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1.
Nonvitamin K Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Renal Dysfunction.
Mahmood, M, Lip, GYH
Revista espanola de cardiologia (English ed.). 2018;(10):847-855
Abstract
Both atrial fibrillation (AF) and chronic kidney disease (CKD) are highly prevalent, especially with increasing age and associated comorbidities, such as hypertension, diabetes, heart failure, and vascular disease. The relationship between both AF and CKD seems to be bidirectional: CKD predisposes to AF while onset of AF seems to lead to progression of CKD. Stroke prevention is the cornerstone of AF management, and AF patients with CKD are at higher risk of stroke, mortality, cardiac events, and bleeding. Stroke prevention requires use of oral anticoagulants, which are either vitamin K antagonists (eg, warfarin), or the nonvitamin K antagonist oral anticoagulants (NOACs). While NOACs have been shown to be effective in mild-to-moderate renal dysfunction, there are a paucity of data regarding NOACs in severe and end-stage renal dysfunction. This review first discusses the evidence for NOACs in CKD. Second, we summarize the current knowledge regarding the efficacy and safety of NOACs to prevent AF-related stroke and systemic embolism in severe and end-stage renal disease.
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Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.
Aachmann-Andersen, NJ, Christensen, SJ, Lisbjerg, K, Oturai, P, Johansson, PI, Holstein-Rathlou, NH, Olsen, NV
Physiological reports. 2018;(5)
Abstract
The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system.
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3.
Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial.
Wanner, C, Heerspink, HJL, Zinman, B, Inzucchi, SE, Koitka-Weber, A, Mattheus, M, Hantel, S, Woerle, HJ, Broedl, UC, von Eynatten, M, et al
Journal of the American Society of Nephrology : JASN. 2018;(11):2755-2769
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Abstract
BACKGROUND Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. METHODS Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). RESULTS Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: -1.46; 95% confidence interval, -1.74 to -1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo -0.02; 95% confidence interval, -0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk. CONCLUSIONS The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.
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SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis.
Seidu, S, Kunutsor, SK, Cos, X, Gillani, S, Khunti, K, ,
Primary care diabetes. 2018;(3):265-283
Abstract
BACKGROUND Sodium-glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of ≥30 and <60ml/min/1.73m2 and/or UACR>300 and ≤5000mg/g] by conducting a systematic review and meta-analysis of available studies. METHODS Randomised controlled trials (RCTs) were identified from MEDLINE, EMABASE, Web of Science, the Cochrane Library, and search of bibliographies to March 2017. No relevant observational study was identified. Summary measures were presented as mean differences and narrative synthesis performed for studies that could not be pooled. RESULTS 42 articles which included 40 RCTs comprising 29,954 patients were included. In populations with renal impairment, SGLT2 inhibition compared with placebo was consistently associated with an initial decrease in eGFR followed by an increase and return to baseline levels. In pooled analysis of 17 studies in populations without renal impairment, there was no significant change in eGFR comparing SGLT2 inhibitors with placebo (mean difference, 0.51ml/min/1.73m2; 95% CI: -0.69, 1.72; p=403). SGLT2 inhibition relative to placebo was associated with preservation in serum creatinine levels or initial increases followed by return to baseline levels in patients with renal impairment, but levels were preserved in patients without renal impairment. In populations with or without renal impairment, SGLT2 inhibitors (particularly canagliflozin and empagliflozin) compared with placebo were associated with decreased urine albumin, improved albuminiuria, slowed progression to macroalbuminuria, and reduced the risk of worsening renal impairment, the initiation of kidney transplant, and death from renal disease. CONCLUSIONS Emerging data suggests that with SGLT2 inhibition, renal function seems to be preserved in people with diabetes with or without renal impairment. Furthermore, SGLT2 inhibition prevents further renal function deterioration and death from kidney disease in these patients.
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Longitudinal assessment of renal function in native kidney after bariatric surgery.
