Andy I. Choi

Age Affects Outcomes in Chronic Kidney Disease

Chronic kidney disease (CKD) is common among the elderly. However, little is known about how the clinical implications of CKD vary with age. We examined the age-specific incidence of death, treated end-stage renal disease (ESRD), and change in estimated glomerular filtration rate (eGFR) among 209,622 US veterans with CKD stages 3 to 5 followed for a mean of 3.2 years. Patients aged 75 years or older at baseline comprised 47% of the overall cohort and accounted for 28% of the 9227 cases of ESRD that occurred during follow-up. Among patients of all ages, rates of both death and ESRD were inversely related to eGFR at baseline. However, among those with comparable levels of eGFR, older patients had higher rates of death and lower rates of ESRD than younger patients. Consequently, the level of eGFR below which the risk of ESRD exceeded the risk of death varied by age, ranging from 45 ml/min per 1.73 m(2) for 18 to 44 year old patients to 15 ml/min per 1.73 m(2) for 65 to 84 year old patients. Among those 85 years or older, the risk of death always exceeded the risk of ESRD in this cohort. Among patients with eGFR levels <45 ml/min per 1.73 m(2) at baseline, older patients were less likely than their younger counterparts to experience an annual decline in eGFR of >3 ml/min per 1.73 m(2). In conclusion, age is a major effect modifier among patients with an eGFR of <60 ml/min per 1.73 m(2), challenging us to move beyond a uniform stage-based approach to managing CKD.

Association of tenofovir exposure with kidney disease risk in HIV infection.

Objective:Despite widespread HAART use, HIV disease remains associated with increased risk of kidney disease. Whether tenofovir use is associated with higher risk of kidney disease is controversial. Design:We evaluated the association of cumulative and ever exposure to tenofovir on kidney outcomes in 10 841 HIV-infected patients from the Veterans Health Administration who initiated antiretroviral therapy from 1997 to 2007. Methods:Cox proportional hazards and marginal structural models evaluated associations between tenofovir and time to first occurrence of proteinuria (two consecutive urine dipstick measurements ≥30 mg/dl), rapid decline in kidney function (≥3 ml/min per 1.73 m2 annual decline), and chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min per 1.73 m2). Results:Median follow-up ranged from 3.9 years (proteinuria) to 5.5 years (CKD), during which 3400 proteinuria, 3078 rapid decline, and 533 CKD events occurred. After multivariable adjustment, each year of exposure to tenofovir was associated with 34% increased risk of proteinuria [95% confidence interval (CI) 25–45, P < 0.0001], 11% increased risk of rapid decline (3–18, P = 0.0033), and 33% increased risk of CKD (18–51, P < 0.0001). Preexisting renal risk factors did not appear to worsen the effects of tenofovir. Other antiretroviral drugs showed weaker or inconsistent associations with kidney disease events. Among those who discontinued tenofovir use, risk of kidney disease events did not appear to decrease during follow-up. Conclusion:Tenofovir exposure was independently associated with increased risk for three types of kidney disease events, and did not appear to be reversible. Because subtle kidney function decline affects long-term morbidity and mortality, the balance between efficacy and probable adverse effects requires further study.

Inflammation and Mortality in HIV-Infected Adults: Analysis of the FRAM Study Cohort

Objective: To determine the association of inflammatory markers, fibrinogen, and C-reactive protein (CRP), with 5-year mortality risk. Methods: Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios after adjustment for demographic, cardiovascular, and HIV-related factors. Results: Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile (>406 mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile (<319 mg/dL). Those with high CRP (>3 mg/L) had 2.7-fold higher adjusted odds of death than those with CRP <1 mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [odds ratio (95% confidence intervals)] per 100 mg/dL increase in fibrinogen: 1.93 (1.57 to 2.37); 1.43 (1.14 to 1.79); 1.43 (1.14 to 1.81); and 1.30 (1.04 to 1.63) for CD4 <200, 200-350, >350 to 500, and >500 cells per microliter, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup. Conclusions: Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500 cells per microliter, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.

Association Between Kidney Function and Albuminuria With Cardiovascular Events in HIV-Infected Persons

