Basic Science: Concise Communication
Relationship between renal dysfunction, nephrotoxicity and death among HIV adults on tenofovir
Brennan, Alanaa,b,c; Evans, Deniseb,e; Maskew, Mhairib,e; Naicker, Saraladevig; Ive, Prudencee; Sanne, Iand,e; Maotoe, Thapelod; Fox, Matthewa,b,c,f
aCenter for Global Health and Development, Boston University, Boston, Massachusetts, USA
bHealth Economics and Epidemiology Research Office, Johannesburg
cUniversity of Witwatersrand, Johannesburg
dRight to Care, Johannesburg
eClinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
fDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA
gDivision of Nephrology, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.
Correspondence to Center for Global Health and Development, Boston University, Crosstown Center, 3rd Floor, 801 Massachusetts Ave., Boston, MA 02118, USA. Tel: +1 617 414 1260; e-mail: firstname.lastname@example.org
Received 3 November, 2010
Revised 6 May, 2011
Accepted 31 May, 2011
Objective: In April 2010, the South African government added tenofovir disoproxil fumarate to its first-line antiretroviral therapy (ART) for HIV patients. We analyzed the relationship between renal dysfunction at tenofovir initiation, nephrotoxicity and mortality.
Design: Cohort analysis of HIV-infected adults who received tenofovir and had a creatinine clearance done at initiation at the Themba Lethu Clinic, Johannesburg, South Africa, between April 2004 and September 2009.
Methods: We estimated the relationship between renal dysfunction, nephrotoxicity [any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] and mortality for patients initiated onto tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up and confounding.
Results: Of 890 patients initiated onto tenofovir, 573 (64.4%) had normal renal function (≥90 ml/min), 271 (30.4%) had mild renal dysfunction (60–89 ml/min) and 46 (5.2%) had moderate renal dysfunction (30–59 ml/min). A total of 2.4% experienced nephrotoxicity, 7.8% died and 9.7% were lost during 48 months of follow-up. Patients with mild [hazard ratio 4.8; 95% confidence interval (CI) 1.5–15.2] or moderate (hazard ratio 15.0; 95% CI 3.4–66.5) renal dysfunction were at greatest risk of nephrotoxicity, whereas those with mild (hazard ratio 1.2; 95% CI 0.7–2.3) or moderate (hazard ratio 3.2; 95% CI 1.3–7.8) renal dysfunction vs. normal renal function were at highest risk of death by 48 months.
Conclusion: Much of the incident renal dysfunction in tenofovir patients is likely related to preexisting renal disorder, which may be exacerbated by tenofovir. With expanded use of tenofovir, screening for renal dysfunction prior to initiation and dose adjustment is necessary to help improve ART outcomes.
It is well known that individuals of African descent are at increased risk of renal failure . Chronic kidney disease is three to four times more frequent in Africa than in industrialized countries in non-HIV patients . Nephrotoxicity has also been shown to be an important complication of HIV infection, particularly in patients with preexisting renal dysfunction [3–7]. It may also be induced by the antiretroviral drug tenofovir disoproxil fumarate [4,8,9]. The prevalence of chronic kidney disease is high (6%) in South African HIV patients , and estimates show that 10% (650 000) of patients will suffer from HIV-related renal failure or renal toxicities throughout the course of their disease [11,12]. As South Africa has recently introduced tenofovir as first-line treatment , accurately measuring the prevalence of renal impairment at ART initiation takes on additional importance as patients with preexisting renal dysfunction may require alternative treatments and intensive monitoring due to a greater risk of renal failure and renal toxicities [14–16].
Tenofovir is eliminated from the kidneys by glomerular filtration and active proximal tubular secretion, which helps to maintain metabolic balance (e.g. stable pH) as the kidneys filter the blood. Tenofovir can accumulate in the proximal renal tubular cells [4,5,17], resulting in renal toxicity, renal tubular acidosis and, ultimately, renal failure [5,7], characterized by a decline in glomerular filtration rates (GFRs) and hypophosphatemia [18–23].
There is little knowledge regarding the effect of renal impairment on treatment outcomes in patients initiating tenofovir in resource-limited settings [14,24]. Some studies show low rates of tenofovir-associated renal failure and nephrotoxicity [decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] [3,4,16,17,21], whereas others suggest a higher risk [4,19,21,22,24] among patients with renal impairment at initiation of tenofovir compared with those with normal renal function. We estimated the relationship between renal dysfunction, nephrotoxicity and mortality for patients initiated onto tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up (LTFU) and confounding in the Themba Lethu Clinic (TLC), Johannesburg, South Africa.