Favre, G, Schiavo, L, Lemoine, S, Esnault, VLM, Iannelli, A
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2018;(9):1411-1418
Abstract
The epidemic of obesity parallels that of chronic kidney disease (CKD). Obesity worsens the course of CKD, mainly defined by an abnormal glomerular filtration rate (GFR). Patients with severe obesity stages (II and III with body mass index >35 kg/m2) are eligible for bariatric surgery (BS), which is the most efficient method of achieving durable weight loss. BS may reverse glomerular hyperfiltration and albuminuria, improve adipocytokine profile, and relieve diabetes and hypertension. Obesity remission after BS might prevent the progression of renal failure in populations with morbid obesity. However, evidence for the beneficial effect of BS on renal function is scant. This lack of knowledge is mainly due to methodologic reasons, which are addressed in this review. The reversibility of hyperfiltration due to the presence of functional renal reserve hampers the interpretation of changes in true GFR after BS. This true GFR is only obtained with the renal clearance of an exogenous filtration marker. Estimation of GFR is generally provided by prediction equations, namely by modification of diet in renal diseases or by chronic kidney disease-epidemiology collaborative group. These equations are not accurate because the serum levels of both creatinine and cystatin C depend on extrarenal factors, which are modified by BS. Comparing the slopes of measured GFR according to various durations of exposure with morbid obesity would be critical in providing reliable data. Herein, we review the current knowledge on the effects of BS on kidney function; we specify the methodologic issues and particularities of the dietary management of CKD patients to propose reliable directions for future clinical research.
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Older Adult Kidney Function Assessment and Rounding Creatinine Led to Medication Dosing Error.
Nguyen, T, Foster, Y, Cekaj, S
American journal of therapeutics. 2018;(4):e439-e446
Abstract
BACKGROUND/AREAS OF UNCERTAINTY Kidney function assessment in older adults can be unreliable because of many factors, and inaccurate assessment can lead to medication dosing error. Practitioners may have adopted the method of rounding creatinine to an arbitrary number 1.0 because of change in muscle mass and age-related change. This has in fact proven to cause more harm than good, potentially leading to underdosing of many medications. DATA SOURCES A literature search performed using PubMed with the following key words (rounding serum creatinine, rounding serum creatinine AND pharmacist or pharmacy, rounding serum creatinine AND doctor or physician or healthcare, rounding serum creatinine AND kidney function) with no restrictions (dates or any other requirement). RESULTS From the PubMed results, articles related to rounding of serum creatinine (Scr) and kidney function assessments were identified and reviewed. Most studies were retrospectives, 1 cross-sectional, 1 meta-analysis, and others were unidentified. These studies included various ways of estimating kidney functions (Tc DTPA clearance, Cockcroft-Gault creatinine clearance, 24-hour urine collection, Modification of Diet in Renal Disease, Chronic Kidney Disease-Epidemiology Collaboration), used various weights (actual body weight, ideal body weight, adjusted body weight), and most studies used 1.0 for rounding up Scr (other studies used 0.8 and 0.85). There was no associated relationship found as related to practicing professions (pharmacists vs. physician) to the practice of rounding Scr. CONCLUSIONS All studies yielded inaccurate kidney function upon rounding of Scr and leading to medication dosing error. All studies suggested against rounding Scr when assessing kidney function in older adults.
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Quantification of NGAL in Urine of Endurance Cycling Athletes.
Machado, JCQ, Volpe, CMO, Vasconcellos, LS, Nogueira-Machado, JA
Journal of physical activity & health. 2018;(9):679-682
Abstract
BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein released during early phases of a postischemic kidney in response to kidney injury, inflammation, and oxidative stress. It can be detected in urine after 2 hours of an ischemic event. The aim was to measure and to correlate the level of urine NGAL (uNGAL) with urea, creatinine, and glomerular filtration rate (GFR) of endurance cycling athletes (n = 19) and physically active individuals (control, n = 17). METHODS Quantification of urea and creatinine were performed by dry chemical method, and GFR was calculated using the modification of diet in renal disease formula, according to Brazilian Society of Nephrology. uNGAL analyses were performed by enzyme linked immunoabsorbent assay. Analyses were performed 48 hours after exercises. RESULTS uNGAL (in ng/mL) levels, expressed as median, minimum, and maximum, in cyclist group, 387.7 (109.7-1691.0), was significantly higher than that observed in control (physically active) group, 141.5 (4.8-657.0), (P < .05). No significant correlations were observed between uNGAL and creatinine, urea, or GFR (P > .05). CONCLUSIONS Results have pointed to increased uNGAL levels in endurance cycling athletes. Increase of uNGAL in absence of clinical signs or alterations in creatinine, urea, or GFR might suggest that there is metabolic adaptation to endurance exercise, or possibly predisposition to acute kidney injury over time.
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Effects of sodium nitrite on renal function and blood pressure in hypertensive vs. healthy study participants: a randomized, placebo-controlled, crossover study.
