Older age and baseline kidney function the key risk factors for CKD in people with HIV

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Older age and lower baseline kidney function are the only significant risk factors for the development of chronic kidney disease (CKD) in HIV-positive adults, investigators from Australia report. No antiretroviral (ARV) drug was associated with a decline in estimated glomerular filtration rate (eGFR) – a key marker of kidney function – below the key 60 ml/min threshold.

Our study was not designed to address ARV treatment decisions; however, in demonstrating increased CKD risk associated with an eGFR of 60-89 ml/min, we have highlighted a subgroup in which earlier tailoring of ART (antiretroviral therapy) may be appropriate,” comment the authors. “Our finding that neither current, nor cumulative TDF (tenofovir disoproxil fumarate) exposure increased the risk of CKD was not in keeping with the wider literature and international guidelines would suggest avoidance of TDF in individuals with a high risk of CKD.”

There is a well-established association between HIV infection and an increased risk of CKD. Reasons include damage caused by the virus, a high prevalence of traditional risk factors such as diabetes and hypertension, and the side-effects of some antiretroviral drugs. Of note, older age is also an acknowledged risk factor for CKD.

With this in mind, investigators at Monash University in Melbourne, Australia, designed a retrospective study involving 748 adult HIV-positive people who received care between 2009 and 2016. All had normal kidney function at baseline (eGFR above 60ml/min). The study’s aims were to identify risk factors associated with the development of CKD and also to see if two widely used risk scores (short D:A:D and Scherzer) were able to accurately predict which people had the highest risk of developing CKD (two consecutive eGFR results less than 60 ml/min).

Study participants were predominately male (91%) and had a median age of 46 years. Data on blood pressure were available for two-thirds of people and 26% of these individuals had hypertension (blood pressure of at least 140/90 mmHg). Medium serum glucose was within the normal range, though 5% of people were classified as diabetic. Most of the participants (93%) were taking ART. Median CD4 cell count was 483 cells/mm3 and two-thirds were virologically suppressed.

Baseline median eGFR was 106ml/min and declined by a median of 0.53min/ml per year. Only a third of people underwent urinary analysis, with 7% of these individuals having proteinuria.

During a median of 4.7 years of follow-up, CKD developed in 5% of people. Individuals who went on to develop CKD had a lower median baseline eGFR compared to those who retained good kidney function (75m/min vs 107 ml/min). They were older (median 55 years vs 46 years).

In initial analysis, older age, diabetes, proteinuria, higher baseline creatinine, lower baseline eGFR, longer duration of HIV infection and lower nadir CD4 cell count were all risk factors for the development of CKD.

In the multivariate analysis that controlled for potential confounders, the only significant factors were older age (OR = 3.03; 95% CI, 1.20-7.65, p = 0.02) and lower baseline eGFR (OR = 10.39; 95% CI, 4.73-22.83, p < 0.001). “ARV use at baseline was not found to be associated with subsequent development of CKD,” comment the authors. “Neither current, nor cumulative TDF exposure was associated with the development of CKD.”

Both risk scores predicted CKD, with results favouring the short D:A:D score. The Scherzer risk score includes age, blood glucose, triglycerides, hypertension, CD4 cell count and proteinuria. The D:A:D risk score takes into account age, sex, injecting drug use, hepatitis C virus co-infection, eGFR and nadir (lowest ever) CD4 cell count.

Limitations of the study include its retrospective, observational, single-centre design. Data were also lacking for many people for key markers or risk factors for CKD, such as hypertension and proteinuria.

“Our results confirm that ageing significantly increases the risk of CKD, which has important implications with respect to the increasing life expectancy of HIV-positive individuals,” write the researchers. “A lower baseline eGFR of 60-89 ml/min was associated with subsequent risk of CKD.”

“Risk prediction tools can assist clinicians to stratify those at highest risk, with most to gain from increased monitoring, judicious ARV selection and aggressive management of risk factors,” they conclude.

Abstract
Objective: The current study aimed to validate existing risk prediction scores and identify predictors of chronic kidney disease (CKD) in the setting of HIV.
Design and methods: A retrospective cohort study of HIV-positive individuals (n = 748) with baseline estimated glomerular filtration rate (eGFR) more than 60 ml/min was conducted at the Alfred Hospital, Melbourne, Australia. Multivariable regression analysis was performed to determine factors associated with development of CKD, defined as two consecutive measurements of eGFR less than 60 ml/min. The performance of CKD risk scores proposed by the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group and Scherzer and colleagues were estimated by the area under the receiver operator curve (AUROC).
Results: CKD developed in 37 individuals (5.0%), at a median of 4.7 (interquartile range 2.2, 6.2) years. Older age [odds ratio (OR) 3.03, 95% confidence interval (CI): 1.20, 7.65, P = 0.02] and lower baseline eGFR (OR 10.39, 95% CI: 4.73, 22.83, P < 0.001) were associated with the development of CKD. Neither current, nor cumulative tenofovir disoproxil fumarate (TDF) use was associated with progression to CKD [current TDF hazard ratio (HR) 1.05, 95% CI: 0.54, 2.07, P = 0.88; cumulative TDF HR 1.03, 95% CI: 0.86, 1.24, P = 0.75]. The short D:A:D and Scherzer scores were well calibrated, with the short D:A:D score demonstrating superior discrimination (short D:A:D AUROC 0.85, Scherzer AUROC 0.78, P = 0.02).
Conclusion: Older individuals and those with a lower baseline eGFR are at higher risk for CKD. Risk prediction tools may be useful in identifying those at greatest risk, who may benefit from aggressive management of risk factors.

Authors
Woolnough, Emily L; Hoy, Jennifer F; Cheng, Allen C; Walker, Rowan G; Chrysostomou, Anastasiac; Woolley, Iana; Langham, Frey; Moso, Michael A; Weeraratne, Achinib; Trevillyan, Janine M

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