Fanconi syndrome,diabetes insipidus,and acute kidney injury due to tenofovir disoproxil fumarate: A case report

Abstract

Background

Tenofovir disoproxil fumarate is widely used in Botswana as part of the first-line antiretroviral regimen in the ‘Treat All’ strategy implemented in 2016 by the Ministry of Health. Its use has been associated with several uncommon adverse renal effects, though rarely all in conjunction or without the combined use of protease inhibitors.

Case presentation

A 49-year-old woman living with HIV whose viral load is suppressed on tenofovir disoproxil fumarate, lamivudine, and dolutegravir presented with 1 day of generalized weakness and myalgia causing an inability to ambulate. This was associated with nausea and vomiting and profound fatigue. She was found to have an acute kidney injury, non-anion-gap metabolic acidosis, hypernatremia, hypokalemia, and hypophosphatemia. Urinalysis revealed pyuria with white blood cell casts, glucosuria, and proteinuria. The diagnosis was made of tenofovir-induced nephrotoxicity. The tenofovir was discontinued, and the patient was initiated on intravenous fluids and electrolyte and bicarbonate supplementation with improvement in her symptoms and laboratory values.

Conclusions

This report suggests the possibility of severe tenofovir-induced nephrotoxicity with combined acute kidney injury, Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of other provoking factors such as use with protease inhibitors or advanced HIV disease, chronic kidney disease, and age. With its wide use in Botswana and other countries, health-care providers should have a high index of suspicion for tenofovir-induced nephrotoxicity for HIV patients on tenofovir with deranged renal function tests and electrolytes.

Background

Tenofovir is a well-known nucleoside reverse transcriptase inhibitor analogue of adenosine used in the management of both human immunodeficiency virus (HIV) and chronic hepatitis B infection. ¹ Tenofovir disoproxil fumarate (TDF) is widely used in Botswana as it is part of the first-line antiretroviral regimen along with lamivudine and dolutegravir, often abbreviated ‘TLD’. Its use has been central to the implementation of the ‘Treat All’ Strategy in Botswana. ² Tenofovir has been known to rarely cause what is collectively termed ‘tenofovir-induced nephrotoxicity’. This term usually refers to the potential complications of renal impairment and Fanconi syndrome, though there have also been reports of nephrogenic diabetes insipidus.^3–7 Risk factors for nephrotoxicity from tenofovir use include older age, low body weight, pre-existing renal impairment, advanced HIV, vascular disease, and concomitant use of protease inhibitors and nephrotoxic drugs. ⁸

Fanconi syndrome is a defect of the proximal tubule leading to malabsorption of various substances including glucose, electrolytes, amino acids and protein, and bicarbonate. ⁹ Thus, the syndrome is characterized by glucosuria, phosphaturia, generalized aminoaciduria, and type II renal tubular acidosis. Often there is also associated hypokalemia, sodium wasting, and dehydration. Cases reported in the literature reveal that most patients present with weakness and myalgia and laboratory studies indicate hypophosphatemia, hypokalemia, metabolic acidosis, and normoglycemic glycosuria.^{4–7,10–12} Fanconi syndrome can be inherited or acquired. The inherited subtype is usually diagnosed in childhood. Acquired causes are not limited to but include monoclonal gammopathy, lead poisoning, and drugs such as nucleoside reverse transcriptase inhibitors. ⁹

Diabetes insipidus is a condition which results from impaired or inadequate antidiuretic hormone secretion (central), or an inability of the kidneys to respond to it (nephrogenic). Patients can present with polyuria, polydipsia, and dehydration with an elevated serum sodium level. Nephrogenic diabetes insipidus can be associated with the use of certain drugs such as lithium, amphotericin B, cidofovir, tenofovir, and foscarnet.^3–7,13

In this paper, we describe a case of an HIV-positive woman on TLD with features suggestive of severe tenofovir-induced nephrotoxicity with an acute kidney injury (AKI), Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of any other predisposing risk factors.

