Variation of serum creatinine, cystatin C, and creatinine clearance tests in persons with normal renal function

To determine the potential sensitivity of several renal function tests for detecting early changes in renal function, we compared the within-individual (W-I) variation over 5 months of serum creatinine, serum cystatin C, and creatinine clearance.

On 31 healthy subjects, blood and timed urine specimens were collected once each month to get 6 collections. Creatinine (enzymatic) in serum and urine and cystatin C (immunonephelometric) in serum were measured and glomerular filtration rate (GFR) by creatinine clearance and the Modification of Diet in Renal Disease (MDRD) equation were calculated. To compare W-I variations between different creatinine methods, we also measured creatinine by both enzymatic and kinetic alkaline picrate methods on 15 sets of frozen samples.

For the 31 volunteers, the mean W-I variations for serum creatinine (5.8%) and cystatin C(5.4%) were both much lower than the W-I variation of creatinine clearance (18.7%). As expected, the MDRD GFR had a similar W-I variation (6.7%) to that of serum creatinine and its values were markedly different than GFR by creatinine clearance. On the 15 sets of frozen samples, the W-I variation of creatinine measured by the enzymatic method (CV 5.2%) was slightly less than by the picrate method (CV 6.2%).

The low W-I variation of both serum cystatin C and serum creatinine suggests that serial measurements of either would detect a changes in renal function earlier than would GFR by creatinine clearance or MDRD equation, which allows reporting only for GFRs < 60 ml/min/1.7 m2. While we measured only creatinine clearance, the large variability, difficulty, and cost of all clearance measurements make them impractical for routine monitoring of patients.



Cystatin C and Creatinine in an HIV Cohort: The Nutrition for Healthy Living Study

Human immunodeficiency virus (HIV)-infected persons have an increased risk of chronic kidney disease (CKD). Serum creatinine level may underestimate the prevalence of CKD in subjects with decreased lean body mass or liver disease. Level of serum cystatin C, an alternative kidney function marker, is independent of lean body mass.

Study Design

Setting & Participants
250 HIV-infected subjects on highly active antiretroviral therapy in the Nutrition for Healthy Living (NFHL) cohort; 2,628 National Health and Nutrition Examination Survey (NHANES) 2001-2002 subjects.

Predictors & Outcomes
Comparison of serum creatinine levels in NFHL to those in NHANES subjects; comparison of CKD in NFHL subjects ascertained using serum creatinine versus cystatin C levels.

Standardized serum creatinine, serum cystatin C, glomerular filtration rate (GFR) estimated from serum creatinine and cystatin C levels.

Creatinine levels were lower in NFHL than NHANES subjects despite greater rates of hepatitis, diabetes, and drug use (mean difference, −0.18 mg/dL; P < 0.001 adjusted for age, sex, and race). Of NFHL subjects, only 2.4% had a creatinine-based estimated GFR less than 60 mL/min/1.73 m2, but 15.2% had a cystatin-based estimated GFR less than 60 mL/min/1.73 m2.

GFR was estimated rather than measured. Other factors in addition to GFR may affect creatinine and cystatin C levels. Measurements of proteinuria were not available.

Serum creatinine levels may overestimate GFRs in HIV-infected subjects. Kidney disease prevalence may be greater than previously appreciated.



Homocysteine, Cystatin C and N-Terminal-Pro Brain Natriuretic Peptide Vascular Risk Markers in Elderly Patients with Mental Illness


There is increasing evidence that vascular disease contributes to cognitive impairment and dementia. Clarification of the role of vascular risk factors in dementia is important because most are modifiable, in contrast to other risk factors such as age and genetics.

In 451 patients with mental illness we have investigated three biochemical markers related to vascular disease, total plasma homocysteine (tHcy), cystatin C, and N-terminal-pro brain natriuretic peptide (NT-proBNP), and their association with vascular disease, diagnoses, and brain imaging findings (CT). Results: Plasma tHcy, serum cystatin C, and serum N-terminal-pro brain natriuretic peptide (NT-proBNP)showed significantly increased frequencies of elevated levels in patients with vascular disease, in patients with a pathological CT finding indicating cerebrovascular disease, and in patients above 75 years of age.

It is possible that the control of conventional vascular risk factors and therapy could be guided by the level of plasma tHcy, serum cystatin C, and serum NT-proBNP. Patients with an elevation of any of these three parameters could be selected for a lower target level of risk factors such as blood pressure, hyperlipidemia etc. than conventional target levels.


Serum cystatin C level for better assessment of glomerular filtration rate in cystic fibrosis patients treated by amikacin.

Monitoring of renal function in cystic fibrosis (CF) patients is essential. The dosage regimen of amikacin is regularly modified according to the patient's glomerular filtration rate (GFR). The aim of the study was to evaluate the use of
cystatin C (CyC) for monitoring amikacin therapy along with other markers of renal tubular and glomerular function, and damage [N-acetyl-beta-d glucosaminidase (NAG), creatinine level and creatinine clearance].

