U.S. study uncovers vitamin C loss and deficiency in some women with HIV

• An American study analysed blood and urine samples from women with and without HIV
• Women with HIV were less likely to retain vitamin C in their bodies
• The cause of the vitamin C loss was not clear and it was linked to a deficiency of this vitamin

Vitamin C is an important nutrient that plays many roles in the body, such as helping to build connective tissue, producing compounds used by brain cells to send signals to each other, and healing wounds. Vitamin C also serves to protect cells from injury arising from exposure to highly active molecules called free radicals. In this latter function of protecting cells from free radicals, vitamin C is called an antioxidant.

About the kidneys

One key function of the kidneys is to filter the blood. As part of the filtration process, waste products are removed and flushed into urine. Nutrients and other useful materials are reabsorbed into the blood.

Study details

A team of researchers at the U.S. National Institute of Diabetes and Digestive and Kidney Disease along with other researchers at Georgetown University in Washington, D.C., performed a detailed analysis of blood and urine samples from 40 women with HIV and 56 healthy women without HIV.

Samples were collected after overnight fasting. Researchers also obtained medical records and limited socio-demographic information from the women. Participants were told not to take vitamin C supplements for two weeks prior to visiting the study clinic. Blood and urine samples were collected at one time only.

On average, women with HIV were older (53 years) compared to women without HIV (37 years). Women with HIV were more likely to use tobacco (54%) compared to women without HIV (4%).

Most women with HIV (86%) were taking treatment (antiretroviral therapy, ART), and most ART users (91%) had a suppressed viral load (less than 50 copies/mL). The average CD4+ count of the women with HIV was nearly 740 cells/mm³. The average time since HIV diagnosis was 17 years.

Key findings

According to the researchers, all women without HIV who had low levels of vitamin C in their blood had “no detectable vitamin C” in their urine. This finding suggests that, overall, their kidneys were attempting to keep vitamin C in their bodies.

The researchers stated that “in contrast, almost all [women with HIV] had detectable vitamin C in their urine.” This detectable level of vitamin C in their urine occurred despite many women with HIV having very low levels of vitamin C in their blood. The proportion of women with HIV who had a vitamin C deficiency was 43% vs. 7% in women without HIV.

The researchers stated that the kidneys of women with HIV were more likely (73%) to leak vitamin C than the kidneys of women without HIV (14%).

Associations with vitamin C loss in the urine

The researchers performed statistical analyses to find possible associations between certain factors and the loss of vitamin C in the urine. These associations can be studied in more detail in a larger and more complex study to confirm their presence and better understand them. The statistical associations linking certain factors to vitamin C leakage were as follows:

• older age
• higher body mass index (BMI)
• high blood pressure
• obesity
• liver inflammation (elevated levels of liver enzymes in the blood)
• reduced kidney function

HIV-related issues

The following factors were not statistically associated with an increased risk for vitamin C loss in the urine:

• duration of HIV infection
• CD4+ cell count
• viral load

However, there may be other factors related to health or HIV that were not measured by researchers that could have had an impact on the risk of kidney leakage. Such factors may include past degree of immune deficiency (prior to initiating ART), a history of AIDS-related infections, or use of certain medicines to treat such infections that could have injured the kidneys.It is also possible that women with a history of a high viral load may have been at higher risk for kidney leakage than women whose viral load was lower.

ART-related issues

Intriguingly, researchers did find a statistical association signal between vitamin C leakage in the urine and the use of ART. Readers need to treat this finding with caution, as it is not conclusive for reasons outlined below:

All participants were taking nucleoside analogues—a class of ART that includes drugs such as tenofovir, FTC (emtricitabine), 3TC (lamivudine), and so on. Tenofovir comes in two formulations: the older formulation is called TDF (tenofovir disoproxil fumarate) and the newer formulation is called TAF (tenofovir alafenamide). While both formulations are generally well tolerated, the newer formulation is considered to be safer for the kidneys. However, researchers reported no differences in vitamin C leakage whether participants took TDF or TAF. At any rate, the study only had 14 women who took TDF-containing regimens and four others who took TAF-containing regimens. This is too small a population from which to draw meaningful conclusions.

There were no differences in the risk of kidney leakage reported for women who took different classes of ART, including integrase inhibitors, protease inhibitors and so on. However, the study was not designed to assess such differences.

Note that some cells of the kidney are a target for HIV infection. If HIV is left untreated, the risk of kidney injury is significantly increased. Overall, the effect of ART in suppressing HIV, improving health and conferring near-normal life expectancy outweighs its potential for side effects. Furthermore, it is plausible that the problem with kidney leakage of vitamin C may not have been caused by ART. Many of the participants with kidney leakage had metabolic issues—being overweight or obese and having high blood pressure. These conditions can adversely affect kidney health. It is also plausible that people had pre-existing kidney injury (prior to initiating ART).

In the present study, more Black people were in the group of people with HIV (84%) than the group of people without HIV (48%). The recruitment process did not select people at random and the proportion of Black people present was affected by who received information about the study, who decided to volunteer for it and who met the requirements for study entry. Nevertheless, a future study needs to investigate whether Black people with HIV are at increased risk for leakage of vitamin C into urine.

