Chronic kidney disease in people with HIV: a review of recent developments in Australia
Chronic kidney disease in people with HIV: a review of recent developments in Australia
HIV Australia | Vol. 11 No. 2 | July 2013
David Gracey discusses why monitoring kidney health is important for HIV-positive people.
As quality of life and life expectancy has improved for people with HIV, noninfectious co-morbidities have become the predominant health consideration for many HIV-positive people. Chronic kidney disease (CKD) is one of the most important of these considerations.1
Because antiretroviral therapies have the potential to be nephrotoxic (have a poisonous effect on the kidneys), it is particularly important for doctors to screen their HIV-positive patients for kidney disease.2
Uncontrolled HIV infection itself is associated with a variety of kidney diseases; the most widely recognised is HIV-associated nephropathy (HIVAN). HIVAN is not common in Australia, as it is seen mainly in African-American patients.3
Despite combination antiretroviral therapy (cART) directly contributing to a reduction in kidney disease, the incidence of CKD is increasing among people with HIV.4
The increase in the incidence of kidney disease among HIV-positive people relates to increases in life expectancy (and consequently older age) due to cART, as well as other metabolic health conditions including hypertension, diabetes and dyslipidaemia (increased levels of cholesterol and/or fat in the blood).5
Antiretroviral medications can themselves be nephrotoxic, or may contribute to the adverse metabolic profile of HIV-positive patients. Leading causes of chronic kidney disease among HIV-positive people compared to HIV-negative people is shown in Table 1.
Table 1
Common causes of kidney disease in the HIV-negative and HIV-positive patients. Adapted from 18 19 20
| HIV-negative patients | HIV-positive patients |
|---|---|
| Diabetes | Diabetes |
| Hypertension | Hypertension |
| Glomerulonephritis | Medications (antiretrovirals and others) |
| Genetic | HIV-specific |
| Other | Other: HIV-related (HCV, HBV co-infection etc.) |
| Other: Non-HIV related |
Overseas, the numbers of HIV-positive people developing end-stage renal failure (ESRF) and requiring dialysis or renal transplantation are increasing.6
In the US the proportion of patients with ESRF and who have HIV has doubled in the last ten years.
In Australia, the number of HIV-positive people with ESRF is unknown, however, in a recent study 6% of patients had an estimated glomerular filtration rate (eGFR – a blood test that measures kidney function) of <60ml/min, and 10% demonstrated significant proteinuria (protein in urine; significant proteinuria is a potential sign of kidney damage).7
Previous studies have reported that up to a third of HIV-positive patients had abnormal kidney function.8 Despite the increased prevalence of abnormal renal function in this patient group, only a minority of patients are recognised as having kidney disease.
This is important, as CKD is associated with poorer outcomes and may be preventable, if recognised early.9
In Australia, there has been increasing interest in the area of kidney disease among HIV-positive people.
Current practices in general practice for the screening and management of kidney disease in patients with HIV were examined in a national study.10
This study identified gaps in current screening practices, with only 75% of patients assessed with renal function testing in the last year, and 30% of patients screened for proteinuria.
Risk factors for kidney disease were common. As well, Australian guidelines for the suitability of HIV-positive patients to undergo kidney transplantation have recently been published.11
Screening for chronic kidney disease in HIV-positive patients
Early detection of kidney disease is important to enable prevention or slow progression of impaired renal function.
Most guidelines recommend screening with a blood test for the eGFR and with a urine test for proteinuria, either with a urinary dipstick test or a protein: creatinine ratio (PCR).12 13
The recommended frequency of testing is at least annually, with more frequent testing in patients at high risk of kidney disease, particularly those with hypertension, diabetes or those taking potentially nephrotoxic antiretroviral therapies.
Measuring renal function
Estimation of renal function is commonly undertaken by measuring the serum creatinine, which is then used to estimate a patient’s renal function by using a formula to adjust for the patient’s age and gender.14
This is done automatically by the laboratory and reported as the eGFR. Creatinine is an indirect measure of renal function and is a waste product of muscle breakdown. It may be influenced by many variables including ethnicity, age, weight and gender.
