TDF associated Fanconi syndrome

Suspected Tenofovir disoproxil fumarate Associated Fanconi Syndrome in a Chronic

Hepatitis B Patient

加護病房查房日誌ICU note

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

Case Report

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.

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

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.

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.

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.

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.

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+)

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.

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.

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.

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.

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.

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.

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.

Discussion

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.

His renal function

Initial tenofovir

DC tenofovirBUN Scr

Potassium level

DC tenofovir

Still hypokalemia if DC potassium supplement until 4-6 months after DC tenofovir

Phosphate level

Phosphate normalized after DC tenofovir

Arterial Blood Gas

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

After DC tenofovir, keep giving sodium bicarbonate until May

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.

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


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.


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

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.

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


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.

Management

• TDF discontinuation is the most effective treatment of TDF associated Fanconi syndrome.


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

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

Purpose

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

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

Results

Baseline Characteristics

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

Monitor Scr Before and During TDF Use

1. 89% pts had Scr data before TDF use2. Only 1 pt had no Scr data before and during TDF use for 9 months3. Other 6 pts had normal Scr data during TDF use

95 % (61)

5 % (3)

1. 94% pts had Scr data during TDF use2. 2 pts only use TDF for 2 months

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

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.

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TDF associated Fanconi syndrome

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