Case Presentation

A 49-year-old woman living with HIV whose viral load is suppressed on TLD presented to the emergency department with a 1 day history of generalized body weakness, cramping, and myalgia causing an inability to ambulate. The patient also reported three episodes of non-bilious, non-bloody vomiting without abdominal pain, diarrhea, hematochezia, or melaena. The patient denied any focal weakness, numbness, headache, blurry vision, or dizziness. There was no fever, weight changes, polyuria, hesitancy, frequency, urgency, or dysuria. The patient was diagnosed with HIV 18 years prior and was virally suppressed as of her admission with a documented undetectable viral load. Her regimen was changed to TLD in 2016 from combination efavirenz, emtricitabine, and tenofovir disoproxil fumarate. There is no record of opportunistic infections. The patient denied trauma. She did not use tobacco, alcohol, or other substances, and denied any other medication use. There was no family history of kidney disease.

On presentation, the patient’s blood pressure was 128/94 mmHg, pulse 100 beats/minute, respirations 18 breaths/minute, SpO2 99% on room air, and temperature 36.5°C. The patient’s physical examination was remarkable for dry mucous membranes, ⅘ strength in the bilateral upper limbs, and ⅗ strength in the lower. The rest of the general and neurological examinations were unremarkable. Laboratory studies revealed a serum sodium level of 160 meq/L, potassium of 2.7 meq/L, chloride of 136 meq/L, urea of 16.8 mg/dL, creatinine of 2.7 mg/dL (unclear baseline prior), glucose of 109 mg/dL, phosphorus of 0.8 mmol/L, magnesium of 1.1 mmol/L, and total calcium of 7.6 mg/dL. On arterial blood gas the pH was 7.12, pCO2 was 38 mmHg, and serum bicarbonate was 12 meq/L. The calculated anion gap without potassium was 12. Serum hemoglobin was 16.5 g/dL, white blood cell count was 10.8 × 10⁹ cells/L, and platelet count was 279 ×10⁹ cells/L. The liver function tests were within the reference ranges. The serum creatinine kinase was 226 U/L (Table 1). Urinalysis revealed a pH of 5, protein 2+, glucose 2+, negative ketones, 0–2 red blood cells per high-powered field (HPF), 50+ white blood cells per HPF, and white blood cell casts (Table 2). Unfortunately, our facility was not able to measure urine electrolytes and osmolarity, quantitative urine protein, antidiuretic protein levels, protein electrophoresis, and vitamin D levels, and these were not performed for the patient.

Table 1.

Relevant serum laboratory values of the patient on presentation and discharge.

Serum test	Reference range	Presentation value	Follow-up value a
WBC (cells/L)	4.5–11 × 109	10.8	9.6
Haemoglobin (g/dL)	12.3–15.3	16.5	14.6
Platelets (cells/L)	150–450 × 109	279	296
Sodium (meq/L)	135–145	160	144
Potassium (meq/L)	3.5–5.1	2.7	3.9
Chloride (meq/L)	98–107	136	117
Creatinine (mg/dL)	0.7–1.3	2.7	1.24
Urea (mg/dL)	7–20	16.8	10.2
Glucose (mg/dL)	70–100	109	(−)
Phosphorus (mmol/L)	0.74–1.42	0.8	(−)
Magnesium (mmol/L)	0.66–1.07	1.1	(−)
Total calcium (mg/dL)	8.6–10.3	7.6	(−)
Bicarbonate (meq/L)	22–29	12	16
VBG pH	7.31–7.41	7.12	7.34
VBG pCO2 (mmHg)	41–51	38	31
Anion gap (meq/L)	6–12	12	11
ALT (U/L)	11–41	24	51
AST (U/L)	12–31	28	58
Total bilirubin (mg/dL)	0.1–1.2	0.46	7.8
ALP (U/L)	<98	155	117
GGT (U/L)	<40	46	39
Albumin (nadir, g/dL)	3.5–5.2	3.6	28
Creatinine kinase (U/L)	<145	226	(−)

WBC, white blood cells; VBG, venous blood gas; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase.

^a4 weeks after presentation to the hospital.

Table 2.

Relevant urine laboratory values of the patient on presentation.

