Understanding the Risks of Kidney Impairment in HIV+ Patients

As HIV infection shifted from a death sentence to a chronic, treatable disease over past two decades, the higher incidence of other chronic medical conditions in HIV-positive individuals became apparent. One such area is renal impairment. An estimated 30% of HIV-positive adults exhibit some form of kidney disease, compared to about 16% of the general population.^1,2

“We’re not entirely sure why this population has an elevated risk of renal impairment,” said Lene Ryom MD PhD of the department of infectious diseases and rheumatology at the Rigshospitalet at the University of Copenhagen in Denmark. However, studies find several possible explanations.

For one, patients with HIV already have higher risks of diabetes and hypertension, and are more likely to smoke, than uninfected individuals. All increase the risk of chronic kidney disease (CKD). Other risk factors include older age, a baseline estimated glomerular filtration rates (eGFR) ≤60 ml/min, low CD4+ cell counts, higher viral loads, and coinfection with viral hepatitis. Patients who were treated for AIDS-related infections such as Pneumocystis pneumonia are also at higher risk, given the nephrotoxic drugs often used.^1,3

Being of certain types of African descent is also a major risk factor, said Dr. Ryom. “We know there’s a genetic predisposition in black people with an African origin that predisposes them to greater kidney-related damage from the virus,” she said.

HIVAN and HIVICK

The two most common forms of HIV-related renal disease are HIV-associated nephropathy (HIVAN), which appears to be caused by the viral genes alone, and HIV-immune-complex kidney disease (HIVICK), which appears to be related to virus replication or the immune response to viral proteins rather than viral gene expression.⁴ Both involve hyperplastic injury within the glomerulus.

HIVAN is most common in persons of African origin, and the risk of HIVAN is higher in patients with CD4 counts less than 200 cells/mm³, but extremely uncommon in those with low viral loads on treatment.¹ Even those who have already developed HIVAN demonstrate a slower progression when started on antiretroviral treatment (ART).

Meanwhile, a nested case-control study comparing risk factors and outcomes of HIVAN and HIVICK in 751 HIV-positive individuals found that those with HIVICK were more likely to have been exposed to ART, have lower HIV viral loads, and higher CD4+ counts and eGFRs than patients with HIVAN. In addition, just 30% of patients with HIVICK advanced to ESRD compared to 82% with HIVAN.⁵ There was also no risk reduction in HIVICK patients who received ART as there was with HIVAN.

Defining Abnormally Rapid Renal Function Deterioration

Clinicians should be particularly sensitive to signs of abnormally rapid renal function deterioration in their HIV-positive patients, in order to detect kidney damage at an early stage when it is most treatable. A recent publication from the Data collection on Adverse events of Anti-HIV Drugs (D:A:D) study, in which Dr. Ryom is involved, suggested a definition of rapid progression (RP): HIV-positive patients with a normal baseline eGFR (≥90 ml/min/1.73 m2) who, over three years follow up with semi-annual tests, demonstrate:⁶

•    An average decline of ≥5 ml/min/m² per year, and
•    An eGFR decline ≥5 ml/min/1.73 m² in two consecutive years, and
•    An eGFR at the end of the three-year period of <90 ml/min/1.73 m²

However, the authors noted that this definition may not identify all patients who progress to incident CKD, but should be used together with other renal measurements to provide early identification and risk assessment of those at risk of developing CKD.

If rapid progression is occuring, identify the cause of the decline and intervene against modifiable risk factors such as diabetes, hypertension, smoking, and dyslipidemia, said Dr. Ryom,  and consider discontinuing potential nephrotoxic drugs if possible.

Antiretroviral Therapy and Kidney Function

Clinicians also need to consider the potential nephrotoxicity of certain ART medications, said Dr. Ryom. “Obviously, it’s better overall to be on treatment than not on treatment,” she said. “Then it’s the matter of which drugs.”

An analysis of data from 22,603 people followed in the D:A:D study for less than five years found that cumulative use of tenofovir (TDF), ritonavir-boosted atazanavir (ATV/r), and ritonavir-boosted lopinavir (LPV/r) were independently associated with chronic renal impairment in patients with no history of kidney problems.⁷ Dr. Ryom and her colleagues noted in the published paper the “substantial” declines in renal function compared to the expected age-related decline.

