Tenofovir disoproxil fumarate (TDF, commonly termed ‘tenofovir’) is the antiretroviral most commonly implicated in antiretroviral-induced nephrotoxicity. As patients on successful antiretroviral therapy (ART) age, their risk for developing renal disease may increase in part because of ART itself, but more importantly, because of HIV-associated and non-HIV-associated comorbidity. Therefore, clinicians need an approach to managing renal disease in people on TDF. TDF as a cause of acute kidney injury (AKI) or chronic kidney disease (CKD) is uncommon, and clinicians should actively exclude other causes (Box 1). In TDF-associated AKI, TDF should be interrupted in all cases, and replaced, or ART interrupted altogether. Tenofovir disoproxil fumarate toxicity can present as AKI or CKD, and as a full or partial Fanconi’s syndrome. TDF has a small but definite negative impact on kidney function (up to a 10% decrease in glomerular filtration rate [GFR]). This occurs because of altered tubular function in those exposed to TDF for treatment and as pre-exposure prophylaxis. Renal function should be assessed using creatinine-based estimated GFR at the time of initiation of TDF, if ART is changed, at 1–3 months, and then ideally every 6–12 months if stable. Specific tests of tubular function are not routinely recommended; in the case of clinical concern, a spot protein or albumin: creatinine ratio is preferable, but in resource-limited settings, urine dipstick can be used. More frequent monitoring may be required in those with established CKD (estimated glomerular filtration rate [eGFR] < 50 mL/min/1.73 m2) or risk factors for kidney disease. The most common risk factors are comorbid hypertension, diabetes, HIV-associated kidney disease, hepatitis B or C co-infection, and TDF in combination with a ritonavir-boosted protease inhibitor. Management of these comorbid conditions must be prioritised in this group. If baseline screening eGFR is < 50 mL/min/1.73 m2, abacavir (the preferred option), and dose-adjusted TDF (useful if concomitant hepatitis B), zidovudine or stavudine (d4T) remain alternatives to full-dose TDF. If there is a rapid decline in kidney function (eGFR drops by more than 25% and decreases to < 50 mL/min/1.73 m2 from of baseline function), or there is new onset or worsening of proteinuria or albuminuria, clinicians should review ART and other potentially nephrotoxic medications and comorbidity and conduct further testing if indicated. If kidney function does not improve after addressing reversible causes of renal failure, then referral to a nephrologist is appropriate. In the case of severe CKD, timeous referral for planning for renal replacement therapy is recommended. Tenofovir alafenamide, a prodrug of tenofovir, appears to have less renal toxicity and is likely to replace TDF in future.

Background: Chronic kidney disease (CKD) is a substantial cause of morbidity and mortality worldwide with disproportionate effects in sub-Saharan Africa (SSA). The optimal methods to estimate glomerular filtration rate (GFR) and therefore to determine the presence of CKD in SSA are uncertain. We plan to measure iohexol excretion to accurately determine GFR in Malawi, South Africa and Uganda. We will then assess the performance of existing equations to estimate GFR and determine whether a modified equation can better improve estimation of GFR in sub-Saharan Africa. Methods: The African Research on Kidney Disease (ARK) study is a three-country study embedded within existing cohorts. We seek to enrol 3000 adults > 18 years based on baseline serum creatinine. Study procedures include questionnaires on socio-demographics and established risk factors for kidney disease along with anthropometry, body composition, blood pressure, blood chemistry and urine microscopy and albuminuria. We will measure GFR (mGFR) by plasma clearance of iohexol at 120, 180 and 240 min. We will compare eGFR determined by established equations with mGFR using Bland-Altman plots. We will use regression methods to estimate GFR and compare the newly derived model with existing equations. Discussion: Through the ARK study, we aim to establish the optimal approach to estimate GFR in SSA. The study has the advantage of drawing participants from three countries, which will increase the applicability of the findings across the region. It is also embedded within established cohorts that have longitudinal information and serial measures that can be used to characterize kidney disease over a period of time. This will help to overcome the limitations of previous research, including small numbers, selected population sub-groups, and lack of data on proteinuria. The ARK collaboration provides an opportunity for close working partnerships across different centres, using standardized protocols and measurements, and shared bio-repositories. We plan to build on the collaboration for this study for future work on kidney disease in sub-Saharan Africa, and welcome additional partners from across the continent.

