertensive patients with CKD. METHODS This cohort study recruited 171 participants from a previous open-labelled, case-controlled, randomized clinical trial that originally consisted of 245 hypertensive CKD patients who were assigned to two groups, intensive low-salt diet or conventional education. We evaluated the renal outcomes, which included the rate of change in estimated glomerular filtration rate (eGFR) per year, the increase in serum creatinine ≥50%, the decrease in eGFR ≥30%, and the percent change in albuminuria throughout the entire study period. RESULTS The baseline characteristics of the cohort participants between the two groups were similar at the time of trial phase randomization. During the whole study period, the rate of renal function decline was significantly faster in the conventional group (0.11 ± 4.63 vs. -1.53 ± 3.04 mL/min/1.73 m2/year, p = 0.01). The percent of incremental change in serum creatinine ≥50% was 1.1% in the intensive group and 8.2% in the conventional group (p = 0.025), and the percent of decremental change in eGFR ≥30% was 3.3% in the intensive group and 11.1% in the conventional group (p= 0.048). With logistic regression analysis adjusted for related factors, we found that the conventional group showed a higher risk for deterioration in serum creatinine and eGFR during the entire study period. Especially, we found that the intensive education program preserved eGFR in participants with one, several, or all of the following characteristics at the time of randomization: older age, female, obese, had higher protein intake, higher amounts of albuminuria, higher salt intake. CONCLUSION This cohort study demonstrated that an intensive low-salt diet education program attenuated the rate of renal function decline in hypertensive CKD patients independent of its effect on lowering salt intake or albuminuria during the 36 months of follow-up.
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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.
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Individualized Hemodialysis Treatment: A Perspective on Residual Kidney Function and Precision Medicine in Nephrology.
Hur, I, Lee, YK, Kalantar-Zadeh, K, Obi, Y
Cardiorenal medicine. 2019;(2):69-82
Abstract
BACKGROUND Residual kidney function (RKF) is often expected to inevitably and rapidly decline among hemodialysis patients and, hence, has been inadvertently ignored in clinical practice. The importance of RKF has been revisited in some recent studies. Given that patients with end-stage renal disease now tend to initiate maintenance hemodialysis therapy with higher RKF levels, there seem to be important opportunities for incremental hemo-dialysis by individualizing the dose and frequency according to their RKF levels. This approach is realigned with precision medicine and patient-centeredness. SUMMARY In this article, we first review the available methods to estimate RKF among hemodialysis patients. We then discuss the importance of maintaining and monitoring RKF levels based on a variety of clinical aspects, including volume overload, blood pressure control, mineral and bone metabolism, nutrition, and patient survival. We also review several potential measures to protect RKF: the use of high-flux and biocompatible membranes, the use of ultrapure dialysate, the incorporation of hemodiafiltration, incremental hemodialysis, and a low-protein diet, as well as general care such as avoiding nephrotoxic events, maintaining appropriate blood pressure, and better control of mineral and bone disorder parameters. Key Message: Individualized hemodialysis regimens may maintain RKF, lead to a better quality of life without compromising long-term survival, and ensure precision medicine and patient-centeredness in nephrology practice.
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Associations between serum apolipoproteins, urinary albumin excretion rate, estimated glomerular filtration rate, and diabetic retinopathy in individuals with type 2 diabetes.
Chung, JO, Park, SY, Cho, DH, Chung, DJ, Chung, MY
Medicine. 2019;(20):e15703
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The published data regarding the role of serum apolipoprotein (apo) A-I, apoB, and the apoB/A-I ratio in the risk of diabetic retinopathy remain inconsistent, and there is limited information about the effect of renal status on their associations in individuals with type 2 diabetes. The aim of this study was to investigate whether serum apoA-I, apoB, and the apoB/A-I ratio are associated with the presence of diabetic retinopathy in type 2 diabetes and to explore whether the relationships between these apolipoproteins and diabetic retinopathy are modified by urinary albumin excretion rate (UACR) and estimated glomerular filtration rate (eGFR).In total, 1215 individuals with type 2 diabetes were included in this cross-sectional study. Serum levels of apoA-I and apoB and the apoB/apoA-I ratio were measured. A logistic regression model was performed to explore associations of apolipoproteins with retinopathy.Individuals with diabetic retinopathy had significantly lower levels of serum apoA-I and higher apoB/apoA-I ratio than those without diabetic retinopathy. In the multivariable analyses, the associations between apoA-I and diabetic retinopathy and between the apoB/apoA-I ratio and diabetic retinopathy were statistically significant after adjustment for the traditional risk factors (odds ratio [OR] per standard deviation [SD] increase in the log-transformed value; 0.55, 95% confidence interval (CI); 0.32 to 0.97, P = .038; OR per SD increase in the log-transformed value; 2.83, 95% CI; 1.18 to 6.76, P = .019; respectively). Additional adjustments for UACR or eGFR removed the significant associations.In individuals with type 2 diabetes, serum apoA-I and the apoB/apoA-I ratio are associated with presence of diabetic retinopathy, which might be attributable to the correlated changes in UACR and eGFR.