It’s becoming increasingly clear that, when it comes to HIV, amongst the most vulnerable organs in the body are those two little waste filters in the small of the back – our kidneys. Guest writer Kelly Safreed-Harmon investigates renal disease and what can be done about it.
Within the first few years of the AIDS epidemic, physicians recognised that one symptom of this devastating new syndrome was a collapse in kidney function. In 1986, an especially severe type of renal (kidney) failure was characterised as a distinct disease: HIV-associated nephropathy (HIVAN).
Research could not find effective treatments for HIVAN until combination antiretroviral (ARV) therapy came along. This rapidly halts the progression of HIVAN in most people. The kidney-related benefits of ARVs can be seen in a sharp decline in renal mortality in the first few years of the new treatment era.1
While the outlook has greatly improved, kidney disease remains a prominent challenge to the management of HIV. A survey of five cohorts of HIV-positive people in Europe, North America and China found between one in eleven and one in twenty people had moderate to severe kidney disease.2
This compares with one in fourteen to one in eighty in the general population under 50, according to which study you pick and how chronic kidney disease is defined.3
These findings are perhaps not surprising to anyone who has followed recent medical trends in relation to HIV, antiretroviral treatment, chronic disease and ageing. The longer we live with HIV, it seems, the more the range of HIV-related health issues keeps expanding. What is notable about renal health in the context of HIV is that it intersects in complex ways with other key aspects of managing the disease.
An overview of kidney function
The kidney is an organ that performs vital tasks related to the filtering of blood and the elimination of waste from the body. In a healthy kidney, about a million tiny structures called nephrons filter waste from substances that the body can still use. The waste travels to the bladder in the form of urine and the other substances re-enter the bloodstream. Proper kidney functioning is necessary for the body to maintain the optimal balance of these substances, which include sodium, phosphorus and potassium.
The kidneys also release hormones that regulate blood pressure, stimulate the creation of red blood cells and help the body absorb the calcium that is required to keep bones strong.
Many different kidney diseases can interfere with these processes. The term chronic kidney disease (CKD) does not refer to a specific type of disease, but rather to the sustained loss of kidney function that can result from various medical conditions. Similarly, the term end-stage renal disease (ESRD) is used to characterise the near-complete loss of kidney function, which quickly results in death without dialysis or a kidney transplant.
The two most important causes of kidney disease are diabetes and high blood pressure – both conditions that can often be successfully prevented or treated. In diabetes, excess glucose in the blood injures the nephrons, while high blood pressure damages the small blood vessels that surround the nephrons: in both cases this makes it harder for the kidneys to sort waste from substances that should be reabsorbed into the body.
How drugs used to manage HIV disease interact with the kidneys
As the kidneys perform their processing functions, they can be exposed to harmful levels of drugs. Some drugs are more likely than others to cause serious organ damage, and some people are more vulnerable than others to drug toxicities. While cases of kidney damage thought to be caused by several ARVs have been documented in the medical literature, only three of those drugs have been consistently associated with adverse kidney-related effects.
There is ample evidence that the protease inhibitor indinavir (Crixivan) causes kidney stones in a sizeable number of people – and this is one reason why this drug is very rarely used now. (Waste products in the kidneys can sometimes form crystals and these can accumulate to form hard lumps called ‘kidney stones’.)
Of more concern are case reports of kidney stones associated with the protease inhibitor atazanavir (Reyataz). They appear to occur much more rarely than with indinavir, but atazanavir is a frequently used drug. A French cohort study found that about one in 100 patients developed atazanavir-related kidney stones after an average of two years on the drug,4 30 cases were reported to the American Food and Drug Administration in the first three years of its use,5 and one patient out of 121 in a trial comparing maraviroc with tenofovir/FTC, both combined with atazanavir, had to pull out due to kidney stones.6
The kidney stones associated with both these drugs, although painful, may be avoidable by drinking plenty of water, and resolve if the drugs are withdrawn.
If I were a patient, I would want to know that whoever is looking after me knows about this potential problem, and has procedures in place to detect it.
