Proximal renal tubular function in HIV-infected children on tenofovir disoproxil fumarate for treatment of HIV infection at two tertiary hospitals in Harare, Zimbabwe

Runyararo Mashingaidze-Mano; Mutsawashe F. Bwakura-Dangarembizi; Charles C. Maponga; Gene D. Morse; Tsitsi G. Monera-Penduka; Takudzwa J. Mtisi; Tinashe Mudzviti; Hilda A. Mujuru

doi:10.1371/journal.pone.0235759

Abstract

Background

Renal abnormalities in HIV infected children may be due to the HIV infection or treatment among other factors. Tenofovir disoproxil fumarate (TDF) is associated with proximal renal tubular dysfunction, proteinuria and decrease in glomerular function. Studies in developed countries have shown variable prevalence of proximal renal tubular dysfunction in children on TDF. There are no known studies in developing countries, including Zimbabwe, documenting the proximal tubular function in HIV infected children on TDF. The aim of this study was to assess renal and proximal renal tubular function in HIV infected children receiving TDF and determine factors associated with proximal tubular dysfunction.

Methods

A descriptive cross-sectional study was conducted in HIV infected patients below 18 years of age attending outpatient clinics at two tertiary hospitals in Harare, who received a TDF-containing antiretroviral regimen for at least six months. Dipstick protein and glucose, serum and urine phosphate and creatinine levels were measured. Fractional excretion of phosphate was calculated. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula. Tubular dysfunction was defined by at least two of the following characteristics: normoglycaemic glycosuria, hypophosphatemia and fractional excretion of phosphate > 18%.

Findings

One hundred and ninety-eight children below 18 years of age were recruited over a period of six months. The prevalence of tubular dysfunction was 0.5%. Normoglycaemic glycosuria occurred in 1 (0.5%), fractional excretion of phosphate >18% in 4 (2%), and hypophosphatemia in 22 [11.1%] patients. Severe stunting was associated with increased risk of hypophosphatemia (OR 9.31 CI (1.18, 80.68) p = 0.03). Reduction in estimated glomerular filtration rate (eGFR) < 90ml/min/1.73m² and proteinuria was evident in 35.9% and 32.8% of children, respectively. Concurrent TDF and HIV-1 protease inhibitor-based regimen was the only independent factor associated with reduction in GFR (OR 4.43 CI (1.32; 4.89) p = 0.016).

Conclusion

Tubular dysfunction was uncommon in Zimbabwean children on a TDF-based ART regimen. Hypophosphatemia, proteinuria and reduction in eGFR were common. Reassessing renal function using more sensitive biomarkers is needed to examine the long-term tolerance of TDF.

Citation: Mashingaidze-Mano R, Bwakura-Dangarembizi MF, Maponga CC, Morse GD, Monera-Penduka TG, Mtisi TJ, et al. (2020) Proximal renal tubular function in HIV-infected children on tenofovir disoproxil fumarate for treatment of HIV infection at two tertiary hospitals in Harare, Zimbabwe. PLoS ONE 15(7): e0235759. https://doi.org/10.1371/journal.pone.0235759

Editor: Franziska Theilig, Anatomy, SWITZERLAND

Received: January 8, 2020; Accepted: June 23, 2020; Published: July 7, 2020

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: Runyararo Mashingaidze-Mano received funding through the Fogarty International Center of the National Institutes of Health (grant numbers D43TW010313 -01 and D43TW007991), for this research as part of the Fogarty International Centre under University at Buffalo [UB] and the University of Zimbabwe (UZ) HIV Research Training Program (HRTP). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Competing interests: The authors declare that no competing interests exist.

List of Abbreviations: ABCC2, ATP binding cassette subfamily C member 2; B2M, β-2 microglobulin; DAIDS, Division of acquired immunodeficiency syndrome; FEp, Fractional excretion of phosphate; IQR, Interquartile range; KDOQI, Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification; MRCZ, Medical Research Council of Zimbabwe; NAG, N-acetyl-β-d-glucosaminidase; PI, Protease Inhibitor; RBP, Retinol binding Protein; TAF, Tenofovir alafenamide; TDF, Tenofovir disoproxil fumarate; TPR, Tubular phosphate reabsorption; uARP, Urine albumin/total protein ratio

Introduction

Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor approved by the World Health Organization (WHO) for the management of HIV infection in children is associated with nephrotoxicity [1]. Toxicity can manifest as proximal tubular or glomerular dysfunction, acute kidney injury, chronic kidney disease and end stage renal disease [2]. Mitochondrial damage to the proximal tubule leads to impaired reabsorption of low molecular weight proteins and other solutes resulting in urinary wasting. TDF-associated tubular dysfunction may affect the serum bicarbonate and glucose concentration and in severe cases lead to Fanconi syndrome, a generalized proximal tubular defect with hypokalemic metabolic acidosis associated with vitamin D resistant metabolic bone disease [3, 4].

Advanced HIV infection and HIV-1 protease inhibitor (PI) containing therapy, are among factors associated with TDF renal impairment [5]. Biomarkers used to assess proximal renal tubular function include; urinary low molecular proteins serum phosphates, phosphaturia, normoglyacemic glycosuria, as well as urinary and serum electrolytes [6]. In Zimbabwe TDF is recommended as part of the first line regimen for adolescents and children weighing at least 25kg [7]. Ideally, children on TDF-based regimen should be monitored for creatinine clearance [8] but in most developing countries such as Zimbabwe, that recommendation is constrained by limited resources. Studies describing renal tubular function in children on TDF are therefore limited to those mostly assessing glomerular function in ART-naïve cases [9, 10]. This study aimed to assess the prevalence and factors associated with proximal renal tubular dysfunction in children receiving TDF. It was assumed that about 80% of the children had vertical transmission of HIV based on a study by Ferrand et al [11].

Methods

Study design and participants

A cross-sectional study was conducted between May and November 2016 at two Paediatric HIV Clinics in Harare, Zimbabwe. The Institutional Review Boards of: Harare Central Hospital Ethics Committee (Ref: HCHEC 140916/62), the Joint Research Ethica Committee For The University of Zimbabwe College of Health Sciences and Parirenyatwa Group of Hospitals (JREC), (Ref: JREC66/16) and the Medical Research Council of Zimbabwe (MRCZ), (Ref: MRCZ/B/1053) approved the study. Written informed consent was acquired from caregivers and assent obtained from children aged six years and older. Children less than 18 years who weighed at least 25 kg and were on a TDF based regimen for at least six months were recruited during routine clinic visits, conducted on Mondays to Thursdays inclusive. A convenience sampling method was used. Patients were recruited in the outpatients clinic as they came either for doctor’s review, medicine pickup or blood collection. Those patients with pre-existing diabetes or hypertension were excluded from the study. The Dobson formula below was used to calculate sample size: where Z_α/2 is the standard normal value corresponding to the desired level of confidence (95%)

d is the maximum allowable error, (0.05) or 5% (width of the confidence intervals)

p is the estimated prevalence of renal tubular dysfunction in children on TDF based regimen The calculated sample size was 196 participants based on a study in Ghana which found a prevalence (p) of proximal renal tubular dysfunction of 15% [12]. The precision for the sample size was 5%.