We compared the GFR, estimated from the serum concentrations of creatinine (Cockcroft-Gault formula) and cystatin C (CyC) (Grubb's formula). Seventy-one patients (mean age 12 years; range 4-28 years) with CF were treated by intermittent intravenous infusion of amikacin. Tubular nephrotoxicity was investigated by measurement of urine NAG/urine creatinine ratio (U-NAG/U-creatinine). Concentrations of all markers were measured before starting amikacin therapy and at days 3, 5, 7, 10 and 12. Fluorescence polarization analysis, turbidimetry, enzymatic phototometric creatinine deaminase method and fluorimetry were used for determination of serum amikacin, serum CyC, creatinine and urine NAG activity. Receiver operating characteristic (ROC) analysis was performed to assess the influence of GFR estimated from serum creatinine and serum CyC for the prediction of amikacin clearance during aminoglycoside therapy.

Significant differences in the rate of U-NAG/U-creatinine were noted before and after treatment with amikacin (P < 0.001). Serum creatinine levels and creatinine clearance at the end of amikacin therapy (12th day) did not show any significant differences in comparison with the levels measured before the start of therapy (0th day). At days 5, 7, 10 and 12, serum CyC levels showed a significant elevation (P < 0.001), and cystatin C (CyC) clearance showed a significant decrease (P < 0.001) in comparison with the levels measured at day 0. The ratio of amikacin clearance/creatinine clearance decreased with therapy whereas the amikacin clearance/CyC and amikacin clearance/CyC clearance increased.

CONCLUSION: We showed that the rate of U-NAG/U-creatinine is a suitable marker for monitoring tubular nephrotoxicity in CF patients. Serum creatinine and estimated creatinine clearance are modest predictors of GFR in CF patients. cystatin C (CyC) appears to be a better marker of GFR than serum creatinine concentration or creatinine clearance in our study. Serum CyC levels and CyC clearance showed greater ability to predict amikacin clearance during therapy than creatinine clearance.


Clinical significance of cardiac troponins I and T in acute heart failure

Elevated cardiac troponin (cTn) levels are relatively common in acute heart failure (AHF).

To evaluate the prevalence and prognostic significance of elevated cTnI and cTnT in AHF.

FINN-AKVA is a prospective, multicenter study in AHF. In this analysis, 364 non-ACS patients with measurements of cTnI and cTnT taken on admission and 48 h thereafter were analyzed.

Of the 364 AHF patients, 51.1% had cTnI and 29.7% cTnT levels above the cut-off value. Six-month all-cause mortality was 18.7%. Both cTnI (OR 2.0, 95% CI 1.2–3.5, p = 0.01) and cTnT (OR 2.6, 95% CI 1.5–4.4, p = 0.0006) were associated with adverse outcome. The mortality risk was proportional to the magnitude of cTn release. On multivariable analysis, Cystatin C (OR 6.3, 95% CI 3.2–13, p < 0.0001), logNT-proBNP (OR 1.4, 95% CI 1.0–1.8, p = 0.03) and systolic blood pressure on admission (/10 mm Hg increase, OR 0.9, 95% CI 0.8–0.9, p = 0.0004) were independent risk markers, whereas the troponins were not significantly associated with increased mortality.

cTn elevations are frequent in AHF patients without ACS. cTnI is more often elevated than cTnT. Both cTnI and cTnT elevations are associated with increased mortality proportional to the degree elevation but they do not act as independent risk markers.


Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.

Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables.

STUDY DESIGN: Test of diagnostic accuracy.

SETTING & PARTICIPANTS: Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438).


INDEX TEST: Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study.

MEASUREMENTS: GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used.

RESULTS: Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables.

LIMITATIONS: Study population composed mainly of patients with CKD.

CONCLUSIONS: Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.


NGAL (neutrophil gelatinase-associated lipocalin) and cystatin C: Are they good predictors of contrast nephropathy after percutaneous coronary interve

The aim of the study was to assess whether neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin C could predict contrast-induced nephropathy in non-diabetic patients (n = 60, mean age 60 ± 11 years) with normal serum creatinine undergoing elective PCI. We found a significant rise in serum NGAL after 2, 4 and 8 h, and in urinary NGAL after 4, 8 and 24 h after PCI. Cystatin C rose significantly 8 and 24 h after the procedure. Prevalence of CIN was 10%. We found 90% sensitivity and 74% specificity of serum and 76% sensitivity and 80% specificity of urinary NGAL increase. NGAL may represent a sensitive early biomarkers of renal impairment after PCI.

H. Bachorzewska-Gajewskaa, 1, J. Malyszkoa, b, , 1, E. Sitniewskaa, J.S. Malyszkoa, B. Poniatowskia, K. Pawlaka and S. Dobrzycki



Serum Cystatin C and Increased Coronary Heart Disease Prevalence in US Adults Without Chronic Kidney Disease

