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1.  Cystatin C, Albuminuria, and 5-Year All-Cause Mortality in HIV-Infected Persons 
Compared with controls, HIV-infected persons have a greater prevalence of kidney disease as assessed by high levels of cystatin C and albuminuria, but not as assessed by creatinine level. However, the clinical importance of elevated cystatin C and albuminuria in the HIV-infected population has not been studied.
Study Design
We conducted an observational cohort study to determine the association of kidney disease (measured by albuminuria, cystatin C, and serum creatinine) with mortality.
Setting & Participants
922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV infection) study.
Serum cystatin C and serum creatinine were used to estimate glomerular filtration rate (eGFR). Albuminuria was defined as a positive urine dipstick (≥1+) or a urine albumin-creatinine ratio > 30 mg/g.
5-year mortality
At baseline, reduced kidney function (eGFRSCysC <60 mL/min/1.73m2) or albuminuria was present in 28% of participants. After five years of follow-up, mortality was 48% among those with both eGFRSCysC <60 mL/min/1.73m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory markers, eGFRSCysC <60 mL/min/1.73m2 and albuminuria were associated with nearly a twofold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m2 did not appear to have any substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73m2 and albuminuria accounted for 17% of the population-level attributable risk for mortality.
Vital status was unknown in 261 participants from the original cohort.
Kidney disease marked by albuminuria or increased cystatin C levels appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice.
PMCID: PMC3164880  PMID: 20709438
kidney disease; mortality; HIV infection
2.  Kidney function of HIV-infected children in Lagos, Nigeria: using Filler's serum cystatin C-based formula 
Limited data is available on kidney function in HIV-infected children in sub-Saharan Africa. In addition, malnutrition in these children further reduces the utility of diagnostic methods such as creatinine-based estimates of glomerular filtration rate. We determined the serum cystatin C level and estimated glomerular filtration rate of 60 antiretroviral-naïve, HIV-infected children and 60 apparently healthy age and sex matched children.
Serum cystatin C level was measured using enzyme-linked immunosorbent assay technique, while glomerular filtration rate was estimated using Filler's serum cystatin C formula. Student t test, Mann Whitney U test, Pearson chi square and Fisher's exact test were used, where appropriate, to test difference between groups.
Compared to the controls, the HIV-infected group had significantly higher median (interquartile range) serum cystatin C levels {0.77 (0.29) mg/l versus 0.66 (0.20) mg/l; p = 0.025} and a higher proportion of children with serum cystatin C level >1 mg/l {10 (16.7%) versus one (1.7%); p = 0.004}. The HIV-infected children had a mean (± SD) eGFR of 96.8 (± 36.1) ml/min/1.73 m2 compared with 110.5 (± 27.8) ml/min/1.73 m2 in the controls (p = 0.021). After controlling for age, sex and body mass index, only the study group (HIV infected versus control) remained a significant predictor of serum cystatin C level (β = -0.216, p = 0.021). The proportion of HIV-infected children with eGFR <60 ml/min/1.73 m2 was eight (13.3%) versus none (0%) in the control group (p = 0.006). However, the serum cystatin C level, eGFR and proportions of children with serum cystatin C level >1 mg/l and eGFR <60 ml/min/1.73 m2 were not significantly different between the HIV-infected children with advanced disease and those with milder disease.
HIV-infected children in Nigeria have higher serum cystatin C level and lower eGFR compared to age and sex matched controls.
PMCID: PMC2888781  PMID: 20482807
3.  Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study 
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
PMCID: PMC3159728  PMID: 21646913
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
4.  Cystatin C and Carotid Intima-Media Thickness in Asymptomatic Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Persons with early kidney disease have an increased risk of cardiovascular events and mortality, but the importance of accelerated atherosclerosis in promoting these outcomes is unclear. We therefore explored whether serum cystatin C level is associated with carotid intima-media thickness (IMT) in ambulatory adults without clinical heart disease.
Study Design
Cross-sectional study.
Setting & Participants
We evaluated 6,557 ethnically diverse persons free of clinical cardiovascular disease aged 45 to 84 years at the baseline visit of the Multi-Ethnic Study of Atherosclerosis.
Kidney function was estimated by using 2 methods: serum cystatin C level and estimated glomerular filtration rate, based on creatinine and cystatin C levels.
