Table 3 Summary of findings for each study

Banda: 2010

TDF was not associated with RD (1.03: 0.45–2.37, 95% CI)

TDF not associated with RD

N/A

Fritzsche: 2017

Protenuria was significantly more prevalent, and creatinine was significantly higher among treatment naive than among those on treatment (52.2% vs 26.1%; p = 0.003 and p = 0.009 respectively. The proportion of pts with an eGFR < 60 ml/min was significantly higher among treatment naive pts than among those on TDF treatment (40.4% vs 24.4%; p = 0.041). Treatment naive pts displayed an improvement in Cr levels and eGFR after 6 months of treatment

TDF appears to be safe and does not appear to be a significant cause of renal impairment

N/A

Kalemeera: 2016

There was no difference between TDF based and non TDF 1st line ART, on the CrCl (95% CI: 102[94–111] vs 95[87–102] ml/min; p = 0.78. In addition, the type of 1st line whether TDF containing or TDF free did not influence the CrCl during second line ART (95% CI 105[96–114] vs 96[87–104] ml/min; p = 0.90

No difference between TDF based and non TDF 1st line ART, on the CrCl. In addition, the type of 1st line whether TDF containing or TDF free did not influence the CrCl during second line ART. The presence of renal impairment during the use of TenolamE or N does not contraindicate the prescription of Tenofovir but the pts’ renal function should be monitored regularly

N/A

Kamkuemah: 2015

The incidence of decline in renal function of > 10 ml/min/1.73 m² in 12 months after ART initiation was 96 per 100 person-years. This incidence was greatest during the first 2 months on ART (208 per 100 person-years). Overall, 3% of patients experienced declines in renal function below 50 ml/min/1.73 m² over 12 months (with seven people detected at month 1, 2 people detected at month 2 and 1 detected at month 4)

Tenofovir can be administered safely in primary health care after the initial pre-ART screening of creatinine clearance, to identify high-risk cases. Renal function generally improves in parallel with other health improvements on ART. Benefits of tenofovir initiation outweigh negative effects it might have, at least during the first 12 months of use

N/A

Mayanja: 2017

Among individuals on long-term ART; there were no differences in renal dysfunction (glomerular function and renal tubular function) between patients on Tenofovir containing and Non-Tenofovir containing ART regimens

Tenofovir based first line ART can safely be initiated even in settings without routine renal function monitoring

N/A

Mpondo: 2014

At the time of follow-up, patients’ eGFRs by CG equation had improved, from a median of 74.1 (55.8–100.1) at baseline to 103.4 (85.3–135.6) at follow-up (p 0.001) (Table 1). At follow-up, 36 of 171 (21.1%) had decreased eGFRs of, 90, and only 2 (1.2%) had eGFRs, 60 compared to 107/171 (62.6%) and 36/171 (21.1%) respectively at baseline (p 0.001 for each). By MDRD, 23 of 171 (13.5%) had eGFRs, 90, and the same two patients had eGFRs, 60. The prevalence of microalbuminuria decreased from 72.1 to 43.9% (p 0.001), and the prevalence of proteinuria decreased from 35.7 to 8.8% (p 0.001) at follow-up. All eight patients who had had initial eGFRs, 60 and were treated with tenofovir had follow-up eGFRs. 60 and stable (n = 3) or improved (n = 5) microalbuminuria and proteinuria

Safe

N/A

Reid: 2008

Up to 96 weeks, the incidence of severe renal impairment was no different between tenofovir DF containing and other ART regimens. Overall, 11 (0.3%) participants died with renal disease contributing to their death; however, these 11 deaths represented only 5% of all deaths to 96 weeks. Despite a relatively high baseline prevalence of mild-to-moderate renal dysfunction in African adults with low CD4+ cell counts, severe eGFR impairment after ART initiation was infrequent with all regimens

Patients have increased risk of reduced eGFR but no increased risk of renal failure

N/A

Salome: 2016

Mean eGFR lower among TDF-ART grp than in non-TDF ART grp (p = 0.001)using CKI-Epi and MDRD formula with race adjustments (p = 0.008) but no differences using CG. Using all formulae, although proportions of participants with abnormal eGFR < 60 were higher among the TDF-ART grp than the non, the differences were insignificant. No sig differences in the adjusted mean differences of eGFR when diff durations on different TDF exposure ART regimens were compared. No differences in fractional tubular phosphate reabsorption