Kidney injury in other studies

A study in New York City focused on 173,884 hospitalized patients of whom 4,718 had HIV. Among people with HIV, a total of 2,532 (53.7%) were virally suppressed and 2,186 (46.3%) were not suppressed. According to the study researchers, “compared to people without HIV, people with HIV with and without viral suppression were at increased risk of acute kidney injury (AKI) and kidney injury requiring [dialysis].” The researchers added: “The elevated risk of AKI across ages of people with HIV was similar in magnitude to older people without HIV. Thus, regardless of virologic control, HIV is an independent risk factor for AKI among hospitalized patients.”

Another study of 33,998 people with HIV in the U.S. found that women were 61% more likely than men to develop chronic kidney disease. The reason(s) for this are not certain.

Taken together, both of the above-mentioned studies suggest that kidney injury is a problem for people with HIV. The first study found that people with HIV, regardless of whether or not their viral load was suppressed, were at risk for acute kidney injury. The second study found that women with HIV were at increased risk to develop chronic kidney disease.

Both of the above studies were relatively large and underscore the issue of kidney health in people with HIV.

For the future

The present study is interesting, but samples of blood and urine were collected at only one point in time. Researchers need to confirm their findings in a larger sample of people with HIV, of both sexes and from different ethno-cultural groups. Such a study needs to have sufficient people to better understand potential factors that could have affected the kidneys of participants and caused them to leak vitamin C. At a minimum, a future comprehensive study needs to do the following:

• include people on different HIV treatment regimens
• include information on the use of other prescribed and over-the-counter medications
• include people with and without cardio-metabolic issues
• screen people for alcohol and drug use
• screen for genes associated with an increased risk for kidney disease
• have detailed information about diet
• include people with viral co-infections (such as hepatitis B and hepatitis C viruses)
• include information on the level of inflammation

The study would also need to collect information about education and income as well as whether food insecurity is an issue.

Like all well-designed large studies, such a comprehensive undertaking will be expensive and will take time to fundraise and implement.

The researchers would also like to study the risk of kidney leakage of vitamin C in people with hepatitis B virus infection (tenofovir also has anti-hepatitis B activity) and in people without HIV who use tenofovir as part of HIV pre-exposure prophylaxis (PrEP).

Once their overall findings about the kidneys leaking vitamin C are confirmed, researchers could also test interventions, such as whether or not supplementation with vitamin C can help restore vitamin C levels in the blood to the normal range.

—Sean R. Hosein

REFERENCES:

1. Ebenuwa I, Violet PC, Michel K, et al. Vitamin C urinary loss and deficiency in human immunodeficiency virus (HIV): cross-sectional study of vitamin C renal leak in women with HIV. Clinical Infectious Diseases. 2023 Oct 13;77(8):1157-1165. 
2. Clergue-Duval V, Azuar J, Fonsart J, et al. Ascorbic acid deficiency prevalence and associated cognitive impairment in alcohol detoxification inpatients: a pilot study. Antioxidants (Basel). 2021 Nov 26;10(12):1892. 
3. Schwenger KJP, Arendt BM, Smieja M, et al. Relationships between atherosclerosis and plasma antioxidant micronutrients or red blood cell polyunsaturated fatty acids in people living with HIV. Nutrients. 2019 Jun 7;11(6):1292. 
4. Drain PK, Kupka R, Mugusi F, et al. Micronutrients in HIV-positive persons receiving highly active antiretroviral therapy. American Journal of Clinical Nutrition. 2007 Feb;85(2):333-45. 
5. Fisher MC, Fazzari MJ, Felsen UR, et al. Association of HIV and viral suppression status with hospital acute kidney injury in the era of antiretroviral therapy. Kidney International. 2023 Nov;104(5):1008-1017.   
6. Hughes K, Chang J, Stadtler H, et al. HIV-1 infection of the kidney: mechanisms and implications. AIDS. 2021 Mar 1;35(3):359-367. 
7. Overton ET, Kantor A, Fitch KV, et al. An evaluation of baseline kidney function in the REPRIEVE trial of pitavastatin in human immunodeficiency virus. Journal of Infectious Diseases. 2020 Jul 9;222(Suppl 1):S41-S51. 
8. Chan L, Asriel B, Eaton EF, et al. Potential kidney toxicity from the antiviral drug tenofovir: new indications, new formulations, and a new prodrug. Current Opinion in Nephrology and Hypertension. 2018 Mar;27(2):102-112. 
9. Wobeser WL, McBane JE, Balfour L, et al. A randomized control trial of high-dose micronutrient-antioxidant supplementation in healthy persons with untreated HIV infection. PLoS One. 2022 Jul 14;17(7):e0270590. 
10. Austin J, Singhal N, Voigt R, et al. A community randomized controlled clinical trial of mixed carotenoids and micronutrient supplementation of patients with acquired immunodeficiency syndrome. European Journal of Clinical Nutrition. 2006 Nov;60(11):1266-76.  
11. Padayatty SJ, Levine M. Standard-dose vs. high-dose multivitamin supplements for HIV. JAMA. 2013 Feb 13;309(6):545-6.
12. Hendricks KM, Mwamburi DM, Newby PK, et al. Dietary patterns and health and nutrition outcomes in men living with HIV infection. American Journal of Clinical Nutrition. 2008 Dec;88(6):1584-92.