Clinical assessment

Demographic data, baseline CD4 count and World Health Organization (WHO) clinical staging were captured from participants and medical records respectively prior to highly active antiretroviral therapy (HAART) initiation. Blood pressure was measured in a sitting position using an appropriate size cuff (Dynamap V100^TM manufactured by Menhold South Africa). Weight and height measurements were taken by a physician or trained clinic nurse. Weight was measured using a calibrated scale (Seca, model 8811021659) estimated to the nearest 0.1kg. Height was measured using a standardized wall mounted stadiometer with inbuilt millimeter ruler and estimated to the nearest 0.1cm. Body mass index calculation was done using the WHO AnthroPlus calculator (2009) [13]. The WHO growth charts (2007) were used to determine nutritional status of the study participants [14–16].

Laboratory assessment

Spot urine samples were collected during the clinic visits. The urine was immediately checked for presence of glucose and protein using the 10 parameter reagent strips (Uricheck M10, Omnipharm). Patients with positive urine glucose (>+1), had a capillary blood glucometer performed immediately (Glucoplus^TM). Qualitative proteinuria was reported on dipstick as negative, 1+(30mg/dL), 2+ (100mg/dL), 3+(300mg/dL) or 4+(1000mg/dL) [17]. Urine protein/creatinine ratio (mg/dL:mg/dL) was further performed on all urine samples. Proteinuria was defined as; normal range proteinuria if urine protein/creatinine <0.2g, further classified into intermediate proteinuria (0.2g - 3.0g) and nephrotic range proteinuria (>3.5g) [18]. The rest of the urine samples including glucose or protein negative dipstick were kept in a carrier cooler bag lined with ice packs between +2°C and +8°C then transported to the University of Zimbabwe, Department of Chemical Pathology laboratory within four hours of collection, for assessment of urine phosphate, creatinine and protein. Blood samples for measurement of serum creatinine and phosphate were collected and transported to the laboratory in carrier bags lined with ice packs maintaining temperature between +2°C and +8°C. Specimens were processed within same day of collection. Urine and serum phosphorus concentration was measured using the Phosphomolybdate method [19]. The pyrogallol red method was used to measure urine protein concentration [20]. Serum and urine creatinine were measured using the modified Jaffe method [21, 22]. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula [23, 24]. A Mindray BS200E Chemistry analyser (Mindray, Shenzhen, China) was used to determine the concentrations of creatinine, phosphate and protein for both urine and serum samples. Calibration of the machine was done every fortnight for creatinine and monthly for phosphate and protein. Proximal tubular function was assessed using normoglyacemic glycosuria, fractional excretion of phosphate (FEp) >18% and hypophosphatemia. The FEp was calculated using a standard formula [25]. Hypophosphatemia was graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity grading [26, 27]. Glomerular dysfunction as indicated by a low eGFR was classified as mild (60–89 ml/min/1.73 m²), moderate (30–60 ml/min/1.73 m²), and severe impairment (15–30 ml/min/1.73 m²) [8, 28]. The full laboratory protocol is found at protocols.io: https://protocols.io/view/pone-d-19-35784-proximal-renal-tubular-function-in-bfzxjp7n [dx.doi.org/10.17504/protocols.io.bfzxjp7n]

Data analysis

Data were analyzed using Epi Info version 7. Descriptive statistics with median and interquartile range (IQR) for continuous, non-nominal variables and percentages for categorical variables were generated. Univariate and multivariate logistic regression analyses were performed to identify factors associated with proximal renal tubular dysfunction. Factors with p < 0.25 in the univariate analysis were entered into a stepwise multivariate analysis model. The results of the logistic regression analyses were expressed as odds ratios (ORs) with 95% confidence intervals(CIs). The MDB file data sets can be found at https://datadryad.org/stash/share/pRmK7SDWzk5Jnd3-usw2hKCGVe71OksxVKbxfTZv5PE and DOI (doi:10.5061/dryad.2fqz612mf).

Results

One hundred and ninety-eight children were enrolled into the study. The demographic and (clinical characteristics are summarized in Tables 1 and 2. The median age of participants was 15 years (IQR 13–16; Range 6–17.11). The median duration on a TDF based regimen was 37 months (IQR 16–52; Range 6–120). Baseline CD4 count was documented in 123 /198 children (62.1%). Fourteen (7%) participants’ BMI was classified as thin, 9 (5.6%) as severe thinness and 13 (6.6%) as overweight. Severe stunting (height for age <-3standard deviation) was recorded in 18 (9.1%).

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Table 1. Demographic and clinical characteristics of HIV infected children, on TDF for at least 6 months, < 18 years old, (n = 198).

https://doi.org/10.1371/journal.pone.0235759.t001

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Table 2. ARV exposure of HIV infected children, on TDF for at least 6 months, < 18 years old, (n = 198).

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Table 3 below shows the frequency of abnormal renal function tests. These tests include serum phosphate decrease, fractional excretion of phosphate >18%, normoglycaemic glycosuria, reduction in glomerular filtration rate and proteinuria.

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Table 3. Proximal renal tubular function; urinary and serum biomarkers and glomerular function abnormalities of HIV infected children, on TDF for at least 6 months, < 18 years.

https://doi.org/10.1371/journal.pone.0235759.t003

Proximal renal tubular function

FEp> 18% was detected in 4 (2%), hypophosphatemia in 22 (11.1%) and normoglycaemic glycosuria in one (0.5%) participant. Mild to moderate decrease in serum phosphate was detected in 16 (8%) of the children while 6 (3%) had severe to life threatening hypophosphatemia. Tubular dysfunction was only detected in one male patient who had FEp> 18% and hypophosphatemia. This patient was older than 14 years and had been on first line ART for 55 months. Severe stunting was associated with increased risk of hypophosphatemia in children younger than 14 years (OR 9.31 CI (1.18, 80.68) p = 0.03). There were no significant factors associated with hypophosphatemia in children older than 14 years (Tables 4 and 5 below).

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Table 4. Factors associated with hypophosphatemia in children <14 years on TDF regimen for at least 6 months.

https://doi.org/10.1371/journal.pone.0235759.t004

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Table 5. Factors associated with hypophosphatemia in children ≥ 14 years of TDF regimen for at least 6 months.

https://doi.org/10.1371/journal.pone.0235759.t005

Proteinuria

Proteinuria with at least 1+ of protein was detected in 31(15.7%) of study participants on dipstick urinalysis. Only one participant had glycosuria on dipstick. Of the 31 participants with positive dipstick proteinuria only 7 (3.6%) were confirmed by spot urine protein:creatinine ratio. Sixty-five of the 193 samples were positive for proteinuria increasing positive to 33.7% (65/193), despite negative dipstick urinalysis in most of the participants. Nephrotic range proteinuria was detected in only 2 (1%) of the children. A protease inhibitor (PI) containing ART regimen was significantly associated with proteinuria in both univariate (OR 3.60 CI (1.62, 7.99) p = 0.002*) and multivariate analysis (0R 3.75 CI (1.59; 8.86) p = 0.003), Fig 1. Duration on TDF was not significantly associated with proteinuria. Children with moderate and severe stunting were more likely to have proteinuria though not statistically significant (Fig 1).

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Fig 1. Factors associated with proteinuria in HIV infected children, on TDF for at least 6 months, < 18 years old, (n = 193)^†.

