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Heart and kidney risks combine to make heart or kidney disease more likely with HIV.

People at high risk for both cardiovascular * (heart) disease and chronic kidney disease ran a much greater risk of cardiovascular or kidney disease than people at high risk for only cardiovascular disease or only kidney disease, according to results of a 27,215-person study. (1) The combined impact of cardiovascular and kidney risk suggests the two diseases should be assessed and cared for together in people with HIV infection.

HIV-positive people run a higher risk of both cardiovascular (heart) disease and kidney disease than people without HIV. Adults taking antiretroviral therapy have a twice higher risk of cardiovascular disease than adults in the general population. (2) And compared with HIV-negative people, those with HIV have almost a 4-fold higher risk of kidney disease. (3) Research in the general population shows that kidney disease boosts risk of cardiovascular disease; (4) and cardiovascular disease in turn makes kidney disease more likely. Combined analysis of 14 studies found evidence that cardiovascular disease and kidney disease together pose a greater health threat than would be expected from simply adding the impact of each diease. (5)

Researchers working with a large HIV study group wanted to assess the impact of high cardiovascular disease risk and high kidney disease risk--separately and together--on future development of each of these diseases.

How the study worked. The researchers focused on HIV-positive adults in an ongoing study of people in Europe, the United States, Argentina, and Australia. Everyone had normal kidney function at one study visit and at least two later kidney function measures. ([dagger]) The study excluded people who already had cardiovascular disease.

Study participants make regular visits to get health checkups and to give samples for testing. Results of these tests and interviews allowed the researchers to calculate each person's risk of cardiovascular (heart) disease and kidney disease. They used cardiovascular and kidney disease risk calculators developed in this patient group. (6,7) With these tools, the researchers calculated 5-year risk of cardiovascular disease and 5-year risk of kidney disease. They grouped people into three 5-year risk groups for each disease: 1% or lower risk, above 1% to 5% risk, and more than 5% risk.

Next the researchers determined how many people in each of these three risk groups (1% or lower, above 1% to 5%, over 5%) developed cardiovascular disease (for example, a heart attack) and how many developed kidney disease (confirmed eGFR below 60 mL/min ([dagger])) during the study period. Finally they used standard statistical methods to calculate the impact of cardiovascular or kidney risk group on development of cardiovascular disease or kidney disease. They also compared disease development rates in people with only high cardiovascular risk, only high kidney risk, and both high cardiovascular and kidney risk.

What the study found. The analysis involved 27,215 HIV-positive adults who had all the study data the researchers needed after a start date of January 1, 2004. Three quarters of the study group were men, and they had a median (midpoint) age of 42 years. Half of this group smoked, and 4% had diabetes when they entered the study.

The risk calculators (6,7) put 3560 people (13.1%) at high risk for cardiovascular disease and 4996 (18.4%) at high risk for kidney disease. During the study period, cardiovascular disease developed in 918 people (3.4%), kidney disease developed in 1415 people (5.2%), and both cardiovascular and kidney disease developed in 154 people (0.57%).

The overall rate of new chronic kidney disease was 7 per 1000 person-years, meaning kidney disease developed in 7 of every 1000 people each year As expected, new kidney disease was more common in each higher kidney risk group (1% or lower, above 1% to 5%, over 5%). But new kidney disease was also more common in each higher cardiovascular risk group. Statistical analysis confirmed that each higher cardiovascular risk group had a higher rate of new kidney disease-regardless of what kidney risk group a person belonged to (Figure 1). This link between cardiovascular risk group and developing kidney disease was statistically significant-meaning a statistical test determined that chance has little likelihood of explaining the link.

The overall rate of new cardiovascular disease was 4.5 per 1000 person-years, meaning heart disease developed in between 4 and 5 of every 1000 people each year. As expected, new cardiovascular disease was more common in each higher cardiovascular risk group. But new cardiovascular disease was also significantly more common in each higher kidney risk group--regardless of what cardiovascular risk group a person belonged to (Figure 2).

Further statistical analysis supported the idea that the combined impact of heart risk and kidney risk should be multiplied (heart risk x kidney risk) rather than added (heart risk + kidney risk). (Providers see note 8 in the References.) For example, if you take a person with more than a 5% 5-year risk of kidney disease and more than a 5% 5-year risk of cardiovascular disease, the combined risk compared with low-risk people would equal 13.81 x 5.63 or a 77.75 times higher risk of kidney disease rather than equaling 13.81 + 5.63, which would be a 19.44 times higher risk (Figure 3). Multiplying rather than adding risks for cardiovascular disease and kidney disease has the same impact on cardiovascular disease risk (Figure 3).