Outcomes & Measurements
Study outcomes were internal and common carotid IMT, measured by using high-resolution B-mode ultrasound. Multivariate linear and logistic regressions were used to evaluate the independent association of kidney function with carotid IMT.
In unadjusted linear analysis, each SD (0.23 mg/L) greater cystatin C level was associated with 0.091-mm greater internal carotid IMT (P < 0.001), but this association was diminished by 70% after adjustment for age, sex, and race/ethnicity (0.027 mm; P < 0.001) and was no longer significant after adjustment for cardiovascular risk factors (0.005 mm; P = 0.5). Similarly, the strong unadjusted associations of cystatin C level with common carotid IMT disappeared after adjustment. Chronic kidney disease, defined by using either creatinine level or cystatin C–based estimated glomerular filtration rate less than 60 mL/min/1.73 m2, had no independent association with internal and common carotid IMT.
There were few participants with severe kidney disease.
Cystatin C level had no independent association with carotid IMT in a population free of clinical heart disease. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.
PMCID: PMC3046734  PMID: 18823684
Cystatin C; intima-media thickness (IMT); atherosclerosis; cardiovascular diseases; kidney
5.  Cystatin C-Based Evaluation of Kidney Function of HIV-Infected Children in Benin City, Southern Nigeria 
Background. Human immunodeficiency virus (HIV) is now a confirmed risk factor for kidney disease with an increased burden in persons of African descent. Method. We measured the serum cystatin C levels of 205 ART-naive, HIV-infected children by an ELISA technique and compared them with the levels of apparently healthy children. Result. The mean ± SD serum cystatin C level of children with HIV infection was 1.01 ± 0.44 mg/L, significantly higher than the mean value in the control group, that is, 0.72 ± 0.20 mg/L (P = 0.000). The mean ± SD cystatin C-based estimated GFR of children with HIV infection was 102.7 ± 31.0 mL/min/1.73 m2, significantly lower than 126.9 ± 28.5 mL/min/1.73 m2 in the control group, (P = 0.014). A significantly higher proportion of HIV-infected children compared to controls had eGFR < 90 mL/min/1.73 m2 (21.5% versus 5.4%; P = 0.00). The prevalence of chronic kidney disease (CKD) among the HIV-infected children was 10.7%. The cystatin C-based eGFR of the HIV-infected children ≥5 years old correlated positively with their CD4 count (r = 0.23;  P = 0.022). Conclusion. There is a high prevalence of CKD among HIV-infected children, requiring regular monitoring of their kidney function using a cystatin C-based method.
PMCID: PMC3507083  PMID: 23213527
6.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
7.  Cystatin C and Aging Success 
Archives of internal medicine  2008;168(2):147-153.
To our knowledge, the effect of kidney function on successful aging has not been examined.
We evaluated the relationship between cystatin C and aging success during a 6-year follow-up in the Cardiovascular Health Study, a community-based cohort of older adults (aged ≥65 years). Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and having intact physical and cognitive functioning. In adjusted analysis, an accelerated failure time model was used to evaluate the percentage reduction in successful years by level of cystatin C. A separate Cox proportional hazards model evaluated whether cystatin C was related to incident physical and cognitive disability.
A total of 2140 participants had cystatin C measured and were free of the previously mentioned conditions at baseline. Their mean age was 74 years. The mean cystatin C level, creatinine level, and estimated glomerular filtration rate were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m2, respectively (to convert cystatin C to nanomoles per liter, multiply by 75; and to convert creatinine to micromoles per liter, multiply by 88.4). A total of 873 participants reached a first event in follow-up, 138 because of cognitive disability, 238 because of physical disability, 34 because of chronic obstructive pulmonary disease, 146 because of cancer, and 317 because of cardiovascular disease. The adjusted percentage reduction in successful life years in the highest vs the lowest quartile of cystatin C was 27% (95% confidence interval, 11%-39%). The highest vs lowest quartile of cystatin C also was independently associated with incident cognitive or physical disability (hazard ratio, 1.39; 95% confidence interval, 1.00-1.98).
A higher cystatin C level, even within a range of relatively normal kidney function, was associated with unsuccessful aging.