In HIV-positive patients, measurement of renal function using the serum creatinine may be particularly problematic because of abnormal metabolism, altered body mass, as well as exposure to medications which may alter the body’s handling of creatinine.
Chronic kidney disease is present when the eGFR is measured on two occasions at least three months apart and is <60ml/min. A sustained reduction in eGFR is also significant, even if the absolute level remains above 60ml/min.15
The clinical classification of chronic kidney disease is shown in Table 2.16
Table 2
The stages of chronic kidney disease (CKD). CKD is defined as either kidney damage or GFR<60ml/min for at least three months. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormal blood or urine tests, or imaging studies.21
| Stage | Description | eGFR |
|---|---|---|
| 1 | Kidney damage with normal eGFR | >90 |
| 2 | Kidney damage with mildly reduced eGFR | 60–89 |
| 3 | Moderate reduction in eGFR | 30–59 |
| 4 | Severe reduction in eGFR | 15–29 |
| 5 | Kidney failure | <15 (or dialysis) |
Referral to a kidney specialist is recommended once the eGFR drops below 60ml/min, or if there has been a sustained reduction in renal function, particularly in the presence of proteinuria or haematuria.17
Measuring proteinuria
Proteinuria may be one of the earliest signs of kidney disease and the level of proteinuria is prognostic of progression to ESRF in the general population.
Screening for proteinuria may be undertaken using a albumin-specific dipstick test or a spot urinary protein:creatinine ratio.
The dipstick test may miss some low-level cases. As well, the uPCR is generally more convenient and provides numerical quantification of the degree of proteinuria that is present.25
Screening in high-risk patients
Screening for renal disease should be more intensive in those patients at particular risk of renal disease.26 Risk factors for renal disease in HIV-positive patients are shown in Table 3.
Table 3
Renal Risk Factors amongst the HIV-positive patient cohort. Many of these risk factors may be modifiable. Those patients at high risk of kidney disease should be screened more frequently for renal abnormalities (adapted from 22 23 24)
| Modifiable renal risk factors | Non-modifiable renal risk factors |
|---|---|
| Diabetes | Increasing age |
| Hypertension | Gender |
| Obesity | Family history |
| Dyslipidaemia | Ethnicity |
| Cigarette smoking | |
| HIV-specific (viral load, CD4 count) | |
| Hepatitis co-infection | |
| Nephrotoxic medications | |
| Other: illicit drugs, protein supplements |
Some of these risk factors may be modifiable to try to reduce a patient’s risk of developing disease, particularly metabolic risks such as obesity, diabetes, hypertension or cigarette smoking.
There is a preponderance of renal risk factors observed among people with HIV, and a majority are at increased risk of renal disease.27
Antiretroviral renal effects
Antiretroviral medications may have specific renal effects, and some may be nephrotoxic.28 Screening for these potential side effects is important, although they are uncommon.
A recent report suggests that the commonest reason for referral of an HIV-positive patient to a kidney specialist was because of concerns about nephrotoxicity relating to the patient’s cART.29
There are many antiretroviral agents with reported nephrotoxic effects. The nucleotide reverse-transcriptase inhibitor tenofovir disoproxil fumarate (TDF) is a highly effective first-line antiretroviral agent with reported renal side effects, although these are uncommonly seen.
For patients initiated on TDF, more frequent screening of renal parameters is recommended, including the serum phosphate, to try and detect renal tubular toxicity early.
There are reports of association with renal toxicity with many other antiretroviral agents, including the protease inhibitors atazanavir and ritonavir.
Overall, these potential renal side effects are uncommon and should be detected early, if the recommended screening practices are followed.
Management of renal disease in people with HIV
Stringent attention to renal risk factors and a reduction of the prevalence of renal disease in people with HIV can reduce associated morbidity and mortality.30
However, it is likely that the prevalence of kidney disease will continue to increase in this patient group, because of the prolonged survival and the increasing rates of hypertension and diabetes observed.
Management of renal risk factors may prevent progression of established renal disease.
Such approaches include aggressive blood pressure control with anti-hypertensives (with preferential use of ACE-inhibitors or angiotensin receptor blockers, if proteinuric), treatment of dyslipidaemia with lipid lowering medications, strict diabetic control, weight loss, exercise and smoking cessation.