Next the researchers looked at individual components of the cardiovascular risk score to see which predicted development of kidney disease. This analysis linked three factors to a higher risk of kidney disease-higher total cholesterol, more years spent taking an antiretroviral from the protease inhibitor class, and more years spent taking an antiretroviral from the nucleoside or nucleotide class. A higher CD4 count when entering the study was linked to a lower risk of kidney disease. A similar analysis of which individual components of the kidney disease risk score predict cardiovascular disease linked a higher lowest-ever CD4 count to a lower risk of cardiovascular disease.

Diabetes is a well-known risk factor for both cardiovascular disease and kidney disease (Table 1). In the whole study group of 27,215 people, 1031 (3.8%) had diabetes when the study began. Among 6225 people with less than 1% 5-year cardiovascular disease risk and less than 1% 5-year kidney disease risk, only 23 (0.4%) had diabetes when the study began. Among the 6026 people with 1% to 5% 5-year cardiovascular disease risk and 1% to 5% 5-year kidney disease risk, 192 (3.2%) started the study with diabetes. And among 1585 people with more than a 5% 5-year cardiovascular disease risk and more than a 5% 5-year kidney disease risk, 366 (23.1%) started the study with diabetes.

What the findings mean for you. Compared with the general population, people with HIV infection have higher rates of cardiovascular (heart) disease and chronic kidney disease. This study produced new information on how risk of cardiovascular disease and risk of kidney disease interact to influence development of each disease.

The study has three main findings: (1) New kidney disease was more likely in people with higher cardiovascular disease risk (as well as in those with higher kidney disease risk). (2) New cardiovascular disease was more likely in people with higher kidney disease risk (as well as in those with higher cardiovascular disease risk). (3) New kidney disease and new cardiovascular disease were more likely in people with higher combined kidney and cardiovascular risk than in people with only high kidney risk or only high cardiovascular risk.

Because cardiovascular disease and kidney disease affect relatively high proportions of HIV-positive people, everyone with HIV should be aware of the risk factors for each disease. And results of this study indicate that people with risk factors for one disease should see if they have risk factors for the other disease. Table 1 lists common risk factors for kidney disease and cardiovascular disease. This list shows that kidney disease and cardiovascular disease share several risk factors--diabetes, high blood pressure, smoking, obesity, and older age. This study also found evidence that high cholesterol is a risk factor for kidney disease, not just for cardiovascular disease. In addition, cardiovascular disease is a major risk factor for chronic kidney disease.

You can't do anything to change certain risk factors, like older age and family history of a disease. But all of the other shared risk factors for cardiovascular and kidney disease can be avoided or managed--diabetes, high blood pressure, smoking, and obesity. Smoking is an especially dangerous habit because it can cause so many diseases. If you smoke, talk to your HIV provider about making a sensible plan to quit. If you already tried to quit and failed, you should know that many people have to try quitting several times before they succeed. A free and easy-to-use Website, https://www. positivelysmokefree.com/, has been developed to help people with HIV stop smoking, and studies show that it works.

Diabetes is another risk factor for both cardiovascular disease and kidney disease. This study shows that people at the highest risk of cardiovascular disease or kidney disease had the highest diabetes rates when the study began. The researchers say this finding "confirms that diabetes is a powerful risk factor for poor outcomes in HIV-positive people." A simple test for sugar levels in blood can detect diabetes or high blood sugar that may lead to diabetes. Health experts recommend that people with HIV get their blood sugar measured every 6 to 12 months. (9)

REFERENCES

(1.) Boyd MA, Mocroft A, Ryom L, et al. Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: a prospective analysis of the D:A:D observational study. PLoS Med. 2017;14:e1002424.

(2.) Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med. 2012;13:453-468.

(3.) Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of renal disease among people living with HIV: a systematic review and meta-analysis. BMC Public Health. 2012;12:234.

(4.) Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382:339-352.

(5.) Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-2081.

(6.) Friis-Moller N, Ryom L, Smith C, et al. An updated prediction model of the global risk of cardiovascular disease in HIV-positive persons: the Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study. Eur J Prev Cardiol. 2016;23:214-223.

(7.) Mocroft A, Lundgren JD, Ross M, et al. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study. PLoS Med. 2015;12:e1001809.

