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1.
Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review.
Erstad, BL, Nix, DE
The Annals of pharmacotherapy. 2021;(1):80-88
Abstract
OBJECTIVES To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity. DATA SOURCES PubMed (1976 to mid-May 2020) was used, with bibliographies of retrieved articles searched for additional articles. STUDY SELECTION AND DATA EXTRACTION Articles using gold standard mGFR to evaluate eClCr, mClCr, and eGFR assessments of kidney function in patients with more extreme forms of obesity were included. DATA SYNTHESIS The overestimation of GFR by mClCr is well established, but mClCr is an alternative to mGFR assessments for determining medication dosing in patients with extremes of body size or muscle mass, or in patients receiving narrow therapeutic index medications when eGFR is likely to be inaccurate. The vast majority of studies comparing eGFR assessments with gold standard indicators of kidney function were attempts to validate eGFR equations for diagnosing and staging chronic kidney disease (CKD). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE For dosing medications in patients with stable kidney function and extreme obesity, a deindexed 4-variable Modification of Diet in Renal Disease or CKD Epidemiology Collaboration equation is an alternative to Cockcroft-Gault. Consistent use of the same equation by provider and between providers within any given setting is of paramount importance. CONCLUSIONS In patients with extreme obesity and stable kidney function, eClCr or eGFR using deindexed values provides estimates of function for dosing adjustments of medications with elimination by the kidneys, but more research is needed with respect to the best size descriptor to use with estimating equations.
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2.
Effects of Exercise on Acute Kidney Injury Biomarkers and the Potential Influence of Fluid Intake.
Juett, LA, James, LJ, Mears, SA
Annals of nutrition & metabolism. 2020;:53-59
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Abstract
Acute kidney injury (AKI) incidence (diagnosed by changes in serum creatinine [Cr]) following prolonged endurance events has been reported to be anywhere from 4 to 85%, and hypohydration may contribute to this. Whilst an increase in serum Cr indicates impaired kidney function, this might be influenced by muscle damage. Therefore, the use of other AKI biomarkers which can detect renal tubular injury may be more appropriate. The long-term consequences of AKI are not well understood, but there are some potential concerns of an increased subsequent risk of chronic kidney disease (CKD). Therefore, this brief review explores the effects of exercise training/competition on novel AKI biomarkers and the potential influence of fluid intake. The increase in novel AKI biomarkers following prolonged endurance events suggests renal tubular injury. This is likely due to the long duration and relatively high exercise intensity, producing increased sympathetic tone, body temperature, hypohydration, and muscle damage. Whilst muscle damage appears to be an important factor in the pathophysiology of exercise-associated AKI, it may require coexisting hypohydration. Fluid intake seems to play a role in exercise-associated AKI, as maintaining euhydration with water ingestion during simulated physical work in the heat appears to attenuate rises in AKI biomarkers. The composition of fluid intake may also be important, as high-fructose drinks have been shown to exacerbate AKI biomarkers. However, it is yet to be seen if these findings are applicable to athletes performing strenuous exercise in a temperate environment. Additionally, further work should examine the effects of repeated bouts of strenuous exercise on novel AKI biomarkers.
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Biosensing methods for determination of creatinine: A review.
Pundir, CS, Kumar, P, Jaiwal, R
Biosensors & bioelectronics. 2019;:707-724
Abstract
Creatinine is a metabolic product of creatine phosphate in muscles, which provides energy to muscle tissues. Creatinine has been considered as indicator of renal function specifically after dialysis, thyroid malfunction and muscle damage. The normal level of creatinine in the serum and its excretion through urine in apparently healthy individuals is 45-140 μM and 0.8-2.0 gm/day respectively. The level of creatinine reaches >1000 μM in serum during renal, thyroid and kidney dysfunction or muscle disorder. A number of conventional methods such as colorimetric, spectrophotometric and chromatographic are available for determination of creatinine. Besides the advantages of being highly sensitive and selective, these methods have some drawbacks like time-consuming, requirement of sample pre-treatment, high cost instrumental set-up and skilled persons to operate. The sensors/biosensors overcome these drawbacks, as these are fast, easy, cost effective and highly sensitive. This review article describes the classification, operating principles, merits and demerits of various creatinine sensors/biosensors, specifically nanomaterials based biosensors. Creatinine biosensors work optimally within 2-900 s, potential range 0.1-1.0 V, pH range 4.0-10.0, temperature range 25-35 °C and had linear range, 0.004-30000 µM for creatinine with the detection limit between 0.01.01 µM and 520 µM. These biosensors measured creatinine level in sera and urine samples and had storage stability between 4 and 390 days, while being stored dry at 4 °C. The future perspective for further improvement and commercialization of creatinine biosensors are discussed.
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Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension.
Singh, Y, Samuel, VP, Dahiya, S, Gupta, G, Gillhotra, R, Mishra, A, Singh, M, SreeHarsha, N, Gubbiyappa, SK, Tambuwala, MM, et al
Biotechnology and applied biochemistry. 2019;(5):715-719
Abstract
Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.
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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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Methods of Estimating Kidney Function for Drug Dosing in Special Populations.