PMCID: PMC2871318  PMID: 18227360
8.  Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality 
A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.
To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.
Design, Setting, and Participants
Prospective cohort study involving 26 643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m2 and ACR of either <30 or ≥30 mg/g.
Main Outcome Measures
All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.
Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26 643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0–5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2–4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9–8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4–1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9–2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4–3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7–40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05–2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6–11.3). Net reclassification improvement for death was 13.3% (P<.001) and for end-stage renal disease was 6.4% (P<.001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.
Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
PMCID: PMC3697771  PMID: 21482744
9.  Association of Cystatin C With Poor Exercise Capacity and Heart Rate Recovery: Data From the Heart and Soul Study 
Cystatin C, an alternative serum measure of kidney function, is a stronger predictor of cardiovascular events than creatinine or estimated glomerular filtration rate (eGFR). We hypothesized that serum cystatin C concentration would have a stronger more linear association with cardiovascular functional status than creatinine-based measures in outpatients with established coronary heart disease (CHD).
We measured serum cystatin C, serum creatinine, and eGFR in 906 outpatients with established CHD. We examined the association of these 3 measures of kidney function with treadmill exercise capacity (metabolic equivalent tasks achieved) and heart rate recovery (HRR) between peak and 1 minute after exercise by using linear and logistic regression.
Higher cystatin C concentrations were associated linearly with worse treadmill exercise capacity and HRR. The proportion of participants with poor exercise capacity (metabolic equivalent tasks achieved < 5) was 45% (99 of 222 participants) among those with cystatin C levels in the highest quartile (>1.30 mg/L) compared with 12% (29 of 241 participants) among those with cystatin C levels in the lowest quartile (<0.92 mg/L; adjusted odds ratio, 3.2; 95% confidence interval, 1.6 to 6.5; P = 0.001). The proportion of participants with poor HRR (<16 beats/min) was 42% (92 of 214 participants) among those with cystatin C levels in the highest quartile compared with 16% (37 of 238 participants) among those with cystatin C levels in the lowest quartile (adjusted odds ratio, 2.2; 95% confidence interval, 1.2 to 4.0; P = 0.01). The lowest quartile of eGFR (<61.8 mL/min [<1.03 mL/s]) was associated with decreased exercise capacity and prolonged HRR, but no difference was observed across the upper 3 quartiles of eGFR.
In patients with established CHD, cystatin C concentrations are associated linearly with worse exercise capacity and HRR. Cystatin C detects an association of impaired kidney function with decreased HRR and exercise capacity that is not fully captured using creatinine-based measurements.
PMCID: PMC2770341  PMID: 17336697
Coronary artery disease; cystatin C; creatinine; renal function; exercise capacity; heart rate recovery
10.  Kidney and liver organ transplantation in persons with human immunodeficiency virus 
Executive Summary
The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+)
Clinical Need: Condition and Target Population
Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV−), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV.
With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed.
Evidence-Based Analysis Methods
Research Questions
What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF?
Literature Search
A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009.
Inclusion Criteria
Systematic review with or without a Meta analysis, RCT, Non-RCT with controls
HIV+ population undergoing solid organ transplantation
HIV+ population managed with HAART therapy
Controls include persons undergoing solid organ transplantation who are i) HIV− ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.
Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.
Studies with a minimum (mean or medium) follow up of 1-year.
English language citations
Exclusion Criteria
Case reports and case series were excluded form this review.
Outcomes of Interest
i) Risk of Death after transplantation
ii) Death censored graft survival (DCGS)
iii) HIV disease progression defined as the post transplant incidence of:
- opportunistic infections or neoplasms,
- CD4+ T-cell count < 200mm3, and
- any detectable level of plasma HIV viral load.
iv) Acute graft rejection,
v) Return to dialysis,
vi) Recurrence of HCV infection
Summary of Findings
No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search.
The results of this review are reported for the following comparison cohorts undergoing transplantation:
i) Kidney Transplantation: HIV+ cohort compared with HIV− cohort
ii) Liver Transplantation: HIV+ cohort compared with HIV− negative cohort
iii) Liver Transplantation: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort
Kidney Transplantation: HIV+ vs. HIV−
Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV− cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV− cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV− groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain.
The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV− cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect.