(8.) Note for providers: The authors explain, "In these models there was no statistical evidence of an interaction between the predicted CKD and CVD risk groups, suggesting that the effects are multiplicative (i.e., additive on a log scale). This means, for example that for an individual with high predicted 5-year risk of both CKD and CVD, the incidence rate ratio (IRR) for CKD events would be 13.81 multiplied by 5.63, which equals 77.75" (rather than 13.81 plus 5.63, which equals 19.44).

(9.) US Department of Health and Human Services Health Resources and Services Administration. HIV/AIDS Bureau. Guide for HIV/AIDS Clinical Care. April 2014. https://hab.hrsa.gov/sites/default/files/hab/clinicalquality- management/2014guide.pdf

* Words in boldface are explained in the Technical Word List at the end of this issue.

([dagger]) The researchers defined normal kidney function as an estimated glomerular filtration rate (eGFR) above 60 mL/min and impaired function as an eGFR at or below 60 mL/min on two later consecutive measures separated by at least 3 months. Glomerular filtration rate is the rate at which filtered fluid flows through the kidneys.
Table 1. Major risk factors for cardiovascular disease and kidney
disease

Cardiovascular disease *   Kidney disease *

                Diseases and conditions

Diabetes                   Diabetes
High blood pressure        High blood pressure
High cholesterol*          Cardiovascular disease

                     Behavior

Smoking                    Smoking
Obesity                    Obesity
Unhealthy diet
Too much alcohol
Physical inactivity

       Family history and other characteristics

Family history of          Family history of
cardiovascular disease     kidney disease

Older age                  Older age
                           Being black, Asian,
                           or Native American

Source: Centers for Disease Control and Prevention. Heart disease.
Heart disease risk factors, https://www/cdc/eov/heartdisease/risk
factors.htm ([dagger]) Source: Mayo Clinic. Chronic kidney disease.
Causes. https://www/mayoclinic/ore/diseases- conditions/
chronic-kidnev-disease/svmptoms-causes/svc-20354521 tin the
study being reviewed, high cholesterol is also a risk factor for
kidney disease.

Figure 1. A study of 27,215 adults with HIV linked higher
kidney disease risk--and also higher cardiovascular
(heart) disease risk--to higher risk that kidney disease
would develop over time. Researchers used a kidney risk
calculator (7) to estimate 1-5% 5-year risk of kidney disease
and more than 5% 5-year risk of kidney disease. Then they
compared rates of new kidney disease in people who fell
into those two risk groups with people who fell into a 1% or
lower risk group. They used a cardiovascular risk calculator (6)
to repeat the process for the two higher cardiovascular risk
groups (1-5% and over 5% versus 1% or lower).

New kidney disease rate
with higher kidney or heart risk

Kidney risk 1-5%         3.46
Kidney risk over 5%     13.81
Heart risk 1-5%          2.70
Heart risk over 5%       5.63

Note: Table made from bar graph.

Figure 2. A study of 27,215 adults with HIV linked higher
cardiovascular (heart) disease risk--and also higher kidney
disease risk--to higher risk that cardiovascular disease
would develop over time. Researchers used a heart risk
calculator (6) to estimate 1-5% 5-year risk of cardiovascular
disease and more than 5% 5-year risk of cardiovascular
disease. Then they compared rates of new cardiovascular
disease in people who fell into those two risk groups with
people who fell into a 1% or lower risk group. They used a
kidney disease risk calculator (7) to repeat the process for the
two higher kidney risk groups (1-5% and over 5% versus 1%
or lower).

New heart disease rate
with higher kidney or heart risk

Heart risk 1-5%          8.43
Heart risk over 5%      26.97
Kidney risk 1-5%         1.19
Kidney risk over 5%      1.31

Note: Table made from bar graph.

Figure 3. When calculating the combined risk of kidney
disease and cardiovascular disease, statistical analysis
indicates that the individual kidney and cardiovascular risks
should be multiplied rather than added. Multiplying results
in much higher combined risks than adding.

Multiplying versus adding kidney
and cardiovascular risk

Risk of kidney disease

Kidney risk     Heart risk   Combined risk

13.81           +5.63=         19.44
13.91           +5.63=         77.75

Risk of cardiovascular disease

Heart risk      Kidney risk   Combined risk

26.97            +1.31 =        28.28
26257            x1.31 =        35.33

Note: Table made from bar graph.
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Title Annotation:ARTICLE 5
Publication:HIV Treatment: ALERTS!
Date:May 1, 2018
Words:2520
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