Safe

N/A

Stöhr: 2011

At ART initiation, median CD4+ T cell count was 86 cells/mm³; 1492 (45%) participants had mild (60 to < 90 ml/min/1.73 m²), 237 (7%) moderate (30 to < 60 ml/min/1.73 m²) and 7 (0.2%) severe (15 to < 30 ml/min/1.73 m²) decreases in eGFR. First-line ART was zidovudine/lamivudine plus tenofovir (74%), abacavir (9%) or nevirapine (17%). By 4 years, cumulative incidence of eGFR < 30 ml/min/1.73 m² was 2.8% (n = 90) and CKD was 5.0% (n = 162). Adjusted eGFR increases to 4 years were 1, 9 and 6 ml/min/1.73 m² with tenofovir, abacavir and nevirapine, respectively (p < 0.001), and 4 and 2 ml/min/1.73 m² for laboratory and clinical monitoring, respectively (p = 0.005; 2 and 3 ml/min/1.73 m² to 5 years; p = 0.81)

Safe

N/A

Shamu: 2015

Incidence of nephropathy was low in this cohort

Safe

N/A

Tewogbade: 2010

The creatinine clearance (MDRD) improved from 47.9 ± 18.42 ml/min/1.73 m² for patients before treatment to 57.9 ± 9.43 ml/min/1.73 m² at 9 months. The eGFR by Cockcroft-Gault did not show any statistically significant difference between pre-treatment and 9 months post treatment values

The plasma creatinine also improved significantly from the pre-treatment value of 131.1 μmol/L to 93.4 μmol/L at 9 months but two patients values increased from 346 and 44 μmol/L to 707 and 563 μmol/L

Desirable safety

N/A

Zannou: 2015

The prevalence of chronic kidney failure is relatively high (18.7%) in this study. Tenofovir was used by 12.9% of patients in this cohort and was not associated with the occurrence of chronic kidney failure

Safe

N/A

Cournil: 2016

Initiation of PI/r-based second-line regimen induced a marked eGFR decline of − 10.5 ml/min/1.73 m² at week 4 in all treatment groups with a greater decrease in TDF/FTC + LPV/r arm (− 15.1 ml/min/1.73 m²). At month 18, mean eGFR in the non-TDF containing regimen recovered its baseline level and was significantly greater than eGFR 18-month levels in the TDF-containing regimens that experienced only partial recovery (difference: − 10.7; CI − 16.8, − 4.6; p = 0.001 in TDF/FTC + LPV/r and − 6.4; CI − 12.5, − 0.3; p = 0.04 in TDF/FTC + DRV/r). At 18 months, prevalence of stage 3 chronic kidney disease was low (< 3%) and not associated with treatment. One treatment discontinuation and five TDF dosage reductions for renal toxicities were reported in TDF-containing arms

These results suggest a reasonable renal tolerance of a regimen associating TDF/FTC + PI/r in African patients with eGFR > 60 ml/ml/1.73 m (2) at baseline

Recommend reassessment of renal function 1 month after initiation of treatment including ritonavir

Gajee: 2016

The CrCl in the younger age group (≥ 20 to < 30 years) exhibited an increase in CrCl at 12 months post-TDF commencement. The older age group (≥ 30 to ≤ 40 years) displayed a decrease in CrCl at 12 months post-TDF commencement for females and males

Safe

Age and gender influence kidney function

Myer: 2013

The median serum creatinine in pregnant women (46 mmol/L) was significantly lower and the median creatinine clearance (163 ml/min/1.73 m²) was significantly higher than other groups (p < 0.001 and p = 0.004, respectively). Fewer than 1% of pregnant women had moderate renal dysfunction before ART initiation, with no instances of severe dysfunction observed, compared to 7% moderate or severe renal dysfunction in non-pregnant women or men (P < 0.001)

Renal dysfunction in HIV-infected pregnant women is significantly less common than in other HIV-infected adults eligible for ART. The risks associated with initiating tenofovir immediately in pregnant women before reviewing serum creatinine results may be limited, and the benefits of rapid ART initiation in pregnancy may outweigh possible risks of nephrotoxicity