Liver Transplantation: HIV+ vs. HIV−
Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV− cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV− cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain.
Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV− groups
Liver Transplantation: HIV+/HCV+ vs. HCV+
Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available.
Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect.
Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low.
Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.
PMCID: PMC3377507  PMID: 23074407
11.  Association of Cystatin C with Adverse Outcomes 
Purpose of Review
To discuss recent studies which have evaluated determinants of cystatin C and to focus on the relationship of cystatin C with mortality, cardiovascular disease (CVD) and non-cardiovascular outcomes.
Recent Findings
In the Chronic Kidney Disease Epidemiology Study cystatin C was associated with demographic characteristics independent of measured glomerular filtration rate (GFR), although this was to a smaller extent than creatinine. In patients with established CKD, cystatin C was strongly and inversely correlated with measured GFR, suggesting that although cystatin C may have other determinants, it is primarily a measure of kidney function. Several cohort studies, particularly in older adults, have now demonstrated that cystatin C is linearly associated with mortality, CVD and non-CVD outcomes, whereas creatinine is primarily associated with risk in individuals with more advanced kidney disease. A recent study has also shown that changes in kidney function as ascertained by cystatin C, even within the relatively normal range, are associated with subsequent CVD and all-cause mortality among older adults.
Cystatin C appears to capture an association of mild kidney disease with increased risk of mortality, CVD and non-CVD outcomes. Future studies should evaluate whether cystatin C can improve medical decision-making and lead to favorable patient outcomes.
PMCID: PMC2890263  PMID: 19374014
cystatin C; kidney disease; cardiovascular disease; mortality
12.  Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients 
Critical Care  2005;9(2):R139-R143.
In critically ill patients sudden changes in glomerular filtration rate (GFR) are not instantly followed by parallel changes in serum creatinine. The aim of the present study was to analyze the utility of serum cystatin C as a marker of renal function in these patients.
Serum creatinine, serum cystatin C and 24-hour creatinine clearance (CCr) were determined in 50 critically ill patients (age 21–86 years; mean Acute Physiology and Chronic Health Evaluation II score 20 ± 9). They did not have chronic renal failure but were at risk for developing renal dysfunction. Serum cystatin C was measured using particle enhanced immunonephelometry. Twenty-four-hour body surface adjusted CCr was used as a control because it is the 'gold standard' for determining GFR.
Serum creatinine, serum cystatin C and CCr (mean ± standard deviation [range]) were 1.00 ± 0.85 mg/dl (0.40–5.61 mg/dl), 1.19 ± 0.79 mg/l (0.49–4.70 mg/l), and 92.74 ± 52.74 ml/min per 1.73 m2 (8.17–233.21 ml/min per 1.73 m2), respectively. Our data showed that serum cystatin C correlated better with GFR than did creatinine (1/cystatin C versus CCr: r = 0.832, P < 0.001; 1/creatinine versus CCr: r = 0.426, P = 0.002). Cystatin C was diagnostically superior to creatinine (area under the curve [AUC] for cystatin C 0.927, 95% confidence interval 86.1–99.4; AUC for creatinine 0.694, 95% confidence interval 54.1–84.6). Half of the patients had acute renal dysfunction. Only five (20%) of these 25 patients had elevated serum creatinine, whereas 76% had elevated serum cystatin C levels (P = 0.032).
Cystatin C is an accurate marker of subtle changes in GFR, and it may be superior to creatinine when assessing this parameter in clinical practice in critically ill patients.
PMCID: PMC1175926  PMID: 15774046
13.  Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate 
All of the components of Metabolic syndrome (MetS) have been regarded as risk factors for coronary artery disease (CAD). Early detection of CAD in asymptomatic patients with MetS remains a challenge. Cystatin C,which has been proposed as a novel marker of renal dysfunction,is correlated with mortality in CAD, The purpose of the study was to evaluate whether cystatin C is a potential marker of asymptomatic CAD in MetS patients with normal kidney function.
A total of 211asymptomatic MetS patients without prior history of CAD patients were included in a cross-sectional study. Patients were divided into MetS with asymptomatic CAD (n = 136) and MetS without CAD (n = 75) groups according to coronary angiograph results. Serum cystatin C levels were measured using particle enhanced immunonephelometric assays. We first assessed whether there is an independent association of cystatin C with the presence and severity of asymptomatic CAD. Then, we investigated the association between cystatin C and other biochemical risk factors for atherosclerosis.