Children less than 18 years who weighed at least 25 kg and were on a TDF based regimen for at least six months were eligible for the study. Participants with pre-existing diabetes or hypertension were excluded from the study. A urine deep stick proteinuria followed by confirmatory urine protein: creatinine ratio to confirm proteinuria was performed for the participants. ^†6 samples not be processed due to a technical fault at the laboratory. *Statistically significant at α = 0.05. ^{^}Only current ART regimen and stunting had p-value less than 0.25 in the univariate analysis. However, all variables were included in the multivariate analysis to control for any confounding effects from these variables.

https://doi.org/10.1371/journal.pone.0235759.g001

Glomerular filtration rate

Estimated GFR > 90ml/min/m² was in 122 (64.2%) of the participants. Among the children with decreased eGFR, 67 had mild, three moderate and one had severe reduction. Exposure to a protease inhibitor (PI) was associated with reduction in eGFR and this was statistically significant (OR 6.08 CI (2.56, 14.45) p<0.001), Fig 2. On multivariate analysis, exposure to PI regimen was the only independent factor associated with reduction in eGFR (p = <0.016) Patients with severe stunting, height for age (HFA) <-3 were more likely to have reduction in eGFR (OR 2.69 CI (1.00, 7.24) p = 0.051). Although age had a p-value greater than 0.25 in the univariate model it was included in the multivariate model to account for any confounding effects age may have on eGFR.

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Fig 2. Factors associated with reduction in eGFR in HIV infected children, on TDF for at least 6 months, < 18 years old, (n.190)^†.

Children less than 18 years who weighed at least 25 kg and were on a TDF based regimen for at least six months were eligible for the study. Participants with pre-existing diabetes or hypertension were excluded from the study. Following serum creatinine determination estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula. ^†8 samples not processed due to a technical fault at laboratory. *Statistically significant at α = 0.05. ^{^}Only age had a p-value greater than 0.25 in the univariate model but it was also included in the multivariate model to account for any confounding effects age may have on eGFR.

https://doi.org/10.1371/journal.pone.0235759.g002

Discussion

This study uniquely describes the prevalence of proximal renal tubular dysfunction in paediatric patients on TDF based ART regimen in a resource constrained clinical setting.

Renal tubular function and dysfunction

There was a low prevalence of proximal tubular dysfunction found in the study population. Similar findings were reported in two studies of children treated with TDF in two developed countries, where renal tubular function remained stable throughout the study period [29, 30]. However, finding in this study were much lower than what was reported in a multicenter study in Spain where tubular dysfunction measured by reduction in tubular phosphate reabsorption (TPR) was observed in 74% and proteinuria 89% of study participants [31]. The study design, definitions and parameters of proximal tubular dysfunction used in the Spanish study may explain the differences. In a study by Chadwick et al and Labarga et al in Ghana, despite assessing similar parameters for proximal tubular renal function used in our study, the prevalence was higher though. However the study population involved older patients compared to this study [12, 32]. Simultaneous measurement of urine albumin and protein may help differentiate tubular from glomerular proteinuria. Urine albumin/total protein ratio (uAPR) < 0.4 identifies tubular pathology in proteinuric patients and this was not measured in our study [33]. Although increased fractional excretion of phosphate, hypophosphatemia and normoglyacemic glycosuria are established markers of proximal tubular dysfunction and are easy to screen for, they are less sensitive than tubular protein excretions (NGAL, B2M and RBP) and have been suggested to be the most appropriate alternatives when these are not available [6, 34, 35]. In addition better markers for proximal tubular function (Retinol-binding protein, β-2 microglobulin and N-acetyl-β-d-glucosaminidase) could not be used due non-availability of tests and cost constraints. Lack of these more sensitive tests might have affected the results and patients with proximal tubular dysfunction missed. A future prospective study on beta-2 microglobulin, aminoaciduria, hypercalciuria and NGAL as markers of tubular function is therefore recommended.

The prevalence of fractional excretion of phosphate >18% was low in this study compared to a study by Chadwick et al, in which 7% of the participants had FEp>18%. However, their sample size was smaller and included adults [12]. In a Swiss Cohort study, also done in adults, FEp >20% occurred in 11.5% of study patients which is much higher than our study [36]. Fractional excretion of phosphate varies with age with lower levels in children. In our study the FEp > 18% was used to define pathological fractional excretion of phosphate. It is possible that the age difference could explain the different findings [37, 38].

Hypophosphatemia reported in 8% of the participants was at least Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity grade 2. The prevalence of hypophosphatemia was higher than reported in other studies [39]. The long term consequence of this hypophosphatemia in patients in the current study was unknown. In one study in children on TDF the phosphorous level normalised in four patients who had DAIDS toxicity grade 1 or 2 without discontinuation of therapy [39]. In a follow up study of 26 children for 132 months, hypophosphatemia occurred 72 months after commencing TDF but was of no clinical significance [40]. In a case series in adult patients on TDF, hypophosphatemia and osteomalacia necessitated discontinuation of therapy [41].

Patients in this study might still be at risk of rickets and or osteomalacia as they grow and continue taking TDF, hence we recommend continued clinical monitoring and follow up of patients with hypophosphatemia. Participants with stunting were more likely to have hypophosphatemia. However the numbers were small to make a general conclusion. The study cannot conclude on the contribution of malnutrition to hypophosphatemia rather than TDF. Future studies following up patients with hypophosphatemia who are stunted and on TDF may answer this question. A longitudinal prospective study of progressive impairment of renal function normalized by nutrition and HIV and phosphate excretion estimated on (a) timed (not 'spot' specimens) and (b) best expressed as tubular maximum of phosphate factored by GFR (i.e. TmP/GFR) is recommended for future studies. Normoglycaemic glycosuria was reported in only one child. This is much lower than reported in other studies in adults [12, 32]. Genetic polymorphism in the ATP binding cassette subfamily C2 (ABCC2) a gene that codes for organic anion transporters in the kidney has been reported as a risk factor for TDF associated nephrotoxicity in previous studies [42–44]. This was not investigated in this study that may also contribute to a lower prevalence of tubular dysfunction.

Proteinuria

Urinary dipstick was positive for protein in 15.7% of participants and this doubled on urine protein/creatinine ratio. Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification (KDOQI) guidelines recommend spot urine dipstick and urine protein/creatinine ratio to confirm proteinuria in children [8, 28]. Although a 24 hour urine collection is considered the gold standard for proteinuria, urine dipstick proteinuria with confirmatory urine protein creatinine ratio is also acceptable [45]. Urine albumin/total protein ratio (uAPR) < 0.4 identifies tubular pathology in proteinuric patients and this was not measured in our study [46]. The prevalence of proteinuria was much higher than what was reported in an earlier study in ART-naïve children in Zimbabwe, where persistent proteinuria was reported in 5% of the study population [10]. The difference in findings could be because the study by Dondo et al was on ART naïve younger patients (2–12 years). The prevalence is also lower than what was reported in studies elsewhere [12, 47]. Longer duration on TDF was a negative predictor of detection of proteinuria. In this study, the odds of having proteinuria in patients on TDF for >60 months was 0.69 CI (0.10; 4.52) compared to those with shorter duration. This was different to findings by Purswani et al, where TDF duration greater than three years was the single predictor of proteinuria [48]. Exposure to PI regimen was a positive predictor for having proteinuria. The findings are similar to other studies which showed the combination of a PI and TDF was associated with proteinuria [49, 50]. Since no other causes of proteinuria were assessed the authors do not conclude that PI is the cause of the proteinuria. Gender and age were not predictors of proteinuria. Patients with advanced disease on this study were less likely to get proteinuria. This was different from findings by Dondo et al., where WHO stage 3 or 4 disease was associated with proteinuria [10]. This could be due to the difference in study population. This study used the WHO clinical stage recorded at HAART initiation.

