This case report describes a 72-year-old man with chronic hepatitis B who developed suspected tenofovir disoproxil fumarate-associated Fanconi syndrome. The man was treated with TDF and entecavir for hepatitis B. Over four months his renal function declined, and he developed hypokalemia, metabolic acidosis, and acute kidney injury. All features improved after discontinuing TDF, supporting the diagnosis of TDF-associated Fanconi syndrome. The report reviews the mechanism and risk factors of TDF nephrotoxicity and recommends monitoring renal function in patients taking TDF.

1. Suspected Tenofovir disoproxil fumarate
Associated Fanconi Syndrome in a Chronic
Hepatitis B Patient
加護病房查房日誌
ICU note

2. Outline
• Case report
– Tenofovir disoproxil fumarate Associated Fanconi
Syndrome in a Chronic Hepatitis B Patient
• Observational study in a teaching hospital
– TDF associated Renal Toxicity in Chronic Hepatitis
B patients

3. Case Report

4. Introduction
• Tenofovir disoproxil fumarate (TDF)
– A nucleoside reverse transcriptase inhibitor
• Human immunodeficiency virus (HIV) infection and
chronic hepatitis B (CHB) infection
• Side effects
– diarrhea (16%), asthenia (11%) and nausea (11%)
• Renal toxicity has been reported in HIV
infected patients, but rare in CHB infection
Ref: Viread (tenofovir) [package insert]. Foster City, CA: Gilead Sciences Inc; October 2013.

5. Case Summary
• A 72-year-old male had type 2 diabetes
mellitus (DM), hypertension (HTN) and CHB
infection
– TDF and entecavir for his CHB infection
– Insulin for type 2 DM
– Valsartan and carvedilol for HTN
• Without baseline renal function and other
electrolyte data

6. Two months later
• His serum creatinine (Scr) was 1.7 mg/dL
– Estimated glomerular filtration rate (eGFR) 42.32
ml/min/1.73m2
• Blood urea nitrogen (BUN) 20 mg/dL
• Sodium level (Na)135 mmol/L
• Potassium level (K) 3.8 mmol/L.

7. Four months later
• He was brought to our emergency department
due to general discomfort and vomiting.
– Body temperature (BT) 36 ℃, Heart rate (HR) 80
beats/min, blood pressure (BP) 148/88 mmHg and
respiratory rate (RR) 18 breaths/min
– Serum white blood count (WBC) 9,780/uL,
segment 72.8%
– Na 136 mmol/L, K 3.4 mmol/L, Scr 4.1 mg/dL
(eGFR 15.32 ml/min/1.73m2), and BUN 56 mg/dL.

8. The nephrologist considered
• His acute kidney injury might be due to pre-
renal factors besides the urinary tract
infection.
• After adequate hydration and antibiotics
treatment, the patient was stable with his
serum creatinine returning to 2.2 mg/dL
(eGFR 31.43 ml/min/1.73m2) and therefore
was discharged.

9. Unfortunately, 4 days after discharge
• He was brought to our emergency department
again.
• Chief complaint was dyspnea.
• BT 38.2 ℃, HR 125 beats/min, BP 78/47
mmHg and RR 36 breaths/min.
• Because of oxygen desaturation, emergent
intubation was conducted.

10. His laboratory data
• Serum WBC 12,700/uL, segment 84%, Na 138
mmol/L, K 1.6 mmol/L, chloride 129 mmol/L,
phosphate <0.4 mg/dL, uric acid 3.1 mg/dL
• Scr 5.1 mg/dL (eGFR 11.91 ml/min/1.73m2), and
BUN 61 mg/dL
• Arterial blood gas revealed metabolic acidosis of
pH 7.122, pCO2 14.7 mmHg and HCO3- 4.7
mmol/L
• Urinalysis showed glucosuria (4+) and proteinuria
(2+)

11. Transferred to intensive care unit
• Chest x-ray showed patch lesion on the right
middle lobe.
• He was diagnosed with pneumonia, septic shock
and acute respiratory failure.
– Broad-spectrum antibiotics (piperacillin/tazobactam
and teicoplanin) and norepinephrine were
administrated for his septic shock.
– Potassium supplements and sodium bicarbonate were
given to correct severe hypokalemia and metabolic
acidosis.

