Filtration Markers Research Articles

Sarcopenia Strongly Affects Serum Levels of Cystatin C in Patients with Heart Failure

Introduction Low muscle mass, or sarcopenia, is commonly seen in patients with heart failure (HF). For any given level of renal function, patients with sarcopenia will have lower levels of serum creatinine because there is less muscle mass to produce creatinine. Thus, the use of creatinine to estimate glomerular filtration rate (GFR) is affected by sarcopenia. In contrast to creatinine, cystatin C is considered a better filtration marker to estimate GFR in the setting of sarcopenia because it not seclusively produced by muscle. However, it has not been demonstrated that serum cystatin C levels are independent of sarcopenia in patients with HF. Hypothesis Serum cystatin C levels will be minimally influenced by muscle mass in patients with heart failure. Methods Serum cystatin C and serum creatinine were measured in patients with decompensated heart failure. Strict timed urine collections were used to measure creatinine excretion rate. Muscle mass was estimated with a validated equation based on urine creatinine excretion (Heymsfield). Creatinine clearance was calculated and used as a surrogate for measured GFR. Results Out of the 295 patients analyzed (average age 65 ±14 years), 65% were male and 61% were obese. Baseline levels of serum creatinine were 1.5±0.6 mg/dL and cystatin C were 1.7±0.7 mg/L. In univariate analysis, serum cystatin C showed a negative correlation with muscle mass (rho -0.37, p Conclusion Serum cystatin C serum levels are strongly associated with muscle mass in patients with HF. This may lead to inaccuracies when cystatin C is used to estimate GFR.

Accuracy of determination of the glomerular filtration marker iohexol by European laboratories as monitored by external quality assessment.

Background Glomerular filtration is the most important kidney function. The most accurate glomerular filtration rate (GFR) estimates are based on the clearance of exogenous filtration markers. Of these, iohexol is the only exogenous marker that is included in an external quality assessment (EQA) scheme. The aim of the present study was to evaluate the performance of the European laboratories participating in Equalis' EQA scheme for iohexol. Methods Weighed amounts of iohexol (Omnipaque) were added to plasma samples and distributed to laboratories participating in the EQA scheme for iohexol. All laboratories performed the assays in a blinded fashion. Results The number of participating laboratories varied between 27 and 34 during the study period. Iohexol was determined by HPLC in 77% of the laboratories and by UPLC/MS/MS methods in 15% of the laboratories. The mean interlaboratory coefficient of variation was 4.7% for the HPLC methods and 6.4% for the UPLC/MS/MS methods. The mean bias between calculated and measured iohexol values was -1.3 mg/L (95% confidence interval ±0.3) during the first part of the study period and 0.1 mg/L (±0.3) during the later part. Conclusions The low interlaboratory variation demonstrates that iohexol can be measured reliably by many laboratories and supports the use of iohexol as a GFR marker when there is a need for high quality GFR measurements.

Development and Validation of Residual Kidney Function Estimating Equations in Dialysis Patients

Rationale & ObjectiveMeasurement of residual kidney function is recommended for the adjustment of the dialysis prescription, but timed urine collections are difficult and prone to errors. Equations to calculate residual kidney function from serum concentrations of endogenous filtration markers and demographic parameters would simplify monitoring of residual kidney function. However, few equations to estimate residual kidney function using serum concentrations of small solutes and low-molecular-weight proteins have been developed and externally validated.Study DesignStudy of diagnostic test accuracy.Setting & Participants823 Chinese peritoneal dialysis (PD) patients (development cohort) and 826 PD and hemodialysis patients from the Netherlands NECOSAD study (validation cohort).Tests ComparedEquations to estimate residual kidney function (estimated clearance [eCl]) using serum creatinine, urea nitrogen, cystatin C, β2-microglobulin (B2M), β-trace protein (BTP), and combinations, as well as demographic variables (age, sex, height, and weight). Equations were developed using multivariable linear regression analysis in the development cohort and then tested in the validation cohort. Equations were compared with published validated equations.OutcomesResidual kidney function measured as urinary clearance (mCl) of urea nitrogen (mClUN) and average of creatinine and urea nitrogen clearance (mClUN-cr).ResultsIn external validation, bias (difference between mCl and eCl) was within ± 1.0 unit for all equations. Accuracy (percent of differences within ± 2.0 units) was significantly better for eClBTP, eClB2M, and eClBTP-B2M than eClUN-cr for both mClUN (78%, 80%, and 81% vs 72%; P < 0.05 for all) and mClUN-cr (72%, 78%, and 79% vs 68%; P < 0.05 for all). The area under the curve for predicting mClUN > 2.0 mL/min was highest for eClB2M (0.853) and eClBTP-B2M (0.848). Results were similar for other validated equations.LimitationsDevelopment cohort only consisted of PD patients, no gold-standard method for residual kidney function measurement.ConclusionsThese results confirm the validity and extend the generalizability of residual kidney function estimating equations from serum concentrations of low-molecular-weight proteins without urine collection.

