Chronic Kidney Disease in HIV-Infected Individuals: Preventable and Treatable

With the transition of HIV from an acute disease with an almost-certain death sentence to one that, with appropriate treatment, can be managed as a chronic condition, new challenges have arisen:  heart disease, osteoporosis, diabetes, and cognitive impairment, among others, in people with HIV, some of which appear prematurely.

One of the most common complications is chronic kidney disease (CKD); up to a third of HIV-infected individuals demonstrating abnormal kidney function. Risk factors include race (African-Americans are 11 times more likely to develop kidney disease than whites), diabetes and hypertension, age, family history, and coinfection with hepatitis C (HCV). Higher viral load and lower baseline CD4+ counts are also linked to reduced renal function.¹ 

People with kidney disease tend to progress faster to AIDS, and have a higher rate of AIDS-related death. They also experience worse outcomes of other chronic conditions, such as heart disease and diabetes.²

Today, people with HIV are a growing percentage of persons on dialysis. Nearly 40% of dialysis centers in the United States reported in 2002 that they provided services for HIV patients, who made up an average of 1.5% of their patients. That percentage is likely much higher; because centers are not required to screen patients for HIV.³

Prevention could be as simple starting patients on antiretroviral therapy (ART) as soon as possible after diagnosis.


Types of Renal Damage

The most common form of kidney damage in HIV-infected individuals is HIV-associated nephropathy (HIVAN), which used to be called AIDS-associated nephropathy. It is found in up to 60% of renal biopsies among HIV-infected individuals with CKD and is the third leading cause of end-stage renal disease (ESRD) in African Americans under age 65.¹

HIVAN is defined as heavy proteinuria associated with focus segmental glomerulosclerosis and microcystic tubular distention that leads to renal enlargement and, eventually, ESRD. Early in the epidemic, patients with HIVAN presented with substantial damage. Today, they may be asymptomatic despite the presence of similar clinical and renal histological features.⁴

Other renal conditions in people with HIV include membranous nephropathy resulting from coinfection with either hepatitis B or C or syphilis, membranoproliferative glomerulonephritis associated with hepatitis C virus coinfection and mixed cryoglobulinemia, diabetic and hypertensive nephropathies, and immune complex glomerulonephritis, in which IgA is directed against HIV antigens.⁵ Only a renal biopsy can identifyconclusively  which condition is responsible for the damage.

Even in the ART era, people with HIV have a two-fold higher incidence of acute renal failure (ARF)  and a five-fold increased incidence of mortality from ARF compared to those without HIV.⁶ Antiretroviral medications, particularly tenofovir, may cause ARF, which is why guidelines call for regular monitoring of kidney function and urine studies for patients on tenofovir. Other medications commonly used in this population that are associated with ARF include nonsteroidal anti-inflammatory drugs (NSAIDs), trimethoprim-sulfamethoxazole, and rifampin.⁷ Other causes of ARF include co-infection with HCV, underlying CKD, and advanced HIV disease.¹Screening for HIV-associated Kidney Disease

Although elevated creatine is a standard measure of kidney function, its specificity varies based on patient age, gender, and muscle mass, and its accuracy is compromised in patients with HIV.⁴

Recent studies suggest that the albumin creatinine ratio (ACR) and levels of interleukin-18 and kidney injury molecule-1 may be more reliable biomarkers for identifying early renal damage as well as assessing patients for ART-related toxicity.² Other markers include N-acetyl-β-D-glucosaminidase, γ-glutamyl transpeptidase, β2-microglobulin, and α1-microglobulin.²Screening and Management of Renal Function in People with HIV

Guidelines from the HIV Medicine Association of the Infectious Diseases Society of America recommend the following:⁵

•    Assess the kidney function of all patients at time of diagnosis with a urine analysis for proteinuria and a calculated estimate of renal function. Screen patients with normal results who are at high risk for kidney disease annually and all patients receiving indinavir or tenofovir biannually..
•    Refer patients with proteinuria of grade ≥1+ by dipstick analysis or reduced renal function (GFR, <60 mL/min per 1.73) to a nephrologist for additional testing, quantification of proteinuria, renal ultrasound, and potentially renal biopsy
•    Begin immediate treatment with ART in patients with HIVAN regardless of the severity of renal dysfunction. In addition to controlling blood pressure medically, consider adding ACE inhibitors or angiotensin receptor blockers (ARBs) if ART does not improve renal function, and, possibly, prednisone in adults.

More recent guidelines from the New York State Department of Health call for educating patients about the links between kidney disease and HIV, the ability of ART to prevent HIVAN, and the need for routine monitoring.

Such monitoring should include a screening GFR and blood urea nitrogen at baseline and every six months thereafter; and a baseline urinalysis and calculation of urine albumin-to-creatinine ratio at baseline and every year thereafter.⁸

The most effective treatment for preventing renal function impairment and slowing its progression to ESRD is ART. In a longitudinal study of nearly 4,000 HIV-infected individuals, the incidence of HVAN was 26.4 per 1000 person years for patients with AIDS; 14.4 for those treated with nucleoside analogue therapy only; and 6.8 for those treated with ART (P<0.001 for trend), a 60% percent risk reduction.⁹

Antiretroviral therapy is also associated with a reduced risk of any CKD. The HIV Outpatient Study found that patients with 56 days or more of ART treatment with nadir CD4+ counts < 200 cells/?L were 4.1 times more likely to be diagnosed with CKD compared to a 13.3-fold increased risk in those with the same CD4 counts who were not receiving ART. Rates in patients with no history of hypertension were 3.8 compared with 29.1 in patients who were hypertensive and treated with ACE inhibitors but who were not receiving ART.¹⁰

In addition, of course it is important to manage other risk factors for and contributors to kidney disease such as hypertension and diabetes.

REFERENCES

1.    Scarpino M, Pinzone MR, Di Rosa M, et al. Kidney disease in HIV-infected patients. Eur Rev Med Pharmacol Sci. (2013) 17(19):2660-2667.
2.    Shlipak MG, Scherzer R, Abraham A, et al.Urinary markers of kidney injury and kidney function decline in HIV-infected women.J Acquir Immune Defic Syndr. (2012) 61(5):565-573.
3.    Finelli L, Miller JT, Tokars JI, et al. National surveillance of dialysis-associated diseases in the United States, 2002. Seminars in Dialysis. (2005) 18(1):52-61.
4.    Ray PE. HIV-associated nephropathy: a diagnosis in evolution. Nephrol Dial Transplant. (2012) 27(11):3969-3972.
5.    Gupta SK, Eustace JA, Winston JA, 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. (2005) 40(11):1559-1585.
6.    Wyatt CM, Arons RR, Klotman PE, et al. Acute renal failure in hospitalized patients with HIV: risk factors and impact on in-hospital mortality.AIDS. (2006) 20(4):561-565.
7.    Choi AI, Rodriguez RA. Renal Manifestations of HIV.HIV InSite. (2008) http://hivinsite.ucsf.edu/InSite?page=kb-04-01-10 - S2.2X. Accessed January 6, 2013.
8.    Justman JE. Kidney Disease in HIV-Infected Patients: Guideline and Commentary. (2012) Medscape. http://www.medscape.com/viewarticle/772341_2. Accessed January 6, 2013.
9.    Lucas GM, Eustace JA, Sozio S, et al.Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study.AIDS. (2004) 18(3):541-546.
10.   Krawczyk CS, Holmberg SD, Moorman AC, et al. Factors associated with chronic renal failure in HIV-infected ambulatory patients. AIDS. (2004) 18(16):2171-2178.