For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney ...failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α1-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.
Background Acute kidney injury (AKI) is common in hospitalized patients. The impact of AKI on long-term outcomes is controversial. Study Design Systematic review and meta-analysis. Setting & ...Participants Persons with AKI. Selection Criteria for Studies MEDLINE and EMBASE databases were searched from 1985 through October 2007. Original studies describing outcomes of AKI for patients who survived hospital discharge were included. Studies were excluded from review when participants were followed up for less than 6 months. Predictor AKI, defined as acute changes in serum creatinine level or acute need for renal replacement therapy. Outcomes Chronic kidney disease (CKD), cardiovascular disease, and mortality. Results 48 studies that contained a total of 47,017 participants were reviewed; 15 studies reported long-term data for patients without AKI. The incidence rate of mortality was 8.9 deaths/100 person-years in survivors of AKI and 4.3 deaths/100 patient-years in survivors without AKI (rate ratio RR, 2.59; 95% confidence interval, 1.97 to 3.42). AKI was associated independently with mortality risk in 6 of 6 studies that performed multivariate adjustment (adjusted RR, 1.6 to 3.9) and with myocardial infarction in 2 of 2 studies (RR, 2.05; 95% confidence interval, 1.61 to 2.61). The incidence rate of CKD after an episode of AKI was 7.8 events/100 patient-years, and the rate of end-stage renal disease was 4.9 events/100 patient-years. Limitations The relative risk for CKD and end-stage renal disease after AKI was unattainable because of lack of follow-up of appropriate controls without AKI. Conclusions The development of AKI, defined as acute changes in serum creatinine level, characterizes hospitalized patients at increased risk of long-term adverse outcomes.
Equations for estimating GFR with serum creatinine overestimate measured GFR in Blacks. The authors report new equations, without race as an inflation factor, using cystatin C and creatinine that ...reduced errors in estimation between Black participants and non-Black participants.
Cystatin C is ready for clinical use Ebert, Natalie; Shlipak, Michael G
Current opinion in nephrology and hypertension,
2020-November, 2020-Nov, 2020-11-00, 20201101, Volume:
29, Issue:
6
Journal Article
Peer reviewed
PURPOSE OF REVIEWThe goal of this update is to raise awareness of clinical scenarios where cystatin C has clear and immediate benefits as an alternative glomerular filtration rate (GFR) biomarker to ...supplement creatinine. An additional goal is to focus the estimated GFR (eGFR) controversy onto medication prescribing for agents with narrow therapeutic windows where better GFR estimation will lead to improved medical care.
RECENT FINDINGSEquations that include cystatin C predict GFR more accurately than serum creatinine in children, adults, and older adults with larger effects among persons who are acutely ill. Numerous studies have evaluated medication dosing based on either GFR estimate; vancomycin was the most frequently studied drug and its target level and elimination were better predicted by cystatin C. Overall, approaches to medication dosing and monitoring that include cystatin C concentrations have been shown to result in a better achievement of drug trough levels. Furthermore, cystatin C offers the opportunity to avoid the race coefficient that is required for any current creatinine-based eGFR equation, which has been appropriately criticized for introducing unnecessary imprecision, assumptions and values on GFR estimation.
SUMMARYHospital laboratories must make cystatin C available for clinical care to improve the safety and efficacy of medications that have narrow therapeutic windows.
Kidney function monitoring using creatinine-based glomerular filtration rate estimation is a routine part of clinical practice. Emerging evidence has shown that cystatin C may improve classification ...of glomerular filtration rate for defining chronic kidney disease in certain clinical populations and assist in understanding the complications of chronic kidney disease. In this review and update, we summarize the overall literature on cystatin C, critically evaluate recent high-impact studies, highlight the role of cystatin C in recent kidney disease guidelines, and suggest a practical approach for clinicians to incorporate cystatin C into practice. We conclude by addressing frequently asked questions related to implementing cystatin C use in a clinical setting.
In this meta-analysis of 16 studies, investigators evaluated the use of cystatin C, alone or with creatinine, to calculate the estimated glomerular filtration rate (eGFR). Measurement of cystatin C ...improved the prediction of outcomes in chronic kidney disease.
The estimated glomerular filtration rate (eGFR) is the clinical standard for the assessment of kidney function.
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The eGFR thresholds for the definition and staging of chronic kidney disease are based on risk,
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but measurement of creatinine to determine the eGFR has limitations in risk prediction, particularly in patients with reduced muscle mass.
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Cystatin C has received much attention as an alternative filtration marker with stronger and more linear risk relationships than creatinine.
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Several studies have suggested that the addition of cystatin C measurements to creatinine measurements in calculating the eGFR significantly improves the risk classification for death, cardiovascular . . .
Objectives The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular ...events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study). Background Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health. Methods A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality. Results There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval CI: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events. Conclusions Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Random assignment to the intensive systolic blood pressure (SBP) arm (<120mmHg) in the Systolic Blood Pressure Intervention Trial (SPRINT) resulted in more rapid declines in estimated glomerular ...filtration rates (eGFRs) than in the standard arm (SBP<140mmHg). Whether this change reflects hemodynamic effects or accelerated intrinsic kidney damage is unknown.
Longitudinal subgroup analysis of clinical trial participants.
Random sample of SPRINT participants with prevalent chronic kidney disease (CKD) defined as eGFR<60mL/min/1.73m2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline.
Urine biomarkers of tubule function (β2-microglobulin B2M, α1-microglobulin A1M), and uromodulin), injury (interleukin 18, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin), inflammation (monocyte chemoattractant protein 1), and repair (human cartilage glycoprotein 40) at baseline, year 1, and year 4. Biomarkers were indexed to urine creatinine concentration and changes between arms were evaluated using mixed-effects linear models and an intention-to-treat approach.
978 SPRINT participants (519 in the intensive and 459 in the standard arm) with prevalent CKD were included. Mean age was 72±9 years and eGFR was 46.1±9.4mL/min/1.73m2 at baseline. Clinical characteristics, eGFR, urinary albumin-creatinine ratio, and all 8 biomarker values were similar across arms at baseline. Compared to the standard arm, eGFR was lower by 2.9 and 3.3mL/min/1.73m2 in the intensive arm at year 1 and year 4. None of the 8 tubule marker levels was higher in the intensive arm compared to the standard arm at year 1 or year 4. Two tubule function markers (B2M and A1M) were 29% (95% CI, 10%-43%) and 24% (95% CI, 10%-36%) lower at year 1 in the intensive versus standard arm, respectively.
Exclusion of persons with diabetes, and few participants had advanced CKD.
Among participants with CKD in SPRINT, random assignment to the intensive SBP arm did not increase any levels of 8 urine biomarkers of tubule cell damage despite loss of eGFR. These findings support the hypothesis that eGFR declines in the intensive arm of SPRINT predominantly reflect hemodynamic changes rather than intrinsic damage to kidney tubule cells.
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Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing ...opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.
Serum Cystatin C for Estimation of GFR Shlipak, Michael G; Inker, Lesley A; Coresh, Josef
JAMA : the journal of the American Medical Association,
09/2022, Volume:
328, Issue:
9
Journal Article
Peer reviewed
An 80-year-old man with type 2 diabetes and hypertension was referred to the nephrology clinic for persistent hyperkalemia. The patient was frail and sedentary, with a BMI of 37. His estimated ...glomerular filtration rate calculated using creatinine was 64 mL/min/1.73 m
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. How would you interpret these results?
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