Abstract
We assessed the association between dolutegravir (DTG)-based antiretroviral therapy and kidney abnormalities among young people living with HIV in Kampala, Uganda. Cross-sectional albumin–creatinine ratio (ACR), proteinuria, and estimated glomerular filtration rate (eGFR) were measured. Among 483 participants, the mean serum creatinine was higher (0.68 vs. 0.59) and creatinine-based eGFR lower (118.8 vs. 113.9), among those on TDF/DTG. Cystatin C–based eGFR, prevalences of elevated ACR (9.6% vs. 13.0%), proteinuria (28.3% vs. 30.2%), and eGFR < 90 ml/min/1.73 m² (40.1% vs. 46.9%) were similar. Kidney abnormalities were not associated with regimen, supporting the need for longitudinal studies to clarify progression risk.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12981-026-00893-2.
Keywords: Kidney function, Dolutegravir, Young people living with HIV, Sub Saharan Africa
Introduction
Antiretroviral therapy (ART) has transformed HIV infection from a fatal illness into a chronic condition [1]. The success of ART means that young people living with HIV (YPLHIV) are increasingly surviving into adulthood and face long-term health challenges [1]. Non-communicable conditions, including chronic kidney disease, have emerged as important contributors to morbidity and mortality [2]. Multiple factors (including direct effects of HIV, coexisting infections, traditional risk factors of hypertension and diabetes, and exposure to nephrotoxic ART) drive kidney abnormalities in YPLHIV [3]. Young people are especially vulnerable because they are likely to be exposed to ART for many decades as they age while on ART, during which cumulative drug effects and ongoing HIV-related immune activation may increase the risk of kidney dysfunction [4].
The recent global transition to DTG based regimens has introduced new complexities in monitoring kidney function. DTG is now the preferred first-line ART in many low- and middle-income countries, including Uganda, because of its high efficacy and favourable tolerability profile [5]. All YPLHIV were switched to a DTG based regimen from 2022 [6]. However, DTG inhibits tubular secretion of creatinine without affecting glomerular filtration, leading to modest but persistent increases in serum creatinine [7]. This pharmacological effect may confound the assessment of kidney function and obscure early signs of true kidney abnormalities. There is a critical need to characterise the burden of kidney abnormalities in YPLHIV on DTG-based ART in Uganda. We set out to describe the prevalence and association of kidney abnormalities with DTG-based regimens among YPLHIV in Uganda.
Methods
We conducted a cross-sectional study in seven urban public health facilities in Kampala, Uganda, which provide comprehensive HIV care and treatment services, mostly for the urban poor.
The study included YPLHIV aged 10–24 years with presumed perinatal HIV infection. Pregnant YPLHIV were excluded. ALL YPLHIV were on ART according to the current Ministry of Health guidance. Systematic random sampling (listing all YPLHIV in the clinics and picking out every other name) was used to identify potential participants to minimise selection bias and ensure that the study sample was representative of the target population, thereby supporting valid statistical inference and generalisability of findings. These were invited to join the study. With a mean serum creatinine of 0.68 and 0.59; sample size of 367 in the tenofovir disoproxil fumarate (TDF) group and 116 in the other group, and alpha set to 0.05, the study had 99% power to detect an association between dolutegravir and kidney abnormalities. Details of the parent study have been published previously [8].
Eligible participants were invited to the HIV clinic through a phone call to those above 18 years or the caregiver for those below 18 years after an overnight fast. After screening and consent, we collected urine samples for the albumin creatinine ratio (ACR), proteinuria on dipstick, and blood samples for serum creatinine and cystatin C. We estimated glomerular filtration rate (eGFR) using the CKDEPI 2021 equation or the Bedside Schwartz (< 18 years).
Participants were interviewed to collect socio-demographic data such as age, sex, and socioeconomic status. Measurements were taken for weight, height, mid-upper arm circumference (MUAC), body mass index (BMI) was calculated as weight over height squared. Participants were considered stunted if they were two standard deviations below normal according to the WHO standards [9]. Muscle mass was determined using a bioimpedance machine and calculated using sex and age-specific cut-offs. Elevated blood pressure was determined using the updated 2017 American Academy of Paediatrics (AAP) clinical practice guidelines that stipulate that hypertension is BP > 95th percentile for age, sex and height for those aged less than 13 years and > 130/90 mmhg for those above 13 years [10]. No ART regimen changes were made during the study.