12. Renal tubular acidosis
• The nephrologist was consulted for acute
kidney injury, metabolic acidosis and
hypokalemia.
• The calculated serum anion gap (4.3 meq/L)
was not elevated and he had no history of
diarrhea.
• Renal tubular acidosis (Fanconi syndrome) was
highly recommended for the diagnosis by the
nephrologist.

13. Drug related ?
• The nephrologist considered drug related?
• Our clinical pharmacist was consulted to
review his medication history and tenofovir
was highly suspected due to previous adverse
drug reports of Fanconi syndrome.

14. Gastroenterologist was consulted
• After checking the total bilirubin, it was 0.57
mg/dL, nonreactive of HBe Ag (0.36), reactive
of HBs Ag (0.88) and undetectable of HBV DNA
• TDF and entecavir were discontinued upon
the suggestion of our gastroenterologist.

15. Five months later
• Entecavir was administrated again for two
weeks due to abnormal level of alanine
aminotransferase (ALT)
• But serum creatinine did not increase during
its use.

16. Six months after the discontinuation of TDF
• His Scr decreased to 1.2 mg/dL
• While the persistent hypokalemia and
metabolic acidosis returned to normal range
even without the supplements of potassium
and sodium bicarbonate.
• A renal biopsy was refused by the patient.

17. The Naranjo probability scale
• 5 points
– A probable relationship between TDF and Fanconi
in this patient
• Due to the rechallenge of entecavir without
recurrence of Fanconi syndrome, we highly
suspected the case to be TDF associated
Fanconi syndrome.
Ref: Naranjo CA et al. A method for estimating the probability of adverse drug reactions.
Clin Pharmacol Ther. 1981 Aug;30(2):239-45.

18. Discussion

19. TDF associated Fanconi syndrome
• TDF associated nephrotoxicity or Fanconi
syndrome in HIV patients have been reported
– Case series and review
• However, rare in CHB monoinfection.
• Our diagnosis of Fanconi syndrome was based on
clinical features of the proximal renal tubular
acidosis
– Generalized glycosuria, phosphaturia, non-anion gap
metabolic acidosis, hypokalemia and proteinuria.

20. His renal function
Initial tenofovir
DC tenofovirBUN Scr

21. Potassium level
DC tenofovir
Still hypokalemia if DC potassium
supplement until 4-6 months after DC
tenofovir

22. Phosphate level
Phosphate normalized after DC
tenofovir

23. Arterial Blood Gas
23
01/14 01/15 01/18 02/10 03/17 05/19
pH(7.35~7.45) 7.122 7.21 7.358 7.289 7.29 7.342
pCO2(35~45) 14.7 16.7 24.5 28.3 40.1 41.7
pO2(80~100) 89.1 189 141.9 167.7 159.6 137.7
HCO3(22~26) 4.7 6.5 13.5 13.3 18.9 22.1
O2 sat.(95~98) 91.1 99.2 98.9 99.2 99.1 98.9
After DC tenofovir, keep giving sodium bicarbonate until
May

24. The pattern of TDF associated Fanconi
syndrome in CHB patients
• Delayed onset
• Recovery may take weeks to months after
stopping TDF treatment
• Gracey et al. reported two patients with CHB
infection and TDF associated Fanconi
syndrome
Ref: Gracey DM Tenofovir-associated Fanconi syndrome in patients with chronic hepatitis B monoinfection.
Antivir Ther. 2013;18(7):945-8. doi: 10.3851/IMP2649. Epub 013 Jul 10.

25. First patient
• Scr increased from 1.06 mg/dL to a peak of
1.7 mg/dL about 6 months after commencing
TDF
• His renal function had improved but not
returned to normal range and he had no
features of Fanconi syndrome 24 months after
discontinuing TDF
Ref: Gracey DM Tenofovir-associated Fanconi syndrome in patients with chronic hepatitis B monoinfection.
Antivir Ther. 2013;18(7):945-8. doi: 10.3851/IMP2649. Epub 013 Jul 10.

26. Second patient
• His serum creatinine increased from 1.06 to 1.53
mg/dL and he had aminoaciduria, glycosuria, low-
grade proteinuria, hypophosphatemia (0.68
mmol/l) and hypouricemia (0.08 mmol/l) 24
months after commencing TDF
• At 3 months after switching from TDF to entecavir,
the serum creatinine decreased to 1.20 mg/dL
with no features of Fanconi syndrome.
Ref: Gracey DM Tenofovir-associated Fanconi syndrome in patients with chronic hepatitis B monoinfection.
Antivir Ther. 2013;18(7):945-8. doi: 10.3851/IMP2649. Epub 013 Jul 10.

