Michael F. Schneider

New Equations to Estimate GFR in Children with CKD

The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.

Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C.

The Chronic Kidney Disease in Children study is a cohort of about 600 children with chronic kidney disease (CKD) in the United States and Canada. The independent variable for our observations was a measurement of glomerular filtration rate (GFR) by iohexol disappearance (iGFR) at the first two visits one year apart and during alternate years thereafter. In a previous report, we had developed GFR estimating equations utilizing serum creatinine, blood urea nitrogen, height, gender and cystatin C measured by an immunoturbidimetric method; however the correlation coefficient of cystatin C and GFR (-0.69) was less robust than expected. Therefore, 495 samples were re-assayed using immunonephelometry. The reciprocal of immunonephelometric cystatin C was as well correlated with iGFR as was height/serum creatinine (both 0.88). We developed a new GFR estimating equation using a random 2/3 of 965 person-visits and applied it to the remaining 1/3 as a validation data set. In the validation data set, the correlation of the estimated GFR with iGFR was 0.92 with high precision and no bias; 91% and 45% of eGFR values were within 30% and 10% of iGFR, respectively. This equation works well in children with CKD in a range of GFR from 15 to 75 ml/min per 1.73 m2. Further studies are needed to establish the applicability to children of normal stature and muscle mass, and higher GFR.

Association of Cigarette Smoking With HIV Prognosis Among Women in the HAART Era: A Report From the Women’s Interagency HIV Study

OBJECTIVE We assessed the association of cigarette smoking with the effectiveness of highly active antiretroviral therapy (HAART) among low-income women. METHODS Data were analyzed from the Womens Interagency HIV Study, a multisite longitudinal study up to 7.9 years for 924 women representing 72% of all women who initiated HAART between July 1, 1995, and September 30, 2003. RESULTS When Coxs regression was used after control for age, race, hepatitis C infection, illicit drug use, previous antiretroviral therapy, and previous AIDS, smokers on HAART had poorer viral responses (hazard ratio [HR]=0.79; 95% confidence interval [CI]=0.67, 0.93) and poorer immunologic response (HR=0.85; 95% CI=0.73, 0.99). A greater risk of virologic rebound (HR=1.39; 95% CI=1.06, 1.69) and more frequent immunologic failure (HR=1.52; 95% CI=1.18, 1.96) were also observed among smokers. There was a higher risk of death (HR=1.53; 95% CI=1.08, 2.19) and a higher risk of developing AIDS (HR=1.36; 95% CI=1.07, 1.72) but no significant difference between smokers and nonsmokers in the risk of death due to AIDS. CONCLUSIONS Some of the benefits provided by HAART are negated in cigarette smokers.

Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study

Objective:To determine the incidence of diabetes mellitus (DM) in a nationally representative cohort of HIV-infected women and a comparison group of HIV-uninfected women. Design:A prospective study between October 2000 and March 2006 of 2088 participants from the Womens Interagency HIV Study who did not have evidence of DM at enrollment (1524 HIV infected and 564 HIV uninfected). Methods:Incident DM was defined as either having fasting glucose ≥ 1.26 g/l, reporting antidiabetic medication, or reporting DM diagnosis (with subsequent confirmation by fasting glucose ≥ 1.26 g/l or reported antidiabetic medication); all were assessed at semi-annual study visits. Results:DM developed in 116 HIV-infected and 36 HIV-uninfected women over 6802 person-years. HIV-infected women reporting no recent antiretroviral therapy had a DM incidence rate of 1.53/100 person-years; those reporting HAART containing a protease inhibitor (PI) had a rate of 2.50/100 person-years and those reporting non-PI-containing HAART a rate of 2.89/100 person-years. None of these rates differed from the HIV-uninfected women (1.96/100 person-years) substantially or beyond levels expected by chance. Among HIV-infected women, longer cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTI) was associated with an increased risk of DM incidence compared with no NRTI exposure: relative hazard (RH) 1.81 [95% confidence interval (CI), 0.83–3.93] for > 0 to 3 years exposure and RH 2.64 (95% CI, 1.11–6.32) for > 3 years exposure. Conclusion:Longer cumulative exposure to NRTI was associated with increased DM incidence in HIV-infected women. Regular DM monitoring is advisable because NRTI form the backbone of effective antiretroviral therapy.