Glomerular filtration rate

The prevalence of decreased eGFR was, comparable to an earlier study in ART naïve children in Zimbabwe [10]. However, studies in adult African patients had variable prevalence, 7.5% -86.5% [51–53]. The differences may be due to the different study methods, populations, adults compared to children and definition and cutoff of reduction in eGFR < 60ml/min/1.73m² versus < 90ml/min/1.73m². Combination with a PI was significantly associated with reduction in eGFR. On multivariate analysis use of PI was the only independent factor associated with reduction in eGFR. These findings were similar to other studies in children elsewhere [36, 54]. Advanced HIV disease, at least WHO stage 3 diseases was also associated with reduction in eGFR. Similar findings were reported by Dondo et al., though patients were younger and ART naïve [10]. Severe stunting was significantly associated with reduction in eGFR. TDF may need to be used with caution in these children. Children on TDF for more than 60 months were 3.5 times likely to have reduction in eGFR. Cianflone et al., reported an increase in reduction in GFR with longer duration of TDF in adult patients initiating HAART [55]. The World health organisation has now included tenofovir alafenamide (TAF) for children greater than 6 years weighing at least 25kg. The use of TAF versus TDF and effect of glomerular function will pave way for future studies[56].

Conclusions

Proximal tubular dysfunction was uncommon among HIV infected children on TDF based regimen attending the outpatient HIV clinics at two tertiary hospitals in Harare. Hypophosphatemia was common and prevalence of proteinuria was high. Severe stunting was associated with hypophosphatemia. Combination with protease inhibitor was a risk factor for proteinuria. Reduction in eGFR was reported in children on a PI and those severely stunted. Combination with a PI drug regimen was the only independent factor associated with reduction in eGFR on multivariate analysis. Tenofovir alafenamide (TAF) that has different metabolism to TDF and is less nephrotoxic may be replacing the latter in the future [57] TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage hence less nephrotoxicity compared to TDF [58]. With future guidelines moving towards the use of integrase inhibitors the interaction with TDF/TAF and renal function is an area of future research. Children on TDF for longer duration for > 60 months may benefit from glomerular filtration measurement to assess their renal function. Further studies in children with hypophosphatemia and malnutrition may be of use in future. Patients with concomitant use of TDF and a PI regimen may benefit from targeted monitoring of glomerular function in resource-limited settings.

Study limitations

This study was a cross-sectional study hence causality could not be determined. This study only looked at patients who were on TDF based regimen without comparing with patients who were on non–TDF. Future studies comparing proximal renal tubular function in children on both TDF and non-TDF based regimen are recommended to ascertain the causality of proximal renal tubular dysfunction by TDF as this was not studied in the current study. Viral load was not done due to financial constraints but this could have helped to relate tubular and glomerular dysfunction to viral load.

Supporting information

S1 File. Original tables for Figs 1 and 2.

https://doi.org/10.1371/journal.pone.0235759.s001

(DOCX)

S2 File. Laboratory protocol can be found at protocols.iohttps://protocols.io/view/pone-d-19-35784-proximal-renal-tubular-function-in-bfzxjp7n and DOI: dx.doi.org/10.17504/protocols.io.bfzxjp7n.

https://doi.org/10.1371/journal.pone.0235759.s002

(DOCX)

S3 File. MDB file for the data sets https://datadryad.org/stash/share/pRmK7SDWzk5Jnd3-usw2hKCGVe71OksxVKbxfTZv5PE and DOI (doi:10.5061/dryad.2fqz612mf).

https://doi.org/10.1371/journal.pone.0235759.s003

(ACCDB)

S4 File. Definition of terms.

https://doi.org/10.1371/journal.pone.0235759.s004

(DOCX)

Acknowledgments

The authors would like to thank the participants and their caregivers for participating in the study. We would like to thank all the nurses who helped us with the work in the clinics. Our great felt gratitude goes to the laboratory staff for processing the samples and the statistician for helping with data analysis. We would also like to thank the department of Pediatrics for supervisory support and proofreading of findings and recommendations during the study period.