N/A

Chadwick, D. R:2015

Pts on TDF had significantly higher uPCRs (10.8 vs 5.7 mg/mmol, p < 0.001) and lower uAPRs (0.24 vs 0.58, p < 0.001). 35% of those on TDF (vs 6% not on TDF)satisfied the criteria for TD

Both proteinuria and TD are common and associated with TDF use in Ghana. TDF significantly independently associated with TD and proteinuria though no clinically significant TD found

No clinical significance found

Agbaji: 2011

sCr in TDF↑18% and in Non TDF↑1.2% b) TDF GFR = ↓4.8% Non TDF↑5.1%

TDF statistically associated with decline in CrCl

Slight

Brennan: 2011

At initiation, 64.4% had normal (> 90 ml/min) renal function, 30.4% had mild (60–90 ml/min) RD, and 5.2% had moderate (30-59 ml/min) RD. After 48 months 21 (2.4%) experienced nephrotoxicity, 6 of these died from it

Pre-existing renal pathology may be exacerbated by TDF

Significant in pts with pre-existing renal pathology

Bygrave: 2011

Among 933 adults for whom baseline creatinine was available, 176 (18.9%) presented with a baseline CrCl < 50 ml/min. Renal function improved during follow-up. 19 patients who developed renal toxicity during follow up remained on TDF; renal function improved (CrCl ≥ 50 ml/min) in all but 3 of these patients. Among 15 patients with a baseline CrCl < 50 ml/min were started in error, none developed severe renal impairment

Rare and transient

Rare and transient

Dekert: 2017

TDF pts had a median eGFR (unadjusted) decrease of − 6.5, TDF-free, − 3.0 and ART switched − 8.5 l/min/1.73 m² over the course of the observation. Three distinct developments observed: (1) some persons with initially normal or mildly impairment eGFR lost renal filtration over time, in addition to the aging effect (2) persons whose renal function was initially severely impaired regained renal filtration most likely because of viral clearance (3) a subgroup of individuals who were identified with impaired renal function deteriorated or remained at a low level despite switching to a TDF free regimen

Individuals always receiving TDF showed only a slight but not significant eGFR reduction

Slight/not significant

Mugomeri, E:2014

In 56 patients (17.9%), TDF was found to be contraindicated. The use of TDF was marginally significant factor for renal toxicity (p 0.054) in univariate analysis, but was insignificant (p 0.122) in multivariate logistic analysis

TDF a weak contributing factor of renal impairment.

Weak. Routine baseline renal function screening should be adopted to prevent patients with impaired renal function receiving TDF

Mulenga: 2014

For the outcome defined as incident episodes of moderate or severe eGFR decrease, the differences reached statistical significance; however, the numbers remained low (1.90% in the TDF vs 1.27% in the non TDF group [P < 0.001] at 6 months and 1.84% vs 1.37% [P = 0.02] at 12 months

Patients receiving TDF were more likely to experience an episode of moderate or severe renal dysfunction than those receiving other regimens during the first year of ART

Rare

Ndagije: 2015

There was one suspected renal toxicity reported for every 200 patients on a tenofovir-based regimen. Some of the serious reactions reported were death in two cases and bone demineralisation in five patients. Hose that had been on tenofovir for more than 4 years had raised serum creatinine levels, emphasising the importance of monitoring for the risk of renal damage

Occurrence of suspected tenofovir renal toxicity of HIV patients is low, there is need to monitor those at risk so as to prevent irreversible kidney injury

Low. Need to monitor those at risk so as to prevent irreversible kidney injury

De Beaudrap: 2010

Between 1–12 months, pts on TDF experienced a↑ of transition from mild renal impairment (60–90 ml/min/1.73 m²) to moderate (30–60 ml/min/1.73 m²) compared with pts not receiving TDF who experienced an ↑ of 4.33 ml/min but change was not significant. For pts on TDF significant ↓ of − 10.4 ml/min observed. After 12 months eGFR remained stable for the non TDF pts but ↓ from month12-42 by − 4.1 ml/min/1.73 m². Proportion of pts on TDF with moderate impairment ↑ from 8.6% at month 12 to 20% at month 42. No↓ in eGFR below 30 ml/min/1.73 m²