Serum cystatin C levels in patients with asymptomatic CAD were significantly higher than those without CAD (P = 0.004). A multiple logistic regression analysis demonstrated cystatin C was independently associated with the presence of asymptomatic CAD (OR = 1.326, 95%CI: 1.086-1.619). On receiver operating characteristics (ROC) analysis, the area under the curve (AUC) was 0.622 (95 % CI: 0543–0.701, P = 0.003), and cystatin C showed a moderate predictive value. Furthermore, cystatin C was independently correlated with Gensini score (standardized β = 0.183, P = 0.007), and serum cystatin C levels increased with the increasing of number of disease vessels (P = 0.005). In a multiple stepwise regression analysis, uric acid (UA)(P < 0.001), body mass index (BMI)(P = 0.002), triglyceride(TG)(P = 0.03), estimated glomerular filtration rate (eGFR)(P < 0.001), and fibrinogen(P = 0.001) were independently associated with cystatin C.
Serum cystatin C in our study was significantly associated with the presence and severity of asymptomatic CAD in MetS patients with normal kidney function, suggesting that cystatin C is probably more than a marker of glomerular filtration rate.
PMCID: PMC3473246  PMID: 22978689
Cystatin C; Gensini score; Metabolic syndrome; Asymptomatic coronary artery disease
14.  Association of renal function with cardiac calcifications in older adults: the cardiovascular health study 
Background. Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.
Methods. From the Cardiovascular Health Study, a community-based cohort of ambulatory adults ≥ age 65, a total of 3929 individuals (mean ± SD age 74 ± 5 years, 60% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.
Results. The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m2 (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m2 was significantly associated with MAC [odds ratio 1.54 (95% CI 1.16–2.06), P = 0.003] and not associated with AAC [1.30 (0.97–1.74), P = 0.085] and AVS [1.15 (0.86–1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05–1.21), P = 0.001] and not associated with AAC [1.07 (1.00–1.15), P = 0.054] and AVS [0.99 (0.93–1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m2 and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m2, increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).
Conclusions. In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m2 and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m2, increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.
PMCID: PMC2721419  PMID: 18840892
chronic kidney disease; cohort; creatinine; cystatin C; elderly
15.  Cystatin C is Associated with Inflammation but not Atherosclerosis in Systemic Lupus Erythematosus 
Lupus  2011;21(3):279-287.
Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independent of conventional measures of renal function. We examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis.
We measured serum cystatin C, creatinine, TNF-α, IL-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR) and other clinical parameters in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models.
Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than controls (1.09[Interquartile range, IQR: 0.85–1.28]mg/L vs. 0.89 [IQR: 0.76–0.99]mg/L; P<0.001 after adjusting for age, race and sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (P=0.04), ESR (P<0.001), CRP (P=0.04), TNF-α (P=0.008) and IL-6 (P=0.01) after adjustment for age, race and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, P= 0.31) and the association remained non-significant after adjustment for age, race, sex and Framingham risk score (P=0.99).
Cystatin C was higher in patients with SLE than control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.
PMCID: PMC3275887  PMID: 22072023
cystatin C; systemic lupus erythematosus; renal function; atherosclerosis; Inflammation
16.  Prevalence of kidney disease in anaemia differs by GFR-estimating method: The Third National Health and Nutrition Examination Survey (1988–94) 
Nephrology Dialysis Transplantation  2010;25(8):2542-2548.
Background. Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.
Methods. We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.
Results. The prevalence of moderate to severe kidney disease (eGFR 15–59 mL/min/1.73 m2) among anaemic persons was 15–16% when based on serum creatinine alone (eGFRSCR) or combined with cystatin C (eGFRSCR + CYSC); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFRCYSC). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFRCYSC than eGFRSCR and eGFRSCR + CYSC in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98–27.36).
Conclusions. Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFRCYSC may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.