References

1. Organization WH. Technical update on treatment optimization: use of tenofovir in HIV-infected children and adolescents: a public health perspective. 2012.
2. Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. Aids. 2007;21(10):1273–81. pmid:17545703
- View Article
- PubMed/NCBI
- Google Scholar
3. Elias A, Ijeoma O, Edikpo NJ, Oputiri D, Geoffrey O-BP. Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies¡ªPart 2. Pharmacology & Pharmacy. 2014;Vol.05No.01:15.
- View Article
- Google Scholar
4. Elias A, Ijeoma O, Edikpo NJ, Oputiri D, Geoffrey O-BP. Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies¡ªPart One. Pharmacology & Pharmacy. 2013;Vol.04No.09:12.
- View Article
- Google Scholar
5. Kalyesubula R, Perazella MA. Nephrotoxicity of HAART. AIDS research and treatment. 2011;2011:562790–. pmid:21860787
- View Article
- PubMed/NCBI
- Google Scholar
6. Fiseha T, Gebreweld A. Urinary Markers of Tubular Injury in HIV-Infected Patients. Biochemistry research international. 2016;2016:1501785–. pmid:27493802
- View Article
- PubMed/NCBI
- Google Scholar
7. Guidelines for Antiretroviral Therapy for the Prevention and Treatment of HIV in Zimbabwe.
8. NKF KDOQI GuidelinesAccessed 15 June 2017. Available from: [http://www2.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g5.htm].
9. Iduoriyekemwen NJ, Sadoh WE, Sadoh AE. Prevalence of renal disease in Nigerian children infected with the human immunodeficiency virus and on highly active anti-retroviral therapy. Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2013;24(1):172–7.
- View Article
- Google Scholar
10. Dondo V, Mujuru HA, Nathoo KJ, Chirehwa M, Mufandaedza Z. Renal abnormalities among HIV-infected, antiretroviral naive children, Harare, Zimbabwe: a cross-sectional study. BMC Pediatr. 2013;13:75. pmid:23663553
- View Article
- PubMed/NCBI
- Google Scholar
11. Ferrand RA, Munaiwa L, Matsekete J, Bandason T, Nathoo K, Ndhlovu CE, et al. Undiagnosed HIV infection among adolescents seeking primary health care in Zimbabwe. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2010;51(7):844–51.
- View Article
- Google Scholar
12. Chadwick DR, Sarfo FS, Kirk ESM, Owusu D, Bedu-Addo G, Parris V, et al. Tenofovir is associated with increased tubular proteinuria and asymptomatic renal tubular dysfunction in Ghana. BMC Nephrology. 2015;16(1):195.
- View Article
- Google Scholar
13. Blossner M, Siyam A, Borghi E, Onyango A, de Onis M, Borghi E, et al. WHO AnthroPlus for Personal Computers Manual: Software for Assessing Growth of the World’s Children and Adolescents.
14. WHO. The WHO Child Growth Standards. 2009.
15. WHO. Height-for-age (5–19 years) [Internet]. WHO. [cited 2017 Jun 12] Available from: http://wwwwhoint/growthref/who2007_height_for_age/en/.
16. WHO. BMI classification tables for children 5–19 years to BMI who—Google Search. Internet[cited 2017 Feb 26] Available from: https://wwwgooglecom/search?q=Table++The+International+Classification+of++5-19+yeaarsadolescents++underweight%2C+overweight+and+obesity+according+to+BMI&ie=utf-8&oe=utf-8#safe=active&q=BMI+classification+tables+for+children+5-19+years+++to+BMI+who. 2017.
17. Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review. American family physician. 2005;71(6):1153–62. pmid:15791892
- View Article
- PubMed/NCBI
- Google Scholar
18. JT D. Handbook of Chronic Kidney Disease Management. 2012:656.
- View Article
- Google Scholar
19. VK B. Serum Inorganic Phosphorus. Clinical Methods: The History, Physical, and Laboratory Examinations. Walker HK HW, Hurst JW, editors, editor. Boston: Butterworths; 1990: C. 198.
20. Orsonneau JL, Douet P, Massoubre C, Lustenberger P, Bernard S. An improved pyrogallol red-molybdate method for determining total urinary protein. Clin Chem 1989; 35:2233–6 pmid:2582622
- View Article
- PubMed/NCBI
- Google Scholar
21. Peake *Michael WM. Whiting M. Measurement of Serum Creatinine–Current Status and Future Goals. Clin Biochem Rev 2006; 27:173–84 pmid:17581641
- View Article
- PubMed/NCBI
- Google Scholar
22. Ou M, Song Y, Li S, Liu G, Jia J, Zhang M, et al. LC-MS/MS Method for Serum Creatinine: Comparison with Enzymatic Method and Jaffe Method. PLOS ONE 2015; 10:e0133912 pmid:26207996
- View Article
- PubMed/NCBI
- Google Scholar
23. Berg UB, Nyman U, Bäck R, Hansson M, Monemi KÅ, Herthelius M, et al. New standardized cystatin C and creatinine GFR equations in children validated with inulin clearance. Pediatr Nephrol 2015; 30:1317–26 pmid:25903639
- View Article
- PubMed/NCBI
- Google Scholar
24. Inker LA WC, Creamer R, Hellinger J, Hotta M, Leppo M, Levey AS, et al. Performance boosted PI+TDF associated with renal function. Conference on Viruses and opportunistic infections:8–11 February 2009; Montreal, Canada.
25. Gaasbeek A, Edo Meinders A. Hypophosphatemia: An update on its etiology and treatment. Am J Med 2005; 118:1094–101. pmid:16194637
- View Article
- PubMed/NCBI
- Google Scholar
26. DAIDS adverse event clarification memo adult and pediatric adverse events grading the severity—table_for_grading_severity_of_adult_pediatric_adverse_events. 2004Accessed 3 March 2016. Available from: http://rsc.tech-res.com/document/safetyandpharmacovigilance/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf.
27. Grade ES.2004Accessed 23 January 2017. Available from: https://www.ucdmc.ucdavis.edu/clinicaltrials/StudyTools/Documents/DAIDS_AE_GradingTable_FinalDec2004.pdf.
28. Levey AS, Eckardt K-U, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International. 2005;67(6):2089–100. pmid:15882252
- View Article
- PubMed/NCBI
- Google Scholar
29. Vigano A, Zuccotti G, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal Safety of Tenofovir in HIV-infected Children. Clin Drug Investig 2007; 27:573–81 pmid:17638398
- View Article
- PubMed/NCBI
- Google Scholar
30. Vigano A, Zuccotti GV, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. Clinical drug investigation. 2007;27(8):573–81. pmid:17638398
- View Article
- PubMed/NCBI
- Google Scholar
31. Soler-Palacin P, Melendo S, Noguera-Julian A, Fortuny C, Navarro ML, Mellado MJ, et al. Prospective study of renal function in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens. Aids. 2011;25(2):171–6. pmid:21076275
- View Article
- PubMed/NCBI
- Google Scholar
32. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. Aids. 2009;23(6):689–96. pmid:19262355
- View Article
- PubMed/NCBI
- Google Scholar
33. Samarawickrama A, Cai M, Smith E, Nambiar K, Sabin C, Fisher M, et al. Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria. HIV Med 2012; 13:526–32. pmid:22413854
- View Article
- PubMed/NCBI
- Google Scholar
34. Perazzo S, Soler-García ÁA, Hathout Y, Das JR, Ray PE. Urinary Biomarkers of Kidney Diseases in HIV-infected children. Proteomics Clin Appl 2015; 9:490–500. pmid:25764519
- View Article
- PubMed/NCBI
- Google Scholar
35. Post FA, Wyatt CM, Mocroft A. Biomarkers of impaired renal function. Curr Opin HIV AIDS 2010; 5:524–30. pmid:20978396
- View Article
- PubMed/NCBI
- Google Scholar
36. Fux C, Opravil M, Cavassini M, Calmy A, Flepp M, Gurtner-Delafuente V, et al. Tenofovir and PI Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction in the Swiss HIV Cohort Study: boosted PI+TDF associated with renal function. Conference on Viruses and opportunistic infections:8–11 February 2009; Montreal, Canada.
37. Cheng S, Vijayan A. The Washington Manual of Nephrology Subspecialty Consult. Lippincott Williams & Wilkins; 2013.
38. Schrier R. Diseases of the Kidney and Urinary Tract.: Lippincott Williams & Wilkins; 2007.
39. Pontrelli G, Cotugno N, Amodio D, Zangari P, Tchidjou HK, Baldassari S, et al. Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors. BMC Infect Dis 2012; 12:18 pmid:22269183
- View Article
- PubMed/NCBI
- Google Scholar
40. Giacomet V, Nannini P, Vigano A, Erba P, Benincaso A, Bedogni G, et al. Long-term Renal Effects of Tenofovir-Disoproxil-Fumarate in Vertically HIV-Infected Children, Adolescents, and Young Adults: A 132-Month Follow-Up Study. Clin Drug Investig 2015; 35:419–26 pmid:26013475
- View Article
- PubMed/NCBI
- Google Scholar
41. Tjen-A-Looi A, Naseer SN, Worthing AB, Timpone JG, Kumar PN. Hypophosphatemic Osteomalacia Associated with Tenofovir Use in HIVInfected Patients: A Case Series and Review of the Literature. J AIDS Clin Res 2012; 01:2155–6113.
- View Article
- Google Scholar
42. Salvaggio SE, Giacomelli A, Falvella FS, Oreni ML, Meraviglia P, Atzori C, et al. Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients. BMC infectious diseases. 2017;17(1):396–. pmid:28583112
- View Article
- PubMed/NCBI
- Google Scholar
43. Dahlin A, Wittwer M, de la Cruz M, Woo JM, Bam R, Scharen-Guivel V, et al. A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. Pharmacogenetics and genomics. 2015;25(2):82–92. pmid:25485598
- View Article
- PubMed/NCBI
- Google Scholar
44. Nishijima T, Komatsu H, Higasa K, Takano M, Tsuchiya K, Hayashida T, et al. Single Nucleotide Polymorphisms in ABCC2 Associate With Tenofovir-Induced Kidney Tubular Dysfunction in Japanese Patients With HIV-1 Infection: A Pharmacogenetic Study. Clinical Infectious Diseases. 2012;55(11):1558–67. pmid:22955427
- View Article
- PubMed/NCBI
- Google Scholar
45. Estrella MM, Fine DM. Screening for chronic kidney disease in HIV-infected patients. Adv Chronic Kidney Dis. 2010;17(1):26–35. pmid:20005486
- View Article
- PubMed/NCBI
- Google Scholar
46. Samarawickrama A, Cai M, Smith E, Nambiar K, Sabin C, Fisher M, et al. Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria. HIV Medicine. 2012;13(9):526–32. pmid:22413854
- View Article
- PubMed/NCBI
- Google Scholar
47. Izzedine H, Hulot JS, Vittecoq D, Gallant JE, Staszewski S, Launay-Vacher V, et al. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naïve HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transplat 2005; 20:743–6
- View Article
- Google Scholar
48. Purswani M, Patel K, Kopp JB, Seage GR, Chernoff MC, Hazra R, et al. Tenofovir Treatment Duration Predicts Proteinuria in a Multi-Ethnic United States Cohort of Children and Adolescents with Perinatal HIV-1 Infection. Pediatr Infect Dis J 2013; 32:495–500 pmid:23249917
- View Article
- PubMed/NCBI
- Google Scholar
49. Cao Y, Gong M, Han Y, Xie J, Li X, Zhang L, et al. Prevalence and risk factors for chronic kidney disease among HIV-infected antiretroviral therapy-naïve patients in mainland China: a multicenter cross-sectional study. Nephrol Carlton Vic 2013; 18:307–12
- View Article
- Google Scholar
50. Izzedine H, Harris M, Perazella MA. The nephrotoxic effects of HAART. Nat Rev Nephrol 2009; 5:563–73. pmid:19776778
- View Article
- PubMed/NCBI
- Google Scholar
51. Fana GT, Ndhlovu CE. Renal dysfunction among anti-retroviral therapy naïve HIV infected patients in Zimbabwe. Cent Afr J Med 2011; 57:1–5.
- View Article
- Google Scholar
52. Msango L, Downs JA, Kalluvya SE, Kidenya BR, Kabangila R, Johnson WD, et al. Renal dysfunction among HIV-infected patients starting antiretroviral therapy. AIDS 2011; 25:1421–5. pmid:21572304
- View Article
- PubMed/NCBI
- Google Scholar
53. Sarfo FS, Keegan R, Appiah L, Shakoor S, Phillips R, Norman B, et al. High prevalence of renal dysfunction and association with risk of death amongst HIV-infected Ghanaians. J Infect 2013; 67:43–50. pmid:23542785
- View Article
- PubMed/NCBI
- Google Scholar
54. Post FA, Moyle G, Stellbrink HJ, Domingo P, Podzamczer D, Fisher M, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr 2010; 55:49–57. pmid:20431394
- View Article
- PubMed/NCBI
- Google Scholar
55. Crum-Cianflone N, Ganesan A, Teneza-Mora N, Riddle M, Medina S, Barahona I. Prevalence and factors associated with renal dysfunction among HIV-infected patients. AIDS Patient Care STDs 2010; 24:353–60. pmid:20515419
- View Article
- PubMed/NCBI
- Google Scholar
56. Organisation WH. Paediatric ARV drug optimization 3 review [Teleconference—12 December 2017,]. 2017 [Summary report]. Available from: https://www.who.int/hiv/pub/meetingreports/pado3-review/en/index4.html.
57. Highleyman L. HIV & AIDS Information: Switching from tenofovi DF to TAF improves bone and kidney safety.Accessed 15 June 2017. Available from: http://www.aidsmap.com/Switching-from-tenofovir-DF-to-TAF-improves-bone-and-kidney-safety/page/3070140/.
58. Novick TK, Choi MJ, Rosenberg AZ, McMahon BA, Fine D, Atta MG. Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report. Medicine (Baltimore). 2017;96(36):e8046–e. pmid:28885375
- View Article
- PubMed/NCBI
- Google Scholar

