Kidney impairment in HIV: an insight into the burden and associated factors among adults on antiretroviral therapy in Zambia. A retrospective cross-sectional study

Abstract

Background:

Kidney disease, ranging from asymptomatic kidney impairment to end-stage renal disease, remains a public health concern globally. Kidney diseases have been shown to be a significant cause of mortality and morbidity among people living with HIV (PLWH). However, there is limited data on the burden and risk factors for kidney impairment in resource-limited settings.

Objectives:

This study aimed to determine the prevalence and factors associated with kidney impairment among PLWH receiving antiretroviral therapy (ART) at a tertiary hospital in Zambia.

Design:

This was a retrospective cross-sectional study.

Methods:

This study consisted of 374 PLWH aged ⩾18 years and on ART for ⩾ 6 months. We obtained clinical, laboratory, and demographic characteristics from a study that focused on metabolic syndrome among PLWH. Kidney impairment was defined as having an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m². Data was analyzed using STATA version 15. Multivariable logistic regression was used to ascertain factors associated with kidney impairment.

Results:

The median age among the study participants was 44 years, and the majority were females, 63.4% (n = 237). The prevalence of kidney impairment was 10.7% (n = 40. After accounting for duration on ART, sex and blood pressure (systolic and diastolic), older age and being on a Dolutegravir (DTG) and tenofovir disoproxil fumarate/lamivudine (TDF/3TC) based regimen was positively associated with kidney impairment (adjusted odds ratio (aOR) 1.09; 95% CI: 1.05, 1.14, p < 0.001) and (aOR 2.44; 95% CI: 1.02, 5.79, p = 0.043), respectively.

Conclusion:

The prevalence of kidney impairment was common among adult PLWH and was significantly associated with older age and the use of a DTG and TDF/3TC-based regimen. There is a need to regularly monitor kidney function among people with HIV, especially older people who are on a DTG and TDF/3TC-based regimen.

Plain language summary

Kidney dysfunction in HIV: an inquiry at the prevalence and factors linked to it among people in Zambia who are on antiretroviral therapy (ART)

Why was the study conducted? Kidney dysfunction is becoming a bigger health problem around the world, especially for people living with HIV (PLWH). Having kidney problems can severely impact health or lead to death. However, little research has been done on the prevalence of kidney disease or the factors that contribute to it in resource-limited settings like Zambia. This study aimed to find out how common kidney disease is and what factors increase the risk of developing it among PLWH in Zambia who are on antiretroviral therapy (ART). What did the researchers do? The medical records of 374 adults on ART for at least six months were reviewed. Key clinical, laboratory, and demographic data were analyzed to identify factors that lead to kidney damage, with kidney impairment defined by an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m². The research team then analyzed the data to find which factors were linked with kidney damage. What did the researchers find? The study found that 10.7% of the participants had kidney dysfunction. Most of the participants were women (63.4%) with an average age of 44 years. Older individuals and those on specific HIV treatments, particularly regimens containing DTG (dolutegravir) and TDF/3TC (tenofovir disoproxil fumarate/lamivudine), were found to be at higher risk for kidney problems. What do the findings mean? The findings out that kidney dysfunction are relatively common among adults living with HIV in Zambia, especially as the age increases for older individuals and those on certain HIV medications like (DTG (dolutegravir) and TDF/3TC (tenofovir disoproxil fumarate/lamivudine). Regular monitoring of kidney function is recommended for these high-risk groups to detect and manage kidney issues early. This could help improve the overall health and well-being of PLWH our setting with limited resources.

