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Validation of a routine two-sample iohexol plasma clearance assessment of GFR and an evaluation of common endogenous markers in a rat model of CKD.

ABSTRACT: Endogenous markers of kidney function are insensitive to early declines in glomerular filtration rate (GFR) and in rodent models, validated, practical alternatives are unavailable. In this study, we determined GFR by modeling the plasma clearance of two compounds, iohexol and inulin, and compared the findings to common endogenous markers. All plasma clearance methods of both iohexol and inulin detected a decline in renal function weeks prior to any increase in endogenous marker. Iohexol plasma clearance and inulin plasma clearance had a very high agreement and minimal bias when using 12-sample models. However, only iohexol could be accurately simplified to a two-sample, one-compartment estimation strategy. Following an IV injection of low-dose iohexol and two timed blood samples at 30 and 90 min, one can accurately approximate a complex 12-sample strategy of plasma clearance. This method is simple enough to use in routine, longitudinal analysis of larger cohort animal studies.

SUBMITTER: Turner ME

PROVIDER: S-EPMC5430119 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Validation of a routine two-sample iohexol plasma clearance assessment of GFR and an evaluation of common endogenous markers in a rat model of CKD.

Turner Mandy E ME Laverty Kimberly J KJ Jeronimo Paul S PS Kaufmann Martin M Jones Glenville G White Christine A CA Holden Rachel M RM Adams Michael A MA

Physiological reports 20170501 9

Endogenous markers of kidney function are insensitive to early declines in glomerular filtration rate (GFR) and in rodent models, validated, practical alternatives are unavailable. In this study, we determined GFR by modeling the plasma clearance of two compounds, iohexol and inulin, and compared the findings to common endogenous markers. All plasma clearance methods of both iohexol and inulin detected a decline in renal function weeks prior to any increase in endogenous marker. Iohexol plasma c ...[more]

PMID: 28483858

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Project description:BackgroundUnlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, β-trace protein (BTP), β2-microglobulin (B2M), and cystatin C, are not well characterized.Study designPooled cross-sectional analysis of 3 studies.Setting & participants3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study.PredictorsDemographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations.OutcomesSerum creatinine, BTP, B2M, and cystatin C levels.ResultsIn multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C.LimitationsFindings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error.ConclusionsLike creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

Project description:Rationale & objectiveDetermining 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.Study designCross-sectional study with multiple collections over less than 4 weeks.Setting & participantsClinically 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).ExposureRepeat measurements from serially collected samples across 3 study visits.OutcomesMeasurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β2-microglobulin (B2M), and beta trace protein (BTP).Analytical approachWe calculated within-person coefficients of variation (CVw) values and corresponding reference change positive and negative (RCVpos and RCVneg) values using log-transformed measurements.ResultsMedian 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.LimitationsSmall 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.ConclusionseGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes.

Project description:BackgroundSeveral reviews have recently detailed the beneficial effects of weight loss surgery for kidney function. However, these studies have a number of limitations, including small sample size, few done in chronic kidney disease (CKD) stages 3 and 4, and many not including the main bariatric surgery procedures used in the United States today.Study designThis was an observational retrospective cohort study comparing propensity score-matched bariatric surgery patients and nonsurgery control patients who were referred for, but did not have, surgery. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy were also compared using propensity matching.Setting & participantsPatients (714 surgery patients; 714 controls) were from a large integrated health care system, a mean of 58±8 (SD) years old, and mostly women (77%) and non-Hispanic whites (56%) and had diabetes mellitus (66%) and/or hypertension (91%).PredictorPredictors at the time of surgery or referral to surgery were age, sex, race/ethnicity, weight, and presence of diabetes and/or hypertension.OutcomesThe primary outcome for this study was change in estimated glomerular filtration rate (eGFR) from serum creatinine level over a median 3-year follow-up period.MeasurementsSerum creatinine was used to calculate eGFR using the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation.ResultsSurgery patients had 9.84 (95% CI, 8.05-11.62) mL/min/1.73m2 greater eGFRs than controls at a median 3 years' follow-up and RYGB patients had 6.60 (95% CI, 3.42-9.78) mL/min/1.73m2 greater eGFRs than sleeve gastrectomy patients during the same period.LimitationsThis study is limited by its nonrandomized observational study design, estimation of GFR, and large changes in muscle mass, which may affect serum creatinine level independent of changes in kidney function.ConclusionsBariatric surgery, especially the RYGB procedure, results in significant improvements for up to 3 years in eGFRs for patients with CKD stages 3 and 4.

Dataset Information

Validation of a routine two-sample iohexol plasma clearance assessment of GFR and an evaluation of common endogenous markers in a rat model of CKD.

Publications

Validation of a routine two-sample iohexol plasma clearance assessment of GFR and an evaluation of common endogenous markers in a rat model of CKD.

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