Investigating the Value of Urine Volume, Creatinine, and Cystatin C for Urinary Biomarkers Normalization for Drug Development Studies.

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there seems to be no standardized normalization method for analyzing these urinary biomarkers, as some users normalize with urinary creatinine (uCr), urine volume (uVol), or leave biomarker un-normalized. More recently, urinary cystatin C is also emerging as a urinary biomarker normalizer, given some of its characteristics as a glomerular filtration marker. The purpose of this study was to identify an optimal drug-induced kidney injury biomarker normalization method that can be adopted more uniformly in the field. To this end, we compared the variability of uVol, urinary cystatin C, and Cr in healthy rats; we evaluated the sensitivity of the renal biomarkers to renal injury after normalization with uVol, uCr, and cystatin C in rats with cisplatin-induced renal injury. We showed that, over time, uCr was less variable than urinary cystatin C and uVol. When the renal biomarkers were normalized with the 3 normalizing end points, the biomarkers showed (1) least variability following normalization with Cr in healthy animals and (2) poor sensitivity when normalized with urinary cystatin C in animals with renal injury. Overall, the results suggested that uCr is better than urinary cystatin C and uVol for normalizing renal biomarkers in rats under controlled preclinical conditions. To our knowledge, this is the first report that compared the variability of uVol, cystatin C, and Cr in the context of renal biomarkers' normalization.

Renal function in prepubertal children born with very low birthweight.

The objective of this study was to evaluate estimated glomerular filtration rates (eGFR) and markers of renal function in very low birthweight (VLBW) children and to relate these parameters to current nutritional status. A cross-sectional and controlled study was performed with prepubertal children between ages 5 and 10, including 44 VLBW participants and 30 healthy participants born at full term with an adequate birthweight (control group). The following data were collected: perinatal history; current weight, height and waist circumference; blood pressure (three measures); blood creatinine, urea, uric acid, cystatin-C, and neutrophil gelatinase-associated lipocalin levels; and urine albumin, creatinine, and calcium levels. Blood pressure, eGFR, albuminuria, concentrations of cystatin-C, neutrophil gelatinase-associated lipocalin, uric acid, urea, creatinine, and fractional calcium excretion did not differ between VLBW and control groups. Regarding the VLBW group, there was no difference in eGFR, albuminuria, and other markers of renal injury in overweight or obese children compared with children with a normal body mass index. Prepubertal children born with VLBW did not have altered renal function, regardless of their current nutritional status.

How best to estimate glomerular filtration rate? Novel filtration markers and their application.

Chronic kidney disease is an increasing health burden. Estimating equations using serum concentrations of creatinine and cystatin C facilitate the assessment of kidney function as reflected in estimated glomerular filtration rate (eGFR). Reduced eGFR is associated with increased risk for numerous adverse outcomes and is an important aspect in many clinical situations. However, current equations are suboptimal in some clinical settings. The review focuses on approaches to improve the estimation of GFR and aims to familiarize the reader with the underlying methodological hypotheses how new markers could contribute to improve the overall performance of estimating equations. Low molecular weight proteins such as β-trace-protein and β-2-microglobulin, as well as newly discovered metabolites, show promise as new filtration markers, as they might be beneficial in populations in which creatinine or cystatin C are inaccurate. We propose that the combination of multiple novel markers, alone or in combination with creatinine, cystatin C or demographics, can potentially improve GFR estimation. For special populations such as dialysis patients, separate equations have been developed to estimate residual kidney function. Current GFR estimating equations are an essential part of routine clinical practice but have limitations. The use of multiple markers combined in a single equation appears to be the most promising approach. Future research is required to validate proposed equations in diverse populations.