Background— Cardiovascular disease (CVD) is now a leading cause of death in HIV-infected persons; however, risk markers for CVD are ill defined in this population. We examined the association between longitudinal measures of kidney function and albuminuria with risk of atherosclerotic CVD and heart failure in a contemporary cohort of HIV-infected individuals. Methods and Results— We followed a national sample of 17 264 HIV-infected persons receiving care in the Veterans Health Administration for (1) incident CVD, defined as coronary, cerebrovascular, or peripheral arterial disease, and (2) incident heart failure. Rates of CVD and heart failure were at least 6-fold greater in the highest-risk patients with an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2 and albuminuria ≥300 mg/dL versus those with no evidence of kidney disease (eGFR ≥60 mL/min per 1.73 m2 and no albuminuria). After multivariable adjustment, eGFR levels 45 to 59, 30 to 44, and <30 mL/min per 1.73 m2 were associated with hazard ratios for incident CVD of 1.46 (95% confidence interval, 1.15 to 1.86), 2.03 (1.47 to 2.82), and 1.99 (1.46 to 2.70) compared with eGFR ≥60 mL/min per 1.73 m2. Similarly, albuminuria levels 30, 100, and ≥300 mg/dL had hazard ratios for CVD of 1.28 (1.09 to 1.51), 1.48 (1.15 to 1.90), and 1.71 (1.30 to 2.27) compared with absent albuminuria. The associations between eGFR and albuminuria with heart failure were larger in magnitude and followed the same trends. Conclusions— In this national sample of HIV-infected persons, eGFR and albuminuria levels were strongly associated with risk of CVD and heart failure. Kidney function and albuminuria provide complementary prognostic information that may aid CVD risk stratification in HIV-infected persons.

Racial Differences in End-Stage Renal Disease Rates in HIV Infection versus Diabetes

Few studies have compared the incidence of end-stage renal disease (ESRD) among individuals with the human immunodeficiency virus (HIV) and diabetes. We followed a national sample of 2,015,891 US veterans over a median peroid of 3.7 years for progression to ESRD. The age- and sex-adjusted incidence of ESRD (per 1000 person-years) among HIV-infected black patients was nearly an order of magnitude higher than among HIV-positive white patients, almost twice that of diabetic whites, and similar to that among diabetic blacks. In multivariate Cox proportional hazards analysis, diabetes was associated with an increased risk of ESRD among white patients, but HIV was not. Among black individuals, however, both HIV and diabetes conferred a similar increase in the risk of ESRD (4- to 5-fold increase compared to white individuals without HIV or diabetes). HIV and diabetes carry a similar risk of ESRD among black patients, highlighting the importance of developing strategies to prevent and treat renal disease among HIV-infected black individuals.

Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons.

Objective:Abacavir use has been associated with cardiovascular risk, but it is unknown whether this association may be partly explained by patients with kidney disease being preferentially treated with abacavir to avoid tenofovir. Our objective was to compare associations of abacavir and tenofovir with cardiovascular risks in HIV-infected veterans. Design:Cohort study of 10 931 HIV-infected patients initiating antiretroviral therapy in the Veterans Health Administration from 1997 to 2007, using proportional hazards survival regression. Methods:Primary predictors were exposure to abacavir or tenofovir within the past 6 months, compared with no exposure to these drugs, respectively. Outcomes were time to first atherosclerotic cardiovascular event, defined as coronary, cerebrovascular, or peripheral arterial disease; and time to incident heart failure. Results:Over 60 588 person-years of observation, there were 501 cardiovascular and 194 heart failure events. Age-standardized event rates among abacavir and tenofovir users were 12.5 versus 8.2 per 1000 person-years for cardiovascular disease, and 3.9 and 3.7 per 1000 person-years for heart failure, respectively. In multivariate-adjusted models, including time-updated measurements of kidney function, recent abacavir use was significantly associated with incident cardiovascular disease [hazard ratio 1.48, 95% confidence interval (CI) 1.08–2.04]; the association was similar but nonsignificant for heart failure (1.45, 0.85–2.47). In contrast, recent tenofovir use was significantly associated with heart failure (1.82, 1.02–3.24), but not with cardiovascular events (0.78, 0.52–1.16). Conclusion:Recent abacavir exposure was independently associated with increased risk for cardiovascular events. We also observed an association between recent tenofovir exposure and heart failure, which needs to be confirmed in future studies.

Long-term clinical consequences of acute kidney injury in the HIV-infected

To evaluate the long-term consequences of acute kidney injury (AKI) in human immunodeficiency virus (HIV)-infected persons, we studied 17,325 patients in a national HIV registry during their first hospitalization. We determined the association of AKI with risk for heart failure, cardiovascular events, end-stage renal disease (ESRD), and mortality beginning 90 days after discharge. Based on AKI Network criteria, 2453 had stage 1; 273 had stage 2 or 3; and 334 had dialysis-requiring AKI. Over a mean follow-up period of 5.7 years, 333 had heart failure, 673 had cardiovascular diseases (CVDs), 348 developed ESRD, and 8405 deaths occurred. In multivariable-adjusted analyses, AKI stage 1 was associated with death and ESRD, but not heart failure or other CVD. Dialysis-requiring AKI had much stronger and significant associations with increased risk for long-term ESRD, and death in addition to heart failure and cardiovascular events. When AKI was reclassified to account for recovery, stage 1 with recovery was still associated with death, but not ESRD. Thus, in this national sample of HIV-infected persons, we found the clinical repercussions of AKI appear to extend beyond the hospital setting contributing to excess cardiovascular risks, ESRD, and mortality. Additionally, AKI affected almost one of six patients with HIV who survived at least 90 days following discharge.

HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy

Objective:To identify risk factors associated with kidney function decline in a contemporary cohort of treated and untreated HIV-infected patients. Methods:We followed individuals enrolled in the Study of the Consequences Of the Protease inhibitor Era cohort for longitudinal changes in kidney function, defined as glomerular filtration rate estimated from serum creatinine (eGFR). eGFR slope was calculated using linear mixed effects models adjusted for age, sex, race, and time-updated CD4 cell count, viral load, antiretroviral therapy (ART), and comorbid conditions. Results:We followed 615 patients for a mean of 3.4 (± 2.5) years. In multivariable adjusted analyses, predictors of eGFR decline included female sex, diabetes, and hyperlipidemia; CD4 cell count and viral load were not associated with eGFR loss. Among patients who initiated treatment, antiretroviral exposure was associated with a +2.8 (95% confidence interval 0.8–4.7) ml/min per 1.73 m2 per year effect on eGFR slope. Although these patients appeared to benefit from ART based on the slowing of their eGFR decline, they continued to lose kidney function at a rate of −1.9 (95% confidence interval −3.7 to −0.1) ml/min per 1.73 m2 per year. In the subgroup of individuals receiving suppressive ART with viral loads maintained below 500 copies/ml, intermittent viremic episodes (blips) were strongly associated with more rapid rates of eGFR loss [−6.7 (95% confidence interval −11.1 to −2.4) ml/min per 1.73 m2 per year]. Conclusion:Although ART appears to help curb kidney function decline, patients who achieved durable viral suppression continue to manifest substantial loss of eGFR. Loss of kidney function may be attributable to treatment-related factors, intermittent viremia, and traditional risk factors for kidney disease.

White/Black Racial Differences in Risk of End-stage Renal Disease and Death

BACKGROUND End-stage renal disease disproportionately affects black persons, but it is unknown when in the course of chronic kidney disease racial differences arise. Understanding the natural history of racial differences in kidney disease may help guide efforts to reduce disparities. METHODS We compared white/black differences in the risk of end-stage renal disease and death by level of estimated glomerular filtration rate (eGFR) at baseline in a national sample of 2,015,891 veterans between 2001 and 2005. RESULTS Rates of end-stage renal disease among black patients exceeded those among white patients at all levels of baseline eGFR. The adjusted hazard ratios for end-stage renal disease associated with black versus white race for patients with an eGFR > or = 90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2, respectively, were 2.14 (95% confidence interval [CI], 1.72-2.65), 2.30 (95% CI, 2.02-2.61), 3.08 (95% CI, 2.74-3.46), 2.47 (95% CI, 2.26-2.70), 1.86 (95% CI, 1.75-1.98), and 1.23 (95% CI, 1.12-1.34). We observed a similar pattern for mortality, with equal or higher rates of death among black persons at all levels of eGFR. The highest risk of mortality associated with black race also was observed among those with an eGFR 45-59 mL/min/1.73 m2 (hazard ratio 1.32, 95% CI, 1.27-1.36). CONCLUSION Racial differences in the risk of end-stage renal disease appear early in the course of kidney disease and are not explained by a survival advantage among blacks. Efforts to identify and slow progression of chronic kidney disease at earlier stages may be needed to reduce racial disparities.

Cystatin C, Albuminuria, and 5-Year All-Cause Mortality in HIV-Infected Persons

BACKGROUND Compared with controls, human immunodeficiency virus (HIV)-infected persons have a greater prevalence of kidney disease, assessed according to high cystatin C level and albuminuria, but not according to creatinine level. However, the clinical importance of increased cystatin C level 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 according to 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. PREDICTOR Serum cystatin C and serum creatinine levels were used to estimate glomerular filtration rates (eGFR(SCysC) and eGFR(SCr), respectively). Albuminuria was defined as a positive urine dipstick result (≥ 1+) or urine albumin-creatinine ratio >30 mg/g. OUTCOME 5-Year mortality. RESULTS At baseline, decreased kidney function (eGFR(SCysC) <60 mL/min/1.73 m(2)) or albuminuria was present in 28% of participants. After 5 years of follow-up, mortality was 48% in those with both eGFR(SCysC) < 60 mL/min/1.73 m(2) and albuminuria, 23% in those with eGFR(SCysC) < 60 mL/min/1.73 m(2) 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 marker levels, eGFR(SCysC) < 60 mL/min/1.73 m(2) and albuminuria were associated with a nearly 2-fold increase in mortality, whereas eGFR(SCr) < 60 mL/min/1.73 m(2) did not appear to have a substantial association with mortality. Together, eGFR(SCysC) <60 mL/min/1.73 m(2) and albuminuria accounted for 17% of the population-level attributable risk of mortality. LIMITATIONS Vital status was unknown in 261 participants from the original cohort. CONCLUSIONS Kidney disease marked by albuminuria or increased cystatin C level 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.