PMCID: PMC2910334  PMID: 20176612
anaemia; chronic kidney failure; creatinine; cystatin C; glomerular filtration rate
17.  Comparison of Measured GFR, Serum Creatinine, Cystatin C, and Beta-Trace Protein to Predict ESRD in African Americans With Hypertensive CKD 
Identification of persons with chronic kidney disease (CKD) who are at highest risk to progress to end stage renal disease (ESRD) is necessary to reduce the burden of kidney failure. The relative utility of traditional markers of kidney function, including estimated glomerular filtration rate (GFR) and serum creatinine, and emerging markers of kidney function, including cystatin C and beta-trace protein (BTP), to predict ESRD and mortality has yet to be established.
Study Design
Randomized clinical trial followed by an observational cohort study.
Setting & Participants
865 African American individuals with hypertensive CKD enrolled in a clinical trial of two levels of blood pressure control and three different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study.
Quintile of measured GFR (mGFR) by iothalamate clearance, serum creatinine, serum creatinine-based estimated GFR (eGFRSCr), cystatin C, and BTP.
Outcomes and Measurements
Incidence of ESRD and mortality.
A total of 246 participants reached ESRD over a median follow-up of 102 months. The incidence rate of ESRD was higher with higher quintiles of each marker. The association between higher BTP and ESRD was stronger than those for the other markers, including mGFR. All the markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates (all p<0.05), with BTP retaining the strongest association (HR for highest versus lowest quintile, 5.7; 95% CI, 2.2-14.9). Associations with the combined endpoint of ESRD or mortality (n=390) were weaker, but remained significant for cystatin C (p=0.05) and BTP (p=0.004).
The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and among individuals with CKD due to other causes is unknown.
Plasma BTP and cystatin C may be useful adjuncts to serum creatinine and mGFR in evaluating risk for progression of kidney disease.
PMCID: PMC3221777  PMID: 21944667
End-stage renal disease; beta trace protein; cystatin C; serum creatinine; iothalamate glomerular filtration rate
18.  Rate of Kidney Function Decline in Older Adults: A Comparison Using Creatinine and Cystatin C 
American Journal of Nephrology  2009;30(3):171-178.
The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C.
In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 ± 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m2).
Mean annual eGFR loss as estimated from creatinine was 0.4 ± 3.6 ml/min/1.73 m2, with 16% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 ± 2.6, with 25% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10% (n = 263) using creatinine and 19% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16–1.65), 1.62 (1.31–1.99) and 2.96 (2.28–3.84) for participants aged 70–74, 75–79 and 80+ at baseline, compared with those aged 65–69.
In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.
PMCID: PMC2820322  PMID: 19349699
Glomerular filtration rate; Creatinine; Cystatin C; Chronic kidney disease
19.  Association of Chronic Kidney Disease Detected by Creatinine and Cystatin C with Death and Cardiovascular Events among Elderly Mexican-Americans: The Sacramento Area Latino Study on Aging (SALSA) 
Chronic kidney disease (CKD) is diagnosed by serum creatinine, which is biased by muscle mass, age and race. We evaluated whether cystatin C, an alternative measure of kidney function, can detect high risk CKD among elderly Mexican-Americans.
Sacramento Area Study of Latinos (SALSA)
1,435 Mexican-Americans ages 60–101 with mean follow-up 6.8 years
We estimated glomerular filtration rate (eGFR, ml/min/1.73m2)by creatinine and cystatin C, and classified persons into four mutually exclusive categories: (1) CKD neither (eGFRcreat ≥60 and eGFRcys ≥60); (2) CKD creatinine only (eGFRcreat <60 but eGFRcys ≥60); (3) CKD cystatin only (eGFRcreat ≥60 but eGFRcys <60); and (4) CKD both (eGFRcreat <60 and eGFRcys <60). We studied the association of each CKD classification with all-cause death and cardiovascular (CVD) death using Cox regression.
At baseline, mean was age 71±7; 34% (N=481) were diabetic and 68% (N=980) hypertensive. Compared with persons with no CKD by either marker, persons with CKD both had the highest risks for death (HR 2.30, 1.78–2.98) and CVD death (HR 2.75, 1.96–3.86) after full adjustment. Persons with CKD by cystatin C only were also at increased risk for death, HR 1.91 (1.37–2.67) and for CVD death, HR 2.56 (1.64–3.99)) compared to no CKD. In contrast, persons with CKD by creatinine only were not at increased risk for CVD death (HR 1.39, 0.71–2.72), but remained at higher risk for all-cause death (HR 1.95, 1.27–2.98).