Globally, chronic kidney disease (CKD) is an emerging public health challenge but accurate data on its true prevalence are scarce, particularly in poorly resourced regions such as sub-Saharan Africa (SSA). Limited funding for population-based studies, poor laboratory infrastructure and the absence of a validated estimating equation for kidney function in Africans are contributing factors. Consequently, most available studies used to estimate population prevalence are hospital-based, with small samples of participants who are at high risk for kidney disease. While serum creatinine is most commonly used to estimate glomerular filtration, there is considerable potential bias in the measurement of creatinine that might lead to inaccurate estimates of kidney disease at individual and population level. To address this, the Laboratory Working Group of the National Kidney Disease Education Program published recommendations in 2006 to standardize the laboratory measurement of creatinine. The primary objective of this review was to appraise implementation of these recommendations in studies conducted in SSA after 2006. Secondary objectives were to assess bias relating to choice of estimating equations for assessing glomerular function in Africans and to evaluate use of recommended diagnostic criteria for CKD. This study was registered with Prospero (CRD42017068151), and using PubMed, African Journals Online and Web of Science, 5845 abstracts were reviewed and 252 full-text articles included for narrative analysis. Overall, two-thirds of studies did not report laboratory methods for creatinine measurement and just over 80% did not report whether their creatinine measurement was isotope dilution mass spectroscopy (IDMS) traceable. For those reporting a method, Jaffe was the most common (93%). The four-variable Modification of Diet in Renal Disease (4-v MDRD) equation was most frequently used (42%), followed by the CKD Epidemiology Collaboration (CKD-EPI) equation for creatinine (26%). For the 4-v MDRD equation and CKD-EPI equations, respectively, one-third to one half of studies clarified use of the coefficient for African-American (AA) ethnicity. When reporting CKD prevalence, <15% of studies fulfilled Kidney Disease: Improving Global Outcomes criteria and even fewer used a population-based sample. Six studies compared performance of estimating equations to measured glomerular filtration rate (GFR) demonstrating that coefficients for AA ethnicity used in the 4-v MDRD and the CKD-EPI equations overestimated GFR in Africans. To improve on reporting in future studies, we propose an ‘easy to use’ checklist that will standardize reporting of kidney function and improve the quality of studies in the region. This research contributes some understanding of the factors requiring attention to ensure accurate assessment of the burden of kidney disease in SSA. Many of these factors are difficult to address and extend beyond individual researchers to health systems and governmental policy, but understanding the burden of kidney disease is a critical first step to informing an integrated public health response that would provide appropriate screening, prevention and management of kidney disease in countries from SSA. This is particularly relevant as CKD is a common pathway in both infectious and non-communicable diseases, and multimorbidity is now commonplace, and even more so when those living with severe kidney disease have limited or no access to renal replacement therapy.

Background: In Africa, true prevalence of chronic kidney disease (CKD) is unknown, and associated clinical and genetic risk factors remain understudied. This population-based cohort study aimed to investigate CKD prevalence and associated risk factors in rural South Africa. Methods: A total 2021 adults aged 20-79 years were recruited between 2017-2018 from the Agincourt Health and Socio-Demographic Surveillance System in Bushbuckridge, Mpumalanga, South Africa. The following were collected: sociodemographic, anthropometric, and clinical data; venous blood samples for creatinine, hepatitis B serology; DNA extraction; spot urine samples for dipstick testing and urine albumin: creatinine ratio (UACR) measurement. Point-of-care screening determined prevalent HIV infection, diabetes, and hypercholesterolemia. DNA was used to test for apolipoprotein L1 (APOL1) kidney risk variants. Kidney Disease Improving Global Outcomes (KDIGO) criteria were used to diagnose CKD as low eGFR (<60mL/min/1.73m2) and /or albuminuria (UACR ≥ 3.0mg/mmol) confirmed with follow up screening after at least three months. eGFR was calculated using the CKD-EPI(creatinine) equation 2009 with no ethnicity adjustment. Multivariable logistic regression was used to model CKD risk. Results: The WHO age-adjusted population prevalence of CKD was 6.7% (95% CI 5.4 - 7.9), mostly from persistent albuminuria. In the fully adjusted model, APOL1 high-risk genotypes (OR 2.1; 95% CI 1.3 - 3.4); HIV infection (OR 1.8; 1.1 - 2.8); hypertension (OR 2.8; 95% CI 1.8 - 4.3), and diabetes (OR 4.1; 95% CI 2.0 - 8.4) were risk factors. There was no association with age, sex, level of education, obesity, hypercholesterolemia, or hepatitis B infection. Sensitivity analyses showed that CKD risk factor associations were driven by persistent albuminuria, and not low eGFR. One third of those with CKD did not have any of these risk factors. Conclusions: In rural South Africa, CKD is prevalent, dominated by persistent albuminuria, and associated with APOL1 high-risk genotypes, hypertension, diabetes, and HIV infection.