TLC is a large government HIV treatment site in Johannesburg, South Africa, that has initiated over 18 500 patients onto antiretroviral therapy (ART). Care at TLC is provided according to South African National Department of Health guidelines .
Use of TLC data was approved by the Human Research Ethics Committee of the University of the Witwatersrand. Approval for analysis of de-identified data was granted by the Institutional Review Board of Boston University.
Participants were HIV-positive patients seen at TLC, 18 years of age or older and either newly initiated or switched onto an ART regimen containing 300 mg of tenofovir daily between April 2004 and September 2009. They had a creatinine clearance done 6 months prior to 2 weeks following tenofovir initiation. Patient data were extracted from an electronic patient record system (TherapyEdge-HIV, Advanced Biological Laboratories, Luxemburg, Luxembourg).
We compared ART outcomes (nephrotoxicity and mortality) by 48 months of follow-up stratified by renal function at tenofovir initiation. Nephrotoxicity was defined as any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs) and documented by a clinician, within 48 months after initiation onto tenofovir. Mortality is ascertained via South African National Vital Registration Infrastructure Initiative for patients who are LTFU [25–27]. LTFU was defined as not having attended the clinic in 4 months. Creatinine clearance was calculated using the Cockcroft–Gault equation, which estimates creatinine clearance on the basis of the serum creatinine, weight and sex . This surrogate measure of GFR has been validated in sub-Saharan Africa . Creatinine clearance was categorized according to the US National Kidney Foundation's Kidney Disease Outcome Quality Initiative (K/DOQI) as normal (≥90 ml/min), mild (60–89 ml/min), moderate (30–59 ml/min) and severe (<30 ml/min) renal dysfunction . There were no patients in our analysis with severe renal dysfunction at baseline. All but three patients had creatinine clearance levels above 40 ml/min, a level previously reported not to be associated with adverse renal outcomes . If a patient had severe renal dysfunction at baseline, clinicians at TLC would not initiate them onto tenofovir. The three patients that were initiated below 40 ml/min were monitored properly by dose adjustment of tenofovir and switched onto a different antiretroviral drug if renal function worsened.
For nephrotoxicity, person-time accrued from ART initiation until the earliest of nephrotoxicity, death, LTFU or close of the dataset (1 September 2010). For death, person-time accrued from ART initiation until the earliest of death, LTFU or close of the dataset (1 September 2010). Patients who transferred were censored at their last clinic visit.
Patient characteristics and outcomes were stratified by renal function at tenofovir initiation and summarized as simple proportions. Marginal structural modeling using inverse probability of treatment weights was used to adjust for confounding and selection bias due to LTFU [31–33]. Marginal structural models are a class of regression models that attempt to create a pseudo-population in which confounding and LTFU are not present by weighting patients rather than including covariates in the regression model. Stabilized weights were obtained by fitting two pooled logistic regression models: one controlling for baseline predictors of LTFU (creatinine clearance level, time on ART, WHO stage III/IV, sex, age, CD4 cell count, BMI and hemoglobin) and a second model controlling for baseline predictors in addition to current predictors (current CD4 cell count, current BMI, current hemoglobin and current viral load status) of becoming lost. We estimated the parameters of our marginal structural Cox model by calculating a stabilized weight for each person-month and fitting a weighted pooled logistic model controlling for baseline covariates and current viral load (<400 or ≥400 copies/ml) to estimate predictors of death and nephrotoxicity.
A total of 1322 patients received a tenofovir-containing regimen at TLC from April 2004 to September 2009. We excluded 432 patients who had no creatinine clearance at initiation. The 432 patients excluded were similar in demographic and clinical characteristics at tenofovir initiation to those included, except they had a slightly lower median CD4 cell count [200 cells/μl; interquartile range (IQR) 97–330]. The remaining 890 patients had a median age of 37.1 years (IQR 32.5–43.2), median CD4 cell count of 245 cells/μl (IQR 115–426), were predominately black (96.3%), were of female sex (73.5%) and were on tenofovir for a median of 10.8 months (IQR 6.5–16.6) (Table 1). A total of 573 (64.4%) patients had normal levels of renal function (≥90 ml/min), 271 (30.5%) had mild (60–89 ml/min) renal dysfunction and 46 (5.2%) had moderate (30–59 ml/min) renal dysfunction at tenofovir initiation.
