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.
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.
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 m annual decline), and chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min per 1.73 m).
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.
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.
Being able to predict whether AKI will progress could improve monitoring and care, guide patient counseling, and assist with enrollment into trials of AKI treatment. Using samples from the ...Translational Research Investigating Biomarker Endpoints in AKI study (TRIBE-AKI), we evaluated whether kidney injury biomarkers measured at the time of first clinical diagnosis of early AKI after cardiac surgery can forecast AKI severity. Biomarkers included urinary IL-18, urinary albumin to creatinine ratio (ACR), and urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL); each measurement was on the day of AKI diagnosis in 380 patients who developed at least AKI Network (AKIN) stage 1 AKI. The primary end point (progression of AKI defined by worsening AKIN stage) occurred in 45 (11.8%) patients. Using multivariable logistic regression, we determined the risk of AKI progression. After adjustment for clinical predictors, compared with biomarker values in the lowest two quintiles, the highest quintiles of three biomarkers remained associated with AKI progression: IL-18 (odds ratio=3.0, 95% confidence interval=1.3-7.3), ACR (odds ratio=3.4, 95% confidence interval=1.3-9.1), and plasma NGAL (odds ratio=7.7, 95% confidence interval=2.6-22.5). Each biomarker improved risk classification compared with the clinical model alone, with plasma NGAL performing the best (category-free net reclassification improvement of 0.69, P<0.0001). In conclusion, biomarkers measured on the day of AKI diagnosis improve risk stratification and identify patients at higher risk for progression of AKI and worse patient outcomes.
Background Despite improvements in survival with human immunodeficiency virus (HIV) infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated ...with the development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals and compare ESRD risk by estimated glomerular filtration rate (eGFR) and proteinuria levels. Study Design Retrospective cohort study. Setting & Participants 22,156 HIV-infected veterans without pre-existing ESRD receiving health care in the Veterans' Affairs medical system between 1996 and 2004. Predictors Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin <3.5 mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and eGFR were identified using the Veterans' Affairs electronic record system. Outcomes ESRD was ascertained by the US Renal Data System. Results 366 cases of ESRD occurred, corresponding to 3 cases/1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5-2.4), diabetes (HR, 1.7; 95% CI, 1.3-2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7-2.7) were associated independently with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/μL (HR, 1.5; 95% CI, 1.2-2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5-2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5-2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8-2.5). Compared with persons without chronic kidney disease, defined as eGFR >60 mL/min/1.73 m2 and no proteinuria, lower eGFR and higher proteinuria categories were associated jointly with exponentially higher ESRD rates, ranging from 6.6 events/1,000 person-years for persons with urine protein excretion of 30-100 mg/dL and eGFR >60 mL/min/1.73 m2 to 193 events/1,000 person-years for persons with urine protein excretion ≥300 mg/dL and eGFR <30 mL/min/1.73 m2. Limitations Results may not be generalizable to female and nonveteran populations. Conclusions In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for chronic kidney disease staging is most effective for stratifying the risk of ESRD.
(See the article by Kalayjian et al, on pages 1796–1805, and the editorial commentary by Dubé and Sattler, on pages 1783–1785.) Background. Human immunodeficiency virus (HIV) replication and immune ...activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers in persons with and without HIV infection. Methods. For persons 45–76 years of age, levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, D-dimer, and cystatin C were compared in 494 HIV-infected individuals in the Strategies for Management of Anti-Retroviral Therapy (SMART) study and 5386 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study. For persons 33–44 years of age, hsCRP and IL-6 levels were compared in 287 participants in the SMART study and 3231 participants in the Coronary Artery Development in Young Adults (CARDIA) study. Results. hsCRP and IL-6 levels were 55% (P<.001) and 62% (P<.001) higher among HIV-infected participants than among CARDIA study participants. Compared with levels noted in MESA study participants, hsCRP, IL-6, D-dimer, and cystatin C levels were 50%, 152%, 94%, and 27% higher, respectively (P<.001 , for each), among HIV-infected participants. HIV-infected participants receiving antiretroviral therapy who had HIV RNA levels ≤400 copies/mL had levels higher (by 21% to 60%) (P<.001) than those in the general population, for all biomarkers. Conclusions. hsCRP, IL-6, D-dimer, and cystatin C levels are elevated in persons with HIV infection and remain so even after HIV RNA levels are suppressed with antiretroviral therapy. Additional research is needed on the pathophysiology of HIV-induced activation of inflammatory and coagulation pathways, to guide potential interventions.
Background Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies ...evaluating this relationship in humans are lacking. Study Design Prospective longitudinal cohort study. Setting & Participants 953 participants enrolled in the Cardiovascular Health Study. Predictor Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples. Outcomes Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision ( ICD-9 ) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion. Results Median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93 μg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio IRR, 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26 μg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58). Limitations Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations. Conclusions High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.
The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary ...study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI).
Observational cohort nested in a clinical trial.
2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m2 at baseline.
Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M) and β2-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH).
Longitudinal changes in eGFR and risk of AKI.
We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression.
From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 95% CI, 1.10-1.37 and 1.23 95% CI, 1.02-1.48, respectively).
The factors require validation in other settings.
EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.
