Single DNA change may identify susceptibility to tenofovir-related kidney damage

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Spanish researchers have identified a single genetic change that increases fivefold the risk of kidney damage among people with HIV taking tenofovir. They say that the result, published in the June 1st issue of Clinical Infectious Diseases, may one day help clinicians to identify patients who would benefit from extra monitoring of kidney function while on tenofovir therapy.

The nucleotide reverse transcriptase inhibitor tenofovir (Viread) is a safe and effective HIV medication that has been associated with kidney damage in a small proportion of users. The cause of kidney damage associated with tenofovir is not known, but may include interference by the drug with molecular pumps in the tubule structures of the kidneys.

Tenofovir itself is excreted from the body via a number of different molecular pumps in these tubules. Scientists hypothesise that tenofovir’s kidney-toxic effects may involve increases in the concentration of the drug in kidney cells due to inefficient pumping of tenofovir. Due to genetic variability, people have slightly different versions of the same pumps, and these different versions may be better or worse at pumping tenofovir. These genetic differences could explain, at least in part, why some people develop kidney damage while taking tenofovir.

Glossary

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

prospective study

A type of longitudinal study in which people join the study and information is then collected on them for several weeks, months or years. 

odds ratio (OR)

Comparing one group with another, expresses differences in the odds of something happening. An odds ratio above 1 means something is more likely to happen in the group of interest; an odds ratio below 1 means it is less likely to happen. Similar to ‘relative risk’. 

nucleotide reverse transcriptase inhibitor

Family of antiretrovirals which includes tenofovir disoproxil and tenofovir alafenamide. It may be abbreviated to NtRTI or NRTI. It is often said that nucleotide reverse transcriptase inhibitors work in a similar way to nucleoside reverse transcriptase inhibitors, but approach from a different angle.

In a cross-sectional study, Spanish investigators at the Hospital Carlos III in Madrid analysed the genetic variability of five molecular pumps associated with tenofovir excretion among people with HIV who started tenofovir therapy at the hospital clinic.

Of the 115 participants enrolled in the study, 19 (16.5%) developed laboratory signs of kidney tubule damage. The average follow-up time for participants was 35 months. Comparing the group that developed kidney damage with the group that did not, investigators found no significant differences in age, sex, body weight, race, co-infection with hepatitis C virus or the duration of tenofovir therapy. Among the group with kidney damage, use of protease inhibitors (74% versus 45% for unaffected participants) and diabetes (37% versus 20%) tended to be more common, though the differences were not statistically significant (p = 0.11 and p = 0.10 respectively).

Investigators then looked for specific changes in the genes encoding five molecular pumps. Of the five, only one gene ABCC2 (adenosine triphosphate-binding cassette C2), which encodes for the pump MRP2 (multi-drug resistant protein 2), was associated with kidney tubule damage. Within the ABCC2 gene, one single genetic variation, a cytosine at position -24, was found to be more common in participants reporting damage. Sixteen of the 19 participants with kidney damage carried two copies of the -24C variant, while two participants carried one copy of the C variant and one copy of a different version (a thymine at position -24).

The C variant was the predominant version of the gene in the study group, representing 76% (175) of the 230 copies of the gene in the group (each person carries two copies of the gene). Carrying two copies of the -24C variant was also common: found in 59% (68 of 115) of all participants. However, having two copies of the variant was not a sure indicator of developing tenofovir-associated kidney tubule damage, as only 24% (16 of 68) of participants carrying two copies of the -24C variant eventually developed the condition.

Multivariate analysis of factors associated with increased risk of developing kidney tubule damage with tenofovir use revealed that carrying two copies of the -24C variant of ABCC2 was associated with a five-fold increase in risk (odds ratio 5.04; 95% CI, 1.2-21) of developing kidney tubule damage. Increasing age and decreasing body weight were also associated with increased risk of developing kidney tubule damage.

Investigators note that while the kidney damage associated with tenofovir use is likely to be a result of both genetic and other factors, the link between this variant of ABCC2 and kidney damage has been found in other studies. If confirmed in future prospective studies, they conclude that close monitoring of tubular function would be warranted for patients receiving tenofovir, particularly those carrying two copies of the -24C variant.

References

Rodriguez-Novoa S et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis 48 (online edition), 2009.