Data management and statistical analysis: Data were collected in REDCap and analysed with STATA statistical software Version 18 (STATA Corp USA). Demographic and clinical data were summarised in percentages or means (standard deviation [SD]) and median (interquartile range [IQR]). We used chi-square tests to compare kidney function parameters of participants on tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and DTG compared with those on DTG combined with other Nucleoside Reverse Transcriptase Inhibitors, such as zidovudine or abacavir, and 3TC (other DTG regimens). The specific regimens are shown in Supplementary Table 1. Cystatin C analyses were restricted to those with suppressed viral load.
Ethical considerations: Ethical approval was received from the Uganda Virus Research Institute (UVRI) Research Ethics Committee (reference number GC/127/946), the Uganda National Council of Science and Technology (HS2578ES) and the London School of Hygiene and Tropical Medicine institutional review board (28797). All participants aged 18 years or older provided written informed consent. Those aged < 18 years, provided written participant assent, and caregiver consent. All participants with suspected CKD were referred to a nephrologist for management.
Results
Of 500 YPLHIV, 483 on a DTG-based regimen were enrolled into the study, with 367 (76%) on TDF/3TC/DTG and 116 (24%) on other DTG regimens. There were slightly more females than males in both groups. There were more underweight and malnourished participants on other DTG regimens. Viral suppression and mean duration on ART were similar in both groups. Table 1.
Table 1.
Demographic and clinical characteristics of the participants by ART regimen
| TDF/3TC/DTG N = 367 | Other/DTG regimens N = 116 | p-value | |
|---|---|---|---|
| Mean (SD)Age (years) | 17.0 (3.5) | 14.4 (3.4) | < 0.001 |
| 10 to 17 | 231 (62.9%) | 93 (80.2%) | < 0.001 |
| 18 to 24 | 136 (37.1%) | 23 (19.8%) | |
| Sex | |||
| Female | 211 (57.5%) | 62 (53.4%) | 0.44 |
| Socioeconomic status | |||
| Lowest | 129 (35.1%) | 44 (37.9%) | 0.86 |
| Middle | 114 (31.1%) | 35 (30.2%) | |
| Highest | 124 (33.8%) | 37 (31.9%) | |
| Body mass index | |||
| Normal | 224 (61.2%) | 44 (37.9%) | < 0.001 |
| Underweight | 106 (29.0%) | 67 (57.8%) | |
| Overweight | 36 (9.8%) | 5 (4.3%) | |
| Stunting* | |||
| Not stunted | 221 (84.0%) | 80 (79.2%) | 0.28 |
| Stunted | 42 (16.0%) | 21 (20.8%) | |
| Mid upper arm circumference (MUAC) | |||
| Normal | 338 (92.3%) | 100 (86.2%) | 0.05 |
| Malnourished | 28 (7.7%) | 16 (13.8%) | |
| Weight (kg) | 51.2 (11.5) | 41.9 (12.7) | < 0.001 |
| Duration on ART | 9.7 (3.9) | 9.2 (3.7) | 0.19 |
| Viral suppression | |||
| Suppressed | 331 (90.9%) | 101 (87.1%) | 0.23 |
| Unsuppressed | 33 (9.1%) | 15 (12.9%) | |
| CD4 T cell count (cells/µL) | |||
| > 500 | 196 (59.8) | 90 (84.1) | < 0.001 |
| 200–500 | 87 (26.5) | 8 (7.5) | |
| < 200 | 45 (13.7) | 9 (8.4) | |
Malnourished participants had a MUAC in either yellow or red. *stunting was measured as two standard deviations for height for age according to the World Health Organization (WHO). Viral suppression was defined as an HIV viral load below 1000 copies per ml
Participants’ kidney parameters by regimen
The mean serum creatinine levels were higher among participants on TDF/DTG compared to those on other DTG regimens, although the mean eGFR and the proportions with eGFR < 90 ml/min/1.73m2 were similar. The mean cystatin C was similar in both groups. The mean eGFR was within normal limits and lower among those on TDF/3TC/DTG compared to those on other DTG regimens. The proportion with eGFR cystatin between 60 and 90 ml/min/1.73m2 was higher among those on TDF/3TC/DTG (33.5% vs. 15.0% p = 0.02). The proportion of YPLHIV with ACR>30 mg/g was higher among those on other DTG regimens, and proteinuria proportions were high but similar (Table 2). The distribution of the eGFRs is shown in Fig. 1 in the supplementary materials.
