DISCUSSION
FS is a proximal tubule dysfunction that results in normoglycemic
glycosuria, as well as urinary loss of phosphate, calcium, uric acid,
amino acids, bicarbonates, and tubular proteins 11Izzedine H,
Launay-Vacher V, Isnard-Bagnis C, Deray G. Drug-induced Fanconi’s
syndrome, Am J Kidney Dis, 2003, vol. 41 (pg. 292-309). Tenofovir can
cause complete or partial Fanconi syndrome. Majority of cases present as
partial with an elevation in creatinine levels, hypophosphatemia and
glycosuria 22Izzedine H, Hulot JS, Vittecoq D, et al. Long-term
renal safety of tenofovir disoproxil fumarate in antiretroviral-naive
HIV-1-infected patients: data from a double-blind randomized
active-controlled multicentre study, Nephrol Dial Transplant, 2005,
vol. 20 (pg. 743-6). Patients on TDF based regimen are at 5 times
greater risk of developing chronic kidney disease in comparison to
patients on a non-TDF based regimen. This rapid decline of estimated GFR
mostly occur in the first 2-3 years of treatment33Jirayu
Visuthranukul, T. R. (2021). Incidence Rate and Time to Occurrence of
Renal Impairment and Chronic Kidney Disease among Thai HIV-infected
Adults with Tenofovir Disoproxil Fumarate Use. Open Aids Journal,
73-80..The prevalence of renal dysfunction induced by TDF is
estimated at 5.6%, and the risk is increased with advanced age, low
BMI, low baseline CD4 count, hypertension and diabetes44Nagalingeswaran
Kumarasamy, S. S. (2018). Prevalence and factors associated with renal
dysfunction in patients on tenofovir disoproxil fumarate-based
antiretroviral regimens for HIV infection in Southern India.Journal of Virus Eradication, 4 (1), 37-40. Retrieved from
https://doi.org/10.1016/S2055-6640(20)30245-4.. Severe nephrotoxicity
to warrant discontinuation has been reported in 1% patients
yearly55Fux, C. A., Simcock, M., Wolbers, M., Bucher, H. C.,
Hirschel, B., Opravil, M., Vernazza, P., Cavassini, M., Bernasconi,
E., Elzi, L., Furrer, H., & Swiss HIV Cohort Study (2007). Tenofovir
use is associated with a reduction in calculated glomerular filtration
rates in the Swiss HIV Cohort Study. Antiviral
therapy , 12 (8), 1165–1173..) Africans with pre-existing
renal disease and advanced age are at a greater risk of statistically
significant TDF associated renal function decline66Mtisi, T.J.,
Ndhlovu, C.E., Maponga, C.C. et al. Tenofovir-associated kidney
disease in Africans: a systematic review. AIDS Res
Ther 16 , 12 (2019).
https://doi.org/10.1186/s12981-019-0227-1. Concomitant protease
inhibitor use has also been suggested to contribute to development of
TDF associated nephrotoxicity77Ryan D. Cooper and others,
Systematic Review and Meta-analysis: Renal Safety of Tenofovir
Disoproxil Fumarate in HIV-Infected Patients, Clinical
Infectious Diseases , Volume 51, Issue 5, 1 September 2010, Pages
496–505, https://doi.org/10.1086/655681. Other factors
including low body weight and low CD4 cell count have been linked to
increased susceptibility of TDF tubulopathy in some
individuals88Nelson, M. R., Katlama, C., Montaner, J. S.,
Cooper, D. A., Gazzard, B., Clotet, B., Lazzarin, A., Schewe, K.,
Lange, J., Wyatt, C., Curtis, S., Chen, S. S., Smith, S.,
Bischofberger, N., & Rooney, J. F. (2007). The safety of tenofovir
disoproxil fumarate for the treatment of HIV infection in adults: the
first 4 years. AIDS (London, England) , 21 (10),
1273–1281. https://doi.org/10.1097/QAD.0b013e3280b07b33. The
diagnostic criteria for TDF related Fanconi syndrome include
normoglycemic glycosuria, proteinuria and hypophosphatemia with
phosphaturia 99Rao, M., Dadey, L., Glowa, T., & Veldkamp, P.
(2021). Fanconi Syndrome Leading to Hypophosphatemic Osteomalacia
Related to Tenofovir Use. Infectious disease
reports , 13 (2), 448–453.
https://doi.org/10.3390/idr13020044 that can be screened for,
through urine and blood tests. Reliance on elevations in eGFR and urine
albumin/creatinine ratio, may lead to missed diagnoses due to their poor
sensitivity as markers of proximal tubular function1010Mothobi NZ,
Masters J, Marriott DJ. Fanconi syndrome due to tenofovir disoproxil
fumarate reversed by switching to tenofovir alafenamide fumarate in an
HIV-infected patient. Therapeutic Advances in Infectious
Disease . 2018;5(5):91-95.
doi:10.1177/2049936118785497.