Keywords

associated factors estimated glomerular filtration rate kidney impairment people living with HIV prevalence

Introduction

The management of HIV has continued to improve significantly in sub-Saharan Africa, with decreased mortality due to expanded antiretroviral therapy coverage in countries such as Zambia.^1,2 This has resulted in an increased life expectancy for individuals living with HIV, thereby increasing the burden of noncommunicable diseases (NCDs), including renal insufficiency.³ The prevalence of kidney dysfunction among people living with HIV (PLWH) in Africa varies widely from 11% to 90%, while in the general population, it ranges from 2% to 41%, depending on their respective case definitions of kidney disease.⁴

Despite Zambia being a high HIV endemic region in Africa, routine screening for NCDs among PLWH remains a challenge due to limited resources.^5,6 This results in missed opportunities to identify people with NCDs and/or at higher risk of NCDs.⁵ Understanding common risk factors for kidney impairment is crucial for prevention and early diagnosis in PLWH.³ Studies have shown multiple factors that are associated with kidney dysfunction in PLWH such as older age, high blood pressure, diabetes, coinfection with hepatitis B and hepatitis C, low CD4 count, poor control of HIV, duration of ART, and the use of nephrotoxic drugs, all of which contribute to kidney damage in individuals with HIV.^7,8 However, there is a paucity of data on the burden and associated factors for kidney impairment in resource-limited settings, such as Zambia. Therefore, this study aimed to determine the prevalence and factors associated with kidney impairment among PLWH receiving ART at a tertiary hospital in Zambia.

Methods

Study design and setting

This was a retrospective cross-sectional study among adults whose data were obtained from a study that focused on metabolic syndrome among PLWH between April 2019 and April 2020 at Livingstone University Teaching Hospital (LUTH).⁹ Livingstone is a town in Zambia located in the Southern Province and has a total population of 136,897. LUTH is a third-level hospital and the main referral hospital in Southern Province. Livingstone has an HIV prevalence of 25%, with about 4000 patients receiving ART. To enhance the reporting for this observational study, we adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (Supplemental Material).¹⁰

Eligibility and selection methods

Data records were obtained from a primary study that investigated metabolic syndrome among PLWH. The primary study excluded pregnant women and those with active opportunistic infections and neoplasms, bringing the sample size to 625 individuals. Participants who had serum creatinine and had been on ART for 6 months or more were included in the study.

Variables in the study

The outcome variable was kidney impairment and was defined as having an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m².¹¹ GFR was calculated using the race-neutral modified four-variable MDRD formula.¹² The formula is as follows:

\begin{array}{l} G F R = 175 \times {(s t a n d a r d i z e d S C r)}^{^-} 1.154 \\ \times {(a g e)}^{^-} 0.203 \times 0.742 (i f f e m a l e) . \end{array}

The independent variables included duration of ART, sex, and blood pressure (systolic and diastolic), duration of ART in months, viral load, CD4 count, hepatitis B, hepatitis C, history of type 2 diabetes mellitus, age, alcohol use, smoking, and ART regimen.

Data collection

Data were collected from the primary study as follows: demographics (age, sex), clinical characteristics (ART regimen, diastolic blood pressure, systolic blood pressure, and duration of ART), and laboratory characteristics (serum creatinine) were collected directly from participants and medical records using a data abstraction form. The primary study measured diastolic and systolic blood pressure using a digital machine (Omron-HEM-7120, USA), and three blood pressure readings were obtained, 1 min apart, for each participant after they rested for 5 min. The readings were averaged to determine the participant’s blood pressure. The ART regimens were ascertained from the electronic medical record (SmartCare) and classified as follows: The non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens included either efavirenz (EFV) or nevirapine (NVP), an integrase strand transfer inhibitor (INSTI) regimen containing dolutegravir (DTG), and the protease inhibitor (PI) regimens included either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) and all three went along with one of the following nucleoside reverse transcriptase inhibitors (NRTIs): abacavir and lamivudine/emtricitabine (ABC/XTC) or tenofovir disoproxil fumarate/lamivudine (TDF/3TC) and zidovudine and lamivudine (AZT/3TC). The duration of ART was also ascertained from SmartCare.

Serum creatinine records were collected. In the primary study, blood samples were collected in clearly labeled sodium heparin vacutainer tubes for analysis of serum creatinine, and ethylenediaminetetraacetic acid (EDTA) containers were used to collect blood for CD4 count and HIV viral load (VL). The samples were immediately transported in cold storage to the laboratory for analysis. The samples were processed within 3 h of collection, after which plasma was kept at −80°C in cryovials. To obtain plasma, samples were centrifuged for 10 min at 10,000 relative centrifugal force. Serum was used to assay serum creatinine using a HumaStar 600 machine, and plasma was used to assay VL using an Ampliprep/Taqman 96 PCR machine.