Table 2.
Participant kidney parameters by ART regimen
| Variable | TDF/3TC/DTG N = 367 | Other DTG-based* N = 116 | p-value |
|---|---|---|---|
| Serum creatinine Mean (SD)# | 0.68 (0.15) | 0.59 (0.14) | < 0.001 |
| eGFR serum creatinine (SD) | 118.8 (19.3) | 113.9 (20.1) | 0.32 |
| eGFR serum creatinine | |||
| > 90 ml/min/1.73m2 | 317 (87.3) | 103 (89.6) | 0.52 |
| < 90 ml/min/1.73m2 | 46 (12.7) | 12 (10.4) | |
| Cystatin C Mean(SD)#a | 0.81 (0.13) | 0.80 (0.12) | 0.80 |
| eGFR cystatin C (SD)a | 114.6 (14.9) | 117.2 (14.8) | 0.13 |
| eGFR cystatin Ca | |||
| > 90 ml/min/1.73m2 | 196 (59.8) | 52 (52.0) | 0.36 |
| 60–90 ml/min/1.73m2 | 128 (39.0) | 47 (47) | |
| < 60 ml/min/1.73m2 | 4 (1.2) | 1 (1) | |
| Albumin creatinine ratio | |||
| Below 30 mg/g | 328 (90.4) | 100 (87.0) | 0.27 |
| 30–299 | 32 (8.2)) | 15 (13.0) | |
| > 300 | 3 (0.8) | 0 (0) | |
| Proteinuria | |||
| Negative | 263 (71.7) | 81 (69.8) | 0.70 |
| Positive | 104 (28.3) | 35 (30.2) | |
| Blood Pressure | |||
| Normal | 263 (72.3) | 72 (62.1) | |
| Elevated | 46 912.6) | 20 (17.2) | 0.11 |
| Hypertensive | 55 (15.1) | 24 (20.7) |
*Regimens with either abacavir or zidovudine together with lamivudine and dolutegravir. # serum creatinine and cystatin C were both measured in mg/dl. a restricted to those with suppressed viral load. N = 428
Discussion
In our study, we found no evidence of a difference in estimated creatinine or cystatin based eGFR between those receiving DTG/TDF versus other DTG regimens but a similar prevalence of abnormal ACR and dipstick proteinuria.
Our findings are consistent with those of the ODYSSEY trial from Uganda, Thailand, Europe, Zimbabwe, and South Africa, which reported no kidney-related adverse effects in 707 children and adolescents living with HIV on DTG-based regimens coupled with NRTIs, including TDF at 96 weeks [11]. A systematic review on the efficacy and safety of DTG among children and adolescents reported data on 11 studies, which did not report any kidney-related adverse events, although the number of children on both DTG and TDF and the duration were not reported [12]. Taken together, these data are reassuring about ongoing use of DTG combined with TDF as first-line ART for YPLHIV initiating treatment in Uganda [5].
There are concerns about DTG obscuring kidney dysfunction, especially when it is co-administered with TDF, which is known to cause kidney abnormalities [13, 14]. This concern has not yet been fully addressed, as there are very few studies done in Africa that involve young people living with HIV on both DTG and TDF [15]. A study done in Nigeria among 170 adult PLHIV found that those on TDF/DTG had impaired kidney function [16]. A pilot clinical trial showed that PLHIV who switched to TDF/DTG combination had a greater decline in eGFR compared to those switched to DTG/lamivudine [17]. A global systematic review and meta-analysis showed a 7% prevalence of chronic kidney disease among those treated with TDF, there was no mention of DTG effects [18]. Since the duration on ART is associated with risk of TDF kidney toxicity [19], and YPLHIV are exposed to TDF for a longer time than adults living with HIV, vigilant monitoring of kidney function is warranted for YPLHIV treated with TDF-containing regimens, to ensure early diagnosis. Use of tenofovir alafenamide (TAF) should also be considered, as this is associated with less kidney toxicity compared to TDF, according to data pooled from 26 clinical trials that also included children [20]. However, weight and metabolic changes should be monitored [21].
