Kidney function estimated from serum creatinine and cystatin C and peripheral arterial disease

Aims: Serum cystatin C, a novel marker of kidney function, is reported to be superior to serum creatinine as a risk factor for atherosclerotic disease, but associations may vary across vascular beds.

Methods and results: A cross-sectional study of chronic kidney disease (CKD) and peripheral arterial disease (PAD) in 3089 adult participants aged 40+ from the 1999–2002 National Health and Nutrition Examination Survey (NHANES). Kidney function, assessed by estimated glomerular filtration rate (eGFR), was determined from serum creatinine and cystatin C using established equations. Peripheral arterial disease defined by an ankle brachial index <0.90.

Glomerular filtration rate estimated using cystatin C was more strongly associated with PAD compared with eGFR using serum creatinine before and after multivariable adjustment. Further, after adjustment for cystatin C, kidney function based on serum creatinine was no longer significantly associated with PAD.

However, cystatin C remained significantly associated with PAD even after adjustment for GFR estimated by serum creatinine. Compared with optimal kidney function (eGFRserum creatinine 60, eGFRcystatin C >90), the odds ratio for PAD was 3.11 (95% confidence interval 1.26–7.64) for preclinical CKD (eGFRserum creatinine 60, eGFRcystatin C <76.7) and 5.07 (3.01–8.52) for ‘confirmed’ CKD (eGFRserum creatinine <60, eGFRcystatin C <60).

Conclusion: Chronic kidney disease was strongly and independently associated with PAD. Cystatin C was a more potent marker of lower extremity PAD when compared with the serum creatinine equation currently used in clinical practice. Our results suggest that cystatin C may have clinical utility when combined with serum creatinine in evaluation of individuals who may have PAD.

Elizabeth Selvin1,2,*, Anna Köttgen1 and Josef Coresh1,2
1 Department of Epidemiology and the Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 2024 E. Monument Street, Suite 2-600, Baltimore, MD 21287, USA
2 Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA


Kidney Function Decline Increases Risk Of Heart Failure And Premature Death

ScienceDaily (Nov. 9, 2009) — cystatin C Research: Declining kidney function is linked to a higher risk of heart failure, heart attack, peripheral arterial disease, and early death in individuals with or without kidney disease, according to a pair of studies appearing in an upcoming issue of the Journal of the American Society Nephrology (JASN).

The findings indicate that poor kidney function may raise an individual's risk for cardiovascular complications. To evaluate heart health, clinicians should factor in not only their patients' current level of kidney function, but also changes in kidney function over time.

Chronic kidney disease (CKD) patients have an increased risk of developing and dying from cardiovascular disease, but the links between kidney function and heart health are not well understood. Michael Shlipak, MD (San Francisco VA Medical Center and University of California, San Francisco), Mark Sarnak, MD (Tufts-New England Medical Center), and their colleagues studied clinical information from individuals who were enrolled in the Cardiovascular Health Study, a community-based study of elderly people.

Using a new blood test of kidney function, called cystatin C , the researchers looked for links between changes in kidney function during a period of seven years with the incidence of heart failure, heart attack, stroke, and peripheral arterial disease (obstruction of large arteries in the arms and legs) during the subsequent eight years. Among 4,378 eligible participants in the study, those with rapid kidney decline (1,083 patients) demonstrated a 32% increased risk of experiencing heart failure, a 48% increased risk of having a heart attack, and a 67% increased risk of developing peripheral arterial disease. (They did not have an increased risk of suffering a stroke.)

Importantly, researchers identified an association between rapid kidney function decline and heart complications in patients with and without CKD. Treatments that slow the decline of kidney function and stabilize it in the normal range, before kidney disease develops, could have substantial health benefits.

In the second study, Kunihiro Matsushita, MD, PhD, Josef Coresh, MD, PhD (Johns Hopkins University), and their colleagues examined the effects of changes in kidney function in 13,029 participants of the Atherosclerosis Risk in Communities (ARIC) Study, a population-based sample of individuals aged 45 to 64 years. The researchers followed patients from 1987 to 2006, and monitored participants' kidney function at the start of the study, three years into the study, and nine years into the study. Investigators found that a large drop in kidney function over time -- regardless of the initial level of function -- increased one's risk of developing heart disease and of dying early. Patients whose kidney function dropped by more than 5.6% per year demonstrated a 30% increased risk of developing heart disease and a 22% increased risk of dying prematurely compared to patients with stable kidney function.