Cystatin C may be a useful alternative in addition to creatinine to detect high risk CKD in elderly Mexican Americans.
PMCID: PMC3545054  PMID: 23252993
chronic kidney disease; Mexican-Americans; elderly; creatinine; cystatin C; cardiovascular disease
20.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Retrospective cohort analysis.
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
21.  Urinary Markers of Kidney Injury and Kidney Function Decline in HIV-Infected Women 
HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women.
In the Women's Interagency HIV Study (WIHS), we measured concentrations of albumin-to-creatinine ratio (ACR), interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) from stored urine among 908 HIV-infected and 289 uninfected participants. Primary analyses used cystatin C based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and two follow-up visits over eight years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes.
Compared with the lowest tertiles, the highest tertiles of ACR (−0.15ml/min/1.73m2, p<0.0001), IL-18 (−0.09ml/min/1.73m2, p<0.0001) and KIM-1 (−0.06ml/min/1.73m2, p<0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all three biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (Relative Risk 1.40; 95%CI 1.04-1.89); ≥5% (1.88; 1.30-2.71); and ≥10% (2.16; 1.20-3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25-2.33) and 10% (1.78; 1.07-2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00-3.87).
Among HIV-infected women in the WIHS cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.
PMCID: PMC3509242  PMID: 23023103
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
22.  Differences in Kidney Function and Incident Hypertension: The Multi-Ethnic Study of Atherosclerosis 
Annals of internal medicine  2008;148(7):501-508.
Kidney disease and hypertension commonly coexist, yet the direction of their association is still debated.
To evaluate whether early kidney dysfunction, measured by serum cystatin C levels and urinary albumin excretion, predates hypertension in adults without clinically recognized kidney or cardiovascular disease.
Observational cohort study using data from 2000 to 2005.
The MESA (Multi-Ethnic Study of Atherosclerosis), a community-based study of subclinical cardiovascular disease in adults age 45 to 84 years.
2767 MESA participants without prevalent hypertension, cardiovascular disease, or clinically recognized kidney disease (an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria).
Cystatin C was measured by using a nephelometer, and urinary albumin and creatinine were measured from a spot morning collection. The primary outcome was incident hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of an antihypertensive medication.
During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. After adjustment for established hypertension risk factors, each 15-nmol/L increase in cystatin C was associated with a statistically significant 15% greater incidence of hypertension (P = 0.017). The highest sex-specific quartile of urinary albumin–creatinine ratio was associated with a statistically insignificant 16% greater incidence of hypertension (P = 0.192) compared with the lowest quartile. No statistical evidence suggested a multiplicative interaction.
Unmeasured characteristics may have confounded observed associations of kidney markers with hypertension. Follow-up was relatively short. Hypertension that may have occurred between study visits or hypertension that was not captured by standard cuff measurements may have been missed.
Differences in kidney function, indicated by cystatin C levels, are associated with incident hypertension among individuals without clinical kidney or cardiovascular disease. These population-based findings complement experimental work implicating early kidney damage in the pathogenesis of essential hypertension.
PMCID: PMC3044648  PMID: 18378946
23.  Serum Cystatin C is a Potential Endogenous Marker for the Estimation of Renal Function in Male Gout Patients with Renal Impairment 
Serum creatinine level is the most commonly used indices for assessment of glomerular filtration rate (GFR), even though these indices have been shown to have some limitations in clinical practice. We investigated the diagnostic efficacy of serum cystatin C compared to that of serum creatinine levels and identified the relating factors associated with changes in serum cystatin C levels in gout patients with renal impairment. A total of 68 gouty patients with renal impairment were enrolled in this study. Diagnostic efficacy of serum cystatin C levels was evaluated through non-parametric receiver operating characteristic (ROC) analysis. The risk factors for changes in serum cystatin C levels were confirmed using multivariate regression analysis. With 24-hr urine creatinine clearance (Ccr) as the reference for GFR, 1/cystatin C (r=0.702, P<0.001) showed a significantly higher correlation with Ccr than 1/creatinine (r=0.665, P<0.001). Multivariate correlation analysis demonstrated that the clinical parameters for increased serum cystatin C are a higher stage of chronic kidney disease, older age, use of allopurinol, and lower high density lipoprotein-cholesterol. The area under the curve (AUC) at ROC plots identified that of serum cystatin C was significantly greater than that of serum creatinine (AUC 0.804 of cystatin C and AUC 0.745 of creatinine). The study suggests that serum cystatin C is a reliable endogenous marker for the assessment of renal function or GFR in gout patients with renal impairment.
