Kidneys, the fist-sized filters facing each other across the spine, do much more than remove waste (and drugs) from the body: they also balance bodily fluids, release hormones that regulate blood pressure, produce vitamin D, and help make red blood cells.91 Every day 200 quarts of fluid sluice through the kidneys, percolating through a million nephrons (Figure 12). The kidneys extract 2 quarts of fluid daily and return 198. The National Kidney Foundation estimates that 26 million adults in the United States have chronic kidney disease, which poses a high threat of heart disease.92
Analysis of 17,264 veterans with HIV -- more than 95% of them men -- found that two indicators of poor kidney function independently raised the risk of a new atherosclerotic cardiovascular event or heart failure.94 When a person had both indicators of poor kidney function, risks for these two outcomes were considerably higher. Kidney nephron shown at upper left, from Servier Medical Art. (See text for variables in model.)
In a nationally representative sample, the CDC recently estimated that 7.6% of HIV-positive adults in care in the United States have stage 3 or worse chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m2.93 Among 20- to 39-year-olds, HIV-positive people had more than a 4 times higher rate of chronic kidney disease than the general population (prevalence ratio [PR] 4.6); among 40- to 59-year-olds, people with HIV had an 80% higher rate (PR 1.8). Among people 60 and older, the general population had a higher rate, probably partly because more HIV-negative than HIV-positive people with chronic kidney disease survive past 60. In HIV-positive adults in care, the CDC identified five factors associated with chronic kidney disease -- older age, female sex (adjusted PR 1.4), HIV duration longer than 10 years (adjusted PR 1.4), an AIDS diagnosis, and a CD4 count under 350 cells/mm3 (adjusted PR 1.6).
Recent cohort studies link poor kidney function -- measured as eGFR, albuminuria, or proteinuria -- with cardiovascular disease in people with HIV. Persistent albuminuria indicates that a damaged kidney is spilling albumin into urine. Researchers at the San Francisco Veterans Affairs Medical Center parsed records of 17,264 HIV-positive people in the Veterans Health Administration to catalog newly diagnosed cardiovascular disease (defined as coronary, cerebrovascular, or peripheral arterial disease) and new cases of heart failure.94
In this national sample the 1194 cohort members with eGFR below 60 mL/min averaged 52 years in age, compared with 46 in the 16,070 members with an eGFR at or above 60 mL/min. About 45% of study participants were black, about 35% white, and only 3% women. Through a median 7 years of follow-up, the investigators counted 370 heart failures and 833 atherosclerotic cardiovascular events.
People with an eGFR below 30 mL/min and albuminuria at or above 100 mg/dL had about a 6-fold higher rate of new cardiovascular disease than people with an eGFR at or above 60 mL/min and no albuminuria. Incidence of atherosclerotic cardiovascular events and albuminuria grew progressively as albumin levels rose (from 0 to 30 to 100 or more mg/dL) and as eGFR waned (from 60 or higher to 30 to 59 to under 30).
A full multivariate model adjusted for age, sex, race, and time-updated hypertension, diabetes mellitus, chronic obstructive lung disease, dyslipidemia, smoking, CD4 count, viral load, and antiretroviral therapy. In this analysis albuminuria above 30 mg/dL and eGFR below 60 mL/min each independently raised the risk of an atherosclerotic cardiovascular event and the risk of heart failure (Figure 12). When a person had both albuminuria and a sub-60 eGFR, the risk of an atherosclerotic cardiovascular event and the risk of heart failure were even higher.
These investigators believe their results "are clinically relevant because they may help providers to identify HIV-infected persons at high risk for CVD events."94 The National Kidney Foundation recommends screening for albuminuria in people with chronic kidney disease risk factors, including diabetes, hypertension, systemic illnesses, age over 60, and family history of chronic kidney disease.95 The Foundation advises confirming a positive test with a second urine test.
A case-control study at the Johns Hopkins HIV Clinic confirmed the graded impact of worsening kidney function on cardiovascular risk.96 This study involved 315 HIV-positive adults, 63 who had a myocardial infarction or a cerebrovascular accident and 252 who did not. The 252 randomly selected control patients had no history of heart disease and matched the 63 case patients by age, race, and sex. Age averaged 49.5 in both groups, 63.5% were men, and 84% were black.