Physicians regularly monitor kidney function in elderly patients and patients with diabetes and hypertension to optimize the dose of prescription drugs excreted by the kidneys. This study indicates that physicians who detect a decline in patients' kidney function over time should view this as a sign of increased risk of heart disease and premature death.

"Our results suggest there may be clinical value in sequential kidney function data, often measured in routine care, even among individuals with mildly reduced kidney function," the authors wrote.

Dr. Shlipak's and Dr. Sarnak's co-authors include Ronit Katz, DPhil, Bryan Kestenbaum, MD, David Siscovick, MD (University of Washington); Linda Fried, MD (VA Pittsburgh Healthcare System); Anne Newman, MD (University of Pittsburgh); and Dena Rifkin, MD (Tufts-New England Medical Center). Dr. Matsushita's and Dr. Coresh's co-authors include Elizabeth Selvin, PhD, Lori Bash, PhD, Brad Astor, PhD (Johns Hopkins University), and Nora Franceschini, MD (University of North Carolina).


cystatin C and CRP:Change of glomerular filtration rate in healthy adults with aging

AIM: In order to determine the relationship between glomerular filtration rate (GFR) and age, the associated factors, and the accurate method of GFR in healthy adults, we conducted a cross-sectional study in community-dwelling adults in Beijing.

METHODS: Renal function of 201 clinically healthy subjects was determined using technetium-99 m-labelled diethylene triamine pentacetic acid ((99m)Tc-DTPA). Estimated GFR was calculated with the Cockcroft-Gault (CG) equation, abbreviated Modification of Diet in Renal Disease (MDRD) equation, and plasma clearance of creatinine (Ccr). Serum cystatin C, biomarkers of inflammatory and endothelial cells were analyzed as well. Protein intake, carotid artery intima-media thickness and plaque formation were assayed as well.

RESULTS: Glomerular filtration rate was negatively associated with age and the correlation coefficient for (99m)Tc-GFR, CG-GFR, MDRD-GFR, Ccr were -0.643, -0.736, -0.55 and -0.619, respectively (P < 0.001), while the correlation coefficient between cystatin C and age was 0.681 (P < 0.001). Estimated GFR were associated with measured GFR, and the correlation coefficient for Ccr, CG-GFR and MDRD-GFR were 0.813, 0.582 and 0.418, respectively (P < 0.001). The area under the receiver-operator curve of Ccr was larger, CG was smaller while MDRD was the smallest, and the difference was significant (P < 0.001). So a predicted equation was presented by cystatin C and C-reactive protein for the elderly.

CONCLUSION: In the clinically healthy adults, GFR declined with age. MDRD and CG equation are not suitable to estimate GFR in healthy adults. The predicted equation established by cystatin C and C-reactive protein may be more accurate.

Sun X, Chen Y, Chen X, Wang J, Xi C, Lin S, Liu X.
Institute of Nephrology of PLA, General Hospital of PLA, Beijing, China


Cystatin C in cerebrospinal fluid as a biomarker of ALS.

Department of Neurology, Graduate School of Medicine, Hokkaido University, Sapporo City, Hokkaido, Japan.

Amyotrophic lateral sclerosis (ALS) is diagnosed on the basis of progressive symptoms in both the upper and lower motor neurons. Because there are no specific biomarkers for ALS, it is difficult to diagnose this disease in its early stages. Cerebrospinal fluid (CSF) samples were obtained from 14 patients in the early stages of ALS, from 13 with polyneuropathy, and from 16 with other neurological disorders. The concentration of cystatin C in the CSF was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. The concentration of cystatin C in the CSF was significantly lower in ALS patients than in the control subjects who were patients with polyneuropathy or other neurological diseases (patients with ALS, polyneuropathy, and other diseases exhibited 5.5 +/- 0.3, 6.7 +/- 0.4, and 6.9 +/- 0.3 mg/L cystatin C, respectively; ALS patients vs. control subjects: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024). Cystatin C may be a useful biomarker of ALS and can be used to distinguish between ALS and polyneuropathy.


Interruption of antiretroviral therapy is associated with increased plasma cystatin C.


AIDS. 23(1):71-82, January 2, 2009.
Mocroft, Amanda a; Wyatt, Christina b; Szczech, Lynda c; Neuhaus, Jacquie d; El-Sadr, Wafaa e; Tracy, Russell f; Kuller, Lewis g; Shlipak, Michael h; Angus, Brian i,j; Klinker, Harting k; Ross, Michael b;

Background: Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4+ cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C.

Methods: Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics.

Results: At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023).

Conclusion: These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function.