[ref1] 1. Organization WH. Technical update on treatment optimization: use of tenofovir in HIV-infected children and adolescents: a public health perspective. 2012.

[ref2] 2. Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. Aids. 2007;21(10):1273–81. pmid:17545703
View Article
PubMed/NCBI
Google Scholar

[3] View Article

[4] PubMed/NCBI

[5] Google Scholar

[ref3] 3. Elias A, Ijeoma O, Edikpo NJ, Oputiri D, Geoffrey O-BP. Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies¡ªPart 2. Pharmacology & Pharmacy. 2014;Vol.05No.01:15.
View Article
Google Scholar

[7] View Article

[8] Google Scholar

[ref4] 4. Elias A, Ijeoma O, Edikpo NJ, Oputiri D, Geoffrey O-BP. Tenofovir Renal Toxicity: Evaluation of Cohorts and Clinical Studies¡ªPart One. Pharmacology & Pharmacy. 2013;Vol.04No.09:12.
View Article
Google Scholar

[10] View Article

[11] Google Scholar

[ref5] 5. Kalyesubula R, Perazella MA. Nephrotoxicity of HAART. AIDS research and treatment. 2011;2011:562790–. pmid:21860787
View Article
PubMed/NCBI
Google Scholar

[13] View Article

[14] PubMed/NCBI

[15] Google Scholar

[ref6] 6. Fiseha T, Gebreweld A. Urinary Markers of Tubular Injury in HIV-Infected Patients. Biochemistry research international. 2016;2016:1501785–. pmid:27493802
View Article
PubMed/NCBI
Google Scholar

[17] View Article

[18] PubMed/NCBI

[19] Google Scholar

[ref7] 7. Guidelines for Antiretroviral Therapy for the Prevention and Treatment of HIV in Zimbabwe.

[ref8] 8. NKF KDOQI GuidelinesAccessed 15 June 2017. Available from: [http://www2.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g5.htm].

[ref9] 9. Iduoriyekemwen NJ, Sadoh WE, Sadoh AE. Prevalence of renal disease in Nigerian children infected with the human immunodeficiency virus and on highly active anti-retroviral therapy. Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2013;24(1):172–7.
View Article
Google Scholar

[23] View Article

[24] Google Scholar

[ref10] 10. Dondo V, Mujuru HA, Nathoo KJ, Chirehwa M, Mufandaedza Z. Renal abnormalities among HIV-infected, antiretroviral naive children, Harare, Zimbabwe: a cross-sectional study. BMC Pediatr. 2013;13:75. pmid:23663553
View Article
PubMed/NCBI
Google Scholar

[26] View Article

[27] PubMed/NCBI

[28] Google Scholar

[ref11] 11. Ferrand RA, Munaiwa L, Matsekete J, Bandason T, Nathoo K, Ndhlovu CE, et al. Undiagnosed HIV infection among adolescents seeking primary health care in Zimbabwe. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2010;51(7):844–51.
View Article
Google Scholar

[30] View Article

[31] Google Scholar

[ref12] 12. Chadwick DR, Sarfo FS, Kirk ESM, Owusu D, Bedu-Addo G, Parris V, et al. Tenofovir is associated with increased tubular proteinuria and asymptomatic renal tubular dysfunction in Ghana. BMC Nephrology. 2015;16(1):195.
View Article
Google Scholar

[33] View Article

[34] Google Scholar

[ref13] 13. Blossner M, Siyam A, Borghi E, Onyango A, de Onis M, Borghi E, et al. WHO AnthroPlus for Personal Computers Manual: Software for Assessing Growth of the World’s Children and Adolescents.

[ref14] 14. WHO. The WHO Child Growth Standards. 2009.

[ref15] 15. WHO. Height-for-age (5–19 years) [Internet]. WHO. [cited 2017 Jun 12] Available from: http://wwwwhoint/growthref/who2007_height_for_age/en/.