Urine test	Reference range	Value
pH	4.5–8	5
Protein	Negative	2+
Glucose	Negative	2+
Ketones	Negative	Negative
Epithelial cells	Negative	1+
RBC	0 per high-powered field	0–2
WBC	0 per high-powered field	50+
Casts	Negative	White cells
Crystals	Negative	Negative

RBC, red blood cells; WBC, white blood cells.

The patient’s tenofovir was discontinued, and she was switched to abacavir, dolutegravir, and lamivudine. She was given hypotonic intravenous fluids, as well a selectrolyte and bicarbonate replacement with improvement in her values before discharge, though the patient continued to have ongoing renal impairment and acidosis. The patient’s symptoms of muscle pain and weakness improved but were not completely resolved at discharge.

Discussion

Tenofovir-induced nephrotoxicity is associated with either proximal tubular dysfunction (Fanconi syndrome) with preserved renal function or proximal tubular dysfunction with decreased renal function. Decreased renal function may be classified as AKI or chronic kidney disease. Tenofovir is associated with a small but increased risk of AKI, which is usually preceded by tubular dysfunction. The AKI is usually non-oliguric but may progress to oliguria requiring dialysis.^1,14,15 Fanconi syndrome due to tenofovir was first reported in the literature in 2002. ⁶ It is a rare but known complication of therapy, occurring in <0.1% of tenofovir-treated people living with HIV. ¹⁵ Although rare, a few reports have suggested tenofovir can cause nephrogenic diabetes insipidus.^3–7 The cases reviewed make it clear that discontinuation of the drug is paramount and usually leads to overall improvement in all aspects of renal function.^{3–7,10–12}

Although our patient’s baseline renal function wasn’t recorded, it can be assumed that her renal impairment was attributed to the effects of tenofovir as it improved substantially after the treatment was discontinued. Several studies have shown that TDF is associated with either AKI or chronic kidney disease through proximal tubal injury, either tubular necrosis or interstitial nephritis.^3,5,6,15 Indeed, our patient had pyuria with white blood cell casts suggestive of interstitial nephritis. Our case illustrates a component of tenofovir-induced Fanconi syndrome evidenced by the non-anion gap metabolic acidosis, normoglycemic glucosuria, proteinuria, hypokalaemia, hypophosphatemia, and a urine pH of 5. This presentation is similar to prior published cases.^10–12 Nephrogenic diabetes insipidus was probable with the patient’s hypernatraemia and dehydration, evidenced by clinical exam and hemoconcentration on laboratory studies. Furthermore, there was no use of diuretics, history of poor access to water intake with insensible losses, or any reason to suspect central diabetes insipidus.

Factors such as advanced age, low body weight, higher serum creatinine levels before starting tenofovir treatment, comorbidities (diabetes mellitus, hypertension, or hepatitis C coinfection), and concomitant use of protease inhibitors increase the risk of tenofovir-induced nephrotoxicity.^1,14 Literature reveals only a few such cases of combined Fanconi syndrome, diabetes insipidus, and acute kidney injury recorded, but all of these cases had pre-existing risk factors such as advanced HIV and use of protease inhibitors.^4–7 Our case uniquely illustrates the possibility of severe disease with all three toxicities occurring at once without associated provoking factors.

Unfortunately, our facility was not able to measure urine electrolytes and osmolarity, quantitative urine protein, antidiuretic protein levels, protein electrophoresis, and vitamin D levels, which would be helpful in the full evaluation of Fanconi syndrome and diabetes insipidus. However, we can be reasonably confident of these diagnoses with the non-anion gap metabolic acidosis, urine pH of 5, proteinuria, euglycemic glycosuria, hypokalemia, hypophosphatemia, and hypernatremia without any other clear etiologies.

Conclusions

Tenofovir disoproxil fumarate (TDF) is part of the regimen used in the treatment of most people living with HIV in Botswana and many around the world, in part because it is well-tolerated, though tenofovir-induced nephrotoxicity is a rare but known complication. Although these effects are most often seen in patients with known risks such as advanced HIV and kidney disease or combined use with protease inhibitors, this report emphasizes the possibility of severe tenofovir-induced nephrotoxicity with AKI, Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of other provoking factors. It is important to have a high index of suspicion for tenofovir-induced nephrotoxicity for HIV patients on TDF with deranged renal function tests and electrolytes.