HIV and the Kidneys

Knowledge of your kidney function and kidney health is important for both HIV-infected and non-HIV-infected persons. It has been known for approximately 20 years that HIV may result in kidney failure.¹ Given that the specific types of kidney diseases seen among HIV-infected persons have a tremendous predilection for black Americans,² the focus to date has been on screening and prevention of kidney disease in people of color. This focus, however, needs to be expanded to all persons with HIV-infection regardless of race, given recent understanding that the risk associated with abnormalities of kidney tests identifies persons at a greater risk of illness and death.

Put simply, everyone with HIV infection should be aware of their kidneys.

How Do You Test Kidney Function?

Kidney function can be assessed by simple blood and urine tests. The two methods to assess kidney function complement each other and should both be performed as the presence of an abnormality in one, the other or both tests provides clues to the type and severity of the kidney disease. In addition, a couple of different mathematical measurements help turn these two test results into a clearer picture of health.

Detection of kidney disease relies almost entirely on the performance of blood and urine tests. While infrequently, clues to the onset and presence of kidney disease -- such as swelling of the legs or face and changes in urinary habits -- may occur, generally symptoms associated with a decreased ability of the kidneys to clear waste products from the blood are vague, including fatigue and loss of appetite, occur only after the majority of kidney function has been lost, and may be confused with other causes.

A urine analysis can provide a tremendous amount of information on the presence and activity of diseases in the kidneys. The presence of small amounts of the protein albumin (albuminuria) or larger amounts of protein (proteinuria) can be assessed using a dipstick of a small amount of urine. Albuminuria or proteinuria usually indicates the presence of kidney disease and may be seen early even prior to loss of kidney function.

A measurement of the creatinine level in the blood can subsequently provide an estimate for the ability of the kidneys to clear the blood of waste products. Creatinine is a molecule excreted by muscle cells on a continuous basis. When the kidneys function well, it is filtered effectively out of the blood, and the blood levels are low. As kidney function declines due to kidney disease, it is less effectively cleared out of the blood, and its blood level rises.

To truly understand how this simple blood test is translated within an individual to the amount of kidney function they have, the level of creatinine must be manipulated. Because the absolute level of creatinine is related not only to kidney function but also to the amount of muscle a person has, for it to really reflect the amount of kidney function it must be converted using a mathematical formula. This is essential to avoid two common and dangerous misconceptions. The first is that a smaller or older individual does not have significant kidney disease simply because their creatinine falls into a "normal range" for a laboratory.

As an example, a 55-year-old caucasian male may have a creatinine of 1.3 mg/dL, which is technically within normal limits for the ranges that many laboratories provide (usually normal is listed as less than 1.4 mg /dL). His estimated kidney function (using the Cockcroft-Gault formula in Table 1) is 54.5 cc/min. Given that "normal" is in the range of 90 to 110 cc/min, this represents a reduction in his kidney function of approximately 45% that would have gone unnoticed had it not been calculated.

The second misconception is that a "small" elevation in creatinine is not a matter of concern. This misconception that a small elevation in creatinine should not result in an investigation of the causes is due to the fact that as kidney function decreases with disease, creatinine doesn't rise at a constant rate accordingly. As with any disease, however, the earlier the diagnosis and treatment, the more likely the cure. This is especially true of kidney disease. In the case of kidney disease early diagnosis may translate to either avoiding or delaying kidney failure, with the subsequent need to start dialysis, a painful, expensive, and complicated procedure.

Early in the course of kidney disease, as creatinine goes from the normal for that individual upwards to the value of 2 mg/dL, that person has likely lost half of their kidney function. Later on in the course of the kidney disease, as the individual's creatinine rises from 4 to 5 mg/dL the loss is much less pronounced. This is shown in Figure 1, plotting the amount of kidney function on the vertical axis against the level of creatinine on the horizontal axis. In this graph, the rate of loss of kidney function is considerably more steep when creatinine rose from 1 to 2 as compared to its decline when creatinine rose from 4 to 5 mg/dL. The key message here is that any elevation needs to be evaluated, and the earlier the better.

The Forest and the Trees

There is an old cliché that warns not to miss the forest for the trees. In this analogy, it is appropriate to consider the trees as the kidneys and the forest the person who owns them. The warning here is based on the fact that kidney disease puts an individual at risk of events even worse than declining kidney function and the prospect of dialysis. This article will first describe the risk of kidney disease to kidney function and then go on to describe the risk of kidney disease to the life of the person him or herself.

The Trees: The Risk of Progressive Kidney Disease

A person with HIV-infection may get many types of kidney diseases, including those related to the virus and those related to conditions such as hypertension or diabetes. The types of kidney diseases that have been described among persons with HIV are listed in Table 2.

If a person has an abnormal kidney test (abnormal urine dipstick or elevated serum creatinine), the only definitive way to determine the exact type of kidney disease that he or she has is by kidney biopsy. While a kidney biopsy is relatively low risk, the risk of bleeding does exist. Therefore, it makes sense to only perform a kidney biopsy on those persons in whom knowledge of the exact type of kidney disease will affect the therapy chosen.