New biomarkers for estimating glomerular filtration rate

Glomerular filtration rate (GFR) is still considered the best indicator for kidney function assessment. In clinical routine, creatinine-based GFR estimation is the most widely used method for the evaluation of kidney function in healthy and kidney-diseased individuals. In recent years, researchers and clinicians have become aware of the limitations when using solely serum creatinine for kidney function assessment as it can lead to inaccurate estimation of GFR, particularly in populations with abnormal muscle mass distribution or generation. Several novel biomarkers have been proposed to improve accuracy and precision of GFR estimation, of which cystatin C, a low molecular weight protein, has proven to contribute considerable benefit to kidney function assessment when combined with creatinine. Importantly, the use of cystatin C as filtration marker has gained even more clinical relevance since the introduction of international reference standards available for assay manufacturers led to a harmonization of cystatin C analysis by minimizing inter- and intra-laboratory variability. Beta-trace protein (BTP) and beta-2 microglobulin (B2M) are two renal biomarkers with established but non-standardized assays that have been proposed as promising novel candidates for improving GFR estimation. In summary, a variety of new filtration markers and methods are available to assist clinicians in the evaluation of kidney function. The ongoing investigations of novel markers and metabolomics will help to identify their utility and may clarify whether they have the potential to improve the care of patients with and without kidney disease. This review will discuss the physiology, measurement and clinical potential of cystatin C, BTP, and B2M, will give a brief overview of current achievements in the field of kidney metabolomics and a short introduction to the concept of “rescaling” renal biomarkers.

GFR measured by iohexol: the best choice from a laboratory perspective

To rigorously assess glomerular filtration rate (GFR), it is necessary to measure renal inulin clearance. This procedure is, however, cumbersome and difficult for routine clinical and can be replaced by determining the clearance of radiolabeled compounds or contrast media that fulfil the criteria for ideal filtration marker. The non-ionic contrast agent iohexol is the most widely used and studied alternative marker for GFR measurement. Plasma clearance is determined after intravenous administration of 5–10 mL of the pharmacological preparation and subsequent multiple sample drawings, according to different schedules or even with single specimen protocols. Iohexol in biological matrices is readily determinable, with sufficient sensitivity and specificity by means of the most commonly used analytical technologies: sample preparation is fast and the compound is quite stable in biological samples, either at room temperature or, for longer-term storage, at −20 or −80 °C. The participation of the laboratory in the international proficiency test acted by Equalis AB, Sweden, is highly recommended to ensure reliable results and enable interlaboratory comparison of the data. To improve patient comfort and reduce pre-analytical steps, simplified procedures for GFR measurement requiring only 10 µL of whole blood [dried blood spot testing (DBS)] are valid alternatives to plasma clearance and require minimal analytical method modification for analysis. Iohexol administration for GFR measurement is a safe procedure, even in repeated investigations in the same subject, with no occurrence of major or sever adverse events. Plasma clearance of iohexol for renal function determination has a number of advantages: it is a cheap, very simple approach that is not technically demanding and is easy to implement in every centre. The choice of iohexol offers both laboratorians and clinicians the opportunity to easily select and adjust to the most appropriate approach for reliable and accurate GFR measurement.

The influence of indolinoren on kidney function in conditions of water and salt load

Diuretics are widely used to correct kidney disorders. In turn, the ionic composition of food, mostly sodium ions, which directly affect the excretory function of the kidneys, can act as modulators of the action of diuretics.The aim of the study was to investigate the effects of the new 2-oxoindoline derivative with the conventional name "Indolinoren" on the state of the excretory function of the kidneys under the conditions of water and salt load.Materials and methods. Studies were performed on white non-linear rats. The water load was modelled by introducing distilled water (5 ml per 100 g of body weight of the animal); salt load - intragastric administration of 0.45 % sodium chloride solution in an amount of 3 % of body weight. Indolinoren and comparison drug furosemide were administered intragastrically at a dose of 29.5 mg / kg and 5 mg / kg, respectively.Results and discussion. It has been established that indolinoren has a saluretic effect in conditions of water load, accompanied by an increase in sodium excretion by 132 % and potassium by 2.4 %. Against the background of the introduction of indolinoren, a significant increase in the sodium-potassium coefficient of urine was established 2.3-fold (p &lt;0.05), which indicates a more pronounced natriuresis than kaliuresis. Under conditions of salt load, indolinoren promotes a significant increase in urine output by 381 % (p &lt;0.05), increases sodium excretion by 127 % (p &lt;0.05), potassium by 7 %. There were no significant differences in creatinine excretion. The expression of diuretic activity in conditions of salt load indolinoren exceeds furosemide and does not have a significant difference under conditions of water load.Conclusion: The increase in natriuresis and, to a lesser extent, the kaliuresis, as well as the absence of significant changes in the excretion of creatinine, a glomerular filtration marker, on the background of the introduction of indolinoren indicates that its diuretic effect is realized due to oppression of tubular reabsorption. In the mechanism of indolinoren action involved inhibition of mineralocorticoid control of the excretory function of the kidney, as evidenced by the increase in the sodium-potassium coefficient of urine. The obtained data justify the need for further in-depth study of indolinoren as a perspective diuretic