[ref16] 16. WHO. BMI classification tables for children 5–19 years to BMI who—Google Search. Internet[cited 2017 Feb 26] Available from: https://wwwgooglecom/search?q=Table++The+International+Classification+of++5-19+yeaarsadolescents++underweight%2C+overweight+and+obesity+according+to+BMI&ie=utf-8&oe=utf-8#safe=active&q=BMI+classification+tables+for+children+5-19+years+++to+BMI+who. 2017.

[ref17] 17. Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review. American family physician. 2005;71(6):1153–62. pmid:15791892
View Article
PubMed/NCBI
Google Scholar

[40] View Article

[41] PubMed/NCBI

[42] Google Scholar

[ref18] 18. JT D. Handbook of Chronic Kidney Disease Management. 2012:656.
View Article
Google Scholar

[44] View Article

[45] Google Scholar

[ref19] 19. VK B. Serum Inorganic Phosphorus. Clinical Methods: The History, Physical, and Laboratory Examinations. Walker HK HW, Hurst JW, editors, editor. Boston: Butterworths; 1990: C. 198.

[ref20] 20. Orsonneau JL, Douet P, Massoubre C, Lustenberger P, Bernard S. An improved pyrogallol red-molybdate method for determining total urinary protein. Clin Chem 1989; 35:2233–6 pmid:2582622
View Article
PubMed/NCBI
Google Scholar

[48] View Article

[49] PubMed/NCBI

[50] Google Scholar

[ref21] 21. Peake *Michael WM. Whiting M. Measurement of Serum Creatinine–Current Status and Future Goals. Clin Biochem Rev 2006; 27:173–84 pmid:17581641
View Article
PubMed/NCBI
Google Scholar

[52] View Article

[53] PubMed/NCBI

[54] Google Scholar

[ref22] 22. Ou M, Song Y, Li S, Liu G, Jia J, Zhang M, et al. LC-MS/MS Method for Serum Creatinine: Comparison with Enzymatic Method and Jaffe Method. PLOS ONE 2015; 10:e0133912 pmid:26207996
View Article
PubMed/NCBI
Google Scholar

[56] View Article

[57] PubMed/NCBI

[58] Google Scholar

[ref23] 23. Berg UB, Nyman U, Bäck R, Hansson M, Monemi KÅ, Herthelius M, et al. New standardized cystatin C and creatinine GFR equations in children validated with inulin clearance. Pediatr Nephrol 2015; 30:1317–26 pmid:25903639
View Article
PubMed/NCBI
Google Scholar

[60] View Article

[61] PubMed/NCBI

[62] Google Scholar

[ref24] 24. Inker LA WC, Creamer R, Hellinger J, Hotta M, Leppo M, Levey AS, et al. Performance boosted PI+TDF associated with renal function. Conference on Viruses and opportunistic infections:8–11 February 2009; Montreal, Canada.

[ref25] 25. Gaasbeek A, Edo Meinders A. Hypophosphatemia: An update on its etiology and treatment. Am J Med 2005; 118:1094–101. pmid:16194637
View Article
PubMed/NCBI
Google Scholar

[65] View Article

[66] PubMed/NCBI

[67] Google Scholar

[ref26] 26. DAIDS adverse event clarification memo adult and pediatric adverse events grading the severity—table_for_grading_severity_of_adult_pediatric_adverse_events. 2004Accessed 3 March 2016. Available from: http://rsc.tech-res.com/document/safetyandpharmacovigilance/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf.

[ref27] 27. Grade ES.2004Accessed 23 January 2017. Available from: https://www.ucdmc.ucdavis.edu/clinicaltrials/StudyTools/Documents/DAIDS_AE_GradingTable_FinalDec2004.pdf.

[ref28] 28. Levey AS, Eckardt K-U, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International. 2005;67(6):2089–100. pmid:15882252
View Article
PubMed/NCBI
Google Scholar

[71] View Article

[72] PubMed/NCBI

[73] Google Scholar

[ref29] 29. Vigano A, Zuccotti G, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal Safety of Tenofovir in HIV-infected Children. Clin Drug Investig 2007; 27:573–81 pmid:17638398
View Article
PubMed/NCBI
Google Scholar

[75] View Article

[76] PubMed/NCBI

[77] Google Scholar

[ref30] 30. Vigano A, Zuccotti GV, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. Clinical drug investigation. 2007;27(8):573–81. pmid:17638398
View Article
PubMed/NCBI
Google Scholar

[79] View Article

[80] PubMed/NCBI

[81] Google Scholar

[ref31] 31. Soler-Palacin P, Melendo S, Noguera-Julian A, Fortuny C, Navarro ML, Mellado MJ, et al. Prospective study of renal function in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens. Aids. 2011;25(2):171–6. pmid:21076275
View Article
PubMed/NCBI
Google Scholar

[83] View Article

[84] PubMed/NCBI

[85] Google Scholar

[ref32] 32. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. Aids. 2009;23(6):689–96. pmid:19262355
View Article
PubMed/NCBI
Google Scholar

[87] View Article

[88] PubMed/NCBI

[89] Google Scholar

[ref33] 33. Samarawickrama A, Cai M, Smith E, Nambiar K, Sabin C, Fisher M, et al. Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria. HIV Med 2012; 13:526–32. pmid:22413854
View Article
PubMed/NCBI
Google Scholar

[91] View Article

[92] PubMed/NCBI

[93] Google Scholar

[ref34] 34. Perazzo S, Soler-García ÁA, Hathout Y, Das JR, Ray PE. Urinary Biomarkers of Kidney Diseases in HIV-infected children. Proteomics Clin Appl 2015; 9:490–500. pmid:25764519
View Article
PubMed/NCBI
Google Scholar

[95] View Article

[96] PubMed/NCBI

[97] Google Scholar

[ref35] 35. Post FA, Wyatt CM, Mocroft A. Biomarkers of impaired renal function. Curr Opin HIV AIDS 2010; 5:524–30. pmid:20978396
View Article
PubMed/NCBI
Google Scholar

[99] View Article

[100] PubMed/NCBI

[101] Google Scholar

[ref36] 36. Fux C, Opravil M, Cavassini M, Calmy A, Flepp M, Gurtner-Delafuente V, et al. Tenofovir and PI Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction in the Swiss HIV Cohort Study: boosted PI+TDF associated with renal function. Conference on Viruses and opportunistic infections:8–11 February 2009; Montreal, Canada.

[ref37] 37. Cheng S, Vijayan A. The Washington Manual of Nephrology Subspecialty Consult. Lippincott Williams & Wilkins; 2013.

[ref38] 38. Schrier R. Diseases of the Kidney and Urinary Tract.: Lippincott Williams & Wilkins; 2007.