Since many therapies are beneficial to the person overall (such as good blood pressure control in a person with high blood pressure and tight blood sugar control in a person with diabetes), it is not always necessary to perform a kidney biopsy initially. Discussion of whether or not a particular individual needs a biopsy should be held with a health care provider specializing in the care of kidney disease, such as a nephrologist. If a kidney biopsy is not initially pursued, that decision should be re-examined periodically, based on the course of the kidney disease and how the person responds to the therapy instituted.

Risk Factors

The type of kidney disease someone is likely to have can be influenced by multiple factors. The most influential of these factors, however, is clearly race. Black Americans without HIV infection are pre-disposed to most kidney diseases as compared to caucasians.² Black Americans with HIV infection also have a greater risk of kidney disease.² Among persons with HIV infection and kidney disease, the types of kidney disease are also quite different among black and caucasian Americans.^{5, 6, 7} Kidney diseases more likely to be associated with HIV, such as HIV-Associated Nephropathy (HIVAN), are significantly more common among black Americans, whereas caucasians are more likely to experience kidney diseases related to their concurrent illnesses, such as hypertension and diabetes. The risk associated with race for developing HIVAN is so great that it is exceptionally rare to diagnose a caucasian with it, and such a diagnosis would be written up as a case report in a medical journal.

Treatment of kidney disease should be directed at the type or suspected type of kidney disease a person is likely to have. Table 3 represents a partial list of the types of kidney diseases and potential recommended interventions to stop, slow, or reverse the effects of the disease on the kidneys. The goal of treatment is to halt or at least slow the progression of kidney disease to delay or perhaps avoid the need for the institution of dialysis.

The Trees: The Association Between Kidney Disease and the Risk of Illness and Death

It has long been known that among persons without HIV infection, such as those with diabetes, heart disease, the elderly, and those with high blood pressure, the presence of kidney disease is associated with an even greater risk of death.⁸ It should therefore not be surprising this association is also present among patients with HIV.

Importantly, this is not only true for persons with elevated serum creatinine levels (and therefore decreased kidney function), but also for individuals whose kidney function is normal but who merely have a little protein in their urine.

Several studies demonstrate that persons with HIV-infection and protein in their urine and/or elevated creatinine have an increased risk of hospitalization and death,^{9, 10} and that these increases in risk are not subtle. A person with either protein in their urine or elevated creatinine is at a 70% increased risk of hospitalization due to new AIDS-defining illness and a 50% increase in risk for overall hospitalization.

Looked at separately, protein in the urine and an elevated creatinine have equally concerning associations with new AIDS-defining illness and risk of death. In the absence of antiretroviral therapy, the presence of protein in the urine is associated with a 31% increased risk of new AIDS-defining illness (ADI) and a 35% increase in risk of death.¹¹ This latter finding is underscored by the fact that a person without proteinuria and a CD4 lymphocyte count of 350 cells/ml3 has a lower risk of death than a person with a CD4 lymphocyte count of 500 who has protein in their urine. This important finding was noted in a study looking at women followed in the Women's Interagency HIV Cohort Study (WIHS), a study of over 2,500 women with HIV.

Initiation of antiretroviral therapy may affect this risk among persons with kidney abnormalities, but improvement in lowering the risk is not tremendous. Even following the initiation of antiretroviral therapy, a person with protein in their urine is at a 121% increased risk of death and a person with an elevated creatinine is at a 42% increased risk of a new ADI.

One of the mechanisms behind these elevated risks may be due to a less vigorous response to the initiation of therapy among people with kidney disease. A single study suggests that individuals with proteinuria may be less likely to respond to antiretroviral therapy with a non-detectable viral load. Clearly a greater understanding of whether or not these findings should result in stronger recommendations than simply starting individuals with kidney disease on antiretroviral therapy early is paramount.

What Do We Know, What Do We Think We Know, What Do We Need to Know, and What Should You Do?

Our knowledge of HIV and how it affects the kidneys is still relatively rudimentary. Significant work remains to be begun to truly understand who is susceptible to kidney disease and why. At present, it would appear that while the overwhelming burden of kidney disease occurs within the black American community, subtle abnormalities in kidney tests may be a risk factor for increased risk of AIDS-defining illness and death among all HIV-positive persons.

Given the ability of early screening to provide a greater likelihood of prevention and treatment, screening is imperative. Screening as simple as a urine analysis and a serum test for creatinine should be employed in every person with HIV. Guidelines from the Infectious Diseases Society of America (IDSA) currently suggest that all persons with HIV infection get screened for kidney disease at least once.¹² If screening results in no apparent abnormalities, persons at increased risk for increased kidney disease should be re-assessed at least yearly. Persons with abnormal screening tests should have further evaluation by their health care provider and potentially be referred to a nephrologist. When given your lab results, if you don't hear anything about your kidneys, it doesn't hurt to ask: "How is my kidney function?"

When it comes to kidney disease the adage "What you don't know can't hurt you" couldn't be less applicable. Please -- remember to pee in the cup!

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Lynda Szczech, M.D., M.S.C.E., specializes in the care of kidney disease among adults with HIV at Duke University Medical Center in Durham, N.C. She has focused her research over the last 10 years on the diagnosis, management, and impact of HIV-related kidney disease. She may be reached via e-mail at szcze001@mc.duke.edu.