Patterns of the hazard of death after AIDS through the evolution of antiretroviral therapy: 1984-2004

Objective:To characterize changing survival patterns after development of clinical AIDS from 1984 to 2004, when different antiretroviral therapies were being introduced. Design:Cohort of homosexual men since 1984 and cohort of women since 1994. Methods:A total of 1504 men and 461 women were followed for all-cause mortality after an incident AIDS diagnosis. Relative hazards of death and relative times to death were determined in five therapy eras: no/monotherapy (July 1984–December 1989), monotherapy/combination therapy (January 1990–December 1994), HAART introduction (January 1995–June 1998), short-term stable HAART use (July 1998–June 2001), and moderate-term stable HAART use (July 2001–December 2003). Results:A total of 1057 (54%) study participants died. The time at which 25% of individuals died after an AIDS diagnosis increased significantly from 0.56 years [95% confidence interval (CI), 0.50–0.64] in the no/monotherapy era to 0.74 (95% CI, 0.67–0.82), 1.78 (95% CI, 1.29–2.44), 4.22 (95% CI, 2.94–6.05) and 5.08 years (95% CI, 2.39–10.79) in the four subsequent therapy eras, respectively. Inferences on the beneficial effects of HAART were confirmed after adjustment by age, sex, type of AIDS diagnosis and CD4 cell count at diagnosis. The pattern of the hazard of death after AIDS changed from increasing in the pre-HAART era to being lower and non-increasing in the eras of HAART. Conclusions:The sustained beneficial effect of HAART, even in individuals with clinical AIDS and extensive treatment histories, attenuates concerns about emergence of resistance but augurs that a substantial number of HIV-infected individuals may require care for very long periods.

Reduced Abuse, Therapeutic Errors, and Diversion Following Reformulation of Extended-Release Oxycodone in 2010

UNLABELLED This study evaluated changes in abuse exposures, therapeutic error exposures, and diversion into illegal markets associated with brand extended-release oxycodone (ERO) following introduction of reformulated ERO. Original ERO and reformulated ERO street prices also were compared. Data from the Poison Center and Drug Diversion programs of the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System were used. Quarterly rates 2 years prior to introduction of reformulated ERO (October 2008 through September 2010) were compared to quarterly rates after introduction (October 2010 through March 2012) using negative binomial regression. Street prices were compared using a mixed effects linear regression model. Following reformulated ERO introduction, poison center ERO abuse exposures declined 38% (95% confidence interval [CI]: 31-45) per population and 32% (95% CI: 24-39) per unique recipients of dispensed drug. Therapeutic error exposures declined 24% (95% CI: 15-31) per population and 15% (95% CI: 6-24) per unique recipients of dispensed drug. Diversion reports declined 53% (95% CI: 41-63) per population and 50% (95% CI: 39-59) per unique recipients of dispensed drug. Declines exceeded those observed for other prescription opioids in aggregate. After its introduction, the street price of reformulated ERO was significantly lower than original ERO. PERSPECTIVE This article indicates that the abuse, therapeutic errors, and diversion of ERO declined following the introduction of a tamper-resistant reformulation of the product. Reformulating abused prescription opioids to include tamper-resistant properties may be an effective approach to reduce abuse of such products.

Carotid Intima-Media Thickness in Children with CKD: Results from the CKiD Study

BACKGROUND AND OBJECTIVES In adults, increased carotid intima-media thickness (cIMT) as assessed by ultrasonography is a valid predictor of cardiovascular events. Children with CKD are known to be at increased cardiovascular risk. This study sought to identify cardiovascular risk factors associated with increased cIMT in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional analysis of cIMT obtained after 12 months of follow-up of 101 children aged 2-18 years with mild to moderate CKD (median GFR 42.9 ml/min per 1.73 m(2)) in the Chronic Kidney Disease in Children cohort study enrolled between April 2005 and September 2009 and 97 healthy pediatric controls between January 2003 and December 2008. An average of six standardized B-mode ultrasound measurements constituted the overall cIMT measurement. RESULTS The median cIMT was 0.43 mm (interquartile range, 0.38-0.48) compared with 0.41 mm in healthy controls (P=0.03 for difference). After multivariable adjustment, the median cIMT was 0.02 mm (95% confidence interval [CI], 0.01-0.05) larger than that of the healthy controls. In a multivariable linear regression analysis, dyslipidemia and hypertension were associated with 0.05 mm (95% CI, 0.01-0.08) and 0.04 mm (95% CI, 0.003-0.08) greater mean cIMT, respectively. Body mass index, CKD etiology, GFR, birth weight, pubertal status, calcium, phosphorus, sex, and race were not associated with cIMT. CONCLUSIONS cIMT is significantly elevated among children with CKD, as is the prevalence of other cardiovascular risk factors. Of these risk factors, hypertension and dyslipidemia are significantly associated with increased cIMT.