PMCID: PMC2800003  PMID: 20052346
Cystatin C; Gout; Creatinine; Kidney Failure; Glomerular Filtration Rate
24.  Differences in urine cadmium associations with kidney outcomes based on serum creatinine and cystatin C 
Environmental research  2011;111(8):1236-1242.
Cadmium is a well known nephrotoxicant; chronic exposure increases risk for chronic kidney disease. Recently, however, associations between urine cadmium and higher creatinine-based estimated glomerular filtration rate (eGFR) have been reported. Analyses utilizing alternate biomarkers of kidney function allow evaluation of potential mechanisms for these observations. We compared associations of urine cadmium with kidney function measures based on serum cystatin C to those with serum creatinine in 712 lead workers. Mean (standard deviation) molybdenum-corrected urine cadmium, Modification of Diet in Renal Disease (MDRD) eGFR and multi-variable cystatin C eGFR were 1.02 (0.65) μg/g creatinine, and 97.4 (19.2) and 112.0 (17.7) mL/min/1.73 m2, respectively. The eGFR measures were moderately correlated (rs = 0.5; p less than 0.001). After adjustment, ln(urine cadmium) was not associated with serum cystatin-C-based measures. However, higher ln(urine cadmium) was associated with higher creatinine-based eGFRs including the MDRD and an equation incorporating serum cystatin C and creatinine (beta-coefficient = 4.1 ml/min/1.73 m2; 95% confidence interval =1.6, 6.6). Urine creatinine was associated with serum creatinine-based but not cystatin-C-based eGFRs. These results support a biomarker-specific, rather than a kidney function, effect underlying the associations observed between higher urine cadmium and creatinine-based kidney function measures. Given the routine use of serum and urine creatinine in kidney and biomarker research, additional research to elucidate the mechanism(s) for these associations is essential.
PMCID: PMC3210933  PMID: 21871619
cadmium; cystatin C; kidney function; serum creatinine; urine creatinine
25.  Associations of blood lead with estimated glomerular filtration rate using MDRD, CKD-EPI and serum cystatin C-based equations 
Nephrology Dialysis Transplantation  2011;26(9):2786-2792.
Background. Low-level lead exposure is widespread and has been implicated as a chronic kidney disease (CKD) risk factor. However, studies evaluating associations of lead dose with newer, potentially more accurate, estimates of kidney function, in participants with a wide range of glomerular filtration rates (GFRs), are scarce.
Methods. We compared associations of blood lead and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and cystatin C single variable, multivariable and combined creatinine/cystatin C equations in 3941 adults who participated in the 1999–2002 National Health and Nutrition Examination Survey cystatin C subsample.
Results. Geometric mean blood lead was 1.7 μg/dL. After multivariable adjustment, differences [95% confidence interval (CI)] in mean eGFR for a doubling of blood lead were −1.9 (−3.2, −0.7), −1.7 (−3.0, −0.5) and −1.4 (−2.3, −0.5) mL/min/1.73 m2, using the cystatin C single variable, multivariable and combined creatinine/cystatin C equations, respectively, reflecting lower eGFR with increased blood lead. The corresponding differences (95% CI) were −0.9 (−1.9, 0.02) and −0.9 (−1.8, 0.01) using the creatinine-based MDRD and CKD-EPI equations, respectively. In participants aged ≥60 years, differences in mean eGFR ranged from −3.0 to −4.5 mL/min/1.73 m2, and odds of reduced eGFR (<60 mL/min/1.73 m2) were increased for all estimates of GFR.
Conclusions. These results support the inclusion of cystatin C-based eGFR in future lead research and provide additional evidence for environmental lead exposure as a CKD risk factor.
PMCID: PMC3203408  PMID: 21248295
blood lead; kidney function; lead exposure; NHANES

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