The reasons for the damage vary, but appear to include urolithiasis and crystalluria from ATV/r; urolithiasis from LPV/r (about 10% of which is excreted in the urine), and Fanconi’s syndrome with TDF. However, said Dr. Ryom, the exact mechanisms need to be identified in mechanistic studies.

However, the D:A:D study found that among those who had not already developed chronic renal impairment while on the drug, stopping the drugs significantly reduced the risk of developing impairment, suggesting that the nephrotoxic effects are due to ongoing exposure. One important point:  Although the decline in kidney function slowed, it wasn’t clear if that it was reversible.

Thus, said Dr. Lyom, clinicians should avoid these drugs in people with renal impairment and consider other possible options for patients who have normal renal function but other risks for kidney impairment, such as hypertension, diabetes, and advanced age. If this latter group receives these drugs, she said, clinicians should closely monitor kidney function. Guidelines from the New York State Department of Health AIDS Institute recommend an eGFR when TDF therapy begins, one month later, and at least every four months thereafter.⁸

Screening, Diagnosis, and Management of Kidney Disease in HIV-Positive Patients

The only US guidelines specific to the screening, diagnosis, and management of kidney disease in this population come from the New York State Department of Health AIDS Institute.⁸ They advise clinicians to:

•   Educate patients about the association between HIV and kidney disease and the role of ART in preventing HIVAN, as well the importance of regular monitoring
•   Routinely assess kidney function, including:
     •  eGFR (baseline and every six months)
     •  Blood urea nitrogen (baseline and every six months)
     •  Urinalysis (baseline and at least annually)
     •  Urine albumin-to-creatinine ratio to detect microalbuminuria in patients with diabetes (baseline and at least annually)

Patients with borderline eGFR should have further diagnostic evaluation of kidney function with urinalysis, quantification of urinary protein excretion, renal sonogram, and physical examination. If the diagnosis is uncertain, kidney disease is progressing rapidly, the patient has stage 4 or 5 CKD, or a kidney biopsy might be required, primary care clinicians should refer to a nephrologist.

The first step in treating people with HIVAN is ART, said Dr. Ryom. “You should begin to see changes in renal function fairly quickly,” she said, with the high proteinuria seen in patients with HIVAN falling dramatically once treatment begins.

Treating HIVICK is more complicated, she said, because it’s a much rarer disease. Once patients begin treatment, she said, “we don’t have as much evidence of how quickly (proteinuria) may change. It’s a matter of measuring renal function continually and looking for proteinuria.” That’s why a referral to a nephrologist is the best option.

The most important step clinicians should take to reduce the risk of advanced kidney disease in HIV-positive patients is to be aware of the potential risk factors and address them annually, said Dr. Ryom. “From the risk profile, try and make rational monitoring decisions. It’s just so simple and cheap to monitor the eGFR and urine and this gives a lot of information on the kidney status,” she said. Plus, many risk factors are in fact modifiable.

References:

1.    Kidney Disease. AIDS.gov (2013)  Accessed May 27, 2014.
2.    Centers for Disease Control and Prevention. National Chronic Kidney Disease Fact Sheet. (2014) Accessed May 27, 2014.
3.    Ryom L, Mocroft A, Kirk O, et al. Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons.AIDS (2014) 28:187-199.
4.    Bruggeman LA, Nelson PJ. Controversies in the pathogenesis of HIV-associated renal diseases. Nature Reviews Nephrology. (2009) 5:574-581.
5.    Foy MC, Estrella MM, Lucas GM, et al. Comparison of risk factors and outcomes in HIV immune complex kidney disease and HIV-associated nephropathy.Clin J Am Soc Nephrol. (2013) 8:1524-1532.
6.    Kamara DA, Ryom L, Ross M, et al.Development of a definition for Rapid Progression (RP) of renal function in HIV-positive persons: the D:A:D study. BMC Nephrol. (2014) 15:51.
7.    Ryom L, Mocroft A, Kirk O, et al.Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study. J Infect Dis. (2013) 207(9):1359-1369.
8.    New York State Department of Health. Kidney Disease in HIV-Infected Individuals (2012)