Data analysis

The categorical data were summarized by calculating the frequencies and proportions. The normality of the data was assessed using the Shapiro-Wilk test and Q–Q plots. The medians and interquartile ranges were used to summarize continuous variables due to the non-normal distribution of the data. The Chi-square and Wilcoxon rank-sum tests were used to ascertain the statistical difference between two categorical variables and two medians, respectively. Fisher’s Exact Test was used when the expected frequencies in the contingency table were less than 5. Multivariable logistic regression was used to determine factors associated with kidney impairment among the study participants. The characteristics in the final model were chosen based on previous literature. Statistical software Stata version 2015 was used for data analysis.

Results

Selection of participants

After excluding participants without serum creatinine, the total size was 374 (Figure 1).

Figure 1.

Selection of participants.

Basic characteristics

The median age of the participants was 44 years (interquartile range (IQR): 37, 52), and 63.4% (n = 237) were females. The median systolic and diastolic blood pressure were 119 (IQR: 110, 135) and 77 (IQR: 71, 85), respectively, and the median duration on ART in months was 108 (60, 144). The majority of the participants were on TDF/3TC and NNRTI (n = 250, 66.8%), followed by TDF/3TC and DTG (n = 65, 17.4%).

The prevalence of kidney impairment among people receiving ART was 10.7% (n = 40). Individuals with kidney impairment were older compared to individuals without kidney impairment (55 vs. 44 years; p < 0.001). Individuals with kidney impairment on TDF/3TC NNRTI, TDF/3TC & PI, TDF/3TC & INSTI (DTG), AZT/3TC & PI, ABC/3TC & NNRTI, ABC/3TC & PI were 16 (40%), 1 (2.5%), 15 (37.5%), 2 (5.0%), 5 (12.5%), and 1 (2.5%), respectively compared to those who did not have in the respectful ART regimen (Table 1).

Table 1.

Basic characteristics of the study participant.

Variable	Number	Median, (IQR) OR frequency (%)	Kidney impairment		p Value
Variable	Number	Median, (IQR) OR frequency (%)	Yes, 40(10.7%)	No, 333(89.3%)	p Value
Age*	374	44 (37, 52)	55.5 (47.5, 63)	44 (36, 50)	<0.001
Sex**	374				0.028
Male		137 (36.6)	21 (52.5)	116 (34.7)
Female		237 (63.4)	19 (47.5)	218 (65.3)
Smoking**	374				0.006
Yes		57 (15.24)	12 (30.0)	45 (13.5)
No		317 (84.76%)	28 (70.0)	289 (86.5)
Alcohol**	373				0.140
Yes		211 (56.6)	27 (67.5)	184 (55.6)
No		162 (43.4)	13 (32.5)	149 (44.7)
Hepatitis B**	373				0.286
Yes		23 (6.2)	4 (10.0)	19 (5.7)
No		350 (93.8)	36 (90.0)	314 (94.3)
Hepatitis C**	374				0.004
Yes		1 (0.3)	1 (2.5)	0 (0.00)
No		373 (99.7)	35 (97.5)	334 (100)
Type 2 diabetes mellitus**	347				0.032
Yes		5 (1.4)	2 (5.4)	3 (0.97)
No		342 (98.6)	35 (94.6)	307 (99.0)
CD4 count*	373	580 (390, 847)	685 (461.5, 962.5)	568 (387, 816)	0.139
Viral load*	374	25.5 (0, 498)	22.5 (0, 854)	27 (0, 488)	0.534
Systolic blood pressure*	374	119 (110, 135)	138 (115, 151)	118 (110, 131)	0.534
Diastolic blood pressure*	374	77 (71, 85)	85 (72, 93)	77 (70, 93.6)	0.149
Duration of cART*	374	108 (60, 144)	126(70, 156)	108 (60, 144)	0.339
ART regimen	374				<0.001
TDF/3TC & NNRTI		250 (66.8)	16 (40.0%)	234 (70.0%)
TDF/3TC & PI		10 (2.7)	1 (2.5%)	9 (2.7%)
TDF/3TC & INSTI (DTG)		65 (17.4)	15 (37.5%)	50 (14.9%)
AZT/3TC & PI		35 (9.4)	2 (5.0%)	33 (9.9%)
ABC/3TC & NNRTI		11 (2.9)	5 (12.5%)	6 (1.8%)
ABC/3TC & PI		3 (0.8)	1 (2.5%)	2 (0.6%)

