Assessment of kidney proximal tubular secretion in critical illness.

BACKGROUNDSerum creatinine concentrations (SCrs) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the intensive care unit (ICU). Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults.METHODSWe collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured 7 endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all 7 solutes and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death.RESULTSThe urine-to-plasma ratios of 6 of 7 secretory solutes were lower in critically ill patients compared with healthy individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = -0.51 and r = -0.53, respectively). Each SD higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% to 38% lower) independent of severity of illness, SCr, and tubular injury markers. Higher urine-to-plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing.CONCLUSIONAmong critically ill adults, tubular secretory clearance is associated with adverse outcomes, and its measurement could improve assessment of kidney function and dosing of essential ICU medications.FUNDINGGrants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH) K23DK116967, the University of Washington Diabetes Research Center P30DK017047, an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers, and the Vanderbilt O'Brien Kidney Center (NIDDK 5P30 DK114809-03). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Contribution of cystatin C- and creatinine-based definitions of chronic kidney disease to cardiovascular risk assessment in 20 population-based and 3 disease cohorts: the BiomarCaRE project.

BACKGROUND: Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts. METHODS: The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts (n = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts (n = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality. RESULTS: The overall prevalence of CKD stage 3-5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts. CONCLUSION: CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value.

Kidney Disease, Race, and GFR Estimation.

Assessment of GFR is central to clinical practice, research, and public health. Current Kidney Disease Improving Global Outcomes guidelines recommend measurement of serum creatinine to estimate GFR as the initial step in GFR evaluation. Serum creatinine is influenced by creatinine metabolism as well as GFR; hence, all equations to estimate GFR from serum creatinine include surrogates for muscle mass, such as age, sex, race, height, or weight. The guideline-recommended equation in adults (the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation) includes a term for race (specified as black versus nonblack), which improves the accuracy of GFR estimation by accounting for differences in non-GFR determinants of serum creatinine by race in the study populations used to develop the equation. In that study, blacks had a 16% higher average measured GFR compared with nonblacks with the same age, sex, and serum creatinine. The reasons for this difference are only partly understood, and the use of race in GFR estimation has limitations. Some have proposed eliminating the race coefficient, but this would induce a systematic underestimation of measured GFR in blacks, with potential unintended consequences at the individual and population levels. We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group. We suggest full disclosure of use of race in GFR estimation, accommodation of those who decline to identify their race, and shared decision making between health care providers and patients. We also suggest mindful use of cystatin C as a confirmatory test as well as clearance measurements. It would be preferable to avoid specification of race in GFR estimation if there was a superior, evidence-based substitute. The goal of future research should be to develop more accurate methods for GFR estimation that do not require use of race or other demographic characteristics.

Assessment of renal function in living kidney donors before and after nephrectomy: A Japanese prospective, observational cohort study.

OBJECTIVE: To investigate the utility of estimated glomerular filtration rate for assessing kidney function in living kidney donors before and after nephrectomy. METHODS: A total of 101 donors underwent inulin clearance measurements before and 1 year after nephrectomy. The mean of three inulin clearance values was used as the measured glomerular filtration rate. Estimated glomerular filtration rate based on serum creatinine and cystatin C levels was calculated using the Japanese estimated glomerular filtration rate equation, Chronic Kidney Disease Epidemiology Collaboration formula and new full age spectrum equation. Age-adjusted chronic kidney disease was defined as glomerular filtration rate <75 mL/min/1.73m2 for donors aged <40 years, <60 mL/min/1.73m2 for donors aged 40-65 years and <45 mL/min/1.73m2 for donors aged >65 years. RESULTS: The postoperative measured glomerular filtration rate <60 mL/min/1.73m2 and age-adjusted chronic kidney disease rate were 36.0% and 27.0%, respectively. In younger donors (aged <50 years), postoperative measured glomerular filtration rate <60 mL/min/1.73m2 and age-adjusted chronic kidney disease rates were 5.3% and 26.3%, respectively. In older donors (aged >70 years), postoperative measured glomerular filtration rate <60 mL/min/1.73m2 and age-adjusted chronic kidney disease rates were 75.0% and 33.3%, respectively. Donor age and measured glomerular filtration rate were significant predictors of postoperative measured glomerular filtration rate. The Japanese estimated glomerular filtration rate equation based on creatinine and cystatin C showed the strongest correlation with measured glomerular filtration rate. However, the Japanese estimated glomerular filtration rate equation based on creatinine overestimated the prevalence of measured glomerular filtration rate <60 mL/min/1.73m2 , whereas the Japanese estimated glomerular filtration rate based on cystatin C underestimated it. CONCLUSIONS: Aged donors might have an increased risk of lower glomerular filtration rate after donor nephrectomy; post-surgery, long-term monitoring of renal function is recommended. Measurement of glomerular filtration rate should be carried out for donors, especially pre-surgery. A more precise glomerular filtration rate equation is required in the future.

Assessment of Glomerular Filtration Rate in Health and Disease: A State of the Art Review.