TDF associated with significant but moderate decline in RD. Consequent impairment persistent after 1st year of treatment

Moderate

Mulubwa: 2016

No significant correlations were found between plasma TFV concentration and eGFR, CrCl, TmPO4/GFR, SCr, UNa, serum urea or serum uric acid (p > 0.05). Nevertheless, a positive correlation was found between TFV plasma concentration and albuminuria (unadjusted r = 0.606; p = 0.001. TFV concentration was independently associated with increased albuminuria

Plasma TFV concentration is independently associated with increased albuminuria in HIV-infected women within this pilot investigation. There was an increase in eGFR and CrCl in the HIV-infected women from baseline

Moderate

De Waal: 2017

Amongst those with a baseline and subsequent eGFR available, mean eGFR change from baseline at 12 months was − 4.4 mL/min (95% CI − 4.9 to − 4.0), − 2.3 (− 2.5 to − 2.1), and 0.6 (0.04 to 1.2) in those with baseline eGFR 90 mL/min; and 11.9 mL/min (11.0 to 12.7), 14.6 (13.5 to 15.7), and 11.0 (10.3 to 11.7) in those with baseline eGFR < 90 mL/min, according to the MDRD, CKD-EPI (n = 11 112), and Cockcroft-Gault (n = 9 283) equations, respectively. Overall, 292 (1.9%) patients developed eGFR < 30 mL/min. Significant associations with low eGFR included older age, baseline eGFR < 60 mL/min, CD4 count < 200 cells/μL, body weight < 60 kg, and concomitant protease inhibitor use

Overall pts on TDF experienced declines in eGFR over time. In the subgroup of pts who had moderate or severe kidney dysfunction at baseline, eGFR improved substantially on treatment regardless of equation used

Small but significant in pts with normal baseline eGFR

Orluwene: 2015

The differences between the values were not statistically significant as observed in the TDF group. In this study estimated glomerular filtration rate (eGFR) increased only slightly at 12 weeks of exposure particularly in the TDF regimen group pointing a delay in the detection of proximal tubular dysfunction compared to IL-18 that shows a marked increased at 4 weeks. There was also an increase in IL-18 levels with time, suggesting a possible progression of renal dysfunction from a subclinical stage to an end stage renal disease

there might exist a possible relationship between nephrotoxicity caused by TDF and increased in IL-18 levels in HIV-infected patients on TDF first line ART

Highly statistically significant

Seedat: 2017

61% of TDF grp had AKI on admission vs 43%. Discharge median sCr was higher in the TDF group and fewer in the TDF group recovered renal function after 3 months

TDF exposed HIV-infected patients who develop AKI have a similar etiology, rate & range of nephrotoxic risk factors as those not receiving TDF. However, data suggest TDF has an added nephrotoxic effect in patients with AKI causing: a more rapid worsening of renal function; a higher proportion with proteinuria and acidosis; and delayed renal recovery

Notably high

Wantakisha; 2017

Point prevalence of renal dysfunction among HIV-positive adults exposed to TDF was 18.6% at 18 months follow up. Patients with a CD4 + cell count > 350 cells/uL had decreased odds of developing renal dysfunction by 81% and this decrease could be as low as 79% to as high as 97% adjusting for other covariates

Renal dysfunction was concentrated in older patients with low CD4 + cell count. Thus, close renal monitoring in these patients when initiating TDF-based treatment should be intensified

High burden

Zachor: 2016

55% experienced RKFD, and 2% developed stage 3 CKD. For every 10 y increase in age and 10 ml/min lower baseline eGFR, the odds of RFKD increased by 70%. Each 10y older age was associated with a 1.9 fold increased risk of developing stage 3 CKD. Women had a 4 fold greater risk of stage 3 CKD than men

TDF associated with both a higher likelihood of RKFD and stage 3 CKD among HIV infected South Africans

High burden

Mwafongo: 2014

3.2% experienced renal events.2% required permanent treatment modification. Events primarily occurred early after starting treatment with a decreasing rate over time

The primary events involving the use of TDF in RSL were uncommon (3%) thereby limiting the power to evaluate possible factors associated with risk

Could not assess