Multivariate analysis (adjusted for diabetes, hypertension, previous cardiac events, dyslipidemia, viral load, and CD4 count) linked every 10 mL/min lower eGFR to 20% higher odds of a cardiovascular event (aOR 1.2, 95% CI 1.1 to 1.4, P = 0.009). In the same analysis proteinuria, defined as a urine dipstick reading at least above 1+, nearly tripled the odds of a cardiovascular event, though that association stopped short of statistical significance (aOR 2.9, 95% CI 0.9 to 9.0, P = 0.070). In a separate analysis, proteinuria compounded the impact of low eGFR on cardiovascular risk.
The Johns Hopkins investigators noted that their findings reflect results in the general population but assume greater importance in people with HIV, who have a 3- to 5-fold higher kidney disease prevalence than people without HIV.93,97,98 They proposed that their findings "suggest the potential value of early screening and treatment of chronic kidney disease in HIV-1-infected patients, particularly those with other cardiovascular risk factors."96
In its report on chronic kidney disease prevalence with HIV, the CDC recommends (1) routine screening for chronic kidney disease, (2) aggressive management of related conditions including diabetes, hypertension, and obesity, and -- among people who do have chronic kidney disease -- (3) avoidance of nephrotoxic drugs and referral to a nephrologist.93
HIV infection is an inflammatory disease marked by ongoing immune activation. Even when cART corrals HIV replication, low-level inflammation and immune activation may persist and tweak up the risk of cardiovascular disease. How? HIV heart guru James Stein explains that relentless inflammation, immune activation, and viremia hamper a blood vessel's ability to dilate and generate an anticoagulant surface.31 And clumpy cells are a big enemy of cardiovascular health.
The literature on inflammation, immune activation, and heart health in people with HIV has ballooned to Brobdingnagian proportions. Searching for cardiovascular disease + HIV + inflammation on pubmed returned 371 articles in April 2013. The same search on Google Scholar gives you "about 52,000" returns. Most of these studies point in the same direction: inflammation is bad for your heart. But James Stein cautions that pinning down the precise inflammation-linked risk, and figuring which markers predict best, "likely will require several thousand subjects, more than a decade of follow-up, reliable biomarker/imaging tests, and strict endpoint adjudication."31
One place to start through the thicket of research on inflammation and HIV-related heart disease is with HCV infection, an overtly inflammatory illness that often coexists with HIV infection. Meta-analysis of 12 studies linked HCV infection to a higher risk of coronary artery disease in the general population.99 Of the 6 best studies analyzed, three found a significant association between HCV and coronary artery disease, two found a nonsignificant association, and one figured HCV protects against coronary artery disease.
Six recent studies on HCV, HIV, and cardiovascular risk yielded divergent results reflecting the different study populations, methods, and endpoints.
Women's Interagency HIV Study (WIHS) investigators measured cIMT and carotid plaque in 1865 HIV-positive women in 2004 and 2005.100 Median cIMT was similar in HCV-infected and HCV/HIV-coinfected women, and higher than in HIV-monoinfected women. But after statistical adjustment for other cardiovascular risk factors, HCV infection was not associated with cIMT or with carotid plaque.
A DAD Study analysis involved 33,347 HIV-positive men and women in Europe, the US, and Australia who had 517 myocardial infarctions during followup for an incidence of 3.3 per 1000 person-years.101 Incidence was marginally lower in HCV-seropositive people than HCV-negative people (2.7 versus 3.3 per 1000 person-years). After statistical adjustment for relevant variables, HCV seropositivity was not associated with incident myocardial infarction (rate ratio 0.86, 95% CI 0.61 to 1.19). There were 295 strokes during the study period (1.47 per 1000 person-years with HCV and 1.91 without HCV), and HCV positivity did not affect stroke risk after statistical adjustment. Active HBV infection did not affect rates of MI or stroke.