John Connolly, University College London
The impact of tenofovir (Viread – also in Truvada and Atripla) on the kidneys remains a matter of greater concern. Since this drug’s approval almost ten years ago, a number of studies have suggested that tenofovir may negatively affect renal functioning in subtle ways. In some people it damages the upper portion of the nephrons, resulting in symptoms similar to a condition called Fanconi’s syndrome.
There is no clear consensus about the importance of the findings, but many clinicians take them seriously.
An Australian study published in early 2010 found that kidney functioning had failed to return to normal in almost half of 24 men with tenofovir-induced renal toxicity more than a year after discontinuing the drug.7
In the EuroSIDA cohort, a group of nearly 7000 patients, cumulative exposure to tenofovir or atazanavir was associated with a 16% and 21% increased risk, respectively, of chronic kidney disease, though the actual proportion of people who developed CKD for any reason was relatively low, at one case per 105 patients a year.8
On the other hand, a US group found no association between tenofovir use and decline in kidney function in a prospective cohort study involving 554 people,9 and a recent meta-analysis of 17 studies involving 11,000 HIV-positive people concluded that from a statistical standpoint, taking tenofovir was indeed associated with higher risk of impaired kidney functioning, but that “the clinical magnitude of this effect was modest”.10
What are we to make of the barrage of data about tenofovir and kidney toxicity? Dr John Connolly of University College London’s Centre for Nephrology encourages HIV-positive people to look at the big picture.
“It’s important to be pragmatic, because tenofovir is a very safe and very good drug overall,” he says.
Connolly characterises tenofovir-induced renal toxicity as “a small problem for a significant minority of people”, and notes that protocols for screening tenofovir users for renal damage are well established.
“If I were a patient, I would want to know that whoever is looking after me knows about this potential problem, and has procedures in place to detect it,” he says. Patients at Connolly’s HIV nephrology clinic provide blood and urine specimens for what he characterises as “simple” screening tests every four to six months.
Antiretroviral toxicity is not the only kidney-related HIV treatment concern. Because kidney damage impairs the body’s ability to process drugs, dose reductions are required when prescribing certain antiretrovirals to people with CKD.
A number of drugs used to treat and prevent opportunistic infections are known to be hard on the kidneys, some to the point of making them hard to use. These include amphotericin B, cidofovir, foscarnet, pentamidine and sulfadiazine and to a lesser extent cotrimoxazole (Septrin) and the herpes drug aciclovir.11,12
Certain non-prescription substances such as most of the over-the-counter pain relievers, herbal supplements (including yohimbe, a component of ‘herbal Viagra’) and recreational drugs are potentially more hazardous to HIV-positive people with existing kidney problems than they are to the general population.
How HIV directly damages the kidneys: HIV-associated nephropathy
HIV itself still has the potential to add considerably to the complexity of kidney disease. A number of HIV-specific kidney diseases have been identified, the most notable being HIV-associated nephropathy (HIVAN). Genetic factors make HIVAN predominantly a disease of people of African ancestry. Before the discovery of potent new antiretroviral regimens in the mid-1990s, HIVAN often led rapidly to end-stage renal disease and death.
ARVs have been found to greatly slow HIVAN-related kidney decline. ARV-naive people diagnosed with HIVAN are therefore advised to start taking HIV treatment, even if they do not show other signs of HIV disease progression.
A category of blood pressure medications known as angiotensin-converting enzyme (ACE) inhibitors may also benefit people with HIVAN, as may corticosteroids.13
Confirming widespread clinical observations, a US cohort study showed a significant drop in HIVAN incidence from 1995-97 to 1998-2001, and also determined that ART use reduced HIVAN risk by 60% in cohort members.14 A more recent study looking at kidney biopsy results in 86 HIV-positive US residents with symptoms of renal impairment found that the most common cause was high blood pressure rather than HIVAN.15
Nonetheless, HIVAN continues to contribute substantially to the burden of HIV-related kidney disease, especially in Africans and people of African descent. Risk factors for HIVAN, besides African ancestry, include decreased CD4 cell count and family history of renal disease.16
How HIV indirectly damages the kidneys: diabetes and high blood pressure
As noted earlier, diabetes and high blood pressure are leading causes of kidney disease. Both conditions are also of growing concern to HIV-positive people in the current treatment era.
