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Risk factors for kidney dysfunction
<p>Sean R. Hosein</p>
February 1, 2013

The immune system is located in an organ called the spleen, the thymus gland, and in small clusters—lymph nodes and lymph tissues—throughout the body. Furthermore, cells of the immune system take up residence in key organ-systems, such as the brain, heart, liver, lungs, kidneys and bones, to help protect them from infection. This widespread distribution of the immune system can have its disadvantages. In the case of germs that attack the immune system, unless the germs are quickly controlled, they inadvertently are spread by cells of the immune system to many parts of the body. This is the case with HIV.

The importance of the kidneys

The kidneys are a pair of bean-shaped, fist-sized organs in the region of the lower back. These vital organs filter waste products from blood, help to produce vitamin D and regulate the level of oxygen-carrying red blood cells.

The kidneys receive a large proportion of the blood (about 20%) pumped by the heart. This flow of blood brings oxygen and nutrients but also waste products to the kidneys. Waste products concentrate in the cells of the kidneys that specialize in filtering blood and reabsorbing nutrients and important substances from the filtered material. As a result of reabsorbing substances from the filtered material, drugs may become concentrated in some parts of the kidney, causing damage. As the amount of drug in the kidney rises, this could also trigger the formation of crystals of the drug. Crystals can act as seeds, attracting more particles of drugs and eventually leading to the formation of stones.

HIV and the kidneys

HIV can infect cells and structures of the kidney. Such infection of kidney cells can occur even in people who are taking anti-HIV therapy and whose viral load in the blood is low. Furthermore, some cells and structures of the kidney appear to act as a reservoir for HIV, allowing this virus to infect cells that produce more HIV. This can happens even when viral load in the blood may be less than 50 copies/ml due to treatment.

Continuous low-level production of HIV in the kidneys likely causes inflammation, which can, over time, slowly degrade the functioning of these vital organs.

In addition to HIV, other conditions or activities can cause kidney dysfunction, including the following:

  • higher-than-normal blood pressure
  • abnormal lipid levels
  • diabetes
  • obesity
  • tobacco smoking
  • hepatitis C virus (HCV)
  • injection of street drugs

Additionally, there are medicines that have been associated with kidney dysfunction, such as the following:

  • chronic use of NSAIDS (non-steroidal anti-inflammatory drugs) commonly used to treat pain and inflammation – Aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex)
  • certain antibiotics – vancomycin and a class of antibiotics called aminoglycosides (such as gentamicin)
  • antifungal drugs – amphotericin B
  • anticancer drugs – doxorubicin, cis-platinum
  • antidepressants – lithium
  • transplant drugs – cyclosporine, tacrolimus
  • antiviral drugs – intravenous acyclovir, foscarnet, cidofovir (Vistide)
  • antiparasite drugs – pentamidine

HIV-positive people who use the drugs listed above and/or have the aforementioned conditions may be at increased risk for kidney dysfunction.

Tenofovir

The drug tenofovir has activity against HIV and hepatitis B virus (HBV). Tenofovir is sold under the brand name Viread and in fixed-dose formulations with other drugs under the following names:

  • Truvada – tenofovir + FTC
  • Atripla – tenofovir + FTC + efavirenz
  • Complera – tenofovir + FTC + rilpivirine
  • Stribild – tenofovir + FTC + cobicistat + elvitegravir

Different types of studies

Tenofovir is an effective part of many HIV treatment regimens. In randomized, controlled clinical trials, tenofovir has been found to be generally safe, and reports of serious kidney dysfunction were uncommon. However, participants in such trials likely have little or no pre-existing health conditions that place them at increased risk for kidney dysfunction. Once a drug is approved by regulatory authorities, it gets prescribed to a wide variety of patients, some of whom likely have pre-existing health issues. To help doctors understand how effective and safe a drug is outside of a randomized clinical trial, observational studies are generally used. Such studies enroll thousands of participants and monitor them for several years.

Caution needed

A major drawback of observational studies is that while they are good at finding associations between a drug and an effect, they cannot prove that a drug caused a particular side effect. Therefore, the results of observational studies, while often headline-grabbing, need to be treated cautiously. Such studies are bedeviled by confounding factors that can cause researchers to inadvertently arrive at incorrect conclusions. Scientists who conduct observational studies are well intentioned and do their utmost to take into account possible confounding factors. Unfortunately, no matter how large an observational study, the research team analysing the data can never be certain that every possible confounding factor has been taken into account.

Observational studies are important but can only serve as a guide to developing further studies of a more robust statistical design to explore important issues.

Our next report examines an observational study that sought to link the use of specific anti-HIV drugs with kidney dysfunction.

—Sean R. Hosein

REFERENCES:

  1. Fierer DS, Klotman ME. Kidney and central nervous system as reservoirs of HIV infection. Current Opinion in HIV/AIDS. 2006 Mar;1(2):115-20.
  2. Marras D, Bruggeman LA, Gao F, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nature Medicine. 2002 May;8(5):522-6.
  3. Winston JA, Bruggeman LA, Ross MD, et al. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. New England Journal of Medicine. 2001 Jun 28;344(26):1979-84.
  4. Harris RC, Neilson EG. Chapter 278. Adaption of the Kidney to Renal Injury. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
  5. Bargman JM, Skorecki K. Chapter 280. Chronic Kidney Disease. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
  6. Waikar SS, Bonventre JV. Chapter 279. Acute Kidney Injury. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrisons Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
  7. Ryom L, Mocroft A, Kirk O, et al. Exposure to antiretrovirals (ARVs) and risk of renal Impairment among HIV-positive Persons with normal baseline renal function: the D:A:D study. Journal of Infectious Diseases. 2013; in press.
  8. Fine DM, Gallant JE. Nephrotoxicity of antiretroviral agents: Is the list getting longer? Journal of Infectious Diseases. 2013; in press.
  9. Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012 Apr 24;26(7):867-75.
  10. Jaffe JA, Kimmel PL. Chronic nephropathies of cocaine and heroin abuse: a critical review. Clinical Journal of the American Society of Nephrology. 2006 Jul;1(4):655-67.


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