Specific evaluation of some of these treatment strategies has not been undertaken among people with HIV and their benefit is extrapolated from studies undertaken in the HIV-negative cohort.
Additionally, dialysis and transplantation may be used in HIV-positive patients with advanced renal disease although, because of the inferior outcomes compared to the HIV-negative population, the focus remains on early detection and prevention of kidney disease in HIV-positive people, wherever possible.31 32
References
1 Phair, J., Palella, F. (2011). Renal disease in HIV-infected individuals. Curr Opin HIV AIDS, 6(4), 285–289.
2 Hall, A., Hendry, B., Nitsch, D.,Connolly, J. (2011). Tenofovir-associated kidney toxicity in HIV-infected patients: A review of the evidence. Am J Kidney Dis, 57(5), 773–780.
3 Phair, J., et al. (2011). op. cit.
4 Adih, W., Selik, R., Hu, X. (2011). Trends in diseases reported on US Death Certificates that mentioned HIV infection, 1996–2006. J Int Assoc Physicians AIDS Care, 10(1), 5–11.
5 Post, F., Holt, S. (2009). Recent developments in HIV and the kidney. Curr Opin Infect Dis, 9, 43–48.
6 Wyatt, C., Murphy, B. (2005). Kidney Transplantation in HIV-infected patients. Seminars in Dial, 18(6), 495–498.
7 Gracey, D., Chan, D., Bailey, M., Richards, D., Dalton, B. (2013). Screening and management of renal disease in human immunodeficiency virus-infected patients in Australia. Int Medicine J, 43(4), 410–416.
8 Gupta, S., Mamlin, B., Johnson, C., Dollins, M., Topf, J., Dubé, M. (2004). Prevalence of proteinuria and the development of chronic kidney disease in HIV-infected patients. Clin Nephrol, 61, 1–6.
9 Estrella, M., Fine D. (2010). Screening for chronic kidney disease in HIV-infected patients. Adv Chronic Kidney Dis, 17(1):26–41.
10 Gupta S., Mamlin B., et al., (2004). op. cit.
11 Campbell, S., Pilmore, H, Gracey, D., Mulley, W., Russell, C., McTaggart, S. (2013). KHA-CARI Guideline: Recipient Assessment for Transplantation. Nephrology, 18(6), 455–462.
12 Gupta, S., Eustace, J., Winston, J., Boydstun, I., Ahuja, T., Rodriguez, R., et al. (2005). 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(11), 1559–85.
13 European AIDS Clinical Society (EACS). Guidelines: clinical management and treatment of HIV infected adults in Europe. Version 6, 2011. Retrieved from: www.europeanaidsclinicalsociety.org
14 Estrella, M., et al. (2010), op. cit.
15 Phair, J., et al. (2011), op. cit.
16 National Kidney Foundation. (2002). K/DOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis, 39: S1–S266 (suppl 1).
17 Estrella, M., Fine, D.,(2010), op. cit.
18 Phair, J., et al. (2011). op. cit.
19 Post, F., et al. (2009). op cit.
20 Gracey, D., Chan, D., Bailey, M. et al., (2013). op. cit.
21 Gupta, S., Eustace, J., Winston, J., et al. (2005). op. cit.
22 Phair, J., et al. (2011). op. cit.
23 Post, F., et al. (2009). op cit.
24 Gracey, D., et al. (2013). op. cit.
25 Estrella, M., Fine, D. (2010). op. cit.
26 Gupta S., Mamlin B., et al. (2004). op. cit.
27 Phair, J., et al. (2011). op. cit.
28 Hall, A., et al. (2011). op. cit.
29 ibid.
30 Phair, J., et al. (2011). op. cit.
31 ibid.
32 Wyatt, C., et al. (2005). op. cit.
Dr David Gracey is a Senior Staff Specialist, Renal and Renal Transplant Physician at Royal Prince Alfred Hospital, Sydney and a Clinical Senior Lecturer at the Faculty of Medicine, Central Clinical School, University of Sydney.