Using the newer Kidney Disease: Improving Global Outcomes criteria, beta-2-microglobulin levels associate with severity of acute kidney injury.

ABSTRACTBeta-2-microglobulin (B2M) is a marker of proximal tubular injury and glomerular filtration. Analyses using older/non-standardized definitions have shown low efficacy of B2M to predict acute kidney injury (AKI). We assessed if elevated levels of B2M would associate with either the diagnosis of AKI [under current Kidney Disease: Improving Global Outcomes (KDIGO) criteria] or recovery from AKI. We performed a retrospective study, including children who had urine B2M (uB2M) and/or serum B2M (sB2M) measured by immunoturbidimetry in our clinical laboratory between January 2011 and December 2015. We defined AKI based on KDIGO criteria [increase of serum creatinine (sCr) 0.3 mg/dL over 48 h or >50% baseline over 7 days] or urine output <0.5 mL/kg/h for 24 h. Recovery from AKI was defined as a return to baseline sCr within 6 months. We calculated receiver operating characteristics (ROC) area under the curve (AUC). Of 529 patients, 245 developed AKI. Serum and uB2M associated with AKI development (AUCs 0.84 and 0.73, respectively). Patients had a graded higher median sB2M and uB2M with each higher AKI stage. sB2M differentiated Stage I from Stage III AKI (P < 0.001) and Stage II from Stage III AKI (P = 0.004). However, neither uB2M nor sB2M levels associated with recovery from AKI. Only older age {hazard ratio [HR] 0.97, [95% confidence interval (CI) 0.94–0.99]} and need for dialysis [HR 0.39 (95% CI 0.23–0.61)] predicted incomplete recovery after AKI. Using KDIGO criteria, sB2M and uB2M associate with the severity of AKI. Given its relative ease and lower cost, we suggest more widespread use of B2M for AKI detection.

Biological Variability of Estimated GFR and Albuminuria in CKD

Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease. Cross-sectional study with multiple collections over less than 4 weeks. Clinically stable outpatients with chronic kidney disease (N=50; mean age, 56.8 years; median eGFR, 40mL/min/1.73m2; median urinary albumin-creatinine ratio (UACR), 173mg/g). Repeat measurements from serially collected samples across 3 study visits. Measurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β2-microglobulin (B2M), and beta trace protein (BTP). We calculated within-person coefficients of variation (CVw) values and corresponding reference change positive and negative (RCVpos and RCVneg) values using log-transformed measurements. Median CVw (RCVpos; RCVneg) values of filtration markers were 5.4% (+16%;-14%) for serum creatinine, 4.1% (+12%;-11%) for cystatin C, 7.4% (+23%;-18%) for BTP, and 5.6% (+17%;-14%) for B2M. Results for albuminuria were 33.2% (+145%;-59%) for first-morning UAC, 50.6% (+276%;-73%) for random spot UAC, 32.5% (+141%;-58%) for first-morning UACR, and 29.7% (124%;-55%) for random spot UACR. CVw values for filtration markers were comparable across the range of baseline eGFRs. CVw values for UAC and UACR were comparable across the range of baseline albuminuria values. Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled. eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to behigh, making it difficult to distinguish random variability from meaningful biologic changes.