While it is important to bear in mind that genetic, lifestyle and environmental factors contribute much of the variation in diabetes incidence across different populations, studies of HIV-positive people taking ARVs have consistently called attention to this problem. One large multicentre study, for example, found that ARV use was associated with a fourfold increase in diabetes.17 The drugs most strongly associated with diabetes are the ‘first-generation’ NRTI drugs (the ‘nukes’ or nucleoside reverse transcriptase inhibitors): AZT (zidovudine, Retrovir), ddI (didanosine, Videx) and especially d4T (stavudine, Zerit).18
HIV-positive people who developed high blood pressure in one German study, had far higher prevalence of elevated urine protein levels, signalling the presence of kidney disease, than those who did not.19
However, with blood pressure, findings are hard to interpret because the kidneys play a role in regulating blood pressure and so kidney disease not only can result from high blood pressure (hypertension), but can cause it too. Nonetheless, since high blood pressure is clearly an independent risk factor for kidney disease (and many other diseases), it makes sense to treat it.
What are the symptoms of kidney disease and how is it diagnosed?
Chronic kidney disease (CKD) can progress for years without causing symptoms and, even when symptoms do occur, they may not be specific enough to lead to an immediate diagnosis. Because of this, many people with CKD are not diagnosed until considerable organ damage has occurred. The damage is often irreversible, but careful medical management and lifestyle changes can help some people avert or delay end-stage renal disease (ESRD).
When kidney function has declined greatly, people may experience a combination of the following:
- loss of appetite
- nausea and vomiting
- a more frequent or less frequent need to urinate
- reduced urine flow
- difficulty concentrating
- darkening of the skin
- muscle cramps
- itching and numbness
- swelling in the hands and feet
- puffiness around the eyes.
Other indications of kidney disease can be detected through medical tests. The most important ones for making the initial diagnosis of kidney disease look for two markers of impaired kidney functioning: protein in the urine and a level of creatinine, a waste product, in the blood. The kidneys are supposed to leave protein in the blood and filter out the waste products; damaged kidneys do the opposite.
On their own, measurements of urine protein levels and serum (blood) creatinine levels provide only a general picture of kidney functioning. Of greater significance is the estimated glomerular filtration rate (eGFR), which takes into account additional variables relating to age, sex and race. A person’s eGFR is expressed in terms of millilitres filtered per minute (ml/min). Someone with healthy kidneys can be expected to have an eGFR of 90 ml/min or greater, and people with eGFRs of over 60 ml/min are unlikely to have symptoms.
Different stages of chronic kidney disease are defined in terms of eGFR and other markers of kidney damage. Stage five CKD, the least severe, is defined as a normal eGFR alongside some evidence of kidney damage such as protein in the urine. At stage one, the most severe stage, an eGFR value of less than 15 ml/min indicates kidney failure, at which point a person cannot be expected to survive for long without being given dialysis or a kidney transplant.
HIV, ageing and the kidneys
With ART enabling such a large number of HIV-positive people in developed countries to achieve long-term viral suppression, health issues associated with ageing are becoming increasingly significant. Some diseases tend to manifest earlier in HIV-positive people than in their HIV-negative counterparts, for reasons that may relate to how both antiretroviral drugs and HIV itself affect the body over time.
A combination of factors may put people living with HIV at a higher risk of kidney disease as they grow older. First, kidney functioning declines in everyone from midlife onward, and older people in general are at higher risk of kidney disease and kidney failure. Second, the likelihood of developing diabetes and high blood pressure increases with age as well.
Kidney disease also has the potential to trigger or exacerbate certain other ageing-related health problems, and is strongly associated with cardiovascular disease.
Bone health is less widely discussed in relation to kidney disease, but the kidneys’ contribution to maintaining bone mass has important implications for HIV-positive people. Both disease-related and ageing-related bone thinning are already a matter of concern for HIV-positive people (see Skeleton key in HTU 196, May 2010). Since kidney disease is associated with the loss of bone mass in the general population, it is logical to speculate that it may further accelerate bone thinning in some HIV-positive people as they grow older.
This is especially important for people susceptible to tenofovir-related kidney disease, as this features a loss of bone minerals and vitamin D.