[ref39] 39. Pontrelli G, Cotugno N, Amodio D, Zangari P, Tchidjou HK, Baldassari S, et al. Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors. BMC Infect Dis 2012; 12:18 pmid:22269183
View Article
PubMed/NCBI
Google Scholar

[106] View Article

[107] PubMed/NCBI

[108] Google Scholar

[ref40] 40. Giacomet V, Nannini P, Vigano A, Erba P, Benincaso A, Bedogni G, et al. Long-term Renal Effects of Tenofovir-Disoproxil-Fumarate in Vertically HIV-Infected Children, Adolescents, and Young Adults: A 132-Month Follow-Up Study. Clin Drug Investig 2015; 35:419–26 pmid:26013475
View Article
PubMed/NCBI
Google Scholar

[110] View Article

[111] PubMed/NCBI

[112] Google Scholar

[ref41] 41. Tjen-A-Looi A, Naseer SN, Worthing AB, Timpone JG, Kumar PN. Hypophosphatemic Osteomalacia Associated with Tenofovir Use in HIVInfected Patients: A Case Series and Review of the Literature. J AIDS Clin Res 2012; 01:2155–6113.
View Article
Google Scholar

[114] View Article

[115] Google Scholar

[ref42] 42. Salvaggio SE, Giacomelli A, Falvella FS, Oreni ML, Meraviglia P, Atzori C, et al. Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients. BMC infectious diseases. 2017;17(1):396–. pmid:28583112
View Article
PubMed/NCBI
Google Scholar

[117] View Article

[118] PubMed/NCBI

[119] Google Scholar

[ref43] 43. Dahlin A, Wittwer M, de la Cruz M, Woo JM, Bam R, Scharen-Guivel V, et al. A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. Pharmacogenetics and genomics. 2015;25(2):82–92. pmid:25485598
View Article
PubMed/NCBI
Google Scholar

[121] View Article

[122] PubMed/NCBI

[123] Google Scholar

[ref44] 44. Nishijima T, Komatsu H, Higasa K, Takano M, Tsuchiya K, Hayashida T, et al. Single Nucleotide Polymorphisms in ABCC2 Associate With Tenofovir-Induced Kidney Tubular Dysfunction in Japanese Patients With HIV-1 Infection: A Pharmacogenetic Study. Clinical Infectious Diseases. 2012;55(11):1558–67. pmid:22955427
View Article
PubMed/NCBI
Google Scholar

[125] View Article

[126] PubMed/NCBI

[127] Google Scholar

[ref45] 45. Estrella MM, Fine DM. Screening for chronic kidney disease in HIV-infected patients. Adv Chronic Kidney Dis. 2010;17(1):26–35. pmid:20005486
View Article
PubMed/NCBI
Google Scholar

[129] View Article

[130] PubMed/NCBI

[131] Google Scholar

[ref46] 46. Samarawickrama A, Cai M, Smith E, Nambiar K, Sabin C, Fisher M, et al. Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria. HIV Medicine. 2012;13(9):526–32. pmid:22413854
View Article
PubMed/NCBI
Google Scholar

[133] View Article

[134] PubMed/NCBI

[135] Google Scholar

[ref47] 47. Izzedine H, Hulot JS, Vittecoq D, Gallant JE, Staszewski S, Launay-Vacher V, et al. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naïve HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transplat 2005; 20:743–6
View Article
Google Scholar

[137] View Article

[138] Google Scholar

[ref48] 48. Purswani M, Patel K, Kopp JB, Seage GR, Chernoff MC, Hazra R, et al. Tenofovir Treatment Duration Predicts Proteinuria in a Multi-Ethnic United States Cohort of Children and Adolescents with Perinatal HIV-1 Infection. Pediatr Infect Dis J 2013; 32:495–500 pmid:23249917
View Article
PubMed/NCBI
Google Scholar

[140] View Article

[141] PubMed/NCBI

[142] Google Scholar

[ref49] 49. Cao Y, Gong M, Han Y, Xie J, Li X, Zhang L, et al. Prevalence and risk factors for chronic kidney disease among HIV-infected antiretroviral therapy-naïve patients in mainland China: a multicenter cross-sectional study. Nephrol Carlton Vic 2013; 18:307–12
View Article
Google Scholar

[144] View Article

[145] Google Scholar

[ref50] 50. Izzedine H, Harris M, Perazella MA. The nephrotoxic effects of HAART. Nat Rev Nephrol 2009; 5:563–73. pmid:19776778
View Article
PubMed/NCBI
Google Scholar

[147] View Article

[148] PubMed/NCBI

[149] Google Scholar

[ref51] 51. Fana GT, Ndhlovu CE. Renal dysfunction among anti-retroviral therapy naïve HIV infected patients in Zimbabwe. Cent Afr J Med 2011; 57:1–5.
View Article
Google Scholar

[151] View Article

[152] Google Scholar

[ref52] 52. Msango L, Downs JA, Kalluvya SE, Kidenya BR, Kabangila R, Johnson WD, et al. Renal dysfunction among HIV-infected patients starting antiretroviral therapy. AIDS 2011; 25:1421–5. pmid:21572304
View Article
PubMed/NCBI
Google Scholar

[154] View Article

[155] PubMed/NCBI

[156] Google Scholar

[ref53] 53. Sarfo FS, Keegan R, Appiah L, Shakoor S, Phillips R, Norman B, et al. High prevalence of renal dysfunction and association with risk of death amongst HIV-infected Ghanaians. J Infect 2013; 67:43–50. pmid:23542785
View Article
PubMed/NCBI
Google Scholar

[158] View Article

[159] PubMed/NCBI

[160] Google Scholar

[ref54] 54. Post FA, Moyle G, Stellbrink HJ, Domingo P, Podzamczer D, Fisher M, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr 2010; 55:49–57. pmid:20431394
View Article
PubMed/NCBI
Google Scholar

[162] View Article

[163] PubMed/NCBI

[164] Google Scholar

[ref55] 55. Crum-Cianflone N, Ganesan A, Teneza-Mora N, Riddle M, Medina S, Barahona I. Prevalence and factors associated with renal dysfunction among HIV-infected patients. AIDS Patient Care STDs 2010; 24:353–60. pmid:20515419
View Article
PubMed/NCBI
Google Scholar

[166] View Article

[167] PubMed/NCBI

[168] Google Scholar

[ref56] 56. Organisation WH. Paediatric ARV drug optimization 3 review [Teleconference—12 December 2017,]. 2017 [Summary report]. Available from: https://www.who.int/hiv/pub/meetingreports/pado3-review/en/index4.html.

[ref57] 57. Highleyman L. HIV & AIDS Information: Switching from tenofovi DF to TAF improves bone and kidney safety.Accessed 15 June 2017. Available from: http://www.aidsmap.com/Switching-from-tenofovir-DF-to-TAF-improves-bone-and-kidney-safety/page/3070140/.

[ref58] 58. Novick TK, Choi MJ, Rosenberg AZ, McMahon BA, Fine D, Atta MG. Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report. Medicine (Baltimore). 2017;96(36):e8046–e. pmid:28885375
View Article
PubMed/NCBI
Google Scholar

[172] View Article

[173] PubMed/NCBI

[174] Google Scholar

Figures

Abstract

Background

Methods

Findings

Conclusion

Introduction

Methods

Study design and participants

Clinical assessment

Laboratory assessment

Data analysis

Results

Proximal renal tubular function

Proteinuria

Glomerular filtration rate

Discussion

Renal tubular function and dysfunction

Proteinuria

Glomerular filtration rate

Conclusions

Study limitations

Supporting information

S1 File. Original tables for Figs 1 and 2.

S2 File. Laboratory protocol can be found at protocols.iohttps://protocols.io/view/pone-d-19-35784-proximal-renal-tubular-function-in-bfzxjp7n and DOI: dx.doi.org/10.17504/protocols.io.bfzxjp7n.

S3 File. MDB file for the data sets https://datadryad.org/stash/share/pRmK7SDWzk5Jnd3-usw2hKCGVe71OksxVKbxfTZv5PE and DOI (doi:10.5061/dryad.2fqz612mf).

S4 File. Definition of terms.

Acknowledgments

References