Approach to the Patient with Kidney Disease

Chronic kidney disease (CKD) has diverse presentations that are frequently subclinical early in its course but symptomatic in more advanced stages. Quite commonly, kidney disease is diagnosed as an incidental finding in blood or urine tests. It is therefore crucial to understand how to assess kidney function tests and know the diverse presentations of kidney diseases in clinical practice. Assessment of kidney function mainly comprises three important steps: measuring glomerular filtration rate (GFR), estimation of urine albumin or protein excretion, and urinalysis/sediment examination. Estimating GFR based on a filtration marker (usually serum creatinine) is now widely accepted as the initial test. Several GFR prediction equations that use serum creatinine or other filtration markers along with certain patient characteristics (such as age, gender, and race) are used to estimate GFR, though several limitations must be considered when interpreting their results. Measurement of proteinuria or albuminuria provides insights into etiology (glomerular versus other parenchymal kidney diseases) and an assessment of risk of progression (ie, greater proteinuria, higher risk of progression). A complete examination of urine should be performed in all kidney patients. Urinalysis/sediment examination provides important information for both differential diagnosis of acute kidney disease (AKD) and CKD and clues for underlying etiologies of kidney disease. Several serologic tests and selected imaging studies complement the assessment of kidney diseases. Renal biopsy is occasionally required to specify the exact diagnosis and direct the treatment. All these investigations should be performed to determine the duration of kidney disease (ie, acute or chronic), designate the specific etiology, assess the risk for progression, and evaluate the presence of complications. Recently, several risk stratification scores or prediction models were developed for early diagnosis or predicting prognosis of acute kidney injury or CKD. These risk models may help to decrease the huge burden of kidney diseases on the individual as well as social level. This review contains 1 figure, 11 tables and 29 references Key Words: albumin-creatinine ratio, albuminuria, biomarkers, eGFR, chronic kidney disease, cystatin C, history, imaging, glomerular filtration rate , physical examination, renal biopsy, serum creatinine, urinalysis

Abstract P051: Circulating Beta-2-microglobulin Predicts Cardiovascular, Cancer, and All-cause Mortality: The Framingham Heart Study

Beta-2-microglobulin (β 2 M), a multifunctional protein involved in immune function, is a filtration marker that has been reported to predict renal failure, cancer, cardiovascular disease (CVD), and all-cause mortality. Previous studies of β 2 M and mortality were limited to select study samples (elderly or patient-based) lacking information on cancer or kidney function. We examined plasma β 2 M as a predictor of all-cause and cause-specific mortality in those with and without chronic kidney disease (CKD). The study sample consisted of Framingham Heart Study participants from the 2 nd (n=3196) and 3 rd (n=3911) generations who attended an on-site examination (2001-2007). Plasma β 2 M concentration was measured using a Luminex bead-based immunoassay. Mortality events were adjudicated by a physician committee. Proportional hazard models were conducted based on standardized values of β 2 M, adjusted for CVD risk factors, prevalent CVD, cancer, and family structure. We additionally analyzed subgroups stratified for CKD (defined as GFR ckdepi &lt; 60 mL/min/1.73 m 2 ). The study sample included 7107 individuals [mean age 50 years, 54% female, 4% with prevalent CKD, mean length of follow-up: 13 years]. In the overall sample, β 2 M concentrations were associated with increased risk of CVD death (HR=1.42 [CI=1.17-1.72]), cancer death (HR=1.27 [CI=1.07-1.5]), and all-cause mortality (HR=1.27 [CI=1.16-1.4]). β 2 M performed better in participants with prevalent CKD than in those free of CKD. Adjusting for cystatin C, a filtration biomarker, did not affect the results. For all-cause mortality, including plasma β 2 M yielded a relative integrated discrimination improvement of 3% (p-value 0.03) beyond the covariate-only model. The net reclassification improvements (NRI) for all-cause mortality was 4% that was not statistically significant (p-value 0.26). We conclude that among middle-aged adults, plasma β 2 M is a predictor of all-cause and cause-specific mortality. Much of the risk associated with β 2 M is concentrated in those with CKD.

Study protocol: rationale and design of the community-based prospective cohort study of kidney function and diabetes in rural New Mexico, the COMPASS study