Rosenbæk, JB, Hornstrup, BG, Jørgensen, AN, Mortensen, J, Pedersen, EB, Bech, JN
Journal of hypertension. 2018;(3):666-679
Abstract
OBJECTIVE Nitric oxide is a key player in regulating vascular tone. Impaired endothelial nitric oxide synthesis plays an important role in hypertension. Replenishing of nitric oxide by sodium nitrite (NaNO2) has not been investigated in patients with essential hypertension (EHT). We aimed to determine the effects of NaNO2 on blood pressure (BP) and renal sodium and water regulation in patients with EHT compared with healthy control study participants (CON). METHODS In a placebo-controlled, crossover study, we infused 240 μg NaNO2/kg/h or isotonic saline for 2 h in 14 EHT and 14 CON. During infusion, we measured changes in brachial and central BP, free water clearance, fractional sodium excretion, and urinary excretion rate of γ-subunit of the epithelial sodium channel (U-ENaCγ), and aquaporin-2 (U-AQP2). RESULTS Placebo-adjusted brachial SBP decreased 18 mmHg (P < 0.001) during NaNO2 infusion in EHT and 12 mmHg (P < 0.001) in CON (Pbetween = 0.024). Brachial DBP and central SBP decreased equally in both groups during NaNO2. In EHT, we found a decrease in U-ENaCγ during NaNO2 infusion. In both groups, we observed a decrease in fractional sodium excretion, free water clearance, and U-AQP2 during NaNO2 infusion. CONCLUSION This study demonstrated an augmented BP-lowering effect of NaNO2 in patients with EHT. We observed an antinatriuretic and antidiuretic effect of NaNO2 in both groups, and a decrease in U-ENaCγ, solely in EHT. In both groups, we detected a nonvasopressin mediated decrease in U-AQP2, which is most likely compensatory to the decline in diuresis.
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Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin.
Cherney, DZI, Cooper, ME, Tikkanen, I, Pfarr, E, Johansen, OE, Woerle, HJ, Broedl, UC, Lund, SS
Kidney international. 2018;(1):231-244
Abstract
Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24-week trials of 2286 patients with type 2 diabetes randomized to empagliflozin or placebo. Reductions in HbA1c with empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 (-5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m2, respectively. Similar trends were observed for diastolic blood pressure. Weight loss with empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with empagliflozin are generally preserved in patients with chronic kidney disease.
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Intravenous Mannitol Versus Placebo During Partial Nephrectomy in Patients with Normal Kidney Function: A Double-blind, Clinically-integrated, Randomized Trial.
Spaliviero, M, Power, NE, Murray, KS, Sjoberg, DD, Benfante, NE, Bernstein, ML, Wren, J, Russo, P, Coleman, JA
European urology. 2018;(1):53-59
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Abstract
BACKGROUND Mannitol is currently used as a renal protective agent to mitigate the effects of renal ischemia during nephron-sparing surgery (NSS). This routine practice lacks rigorous methodological study. OBJECTIVE To assess the effect on renal function outcomes after surgery of mannitol infusion prior to renal ischemia during NSS. DESIGN, SETTING, PARTICIPANTS This prospective, randomized, placebo-controlled, double-blind trial included 199 patients with a preoperative estimated glomerular filtration rate (eGFR) >45ml/min/1.73m2 scheduled for NSS; the trial was conducted between July 2012 and July 2015. INTERVENTION Patients undergoing NSS were randomized to receive mannitol (12.5g) or placebo intravenously within 30min prior to renal vascular clamping. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the difference in eGFR (renal function) between the two groups at 6 mo following surgery assessed with an analysis of covariance model using preoperative eGFR, treatment group, and surgical approach as covariates. RESULTS AND LIMITATIONS At baseline, the median age of the patients was 58 yr, and the median eGFR was 88ml/min/1.73m2. Comparing placebo with mannitol infusion, the adjusted difference of 0.2 eGFR units at 6 mo was not significant (p=0.9), with the upper bound of the 95% confidence interval (-3.1 to 3.5) excluding a clinically relevant effect of mannitol. Limitations include evaluation of a single mannitol dose and patients all had excellent preoperative renal function. CONCLUSIONS Intraoperative 12.5g mannitol infusion during NSS has no demonstrable clinical benefit when compared with standardized fluid hydration in patients with normal preoperative renal function, and its use in this setting is not warranted. PATIENT SUMMARY In this randomized trial, patients with normal kidney function who received mannitol during surgery to remove part of their kidney had no better kidney function 6 mo after surgery than those who did not receive mannitol. We conclude that this routine practice should be discontinued.