Background: Reliable serum creatinine measurements in glomerular filtration rate (GFR) estimation are critical to ongoing global public health efforts to increase the diagnosis and treatment of chronic kidney disease (CKD). We present an overview of the commonly used methods for the determination of serum creatinine, method limitations, and method performance in conjunction with the development of analytical performance criteria. Available resources for standardization of serum creatinine measurement are discussed, and recommendations for measurement improvement are given. Methods: The National Kidney Disease Education Program (NKDEP) Laboratory Working Group reviewed problems related to serum creatinine measurement for estimating GFR and prepared recommendations to standardize and improve creatinine measurement.
IMPORTANCE Low-density lipoprotein cholesterol (LDL-C), a key cardiovascular disease marker, is often estimated by the Friedewald or Martin equation, but calculating LDL-C is less accurate in patients with a low LDL-C level or hypertriglyceridemia (triglyceride [TG] levels Ն400 mg/dL). OBJECTIVE To design a more accurate LDL-C equation for patients with a low LDL-C level and/or hypertriglyceridemia. DESIGN, SETTING, AND PARTICIPANTS Data on LDL-C levels and other lipid measures from 8656 patients seen at the National Institutes of Health Clinical Center between January 1, 1976, and June 2, 1999, were analyzed by the β-quantification reference method (18 715 LDL-C test results) and were randomly divided into equally sized training and validation data sets. Using TG and non-high-density lipoprotein cholesterol as independent variables, multiple least squares regression was used to develop an equation for very low-density lipoprotein cholesterol, which was then used in a second equation for LDL-C. Equations were tested against the internal validation data set and multiple external data sets of either β-quantification LDL-C results (n = 28 891) or direct LDL-C test results (n = 252 888). Statistical analysis was performed from August 7, 2018, to July 18, 2019. MAIN OUTCOMES AND MEASURES Concordance between calculated and measured LDL-C levels by β-quantification, as assessed by various measures of test accuracy (correlation coefficient [R 2 ], root mean square error [RMSE], mean absolute difference [MAD]), and percentage of patients misclassified at LDL-C treatment thresholds of 70, 100, and 190 mg/dL. RESULTSCompared with β-quantification, the new equation was more accurate than other LDL-C equations (slope, 0.964; RMSE = 15.2 mg/dL; R 2 = 0.9648; vs Friedewald equation: slope, 1.056; RMSE = 32 mg/dL; R 2 = 0.8808; vs Martin equation: slope, 0.945; RMSE = 25.7 mg/dL; R 2 = 0.9022), particularly for patients with hypertriglyceridemia (MAD = 24.9 mg/dL; vs Friedewald equation: MAD = 56.4 mg/dL; vs Martin equation: MAD = 44.8 mg/dL). The new equation calculates the LDL-C level in patients with TG levels up to 800 mg/dL as accurately as the Friedewald equation does for TG levels less than 400 mg/dL and was associated with 35% fewer misclassifications when patients with hypertriglyceridemia (TG levels, 400-800 mg/dL) were categorized into different LDL-C treatment groups. CONCLUSIONS AND RELEVANCEThe new equation can be readily implemented by clinical laboratories with no additional costs compared with the standard lipid panel. It will allow for more accurate calculation of LDL-C level in patients with low LDL-C levels and/or hypertriglyceridemia (TG levels, Յ800 mg/dL) and thus should improve the use of LDL-C level in cardiovascular disease risk management.
Background: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i's) improve heart failure (HF) related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics, such as furosemide, induce substantial neurohormonal activation contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the SGLT-2i's may help circumvent these limitations. Methods: 20 patients with type-2 diabetes and chronic, stable HF completed a randomized placebo-controlled crossover study of empagliflozin 10mg daily vs. placebo. Patients underwent an intensive 6-hour biospecimen collection and cardio-renal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with repeat of the above protocol. Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (p<0.0001). Fractional excretion of sodium (FENa) increased significantly with empagliflozin monotherapy vs. placebo (FENa 1.2 ± 0.7% vs. 0.7 ± 0.4% p=0.001) and there was a synergistic effect in combination with bumetanide (FENa 5.8 ± 2.5% vs. 3.9 ± 1.9%, p=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208mL, IQR -536 to 153 mL vs -14mL, IQR -282 to 335 mL, p=0.035), and plasma volume (-138mL, IQR -379 to 154mL ± 453 mL, p=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation as change in norepinephrine was superior (p = 0.02) and all other neurohormones similar (p<0.34) during the empagliflozin vs. placebo period. Furthermore, there was no evidence of potassium wasting (p=0.20), or renal dysfunction (p>0.11 for all biomarkers), whereas both serum magnesium (p<0.001) and uric acid levels (p=0.008) improved. Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in HF patients and may represent a mechanism contributing to the superior long-term HF outcomes observed with these agents. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03029760
Improving outcomes for chronic kidney disease (CKD) requires early identification and recognition by physicians. There are few data on rates of testing or use of diagnostic codes for CKD. A cross-sectional analysis was performed of patients who were older than 40 yr and had one or more laboratory tests between April 1, 2002, and March 31, 2003, at a Laboratory Corporation of America regional laboratory. Objectives were to determine the frequency of testing for serum creatinine; prevalence of CKD, defined as estimated GFR <60 ml/min per 1.73m 2 ; and sensitivity of diagnostic codes for CKD for patients with and without risk factors for CKD and with or without cardiovascular disease (CVD). Of the 277,111 patients, 19% had serum creatinine measured, compared with 33 and 71% who had measurements of serum glucose and lipids, respectively. Patients with hypertension, diabetes, and age >60 yr were more likely to be tested for serum creatinine with odds ratio (OR; 95% confidence interval) of 2.09 (2.05 to 2.14), 1.22 (1.19 to 1.25), and 1.24 (1.22 to 1.27) respectively. Among patients tested, 30% had CKD. Sensitivity and specificity of kidney disease diagnostic codes compared with CKD defined by estimated GFR <60 ml/min per 1.73 m 2 were 11 and 96%, respectively. In patients with hypertension, diabetes, age >60 years, and CVD, rates of testing and sensitivity of diagnostic codes were 53 and 14%, respectively. Low rates of testing for serum creatinine and insensitivity of diagnostic codes for CKD, even in high-risk patients, suggests inadequate physician awareness of CKD and limited utility of administrative databases for identification of patients with CKD.
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