But a large Veterans Affairs study did link HCV/HIV infection to a higher risk of cerebrovascular disease (stroke and transient ischemic attack) and to a trend toward a higher MI rate.102 This analysis involved 19,424 HIV-positive veterans, 32% of them coinfected with HCV and HIV and 97% of them men. The investigators identified HCV infection by diagnostic codes and HCV-antibody positivity. There was no HCV/HIV-negative control group. After statistical adjustment for potentially confounding factors, HCV/HIV coinfection was linked to a 20% higher risk of cerebrovascular disease compared with HIV alone (adjusted hazard ratio 1.20, 95% CI 1.04 to 1.38, P = 0.013), while coinfection was nonsignificantly associated with a 25% higher risk of acute MI (adjusted hazard ratio 1.25, 95% CI 0.98 to 1.61, P= 0.072).
Another US veterans study did find an independent (though small) association between HCV infection and acute myocardial infarction in a comparison of HIV-positive and negative veterans.18 This Veterans Aging Cohort Study involved 27,350 HIV-positive and 55,109 age-, race-, and site-matched HIV-negative veterans, 97% of them men. No one had a history of cardiovascular disease. The researchers defined HCV infection by ICD-9 code or positive HCV antibody. During 5.9 years of follow-up, 871 veterans had an acute MI. Statistical analysis adjusted for multiple risk factors associated HCV infection with about a 20% higher MI risk when compared with HCV-negative vets (adjusted hazard ratio 1.19, 95% CI 1.01 to 1.40).
A medical record review at the University of Rochester compared 239 people with HIV, 167 with HCV, and 182 with both HIV and HCV with gender-, race-, and age-matched uninfected people in the NHANES database.103 After statistical adjustment for confounders, HCV/HIV-coinfected people had a 2% higher Framingham Risk Score than the general population (P = 0.03) and a 4.1-year older vascular age (P = 0.01). People infected with HCV but not HIV had a 2.4% higher Framingham Risk Score than the general population (P < 0.001) and a 4.4-year older vascular age (P < 0.001). But HIV infection alone did not confer a higher Framingham score or an older vascular age.
Comparing 18 HCV/HIV-coinfected people with 22 HIV-monoinfected people, French investigators recorded a significantly higher prevalence of subclinical carotid plaque in the coinfected group, even though LDL cholesterol and blood pressure were lower in coinfected people.104 Chronic HCV infection was associated with 10-fold higher odds of plaque (OR 10, 95% CI 1.5 to 72, P = 0.02).
The French team suggested that "HCV infection might be considered as not only a liver infection but also as a metabolic disease in HIV patients, justifying regular cardiovascular surveillance."104 The VA team observed, though, that HCV may inflate rates of some cardiogenic conditions, including metabolic syndrome and diabetes, while it appears to lower levels of total cholesterol, LDL cholesterol, and triglycerides.102 Of the three studies that assessed HCV impact on clinical endpoints, the two predominantly male VA studies uncovered evidence implicating HCV in MI and stroke,18,102 but the DAD study (with 74% of participants men) saw no HCV tie to MIs (Table 5).101
|Table 5. Cardiovascular Disease Risk With HCV in Clinical Endpoint Studies|
|Study||n (% Men)||Comparison Groups||Study Years (Follow-Up)||Endpoints||HCV Association|
|VACS18||27,350 (97%)||55,109 matched HIV-negative veterans||2003-2009 (median 5.9 y)||Acute MI||19% higher MI risk|
|Veterans102||19,424 (97%)||6136 HIV/HCV+ vs 13,288 HIV+ only||1996-2004 (mean 3.9 y)||Acute MI, cerebrovascular disease (CVD)||25% higher MI risk;* 20% higher CVD risk|
|DAD101||33,347 (74%)||5084 HCV/HIV+ vs 16,731 HIV only†||1999-2007||MI, stroke||No association|
VACS, Veterans Aging Cohort Study.
* Not significant.
† 11,532 had unknown HCV status.
The DAD team tabulated results of 18 previous general-population studies assessing cardiovascular disease risk with HCV: eight found an association and 10 did not. Nailing down whether HCV substantially inflates an already high cardiovascular risk in people with HIV requires further study.