HIV and end-stage renal disease
HIV-positive people with ESRD can potentially benefit from both dialysis and transplantation, the only two interventions that can avert the death of someone experiencing complete renal failure. Dialysis, which involves using medical technology to filter waste from the blood, is a standard component of the management of ESRD in HIV-positive people. And in recent years, kidney transplantation has become an increasingly viable option for HIV-positive people with good viral control.20
Protecting kidney functioning in the context of HIV infection
The renal health issues associated with HIV may seem vast, but the good news is that a complex strategy is not required for most people to act on this body of information. Perhaps the simplest measure HIV-positive people can take to protect their renal health is to follow screening guidelines. The European AIDS Clinical Society has issued guidelines that call for kidney functioning to be evaluated at the time of HIV diagnosis for everyone, and on an annual or twice-yearly basis after that for HIV-positive people at higher risk of kidney disease.21
Factors often considered to put people at higher risk include a low CD4 cell count; a high viral load; a diagnosis of diabetes, high blood pressure or hepatitis C; cigarette smoking; prior use of nephrotoxic drugs; a family history of kidney disease; and African ancestry.22,23
It is also advisable for HIV-positive people to consider what they can do about the risk factors that are modifiable. Key steps may already be on the self-care agenda, since there is a great deal of overlap among modifiable risk factors for kidney disease, diabetes, high blood pressure and other diseases associated with metabolic and cardiovascular functioning.
All of the following well-known health-promoting measures can reduce the risk of kidney disease:
- giving up smoking
- eating a healthy low-fat diet
- exercising regularly
- not using recreational drugs
- getting regular medical check-ups
- reducing high blood pressure levels
- for people with diabetes, keeping blood glucose under control.
- Schwartz EJ et al. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol 16: 2412-2420, 2005.
- Post FA et al. Recent developments in HIV and the kidney. Curr Opin Infect Dis 22: 43-48, 2009.
- Zhang QL et al. Prevalence of chronic kidney disease in population-based studies: Systematic review. BMC Public Health 8:117, 2008.
- Couzigu C et al. Urolithiasis in HIV-positive patients treated with atazanavir. Clin Infect Dis 45 (online edition), 2007.
- Chan-Tack KM et al. Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration’s adverse event reporting system. AIDS 21(9)31:1215-1218, 2007.
- Mills A et al. Safety and immunovirological activity of once daily maraviroc (MVC) in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine 200mg/tenofovir 300mg QD (TDF/FTC) + ATV/r in treatment-naive patients infected with CCR5-tropic HIV-1 (Study A4001078): A week 24 planned interim analysis. 18th International AIDS Conference, Vienna, abstract THLBB203, 2010. Abstract and presentation available online: http://pag.aids2010.org/Session.aspx?s=1990
- Wever K et al. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr (online edition), 2010.
- Mocroft A et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS 24: 1667-1678, 2010.
- Longenecker CT et al. HIV viremia and changes in kidney function. AIDS 23: 1089-1096, 2009.
- Cooper RD et al. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis 51: 496-505, 2010.
- Fine DM et al. Renal disease in patients with HIV infection: epidemiology, pathogenesis and management. Drugs 68: 963-980, 2008.
- de Silva et al. HIV-1 infection and the kidney: an evolving challenge in HIV medicine. Mayo Clin Proc, 2007.
- Fine DM et al. Op. cit.
- Lucas GM et al. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS 18:541-546, 2004.
- Estrella M et al. HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients. Clin Infect Dis 43: 377-380, 2006.
- Gupta SK et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 40: 1559-1585, 2005.
- Brown TT et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 165: 1179-1184, 2005.
- De Wit S et al. Relationship between use of stavudine and diabetes mellitus. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL9.5, 2006.
- Jung O et al. Hypertension in HIV-1-infected patients and its impact on renal and cardiovascular integrity. Nephrol Dial Transplant 19: 2250-2258, 2004.
- Frassetto LA et al. Renal transplantation in patients with HIV. Nat Rev Nephrol 5: 582-589, 2009.
- See www.europeanaidsclinicalsociety.org/guidelines.asp
- Fine DM et al. Op. cit.
- Gupta SK et al. Op. cit.