BackgroundRural areas in the state of New Mexico have been the “ground-zero” for the epidemic of diabetic Chronic Kidney Disease (CKD) in the United States. However, there is limited research about risk factors of diabetic CKD in this area and scarce data regarding the performance of emerging markers of renal filtration and epigenetic biomarkers of renal function and diabetes in this area with its unique ethnic/racial population. We designed the COMPASS study as a community-based program in rural New Mexico aiming to screen for CKD and to discover CKD-related translational biomarkers.Methods/designThe study involves a prospective, longitudinal cohort design involving individuals living in rural New Mexico. Participants undergo a screening for kidney disease using markers of abnormal renal filtration (impaired glomerular filtration rate) or damage (albuminuria). Those found to have CKD on the basis of these tests or those at risk for CKD are enrolled in a prospective longitudinal cohort. We measure markers of renal function, insulin resistance and epigenetics (microRNAs) on patients. Individuals are invited to participate in interviews and focus groups in order to characterize their attitudes towards research and barriers or facilitators to participation in future research studies about kidney disease.DiscussionThis study will provide important data about the local epidemiology of kidney disease in a high-risk rural setting and the utility of emerging renal filtration markers (Beta 2 Microglobulin and Cystatin C), while generating data and methods for the analyses of microRNA biomarkers. The qualitative research subproject will identify factors associated with increased willingness to participate in future translational research projects. With its geographical focus, this study will address a critical disparity in kidney disease research, while generating novel epigenetic data that are relevant for future studies in the general population.

Challenges in Measuring Glomerular Filtration Rate: A Clinical Laboratory Perspective.

The assessment of kidney function is a cornerstone in the clinical management and health of the patient. Although the kidneys perform many physiologic functions and are essential for maintaining homeostasis, kidney function is typically evaluated, quantitated, and understood using the glomerular filtration rate (GFR). Although GFR can be directly measured using a variety of externally administered glomerular filtration markers, in general practice, the GFR is usually estimated (eGFR) using endogenous markers that are cleared primarily by kidney filtration. Common situations exist where the GFR needs to be measured (mGFR) in order to proceed with care. This manuscript will review laboratory challenges in the assessment of GFR. Key points to consider when implementing a mGFR testing protocol are the following: marker selection, clearance methodology (urinary vs solely plasma measurements of filtration marker), sample collection, number of samples to collect, staff required, and analytical measurement technology for the filtration marker selected. We suggest those wanting to implement mGFR testing examine site-specific institutional resources along with patient population and proceed with the approaches best suited for their clinical needs and laboratory resources available.

Estimated Glomerular Filtration Rate From a Panel of Filtration Markers-Hope for Increased Accuracy Beyond Measured Glomerular Filtration Rate?

The recent Kidney Disease Improving Global Outcomes 2012 CKD guidelines recommend estimating GFR from serum creatinine (eGFRcr) as a first-line test to assess kidney function and using cystatin C or measured glomerular filtration rate (GFR) as confirmatory tests. eGFRcr may be inaccurate in people with variation in muscle mass or diet, and eGFRcys is not more accurate than eGFRcr. eGFRcrcys is more accurate than either, but it is not independent of eGFRcr. Measured GFR is not practical and is susceptible to error due to variation in clearance methods and in the behavior of exogenous filtration markers. Over the past few years, we have hypothesized, and begun to test the hypothesis, that a panel of filtration markers (panel eGFR) from a single blood draw would require fewer demographic or clinical variables and could estimate GFR as accurately as measured GFR. In this article, we describe the conceptual background and rationale for this hypothesis and summarize our work thus far including evaluation of novel low-molecular-weight proteins and metabolites and then outline how we envision that such a panel could be used in clinical practice, research, and public health.

Kidney Function in Obesity-Challenges in Indexing and Estimation.

As the prevalence of obesity continues to increase worldwide, an increasing number of people are at risk for kidney disease. Thus, there is a critical need to understand how best to assess kidney function in this population, and several challenges exist. The convention of indexing glomerular filtration rate (GFR) to body surface area (BSA) attempts to normalize exposure to metabolic wastes across populations of differing body size. In obese individuals, this convention results in a significantly lower indexed GFR than unindexed GFR, which has practical implications for drug dosing. Recent data suggest that "unindexing" estimated GFR (multiplying by BSA/1.73m2) for drug dosing may be acceptable, but pharmocokinetic data to support this practice are lacking. Beyond indexing, biomarkers commonly used for estimating GFR may induce bias. Creatinine is influenced by muscle mass, whereas cystatin C correlates with fat mass, both independent of kidney function. Further research is needed to evaluate the performance of estimating equations and other filtration markers in obesity, and determine whether unindexed GFR might better predict optimal drug dosing and clinical outcomes in patients whose BSA is very different than the conventional normalized value of 1.73m2.

Assessment of Kidney Function in Patients With Cancer.