The Association between Abnormal Birth History and Growth in Children with CKD

BACKGROUND AND OBJECTIVES Poor linear growth is a well described complication of chronic kidney disease (CKD). This study evaluated whether abnormal birth history defined by low birth weight (LBW; <2500 g), prematurity (gestational age <36 weeks), small for gestational age (SGA; birth weight <10th percentile for gestational age), or intensive care unit (ICU) at birth were risk factors for poor growth outcomes in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Growth outcomes were quantified by age-sex-specific height and weight z-scores during 1393 visits from 426 participants of the Chronic Kidney Disease in Children Study, an observational cohort of children with CKD. Median baseline GFR was 42.9 ml/min per 1.73 m(2), 21% had a glomerular diagnosis, and 52% had CKD for ≥ 90% of their lifetime. RESULTS A high prevalence of LBW (17%), SGA (14%), prematurity (12%), and ICU after delivery (40%) was observed. Multivariate analyses demonstrated a negative effect of LBW (-0.43 ± 0.14; P < 0.01 for height and -0.37 ± 0.16; P = 0.02 for weight) and of SGA (-0.29 ± 0.16; P = 0.07 for height and -0.41 ± 0.19; P = 0.03 for weight) on current height and weight. In children with glomerular versus nonglomerular diagnoses, the effect of SGA (-1.08 versus -0.18; P = 0.029) on attained weight was more pronounced in children with a glomerular diagnosis. CONCLUSIONS LBW and SGA are novel risk factors for short stature and lower weight percentiles in children with mild to moderate CKD independent of kidney function.

Antiretroviral therapy exposure and insulin resistance in the Women's Interagency HIV study.

Background:Evidence suggesting an increased risk of cardiovascular disease in HIV-infected individuals has heightened the need to understand the relation of HIV infection, antiretroviral therapy use, and non-HIV-related factors with insulin resistance (IR). Methods:Prospective study of 1614 HIV-infected and 604 HIV-uninfected participants from the Womens Interagency HIV Study between October 2000 and March 2007. Homeostasis model assessment (HOMA)-estimated IR at 11,019 semiannual visits. Results:HIV-infected women reporting highly active antiretroviral therapy (HAART) had higher median HOMA than HIV-uninfected women {1.20 [95% confidence interval (CI): 1.11 to 1.30] times higher for those reporting protease inhibitor-containing HAART; 1.10 (95% CI: 1.01 to 1.20) times higher for those reporting non-protease inhibitor-containing HAART}. Among HIV-infected, cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTIs) of >3 years was associated with HOMA 1.13 (95% CI: 1.02 to 1.25) times higher than the HOMA without any cumulative NRTI exposure. Cumulative exposure to the NRTI stavudine of >1 year was associated with HOMA 1.15 (95% CI: 1.05 to 1.27) times higher than the HOMA without any cumulative stavudine use. Family history of diabetes, hepatitis C virus seropositivity, higher body mass index, or reporting menopause was associated with higher HOMA. Conclusions:Longer cumulative exposure to NRTI; in particular, stavudine is associated with greater IR in HIV-infected women.

Prevalence and Correlates of Multiple Cardiovascular Risk Factors in Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Although prevalence of traditional cardiovascular risk factors (CVRF) has been described in children with CKD, the frequency with which these CVRF occur concomitantly and the clinical characteristics associated with multiple CVRF are unknown. This study determined the prevalence and characteristics of multiple CVRF in children in the Chronic Kidney Disease in Children study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using cross-sectional data from first follow-up visits, we determined the prevalence of four CVRF: hypertension (casual BP >95(th) percentile or self-reported hypertension with concurrent use of anti-hypertensive medication), dyslipidemia (triglycerides >130 mg/dl, HDL <40 mg/dl, non-HDL >160 mg/dl, or use of lipid-lowering medication), obesity (BMI >95(th) percentile), and abnormal glucose metabolism (fasting glucose >110 mg/dl, insulin >20 μIU/ml, or HOMA-IR >2.20, >3.61, or >3.64 for those at Tanner stage 1, 2 to 3, or 4 to 5, respectively) in 250 children (median age 12.2 years, 74% Caucasian, median iohexol-based GFR 45.2 ml/min per 1.73 m(2)). RESULTS Forty-six percent had hypertension, 44% had dyslipidemia, 15% were obese, and 21% had abnormal glucose metabolism. Thirty-nine percent, 22%, and 13% had one, two, and three or more CVRF, respectively. In multivariate ordinal logistic regression analysis, glomerular disease and nephrotic-range proteinuria were associated with 1.96 (95% confidence interval, 1.04 to 3.72) and 2.04 (95% confidence interval, 0.94 to 4.43) higher odds of having more CVRF, respectively. CONCLUSIONS We found high prevalence of multiple CVRF in children with mild to moderate CKD. Children with glomerular disease may be at higher risk for future cardiovascular events.