Data presented as median (interquartile range).

Data presented as frequency (%).

ABC/3TC, abacavir/lamivudine; ATV/r, atazanavir/ritonavir; AZT/3TC, zidovudine/lamivudine; DTG, dolutegravir; EFV, efavirenz; INSTI, integrase strand transfer inhibitor; LPV/r, lopinavir/ritonavir; NNRTI, non-nucleoside/nucleotide reverse transcriptase inhibitor; NRTI, nucleotide reverse transcriptase inhibitor; NVP, Nevirapine; PI, protease inhibitor; TDF/3TC, tenofovir alafenamide/lamivudine.

Logistic regression analysis of factors associated with kidney impairment

Table 2 shows univariable and multivariable analyses of factors associated with kidney impairment. At crude analysis, a unit (year) increase in age was significantly associated with a 1.11 odds of having kidney impairment. A unit increase in systolic blood pressure increases the chances of 1.01 times having kidney impairment. Participants on a DTG and TDF/3TC-based regimen had 4.39 odds of having kidney impairment compared to those on an NNRTI and TDF/3TC-based regimen. Women, compared to men, had a significantly 52% reduced odds of having an impairment.

Table 2.

Univariable and multivariable analysis of factors associated with kidney impairment.

Variable	Crude analysis		p Value	Adjusted analysis		p Value
Variable	OR	95% CI	p Value	OR	95% CI	p Value
Age	1.11	(1.07–1.15)	<0.001	1.09	(1.05–1.14)	<0.001
Sex
Male	Ref			Ref
Female	0.48	(0.25–0.93)	0.030	0.84	(0.39–1.78)	0.643
Systolic blood pressure	1.01	(1.01–1.03)	0.002	1.00	(1.05–1.14)	0.580
Diastolic blood pressure	1.02	(0.99–1.04)	0.064	1.00	(0.94–1.03)	0.429
Duration of art (months)	0.99	(0.99–1.00)	0.941	1.00	(0.99–1.00)	0.429
ART regimen
TDF/3TC & NNRTI	Ref			Ref
ABC/3TC & NNRTI	12.2	(3.35–44.29)	<0.001	4.29	(0.96–19.00)	0.056
ABC/3TC & PI	7.31	(0.63–85.0)	0.089	6.58	(0.51–83.74)	0.147
AZT/3TC & PI	0.89	(0.87–0.19)	0.978	0.96	(0.19–4.75)	0.964
TDF/3TC & PI	1.62	(0.65–0.19)	0.965	3.14	(0.30–32.60)	0.304
TDF/3TC & INSTI (DTG)	4.39	(2.04–9.45)	<0.001	2.44	(1.02–5.79)	0.043

In multivariable analysis, a year increase in age was significantly associated with 9% increased odds of having kidney impairment, and participants on a DTG and TDF/3TC-based regimen compared to those on an NNRTI and TDF/3TC regimen were 2.44 times more likely to have kidney impairment.

Discussion

We found a high prevalence of kidney impairment (10.7%) among PLWH at LUTH who had been on ART medication for more than six (6) months. Kidney impairment was associated with older age and being on DTG and TDF/3TC treatment. These findings highlight the burden of noncommunicable diseases among PLWH, which are linked to poor health outcomes if left untreated.