Cancer patients are living longer. The sequelae of cancer treatment and the role of comorbid conditions present before the diagnosis, such as CKD, have been increasingly recognized. The interface between CKD and cancer is multifaceted. CKD is frequently observed in patients with cancer, and cancer treatment contributes to CKD development and progression. In addition, CKD has been recognized as an important risk factor for cancer development and reduced specific cancer survival. In this context, an accurate evaluation of the glomerular filtration rate (GFR) during oncologic treatment is pivotal and is used to define surgery strategies, program prophylactic management of contrasted examinations, make decisions on cisplatin eligibility, and adjust drug prescriptions, particularly chemotherapy agents. Although the most commonly used equations to estimate GFR based on serum creatinine levels in clinical practice (Cockcroft-Gault, Modification of Diet in Renal Disease Study, and CKD Epidemiology Collaboration equations) have not been validated in patients with cancer in large prospective studies, there is increasingly evidence supporting the use of CKD Epidemiology Collaboration equation to assess the GFR in patients with cancer, including for the use of chemotherapy prescriptions. Many patients with cancer may have changes in nutrition status and clearance measurements such as exogenous filtration markers might be extremely useful when clinical decisions differ depending on the GFR level. Future perspectives include the advent of new serum GFR biomarkers such as cystatin C, beta-trace protein, and beta-2 microglobulin as well as the GFR assessment by measuring total kidney parenchymal volume through image examinations.

Real-time measurement of glomerular filtration rate.

Measurement of glomerular filtration rate is an essential tool for determining the health or dysfunction of the kidney. The glomerular filtration rate is a dynamic function that can change almost instantaneously in response to stressors. Despite its central role in nephrology, there are no techniques available to the clinician for monitoring glomerular filtration rate in real time. Recent advances in technology to measure fluorescent compounds through the skin are providing a new approach for real-time monitoring of glomerular filtration rate. This review frames these technologies within how such measurements might be used in clinical medicine. Fluorescent molecules that act as ideal filtration markers are now available. Using transdermal sensors, the plasma disappearance rate of these exogenous markers can be measured rather than their steady state concentration. This eliminates the delay inherent in using an endogenous marker of filtration and permits continuous monitoring of GFR. These new technologies provide enhanced opportunities for diagnosis of kidney dysfunction and therapeutic monitoring. Accurate assessment of measured GFR will eliminate the erroneous diagnosis of chronic kidney disease (CKD) from many patients. Assessment of renal reserve will provide a new risk factor for progression of CKD. Real-time monitoring of GFR in critically ill patients will allow for earlier diagnosis of acute kidney injury and a dynamic metric to guide therapeutics. These are but a few of the many opportunities that this new technology will provide in both the clinical and research arenas.

Hypothesis: Potential Utility of Serum and Urine Uromodulin Measurement in Kidney Transplant Recipients?

Seventy years after its discovery, studies of the myriad properties, and potential disease associations of uromodulin are now burgeoning. Although normative ranges for serum/plasma uromodulin concentrations were established over 30 years ago, their external validation occurred only in very recent, larger studies. As tubular function indices, serum and urinary uromodulin may be more sensitive indicators of kidney graft dysfunction undetected by glomerular filtration markers, or proteinuria. Moreover, 2 sizable, just published longitudinal reports revealed that lower serum uromodulin levels were associated with cardiovascular disease (CVD) outcomes, total mortality, and infectious disease deaths, in patients with known or suspected coronary heart disease. Preliminary longitudinal studies have reported that reduced levels of plasma or serum uromodulin were linked to progression to end-stage renal disease in chronic kidney disease patients, and graft failure in kidney transplant recipients (KTRs). Conflicting data on the associations, or lack thereof, between lower urinary uromodulin concentrations and accelerated loss of renal function, or renal failure, in nontransplant chronic kidney disease patients, are perhaps due, in part, to analytical limitations in determining urine uromodulin. Potential longitudinal associations between serum and urinary uromodulin concentrations, and CVD outcomes, graft failure, and all-cause mortality, await validation in large, diverse cohorts of chronic KTRs. Taking advantage of an efficient case-cohort design scheme, we demonstrate how the completed FAVORIT clinical trial cohort might be ideally suited to evaluate these associations. Using available case-cohort sample data, statistical power simulations are provided to detect relative risk estimates of 1.50 for CVD (n = 309 events), 1.56 for graft failure (n = 223 events) or 1.50 for death from any cause (n = 320 events), comparing values below the median, to values equal to or above the median for serum uromodulin values. Edifying data such as these would advance our understanding of the hypothetical utility of uromodulin measurement in KTRs considerably.