27. Our patient
• His serum creatinine increased to 5.1 mg/dl
– much higher than the previous reports
– In addition to TDF, it could be related to septic shock
– Similar clinical features of Fanconi syndrome
• including metabolic acidosis, hypokalemia,
hypophosphatemia, hypouricemia, glycosuria and
proteinuria
– The complete recovery of renal function and Fanconi
syndrome in our patient
• 4 months after stopping TDF

28. Mechanism
• Current evidences suggest that TDF can be
toxic to proximal tubule mitochondria.
• If proximal tubule mitochondria is injured,
tubular cells cannot ensure reabsorption of
ions and small molecules such as potassium,
glucose, phosphate, uric acid, and amino acids
Ref: Fernandez-Fernandez B, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Res
Treat. 2011:354908.(doi):10.1155/2011/354908. Epub 2011 Jun 7.

29. Risk factors
• The development of TDF associated Fanconi
syndrome in HIV-infected patients
– Age
– Pre-existing renal impairment
– Concomitant use of nephrotoxic medications
– Comorbidities such as diabetes and hypertension
– The use of certain protease inhibitors
Ref: Fernandez-Fernandez B, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Res
Treat. 2011:354908.(doi):10.1155/2011/354908. Epub 2011 Jun 7.

30. Prevention
• Dose reduction is advised when GFR is low
• The European Society for the Study of the
Liver recommends
– Monitoring of Scr and serum phosphate levels in
all patients with CHB taking TDF
– every 3 months in the first year and every 6
months thereafter
– Any detection of renal dysfunction and there is an
effective alternative agent, TDF treatment should
be discontinued immediately
Ref: EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009 Feb;50(2):227-42.

31. Management
• TDF discontinuation is the most effective
treatment of TDF associated Fanconi
syndrome.
Ref: Fernandez-Fernandez B, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Res
Treat. 2011:354908.(doi):10.1155/2011/354908. Epub 2011 Jun 7.

32. Conclusion
• TDF associated Fanconi syndrome still could
happen in a CHB patient
• Discontinuing TDF and giving supportive care
may recover the renal function and normalize
the Fanconi syndrome completely

33. Observational Study of TDF
associated Renal Toxicity in Chronic
Hepatitis B patients

34. Purpose
• To evaluate the renal function of a chronic
hepatitis B patients who received TDF

35. Methods
• A Retrospective study in a teaching hospital
• Inclusion criteria: CHB pts who received TDF
during June 2014
• Observational duration: Jan/30/2012 to
Aug/31/2014
• Using electronic medical chart to collect the
serum creatinine of pts as primary outcome
before and during TDF administration.
– Normal Scr: 0.8-1.3 mg/dL

36. Results

37. Baseline Characteristics
• Pts number: 64 persons
• Age: 49 ± 12 years old
• Sex: 75% male
• Indications of TDF: chronic hepatitis B

38. Monitor Scr Before and During TDF Use
1. 89% pts had Scr data
before TDF use
2. Only 1 pt had no Scr data
before and during TDF use
for 9 months
3. Other 6 pts had normal
Scr data during TDF use
95 % (61)
5 % (3)
1. 94% pts had Scr data
during TDF use
2. 2 pts only use TDF for 2
months

39. Scr Increased over 1.3 mg/dL
Case Onset of
increased
Scr after
TDF use
Baseline
Scr
Increased
Scr during
TDF use
Management Follow up
Scr data
1 12 months 1 mg/dL 1.4 mg/dL Shift to
entecavir
0.9 mg/dL
after 3
months
2 15 months 0.8 mg/dL 1.5 mg/dL Keep TDF use 1.1 mg/dL
after 4
months
3 1.4 mg/dL Keep 1.4 mg/dL during TDF use

40. Conclusions
• Most pts had Scr monitoring regularly and had
normal Scr data.
• 3 % (2/61) had mild increased Scr during TDF
use for 12-15 months and it will return to
normal while shift to entecavir or keep TDF
use.

41. Thank you for listening
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