Approximately half of the patients attain partial or full recovery of
renal function after 1 year of TDF discontinuation, defined as
>70% of pre- TDF creatinine clearance with majority of
major markers of proximal tubulopathy resolving within 8 weeks of drug
discontinuation1111Samir K. Gupta, A. M.-G. (2014, March). Fanconi
Syndrome Accompanied by Renal Function Decline with Tenofovir
Disoproxil Fumarate: A Prospective, Case-Control Study of Predictors
and Resolution in HIV-Infected Patients. PLOS ONE, 9(3), 1-7.
Retrieved from
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0092717&type=printable.
However, full reversibility of TDF –related renal toxicity is not
always the rule1212Wever, K., van Agtmael, M. A., & Carr, A.
(2010). Incomplete reversibility of tenofovir-related renal toxicity
in HIV-infected men. Journal of acquired immune deficiency
syndromes (1999) , 55 (1), 78–81.
https://doi.org/10.1097/QAI.0b013e3181d05579. Early switching
of TDF in patients with proximal renal tubulopathy has been associated
with better chances of complete renal recovery as well as low levels of
urine dipstick proteinuria at the time of discontinuation1313Patamatamkul,
S., Songumpai, N., Payoong, P., Katavetin, P., & Putcharoen, O.
(2022). Early switching of tenofovir disoproxil fumarate (TDF) in
HIV-infected patients with TDF-induced nephrotoxicity: a prospective
study. HIV research & clinical practice , 23 (1),
99–106..
This case illustrates a patient from an underserved region of a Low
Middle-Income Country on Tenofovir based regimen for 12 years. She has
excellent adherence as confirmed by the consistent undetectable viral
load. However, she is unable to afford annual renal function tests as
recommended by HAART guidelines1414Izzedine H, Hulot JS, Vittecoq
D, et al. Long-term renal safety of tenofovir disoproxil fumarate in
antiretroviral-naive HIV-1-infected patients: data from a double-blind
randomized active-controlled multicentre study, Nephrol Dial
Transplant, 2005, vol. 20 (pg. 743-6). It follows a trivial fall with
persistent and worsening body and bone pains that the patient gets to be
admitted. Further work up revealed normoglycemic glycosuria, increase in
creatinine with declining glomerular filtration rate (GFR), proteinuria,
hypouricemia, hyperchloremia, hypocalcemia and osteopenia. These
laboratory findings are in keeping with FS where 5 out of 7 nondiabetic
patients biopsied for Tenofovir nephrotoxicity had glycosuria with
increased serum creatinine1515Herlitz LC, Mohan S, Stokes MB,
Radhakrishnan J, D’Agati VD, Markowitz GS. Tenofovir nephrotoxicity:
acute tubular necrosis with distinctive clinical, pathological, and
mitochondrial abnormalities. Kidney International.
2010;78(11):1171–1177. Inability to do Arterial Blood Gases and
phosphates in the resource limited regions further stifles the ability
to clinch the diagnosis earlier1616Badiou S, Merle De Boever C,
Terrier N, Baillat V, Cristol JP, Reynes J. Is tenofovir involved in
hypophosphatemia and decrease of tubular phosphate reabsorption in
HIV-positive adults? Journal of Infection. 2006;52(5):335–338.. The
bone pain and generalized body aches are possibly a consequence of
osteomalacia, which is a late manifestation of proximal tubulopathy
secondary to phosphate wasting and/calcitriol deficiency, since
calcitriol is synthesized by the mitochondria in the proximal
tubules1717Perrot S, Aslangul E, Szwebel T, Caillat-Vigneron N, Le
Jeunne C. Bone pain due to fractures revealing osteomalacia related to
tenofovir-induced proximal renal tubular dysfunction in a human
immunodeficiency virus-infected patient. Journal of Clinical
Rheumatology. 2009;15(2):72–74 .
The proposed risk factors in this case includes and is not limited to
prolonged TDF use1818Woodward C, Hall A, Williams I,
Tenofovir-associated renal and bone toxicity. HIV Med 2009;10(8):482-7,
low body weight and advanced age1919Nelson MR, Katlama C, Montaner
JS, et al. The safety of tenofovir disoproxil fumarate for the
treatment of HIV infection in adults: the first 4 years. AIDS.
2007;21(10):1273–1281.. The patient symptoms and renal function
markedly improved following TDF discontinuation. 6 weeks later, she had
no glycosuria, proteinuria, hypocalcemia and had reduced creatinine
levels. Alexandre Karras et al2020Karras A, Lafaurie M, Furco A,
Bourgarit A, Droz D, Sereni D, Legendre C, Martinez F, Molina JM.
Tenofovir-related nephrotoxicity in human immunodeficiency
virus-infected patients: three cases of renal failure, Fanconi
syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis. 2003
Apr 15;36(8):1070-3. doi: 10.1086/368314. Epub 2003 Apr 4. PMID:
12684922. reported that most of laboratory values in TDF tubulopathy
returned to normal following its discontinuation.
In conclusion, we would like to emphasize the need for routine
monitoring of renal function of patients on TDF based regimen for
nephrotoxicity, even years after initiation of drugs. On any occasion
TDF tubulopathy signs are recognized, the drug should be stopped to
prevent further complications.