A total of 190 patients were ART-naive at tenofovir initiation, whereas 700 were switched onto tenofovir. Among the 700 patients switched, over 45% did not have a reason for switching listed; for those that did, the most common reasons were stavudine toxicity (48.4%), severe anemia (3.6%) and virologic failure (2.4%). Patients with below normal renal function at tenofovir initiation were older and more likely to present with WHO stage III/IV, a lower median CD4 cell count, lower hemoglobin and lower BMI at initiation compared with those with normal renal function (Table 1). Patients who had moderate renal dysfunction at initiation of tenofovir had a shorter time on tenofovir (7.5 months; IQR 1.8–16.7) compared with those with normal (10.9 months; IQR 6.9–16.8) or mild (10.9 months; IQR 5.6–16.0) dysfunction.
Among 890 patients, 21 (2.4%) experienced nephrotoxicity, 69 (7.8%) died and 86 (9.7%) were LTFU during 48-months of follow-up (Table 1). Median follow-up time for patients who experienced nephrotoxicity or died was 3.6 months (IQR 1.0–12.5) and 2.6 months (IQR 0.9–5.3), respectively. Rates of nephrotoxicity (normal 0.4/100 person-years, mild 2.5/100 person-years and moderate 10.7/100 person-years) and death (normal 3.0/100 person-years, mild 5.5/100 person-years and moderate 21.9/100 person-years) increased with decreasing renal function (Table 2). Of the 21 patients who developed nephrotoxicity, none were LTFU; however, six went on to die within 2.3 months (IQR 2.2–2.5) after diagnosis. When stratified by baseline creatinine clearance level, one patient with normal renal function died within 2.2 months, whereas three with mild renal dysfunction died within 2.5 months (IQR 2.3–7.3) and two with moderate renal dysfunction died within 2.1 months (IQR 1.9–2.3) of being diagnosed with nephrotoxicity.
In adjusted models, the strongest risk factor for nephrotoxicity was having mild (hazard ratio 4.8; 95% CI 1.5–15.2) or moderate (hazard ratio 15.0; 95% CI 3.4–66.5) renal dysfunction compared with patients with normal renal function (Table 2). Patients 40 or more years of age, those with low hemoglobin, those with a low CD4 cell count and those with a current detectable viral load were also at increased risk of nephrotoxicity. Additionally, we stratified our analysis by treatment status (naive or switched) at tenofovir initiation. Although the estimates lacked precision when stratified, we found that among patients who were switched onto tenofovir, those with a mild (hazard ratio 5.3; 95% CI 1.4–19.8) or moderate (hazard ratio 24.5; 95% CI 3.2–188.2) renal dysfunction appeared at higher risk of nephrotoxicity compared with patients naive at tenofovir initiation (mild, hazard ratio 4.4; 95% CI 0.4–45.8; moderate, hazard ratio 14.3; 95% CI 1.4–149.5).
Patients with mild (hazard ratio 1.2; 95% CI 0.7–2.3) or moderate (hazard ratio 3.2; 95% CI 1.3–7.8) renal dysfunction were at greatest risk of death during follow-up compared with those with normal renal function. Male patients, those with lower CD4 cell count, those with low hemoglobin and those with low BMI at tenofovir initiation were also at increased risk of mortality. When we stratified by treatment status (naive or switched) at tenofovir initiation, we again found variation in the estimates. Patients who were switched onto tenofovir and had a moderate renal dysfunction were at higher risk (hazard ratio 5.2; 95% CI 1.6–17.0) of death compared with patients naive at tenofovir initiation also with moderate renal dysfunction (hazard ratio 1.6; 95% CI 0.4–6.6).
As a result of limited use of tenofovir in resource-limited settings, this is one of the first studies to examine the relationship between renal dysfunction at tenofovir initiation, diagnosis of nephrotoxicity and mortality. The frequency of nephrotoxicity in this cohort (2.4%) is similar to that reported in other studies [12,34–36]. As expected, the risk of nephrotoxicity and death by 48 months of follow-up increased with decreasing renal function at initiation of tenofovir. Additionally, patients switched onto tenofovir had a higher risk of nephrotoxicity and death compared with ART-naive patients. However, unlike previous studies, ours did not find that women were at higher risk of developing nephrotoxicity than men in this cohort [3,9,37]. Additionally, because our cohort is 96.3% black, we were not able to determine potential differences in risk of clinical outcomes between races as previously reported .