Two recent studies saw links between markers of inflammation and all-cause mortality in people with HIV, and one of them extended that association to atherosclerotic cardiovascular disease and heart failure. Albumin levels fall in the face of inflammation, providing an inverse marker of the inflammatory process.105 To gauge the impact of serum albumin on mortality and heart disease in people with HIV, University of California San Francisco researchers turned to a national veterans database, the HIV Clinical Case Registry.106 This analysis included 25,522 HIV-positive veterans enrolled between 1986 and 2007 who had serum albumin, serum creatinine, and urine dipstick measures between 1986 and 2007. The three primary outcomes were time to death, atherosclerotic cardiovascular disease, and hospital admission for heart failure. The investigators broke serum albumin levels into five brackets: at or above 4.0, 3.5 to 3.9, 3.0 to 3.4, 2.5 to 2.9, and under 2.5 g/dL.
Compared with the highest albumin bracket, each lower bracket independently boosted chances of mortality -- both with baseline albumin and (even more so) with time-updated albumin. Lower baseline albumin did not affect chances of atherosclerotic cardiovascular disease, but lower updated albumin did. Both lower baseline and lower updated albumin hoisted hazard ratios for heart failure:
Hazard ratios (and 95% CIs) for mortality:
Hazard ratios (and 95% CIs) for atherosclerotic cardiovascular events:
Hazard ratios (and 95% CIs) for heart failure:
The associations between low albumin and mortality were strongest in the first year of follow-up, though still usually significant after 2 or 3 years.
The investigators106 acknowledged the difficulty in explaining why low serum albumin (versus high urine albumin in the just-described study94) predicts dire clinical outcomes. Serum albumin levels can fall because of poor nutrition, liver disease, kidney disease, and chronic inflammation. But a sensitivity analysis that excluded people with liver and kidney dysfunction found nearly identical associations between low serum albumin and the three endpoints. That result suggested to the investigators "that a more transient process such as inflammation is responsible for the lower levels of albumin."106 They proposed that "serum albumin captures a dynamic process of inflammation in HIV infection that has clinical importance in the short-term."
A prospective study of 327 HIV-positive people at Boston's Tufts University found significantly higher risks of all-cause mortality with higher high-sensitivity C-reactive protein (hsCRP), a classic marker of inflammation, and with cIMT, a verified signal of subclinical atherosclerosis.107 The study involved 242 men and 85 women, 52% of them white, with an average age of 44 years. None of them had overt cardiovascular disease. Through a median followup of 3.1 years, 38 people (12%) died. Five of these deaths (13%) had primary or secondary cardiovascular causes, and one was sudden and unexplained.
Statistical analysis adjusted for age, gender, race, body mass index, cigarette smoking, CD4 count, viral load, LDL cholesterol, HDL cholesterol, and hsCRP determined that cIMT above versus below 0.655 mm almost tripled the risk of death (adjusted hazard ratio 2.74, 95% CI 1.26 to 5.97, P = 0.01). In a similar analysis adjusted for cIMT, hsCRP at or above versus below 3 mg/L more than doubled the risk of death (adjusted hazard ratio 2.38, 95% CI 1.15 to 4.90, P = 0.02). hsCRP was almost 3 times higher in people who died than in those who did not (3.2 versus 1.3 mg/L, P < 0.001), and a significantly higher proportion of people who died had hsCRP above 3 mg/L (51% versus 25%, P < 0.001). An earlier study of 209 HIV-positive US women identified baseline CRP as an independent predictor of mortality through a median 45 months of follow-up.108
In Boston's Partners HealthCare System, elevated CRP and HIV each independently doubled chances of acute myocardial infarction.109 This analysis involved 487 HIV-positive patients and 69,870 HIV-negative people in care between January 1997 and December 2006. Everyone had CRP measured in the past 3 years and more than 1 week before an acute MI. A statistical model adjusted for age, sex, race, hypertension, diabetes, dyslipidemia, elevated CRP, and HIV status determined that high CRP and HIV each independently doubled the odds of acute MI (Figure 13). People with HIV and elevated CRP had quadrupled odds of acute MI compared with HIV-negative people with normal CRP levels. At the end of the third review article in this issue of RITA!, this study's principal investigator, Steven Grinspoon, offers his insights on when measuring CRP in people with HIV may pay off in practice.
In 487 HIV-positive and 68,870 HIV-negative people in care in Boston, elevated CRP and HIV infection each independently doubled the odds of acute MI.109 People with HIV and elevated CRP had quadrupled odds of acute MI compared with HIV-negative people with normal CRP.
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