The main limitation of our study was the inability to compare the kidney function of YPLHIV on DTG based regimens to others who were not exposed to DTG, since most YPLHIV were switched to DTG following the WHO recommendations. We also didn’t enrol any HIV negative participants and are unable to compare our findings. We did not account for the regimen changes over time with the changing recommendations over the lifetime of the YPLHIV. It was also a cross-sectional study, and more information about long-term toxicity should be collected from longitudinal studies. We did not measure the protein creatinine ratio and were unable to determine if proteinuria was glomerular or tubular. Although we measured haematuria, all the five people with positive results were female and could have been in their monthly menses. The strengths are that the study was adequately powered to detect an association, and our findings are generalisable to YPLHIV living in settings similar to ours.
Conclusion
We found that YPLHIV on DTG-based regimens had a high prevalence of proteinuria and elevated ACR regardless of the nucleoside analogues utilized alongside DTG. However, eGFR calculated from both serum creatinine and cystatin C was largely within normal limits. Extended longitudinal follow-up is needed to assess the onset and risk of CKD development among ageing YPLHIV and to elucidate factors associated with disease progression, including the long-term safety of antiretroviral therapy regimens.
Supplementary Information
Acknowledgements
We wish to acknowledge the participants, their caregivers and the facility staff where this study took place. We also acknowledge the study team, Miss Evelyn Natuha, Miss Stella Mirembe and Mr. Malcolm Lwanga. We acknowledge the KCCA leadership and the PEPFAR program that supports HIV care for the YPLHIV.
Abbreviations
- ACR
Albumin Creatinine Ratio
- ART
Anti-Retroviral Therapy
- BMI
Body Mass Index
- CKD
Chronic Kidney Disease
- CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
- DTG
Dolutegravir
- eGFR
Estimated Glomerular Filtration Rate
- HIV
Human Immunodeficiency Virus
- IQR
Interquartile Range
- KDIGO
Kidney Disease Improving Global Outcomes
- MUAC
Mid upper arm circumference
- SD
Standard Deviation
- SSA
Sub-Saharan Africa
- USA
United States of America
- WHO
World Health Organization
- YPLHIV
Young People Living with HIV
Author contributions
EN, RH, CD, HW contributed to the conceptualization and design of the study, data collection, analysis, interpretation, and editing the manuscript. EN, RH and HW drafted the manuscript. RK contributed to the interpretation of results and edited the manuscript for important scientific content. All authors reviewed and approved the manuscript before submission for publication. All authors are accountable for the work in this paper.
Funding
Support for the studies was provided by Fogarty International Centre, National Institutes of Health (grant #2D43TW009771-06) HIV and co-infections in Uganda. Esther Nasuuna, Doctoral Research Fellow, NIHR131273 is funded by the NIHR for this research project. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care. The funders had no role in the study design, collection, analysis or interpretation of data. Neither did they choose where this work gets published.
Data availability
To protect the confidentiality of the participants who provided the clinical data, the data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The Uganda Virus Research Institute (UVRI) Research Ethics Committee (GC/127/946), the Uganda National Council of Science and Technology (HS2578ES), and the London School of Hygiene and Tropical Medicine (reference 28797) approved this study. All participants regardless of age provided informed consent/assent after provision of age-appropriate study information. Participants > 18 years s provided a written informed consent. Children < 18 years provided written assent, and their caregivers provided a written informed consent. The studies were conducted in accordance with the Declaration of Helsinki.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
To protect the confidentiality of the participants who provided the clinical data, the data that support the findings of this study are available from the corresponding author upon reasonable request.