Previous studies indicated that serum cystatin C, a marker of renal function, was associated with cardiovascular disease (CVD). However, few data about this association are available for persons without chronic kidney disease or albuminuria. Data from 4,991 subjects in the Third National Health and Nutrition Examination Survey with an estimated glomerular filtration rate ≥60 ml/min/1.73 m2 without micro- or macroalbuminuria were analyzed. Subjects were categorized into quartiles of serum cystatin C and compared for prevalence of CVD. CVD was defined as a history of myocardial infarction, angina, or stroke. After age standardization, prevalences of CVD from the lowest to highest quartile of serum cystatin C were 6.0%, 8.8%, 11.8%, and 16.7% (p-trend = 0.006). Also, age-standardized prevalences of myocardial infarction across quartiles of serum cystatin C were 1.9%, 4.4%, 6.6%, and 8.6%; age-standardized prevalences of angina were 2.4%, 4.4%, 4.2%, and 7.1%; and age-standardized prevalences of stroke were 2.5%, 1.6%, 3.5%, and 4.4% (each p-trend <0.05). Each 1-SD higher serum cystatin C level was associated with a multivariate prevalence ratio of CVD of 1.55 (95% confidence interval [CI] 1.13 to 2.13), and multivariate-adjusted prevalence ratios were 1.44 (95% CI 1.01 to 2.07), 1.64 (95% CI 1.02 to 2.64), and 1.65 (95% CI 1.06 to 2.56) for myocardial infarction, angina, and stroke, respectively. In conclusion, a graded association exists between higher serum cystatin C and increased CVD prevalence in patients without established chronic kidney disease.

Paul Muntner PhDa, , , Devin Mann MD, MSb, Jonathan Winston MDb, Sameer Bansilal MDc and Michael E. Farkouh MD, MScc

Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, New York USA.

Department of Medicine, Mount Sinai School of Medicine, New York, New York USA.

The Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, New York


Small kidney changes linked to high blood pressure

NEW YORK (Reuters Health) - Changes in kidney function appear to influence the occurrence of high blood pressure in individuals without overt kidney or cardiovascular disease , according to a report in the Annals of Internal Medicine.

The results suggest that early-stage kidney damage plays an important role in the development of high blood pressure, also referred to as hypertension, Dr. Bryan Kestenbaum, from the University of Washington in Seattle, and associates state.

The researchers evaluated the kidney function of 2,767 subjects who participated in the Multi-Ethnic Study of Atherosclerosis, a community-based study focusing on symptom-free cardiovascular disease. None of the subjects had hypertension, cardiovascular disease or symptoms of kidney disease when the study began.

The main outcome measure was the development of hypertension, defined as a blood pressure of at least 140/90 mm Hg, or the use of antihypertensive medications. Kestenbaum's group also monitored levels of cystatin C, a blood protein filtered out of the blood by the kidneys that is commonly used as a measure of kidney function. High cystatin C levels after some heart attacks predict a poor patient outcome.

Nearly 20 percent of the subjects developed hypertension after an average of 3.1 years, the report indicates.

When the investigators analyzed the data, taking into account other factors that may have contributed to an increase in blood pressure, they found that for each 15-nmol/L rise in cystatin C levels, there was a 15-percent increase in the risk of developing hypertension.

By contrast, the subjects with the highest ratios of albumin - creatinine , which is also associated with irregular kidney function and a risk of cardiovascular disease, was not associated with an increased risk of hypertension when compared with those with the lowest levels.

While the findings suggest that variation in kidney function influences the risk of hypertension, the reason for such variation is unclear, the authors note.

Some explanations are that these individuals have been born with an abnormal number of nephrons, basic structure, or they were exposed early in life to heavy metals, such as lead, which both can cause kidney disease.

SOURCE: Annals of Internal Medicine. April 1, 2008.


Cystatin C and other cardiovascular markers in hypertension

BACKGROUND AND OBJECTIVE: The aim of the study was to assess the relationship of cystatine C to other cardiovascular risk factors in hypertension .

PATIENTS AND METHOD: Cross-sectional study in hypertensive outpatients with normal creatinine values (< 1.6 mg/dl for males and < 1.4 mg/dl for women). Cystatin C was analyzed by immunonephelometry.

RESULTS: 283 patients (47% male) were evaluated. Cystatin C values were 0.65 (0.27) mg/l (median, intercuartile range, percentile 70 = 0.76 mg/l), and were correlated to the estimated glomerular filtration rate (GFR) (ml/min/1.73 m2), C reactive protein , and urinary albumin excretion (UAE). In multiple regression analysis the GFR was the most significant factor and explained 38% of cystatine C variability. GFR, (odds ratio [OR] = 5.84; 95% confidence interval [CI], 2.27-15.03; p < 0.001), age (OR = 1.05; 95% CI, 1.02-1.08; p < 0.001), and CRP (OR = 2.03; 95% CI, 1.07-3.84; p = 0.03), but not UAE >= 30 mg/24 h, were independent factors related to the presence of high levels (> 0.76 mg/l) of cystatine C in a logistic regression analysis. 58% of patients with UAE >= 30 mg/24h had cystatin C values < 0,76 mg/l.

CONCLUSIONS: In hypertensive patients, the GFR is the most important factor related to cystatine C values. Increased levels of cystatine C do not correspond to UAE augmentation.

Med Clin (Barc). 2008 Jan 19;130(1):1-5.Unidad de Hipertensión Arterial y Riesgo Vascular. Servicio de Medicina Interna. Hospital de Sagunto. Agencia Valenciana de Salud. Valencia. España