Acute and chronic kidney diseases affect pharmacokinetics and pharmacodynamics. There has been substantial progress in the past 20 years in the use of glomerular filtration rate (GFR) estimating equations. In principle, use of a single equation for each filtration marker (creatinine, cystatin C, or the combination) for detection, evaluation, and management of kidney disease and for drug development and dosing would facilitate clinical practice. We review the principles for assessment of GFR, provide historical perspectives and updates regarding use of GFR estimating equations, including assay methods for filtration markers, performance of estimating equations, and recommendations by clinical practice guideline groups and regulatory agencies. We conclude that it is time to change from rigid adherence to the use of the Cockcroft-Gault equation for use in drug development and drug dosing to the more accurate and more widely used Modification of Diet in Renal Disease (MDRD) study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.

Assessment of Kidney Graft Function Evolution Measured by Creatinine and Cystatin C.

INTRODUCTION: The 2013 Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline suggests measuring cystatin C (sCys) in adults with glomerular filtration rate (GFR) based on creatinine (sCr) between 45 and 59 mL/min/1.73 m2 if confirmation of chronic kidney disease (CKD) is required. There is not enough evidence to recommend the use of sCys or sCr to estimate GFR in kidney transplant recipients. OBJECTIVES: Our aims were to describe the evolution of sCr, sCys, and GFR in a group of kidney transplant patients and to determine their association with some markers of morbidity at 1 year. METHODS: A total of 54 patients were included. Analytical and clinical data were recorded. Renal function was analyzed using the CKD Epidemiology Collaboration (EPI) sCr equation and CKD-EPI sCys equation. RESULTS: sCys-estimated GFR was higher than estimated from sCr by CKD-EPI. The values of sCys have more variability than those of sCr. The agreement between the stages of CKD by sCr or sCys-estimated GFR measured by Cohen's kappa coefficient was only fair. One-year CKD-associated variables correlated differently with sCr and sCys-estimated GFR. Hemoglobin, uric acid, calcium, and phosphorus related to sCr-estimated GFR, whereas serum albumin was associated with sCys-estimated GFR. CONCLUSIONS: sCys values have a higher variability than sCr in kidney transplant recipients. sCys- or sCr-based GFRs have a nonsimilar behavior in these patients with weak agreement to stratify CKD stages and a different relationship to CKD-related comorbid conditions.

Assessment of glomerular and tubular function.

At birth, GFR and tubular function of neonates is compromised as compared to older children and adults. These functions are even less developed in premature infants. These facts have a direct bearing on drug dosing, fluid and electrolyte administration, and maintenance of acid-base balance in neonates. Although many detailed methods of assessing renal functions have been provided in this article, laboratory and radiologic studies available in most healthcare facilities are often sufficient to provide a clinically relevant data in most patients, including neonates.

Understanding kidney function assessment: the basics and advances.

PURPOSE: Multiple kidney function assessment modalities are available, but their appropriateness is constantly questioned. This review provides practitioners with in-depth understanding of kidney function assessment methods, their clinical utility, and comparisons. DATA SOURCES: PUBMED search was conducted by relevant subject headings. CONCLUSIONS: Glomerular filtration rate (GFR) is the best indicator of kidney function. Exogenous compounds like inulin help measure GFR, but endogenous substances (like creatinine) are more convenient, although exhibiting greater variability. Cystatin C is advocated as a functional marker; its clinical significance is under study. Proteinuria adds value to GFR estimation. There are commonly used equations estimating GFR like the creatinine-based Cockcroft-Gault and the modification of diet in renal disease. The new creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation demonstrates higher accuracy of patient classification in earlier stages of disease. Recently, the Chronic Renal Insufficiency Cohort (CRIC) study has devised an equation combining serum creatinine and cystatin C in longitudinal modeling of kidney function. IMPLICATIONS FOR PRACTICE: Current GFR estimation methods have limitations, and are useful for populations they have been tested in. Practitioners should be well informed on emerging equations that provide greater accuracy in CKD diagnosis; this would help implement appropriate prevention and intervention strategies.

Multicenter study of plasma diafiltration in patients with acute liver failure.

Plasma diafiltration (PDF) is a blood purification therapy in which simple plasma exchange (PE) is performed using a selective membrane plasma separator while the dialysate flows outside the hollow fibers. A prospective, multicenter study was undertaken to evaluate the changes in bilirubin, IL-18, and cystatin C, as well as the 28-day and 90-day survival rates, with the use of PDF according to the level of severity as measured by the Model for End-Stage Liver Disease (MELD) score. Twenty-one patients with liver failure were studied: 10 patients had fulminant hepatitis and PDF therapies were performed 28 times; 11 had acute liver failure with the therapy performed 96 times. Levels of total bilirubin, IL-18, and cystatin C decreased significantly after treatment. The 28-day survival rate was 70.0% and that at 90 days was 16.7%. According to the severity of the MELD score, each of the results compared well with the use of Molecular Adsorbent Recirculating System or Prometheus therapy. In conclusion, PDF appears to be one of the most useful blood purification therapies for use in cases of acute liver failure in terms of medical economics and the removal of water-soluble and albumin-bound toxins.