Elevated serum creatinine in the context of HIV – who is the culprit? Over-the-counter supplements vs. antiretrovirals

Introduction

We report a case of apparent decline in renal function in a person living with HIV (PLWH). Subsequent direct measurement of glomerular filtration rate (GFR) using radio-labelled nuclear medicine imaging exposed a discrepancy between the estimated GFR, and the absolute GFR, confirming the absence of significant renal impairment.

A 53-year-old White British male with a background of well controlled HIV (CD4 666 cells/mm³, viral load <50 copies/ml), and chronic kidney disease (CKD) category 3 secondary to hypertension, was noted to have an acute elevation in serum creatinine, from baseline values of creatinine 118 umol/l and eGFR 60 mL/min, to 237 umol/l and 26 mL/min, respectively. He denied any recent illness and was asymptomatic. Of note, immunology screen including complement C3/C4, antinuclear antibody, and testing for small and medium vessel vasculitides was unremarkable. Serum protein electrophoresis and hepatitis C serology were negative, and syphilis serology was consistent with successfully treated syphilis. Renal ultrasound scan was unremarkable with no evidence of hydronephrosis and normal-sized kidneys. Urinalysis was negative for blood and protein. He was taking aspirin, omeprazole, irbesartan and the combination of tenofovir alafenamide/emtricitabine and dolutegravir for HIV. He had been established on this combination for six months, and had switched from abacavir/lamivudine in view of a high cardiovascular risk. He had a fully susceptible virus, and had previously been switched from nevirapine to dolutegravir due to a low-level viraemia. Subsequently, given his apparent renal deterioration with an eGFR <30ml/min, tenofovir alafenamide/emtricitabine was replaced with darunavir and ritonavir. He continued on dolutegravir. Further questioning revealed the patient had recently purchased creatine supplements to build muscle mass, and had been using them daily for the past three months. These supplements contained creatine monohydrate, magnesium stearate and a bulking agent – microcrystalline cellulose.

He underwent specialist renal review. Examination was unremarkable. Repeat testing again revealed creatinine 321umol/l and eGFR 18 ml/min. The renal specialists urgently investigated further with chromium-labelled GFR measurement. Plasma clearance of chromium-51 EDTA revealed a true GFR 70 ml/min when normalised to body surface area.

This confirmed the patient did not have significant renal impairment. He was advised to discontinue the supplements altogether. Subsequent biochemistry testing revealed a recovery with serum creatinine 138 umol/l and eGFR 50 ml/min. He remains fully suppressed on dual therapy with darunavir/ritonavir and dolutegravir, with most recent eGFR 56 ml/min. He continues with regular monitoring in both HIV and nephrology clinics.

Discussion

It is important to note that the patient’s renal function was normal for him. It was primarily the use of creatine supplements that resulted in an elevated creatinine and therefore misleading estimated GFR result.

Creatine supplements in particular are being utilised in the general population to gain muscle mass. Creatine is metabolised by the kidney, which then excretes creatinine as a by-product. The creatinine elevation can lead to difficulty in interpretation of traditional renal tests including creatinine, as it results in a falsely low eGFR. Although this physiological mechanism has been widely reported, ¹ alternative investigations that can be carried out in such circumstances are not as well known. Serum cystatin C, a non-glycosylated protein, has been utilised instead of serum creatinine to estimate GFR, and is a reliable marker for detecting and monitoring renal disease. Significantly, the concentration of cystatin C is not affected by muscle mass, age, gender and ethnicity, ² therefore may be a suitable alternative when these confounders are present. Limitations include its interpretation in the context of obesity and thyroid dysfunction, which may be applicable when managing PLWH with other comorbidities. ³ Locally, this blood test is available following specialist request and is more costly. The highly-sensitive chromium-labelled scan makes use of nuclear medicine radio-labelled tracers that are exclusively cleared by glomerular filtration, ⁴ therefore eliminating any uncertainty in circumstances where serum creatinine may be unreliable. Again, whilst locally this investigation is only available following specialist request, it is considered safe and accurate, with the level of radiation exposure similar to that of a chest X-ray. ⁴ Potential errors may occur if there is inaccuracy in the timing of the injection or blood sampling, or if there is third spacing e.g. due to oedema, but this is accounted for through implementation of quality control checks and following British Nuclear Medicine Society guidance. ⁴

In our cohort, based on observation, we estimate up to 20% utilise over-the-counter (OTC) supplements. This is difficult to quantify further, but certainly the OTC supplements industry in the UK was worth over £431 million in sales in 2019, ⁵ suggesting their use is widespread. This can lead to difficulty in ascertaining whether a perceived decline in renal function is due to antiretrovirals, or an alternative cause. Subsequently, it has become routine practice to enquire about the use of OTC agents in all PLWH as part of medicines reconciliation, with judicious prescribing of antiretrovirals in cases where renal dysfunction is present. A review of dietary supplements with potential to cause nephrotoxicity include widely-available liquorice and willow bark, as well as creatine. ⁶

All major classes of antiretrovirals have the potential to cause true or perceived renal deterioration via different mechanisms. Tenofovir-DF is directly nephrotoxic and can cause Fanconi syndrome, nephrogenic diabetes insipidus, renal tubular acidosis or urinary concentration defects. ⁷ Withdrawal of tenofovir-DF results in improvement in renal function over a number of months, but it may not revert to baseline. ⁸ The onset of renal deterioration is acute within days-weeks of initiation, hence British HIV Association guidance recommends assessing renal function after 2–4 weeks of treatment, and at regular intervals thereafter. Atazanavir can cause nephrolithiasis and is associated with CKD. ⁷

Other antiretrovirals may result in spurious creatinine readings through similar physiological pathways as stated previously. For example, dolutegravir inhibits the OCT2 transporter located in the proximal renal tubule, leading to reduced tubular uptake of creatinine and therefore elevated levels of creatinine without a true deterioration in the GFR. ⁹ Rilpivirine and cobicistat exert their effect in a similar fashion. ⁹

Conclusion

OTC supplements are widely used and may be responsible for elevation in serum creatinine. In the short term they may not have pathological consequences, but recognising and ceasing the offending agent is paramount in ensuring correct management of these cases, particularly where comorbidities may further compound the issue. It is useful for HIV clinicians to be aware of the availability of alternative investigations such as serum cystatin C measurement, or chromium-labelled scanning in suspected cases of apparent decline in renal function, particularly if antiretroviral options are limited.