The prevalence observed in our study was lower than that reported in a study done in Ghana found 14.3%¹³ but higher than the prevalence found in a study from North-West Ethiopia, which found 7.6%.¹⁴ Kidney impairment is one of the leading health concerns among V individuals living with HIV, as it contributes to morbidity and mortality, thereby reducing the quality of life.¹⁵ Hence, regular monitoring of the renal function should be intensified as it will result in early diagnosis and improve prognosis and the quality of health, as we aim for viral suppression and increased life expectancy.

Our study found an association between age and kidney impairment, with older individuals being at a higher risk. This is consistent with a study conducted in South Africa, which showed that older adults were nearly five times more likely to have HIV comorbidities than younger adults.¹⁶ This can be explained by the natural decline in nephron count with aging. Furthermore, HIV directly infects the kidney cells, leading to inflammation and scarring, increasing the risk of kidney impairment.^17,18 Therefore, there is a need to include routine kidney function tests in HIV care in high HIV burden settings, especially among older adults, to avoid complications and maximize the benefits gained by advances in HIV therapy.¹⁹

Individuals receiving a DTG and TDF/3TC-based regimen were at an increased risk of kidney impairment. Our finding aligns with a study by Casado et al., which showed that individuals on a DTG-containing therapeutic regimen presented higher serum creatinine and decreased estimated glomerular filtration rate.²⁰ However, other studies have suggested that DTG has no significant negative effects on renal function, indicating variability in individual responses to DTG.^21,22 DTG is known to inhibit the renal transporter OCT2, leading to a mild-to-moderate increase in serum creatinine concentrations and moderate reduction in serum creatinine estimated glomerular filtration rate (eGRF-scr), particularly within the first few weeks of treatment.²⁰ The patients on DTG who had increased chances of having kidney impairment were on TDF/3TC. A systematic review of kidney impairment among Africans found a significant decline in renal function associated with TDF use.²³ High tenofovir plasma levels result in intracellular accumulation in the renal tubular cells, a consequent increased risk of renal toxicity.²⁴ Thus, regular kidney function monitoring is recommended for individuals on a DTG-based regimen as well as those on TDF/3TC. Healthcare providers should be aware of this interaction when interpreting creatinine-based GFR estimates and should conduct additional tests to confirm kidney impairment.²⁵

This study has both strengths and weaknesses. One strength is that it contributes to the growing body of literature on the burden and factors associated with kidney dysfunction among people living with HIV in a resource-limited setting. However, the absence of other clinical details and ultrasound scans, coupled with the fact that this was a retrospective study that analyzed data and GFR at one point, limited our ability to differentiate between acute kidney injury and chronic kidney disease and determine causality.

Conclusion

The prevalence of kidney impairment was high in this cohort (100 per 1000 patients) and was associated with older age and being on a TDF/3TC and DTG-based regimen. There is a need for regular kidney function monitoring among PLWH, particularly older individuals who are on a TDF/3TC and DTG-based regimen. Furthermore, longitudinal studies with larger sample sizes, frequent follow-ups, and baseline kidney function assessments should be conducted to better understand the burden of kidney impairment and its associated factors.

Supplemental Material

sj-docx-1-tai-10.1177_20499361251340795 – Supplemental material for Kidney impairment in HIV: an insight into the burden and associated factors among adults on antiretroviral therapy in Zambia. A retrospective cross-sectional study

Supplemental material, sj-docx-1-tai-10.1177_20499361251340795 for Kidney impairment in HIV: an insight into the burden and associated factors among adults on antiretroviral therapy in Zambia. A retrospective cross-sectional study by Matenge Mutalange, Lukundo Siame, Chilala Cheelo, Sepiso K. Masenga and Benson M. Hamooya in Therapeutic Advances in Infectious Disease

Footnotes

Acknowledgements

We would like to extend our gratitude to the HAND group, chaired by Professor Masenga and Dr Hamooya, for their support.

Declarations

ORCID iDs

Matenge Mutalange

Lukundo Siame

Supplemental material

Supplemental material for this article is available online.

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