Research has shown that the APOL1 risk alleles, found on chromosome 22, were present in more than 30% of individuals of African descent with focal segmental glomerulosclerosis, the glomerular lesion of HIV-associated nephropathy . A recent renal biopsy study confirmed that tenofovir is a mitochondrial toxin in renal tubular cells  and that exposure to tenofovir can result in renal injury in a small subset of HIV-positive patients. Additionally, research has documented a single-nucleotide polymorphism in the multidrug resistance protein 2 (MRP-2) efflux transporter gene (ABCC2) in HIV-positive patients who developed tenofovir-induced nephrotoxicity . This is significant because tenofovir is transported via the organic anion transporter-1 (OAT-1) from the basolateral circulation into proximal tubular cells, where it is eventually translocated into the urine through apical efflux transporters such as MRP-2 and MRP-4. This evidence coupled with the limited care for this disease in resource-limited settings makes it critical to prevent or slow its progression to end-stage renal disease .
Regular measurement of kidney function in HIV-infected individuals at presentation and throughout tenofovir use is essential [10,42]. The new South African antiretroviral treatment guidelines recommend measurement of serum creatinine and creatinine clearance at ART initiation, at 3 and 6 months and yearly thereafter for patients on tenofovir . Our results show median time to nephrotoxicity after tenofovir initiation is 3.6 months, confirming the importance of the 3-month creatinine clearance. Only patients with a calculated creatinine clearance of more than 50 ml/min can safely start tenofovir . If toxicity develops, the dosage interval of tenofovir can be reduced to either every 48 h, bi-weekly or every 7 days with hemodialysis. Alternatively, patients can be switched onto zidovudine–lamivudine–efavirenz/nevirapine .
This study represents patients from only one government ART site and may, therefore, not be generalizable to other clinics. Additionally, our findings should be considered in light of the study limitations. First, the exclusion of over 400 patients due to missing creatinine clearance data could have introduced selection bias. However, apart from lower CD4 cell counts, the demographic and clinical characteristics of this group were similar to those included in the analysis. Second, the small sample size and few nephrotoxicity events resulted in a lack of precision for this outcome in our study and may have limited our ability to accurately estimate this relationship. Third, urine and serum phosphate are not routinely measured, so the analysis was restricted to creatinine clearance as a measure of nephrotoxicity. Fourth, we acknowledged that the relationship between tenofovir and renal dysfunction in this analysis may have been confounded by the fact that patients with more advanced disease were using tenofovir during the first years the drug was available. Fifth, previous studies conducted on HIV-negative black populations found that the association between rate of renal events and baseline renal dysfunction was greater at creatinine clearance values of less than 40 vs. 40 ml/min or more, suggesting that the nephrotoxicity attributed to tenofovir in our study may have been coincidental in some cases . Finally, data on co-administration of nephrotoxic drugs and information about appropriate dose reduction of tenofovir were not available.
The high prevalence of kidney disease in South Africa [10,11] coupled with starting all new ART initiates on tenofovir  highlights the need to screen patients for baseline renal dysfunction to reduce the burden of nephrotoxicity and improve treatment outcomes in this population. Additional research is needed to accurately assess the association between baseline renal insufficiencies and ART outcomes among patients on tenofovir.
We express our gratitude to the directors and staff of TLC and to RTC, the NGO supporting the study site through a partnership with USAID. We also thank the Gauteng and National Department of Health for providing for the care of the patients at TLC as part of the Comprehensive Care Management and Treatment plan. Most of all we thank the patients attending the clinic for their continued trust in the treatment provided at the clinic.
Conflicts of interest
Funding for this study was provided by the South Africa Mission of the US Agency for International Development (USAID) under the terms of Associate Cooperative Agreement No. 674-A-00-09-00018-00 under Cooperative Agreement 674-A-00-02-00018 to Right to Care (RTC). M.F. was also supported by award number K01AI083097 from the National Institute of Allergy and Infectious Diseases (NIAID). S.N. was supported in part by the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR), an NIH funded program number P30 AI50410. The opinions expressed herein are those of the authors and do not necessarily reflect the views of NIH, NIAID, USAID, the Themba Lethu Clinic (TLC) or RTC.
RTC provided some of the funding for the current research and also supports the provision of treatment for the patients in the study.
There are no conflicts of interest.
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