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Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR ...(eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories ≥60, 45-59, 30-44, and <30 ml/min per 1.73 m(2), respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 ml/min per 1.73 m(2) had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P<0.001) relative to subjects with eGFR≥60 ml/min per 1.73 m(2). This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m(2) also significantly associated with LVH and abnormal LV geometry compared with eGFR≥60 ml/min per 1.73 m(2). In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables.
Random assignment to intensive blood pressure (BP) lowering (systolic BP<120mmHg) compared to a less intensive BP target (systolic BP<140mmHg) in the Action to Control Cardiovascular Risk in Diabetes ...BP (ACCORD-BP) trial resulted in a more rapid decline in estimated glomerular filtration rate (eGFR). Whether this reflects hemodynamic effects or intrinsic kidney damage is unknown.
Longitudinal analysis of a subgroup of clinical trial participants.
A subgroup of 529 participants in ACCORD-BP.
Urine biomarkers of tubular injury (kidney injury molecule 1, interleukin 18 IL-18), repair (human cartilage glycoprotein 39 YKL-40), and inflammation (monocyte chemoattractant protein 1) at baseline and year 2.
Changes in eGFR from baseline to 2 years.
We compared changes in biomarker levels and eGFRs across participants treated to an intensive versus less intensive BP goal using analysis of covariance.
Of 529 participants, 260 had been randomly assigned to the intensive and 269 to the standard BP arm. Mean age was 62±6.5 years and eGFR was 90mL/min/1.73m2. Baseline clinical characteristics, eGFRs, urinary albumin-creatinine ratios (ACRs), and urinary biomarker levels were similar across BP treatment groups. Compared to less intensive BP treatment, eGFR was 9.2mL/min/1.73m2 lower in the intensive BP treatment group at year 2. Despite the eGFR reduction, within this treatment group, ACR was 30% lower and 4 urinary biomarker levels were unchanged or lower at year 2. Also within this group, participants with the largest declines in eGFRs had greater reductions in urinary IL-18 and YKL-40 levels. In a subgroup analysis of participants developing incident chronic kidney disease (sustained 30% decline and eGFR<60mL/min/1.73m2; n=77), neither ACR nor 4 biomarker levels increased in the intensive treatment group, whereas the level of 1 biomarker, IL-18, increased in the less intensive treatment group.
Few participants with advanced baseline chronic kidney disease. Comparisons across treatment groups do not represent comparisons of treatment arms created solely through randomization.
Among a subset of ACCORD-BP trial participants, intensive BP control was associated with reductions in eGFRs, but not with an increase in injury marker levels. These findings support that eGFR decline observed with intensive BP goals in ACCORD participants may predominantly reflect hemodynamic alterations.
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Persons with chronic kidney disease (CKD) are often unaware of their disease status. Efforts to improve CKD awareness may be most effective if focused on persons at highest risk for progression to ...kidney failure.
Serial cross-sectional surveys.
Nonpregnant adults (aged≥20 years) with CKD glomerular filtration rate categories 3-4 (G3-G4) who participated in the National Health and Nutrition Examination Survey from 1999 to 2016 (n = 3,713).
5-year kidney failure risk, estimated using the Kidney Failure Risk Equation. Predicted risk was categorized as minimal (<2%), low (2%-<5%), intermediate (5%-<15%), or high (≥15%).
CKD awareness, defined by answering “yes” to the question “Have you ever been told by a doctor or other health professional that you had weak or failing kidneys?”
Prevalence of CKD awareness was estimated within each risk group using complex sample survey methods. Associations between Kidney Failure Risk Equation risk and CKD awareness were assessed using multivariable logistic regression. CKD awareness was compared with awareness of hypertension and diabetes during the same period.
In 2011 to 2016, unadjusted CKD awareness was 9.6%, 22.6%, 44.7%, and 49.0% in the minimal-, low-, intermediate-, and high-risk groups, respectively. In adjusted analyses, these proportions did not change over time. Awareness of CKD, including among the highest risk group, remains consistently below that of hypertension and diabetes and awareness of these conditions increased over time.
Imperfect sensitivity of the “weak or failing kidneys” question for ascertaining CKD awareness.
Among adults with CKD G3-G4 who have 5-year estimated risks for kidney failure of 5%-<15% and≥15%, approximately half were unaware of their kidney disease, a gap that has persisted nearly 2 decades.
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Cystatin C is a cysteine protease inhibitor that is freely filtered by the glomerulus and is therefore a measure of renal function. In this study of elderly persons, the serum cystatin C level was a ...better predictor of the risk of death and cardiovascular disease than was the serum creatinine level. Cystatin C is a useful alternative measure of renal function, as well as an effective prognostic tool.
In this study of elderly persons, the serum cystatin C level was a better predictor of the risk of death and cardiovascular disease than was the serum creatinine level.
The presence of renal dysfunction in elderly persons has been associated with an increased risk of death among healthy persons in outpatient care
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and among those with several clinical factors, including heart failure,
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acute hospitalization,
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inpatient surgery,
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and acute myocardial infarction.
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However, the primary clinical tool for measuring renal function, the serum creatinine level, is insensitive for the detection of moderate reductions in renal function and is affected by factors unrelated to renal function, such as age, sex, race, and lean muscle mass. Creatinine-based equations to estimate the glomerular filtration rate (GFR) have been derived to compensate . . .
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