Hart, LA, Anderson, GD
Clinical pharmacokinetics. 2018;(8):943-976
Abstract
International guidelines recommend the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method to monitor kidney function in chronic kidney disease using either creatinine- or cystatin C-based estimation methods. The choice of an estimation method to determine dosage for renally eliminated drugs is not as clear. For the majority of currently marketed drugs, the Cockcroft-Gault equation with the Jaffe method, a non-isotope dilution mass spectrometry, standardized serum creatinine, was used to estimate kidney function to recommend dosing adjustment in kidney impairment. As the Cockcroft-Gault equation cannot be converted for isotope dilution mass spectrometry-traceable creatinine values and clinical laboratories now report estimated glomerular filtration (eGFR) rate by the Modified Diet in Renal Disease (MDRD) Equation or CKD-EPI, the eGFR is now more widely accepted for dosage adjustment recommendations. Cockcroft-Gault, MDRD Equation, and CKD-EPI creatinine-based methods were developed in specific populations, which included either none or a low proportion of obese individuals, pregnant women, older adults, and those with significant comorbid conditions. Clinical studies in these special populations have identified significant decreased accuracy, precision, and bias in the creatinine-based methods. Newer cystatin C-based estimation methods may significantly improve the ability to estimate kidney function to determine doses in the future. At this time, the increased cost and lack of standardization of serum cystatin C hinder routine use.
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Neonate acute kidney injury.
Yang, H, Zhu, B, Zhang, R
Minerva pediatrica. 2017;(3):213-218
Abstract
Acute kidney injury (AKI) is characterized by the abrupt inability of the kidneys to adequately excrete waste products and regulate fluid and electrolyte homeostasis appropriately. This results in an at least partially reversible increase in the blood concentration of creatinine and nitrogenous waste products. Moreover, medication eliminated via renal routes will accumulate that in turn result in a "second hit" to the already injured kidneys. Furthermore, fluid management and nutrition will be hampered by oliguria. Neonatal AKI is a frequent complication in children admitted to an ICU and is associated with significant morbidity and mortality. Moreover, in newborns the diagnosis of AKI is more difficult since at birth serum creatinine (SCr) predominantly reflects maternal renal function. Furthermore, neonates are especially susceptible to hypovolemic kidney injury due to an inadequate renal auto regulation Thus, accurate assessment of renal function in children is important in numerous clinical situations including screening and/or monitoring of renal disease. The present narrative review article will deal with the latest innovations in diagnostic as well as management options available for AKI in children.
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How to use… serum creatinine, cystatin C and GFR.
Pasala, S, Carmody, JB
Archives of disease in childhood. Education and practice edition. 2017;(1):37-43
Abstract
Glomerular filtration rate (GFR) is the best overall measure of kidney function. The GFR is relatively low at birth but increases through infancy and early childhood to reach adult levels of approximately 120 mL/min/1.73 m2 by age 2. While GFR can be measured most accurately by the urinary clearance of an exogenous ideal filtration marker such as inulin, it is more clinically useful to estimate GFR using a single serum measurement of an endogenous biomarker such as creatinine or cystatin C. When in steady state, there is an inverse relationship between creatinine/cystatin C and GFR, allowing GFR to be estimated from either using simple equations. Because of the non-linear relationship between creatinine/cystatin C and GFR, relatively small initial increases in these markers represent significant decreases in GFR. While cystatin C is produced by all nucleated cells, creatinine is a waste product of muscle metabolism and is therefore influenced by diet and muscle mass/body habitus. Decreased GFR is used to diagnose and stage chronic kidney disease (CKD) using the Kidney Disease: Improving Global Outcomes system. A diagnosis of CKD requires GFR <60 mL/min/1.73 m2 for more than 3 months; higher GFR also represents CKD if evidence of kidney damage (such as albuminuria or abnormal imaging) is present. Changes in serum creatinine and urine output are used to diagnose acute kidney injury. It is possible to calculate a kinetic GFR when the creatinine is changing rapidly, though more complex calculations are required.
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Systematic review and meta-analysis of randomised controlled trials on the effects of potassium supplements on serum potassium and creatinine.
Cappuccio, FP, Buchanan, LA, Ji, C, Siani, A, Miller, MA
BMJ open. 2016;(8):e011716
Abstract
OBJECTIVES High potassium intake could prevent stroke, but supplementation is considered hazardous. We assessed the effect of oral potassium supplementation on serum or plasma potassium levels and renal function. SETTING We updated a systematic review of the effects of potassium supplementation in randomised clinical trials carried out worldwide, published in 2013, extending it to July 2015. We followed the PRISMA guidelines. PARTICIPANTS Any individual taking part in a potassium supplementation randomised clinical trial. Studies included met the following criteria: randomised clinical trials, potassium supplement given and circulating potassium levels reported. INTERVENTION Oral potassium supplementation. PRIMARY OUTCOME MEASURES Serum or plasma potassium and serum or plasma creatinine. RESULTS A total of 20 trials (21 independent groups) were included (1216 participants from 12 different countries). All but 2 were controlled (placebo n=16, control n=2). Of these trials, 15 were crossover, 4 had a parallel group and 1 was sequential. The duration of supplementation varied from 2 to 24 weeks and the amount of potassium given from 22 to 140 mmol/day. In the pooled analysis, potassium supplementation caused a small but significant increase in circulating potassium levels (weighted mean difference (WMD) 0.14 mmol/L, 95% CI 0.09 to 0.19, p<1×10(-5)), not associated with dose or duration of treatment. The average increase in urinary potassium excretion was 45.75 mmol/24 hours, 95% CI 38.81 to 53.69, p<1×10(-5). Potassium supplementation did not cause any change in circulating creatinine levels (WMD 0.30 µmol/L, 95% CI -1.19 to 1.78, p=0.70). CONCLUSIONS In short-term studies of relatively healthy persons, a moderate oral potassium supplement resulted in a small increase in circulating potassium levels and no change in renal function.
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The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?
Chu, X, Bleasby, K, Chan, GH, Nunes, I, Evers, R
Drug metabolism and disposition: the biological fate of chemicals. 2016;(9):1498-509
Abstract
In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic.