Chest Deformity and Disability due to Tenofovir-Induced Hypophosphatemic Osteomalacia: Case Report and Call for Improved Global Access to Laboratory Testing

Abstract

Millions of people worldwide take tenofovir disoproxil fumarate (TDF) for the treatment of human immunodeficiency virus (HIV) and/or hepatitis B infection. Although generally safe and well tolerated, clinicians need to be aware that TDF can cause proximal renal tubular dysfunction and loss of bone mineral density, especially in patients with concomitant renal disease or other risk factors. We present the case of a patient with chronic HIV infection and urethral stricture who developed TDF-related proximal renal tubular dysfunction with hypophosphatemia and osteomalacia, presenting with bone pains, skeletal deformity, and disability. We review risk factors for TDF-related renal tubular toxicity and recommendations for monitoring creatinine, phosphate, alkaline phosphatase, and urinalysis.

Introduction

In 2016, the World Health Organization (WHO) and most national guidelines recommend tenofovir disoproxil fumarate (TDF) as part of the first-line regimens for the treatment of human immunodeficiency virus (HIV) and chronic hepatitis B infection. It is an excellent drug, generally well tolerated, and millions of people around the world are benefiting from its use. However, it is not entirely without risk. Tenofovir disoproxil fumarate can cause kidney injury and proximal renal tubular cell dysfunction. ¹ Although the incidence of clinically significant renal toxicity has been reported as less than 1% in randomized controlled trials, the incidence may be higher in general practice and in persons with underlying renal disease. ² If unrecognized, the complications of TDF nephrotoxicity can be severe and disabling. ³

Generalized proximal tubular dysfunction, or Fanconi syndrome, is a rare but serious side effect of TDF. ¹ It is characterized by impaired renal tubular reabsorption of phosphate, bicarbonate, glucose, and amino acids leading to hypophosphatemia, metabolic acidosis, proteinuria, and glucosuria. It can occur even if the serum creatinine level is not elevated. If unrecognized, renal phosphate loss can lead to demineralization of the bones, resulting in osteomalacia and weakening of the bones with pain, potential fractures, skeletal deformity, and disability. ¹

Case Report

A 45-year-old man presented to a hospital in Gulu, northern Uganda with urinary retention, chronic pain, especially in his legs, and difficulty walking. He had been diagnosed with HIV over 10 years ago and initiated antiretroviral therapy in 2007 with a baseline CD4 count of 18 cells/mm³. He had been taking his current regimen, TDF, lamivudine, and efavirenz, for the past 5 years. His CD4 count approximately 6 months prior to admission was only 138 cells/mm³.

One to 2 years prior to admission, he began to experience diffuse musculoskeletal-type aches and pains, particularly in his legs and over his sternum. Due to progressive pain and generalized weakness, he began to have difficulty walking. He was prescribed amitriptyline, but it did not help reduce his pain.

Approximately 9 months prior to admission to the hospital, blood work ordered by clinicians at the HIV clinic documented a creatinine level of 0.9 mg/dL (79.6 µmol/L). This was mistakenly interpreted as ruling out TDF-related renal tubular dysfunction. Previous renal function results and urinalysis were not available. Serum electrolyte and phosphate testing was not performed; the testing was not available at the government-funded laboratory affiliated with the HIV clinic.

The patient reported difficulty passing urine and had a long-standing reduction in his urinary stream. On the day of admission to the hospital, he was unable to empty his bladder and experienced marked suprapubic pain.

On examination on admission to the hospital, he was cachectic and had an obvious deformity of his sternum (see Figure 1). There was tenderness with firm pressure over his sternum, femur, tibia, and other bones, but no tenderness with squeezing the overlying soft tissue. He had a distended bladder. There was no palpable prostatic mass or hypertrophy, but a Foley catheter could not be passed. He was diagnosed with a probable urethral stricture, and a suprapubic catheter was inserted.

Figure 1.

Chest wall deformity that developed as a result of tenofovir disoproxil fumarate (TDF)–induced hypophosphatemic osteomalacia.

His blood work documented an elevated creatinine (1.9 mg/dL; normal range: 0.3-1.2 mg/dL), glucose 8.2 mmol/L, and very elevated alkaline phosphatase (ALP; 1223 IU/L; normal range: 116-292 IU/L). A urine dipstick documented proteinuria (+) and glycosuria (+++).

He was diagnosed with multifactorial kidney injury, proximal renal tubular dysfunction, and probable TDF-related osteomalacia. His TDF was switched to abacavir. Subsequent blood work confirmed low phosphate levels. Gradually, over the next few weeks, following the correction of his urinary obstruction and changes in his HIV medication, he experienced marked improvement in his bony pains and his overall well-being.

Discussion

Clinicians need to be aware that, although rare, TDF can cause kidney injury, proximal renal tubular dysfunction, and loss of bone mineral density. ^1,3

Risk factors for TDF-associated nephrotoxicity include preexisting renal disease, age > 50 years, body mass index <18.5 or body weight <50 kg, advanced HIV, untreated diabetes, untreated hypertension, and concomitant use of nephrotoxic drugs or a boosted protease inhibitor (see Figure 2).

Figure 2.

Risk factors for tenofovir disoproxil fumarate (TDF)–related nephrotoxicity: underlying renal disease, older than 50 years of age, body mass index (BMI) <18.5 or low body weight (<50 kg), cirrhosis, untreated diabetes, untreated hypertension, use of other potentially nephrotoxic drugs, and use of a boosted protease inhibitor (PI).

Our patient was at particularly high risk of TDF-related renal toxicity because of his concomitant urinary obstruction. Because both urinary obstruction and TDF can cause kidney injury, it can be difficult to tease apart the underlying causes of his renal dysfunction. However, unlike obstruction, TDF toxicity affects primarily the proximal renal tubules, impairing the reabsorption of phosphate, bicarbonate, glucose, and amino acids. This can lead to low serum levels of phosphate, progressive bone mineral density loss, and osteomalacia.

There are only few published reports of TDF-associated Fanconi syndrome with hypophosphatemic osteomalacia. ^3,4 Although certainly an uncommon occurrence, many cases of bone disease related to TDF may go unrecognized and unreported and these reports may be just the tip of the iceberg—or the ears of the hippo. ⁵

It is important to recognize that significant renal tubular dysfunction can occur in the absence of an elevated serum creatinine. ¹ It is also important to note that creatinine values in patients with low body weight may overestimate true renal function, masking renal impairment. Creatinine values should be interpreted in conjunction with weight and age by calculating an estimated glomerular filtration rate (eGFR). Serial measurements of creatinine are also more sensitive at detecting renal injury compared to single one-time measurements.

Ideally, all patients receiving TDF should have renal function testing including serum creatinine, phosphate, electrolytes, and urinalysis for glucose and protein at baseline and monitored regularly. The frequency of monitoring can be adjusted based on the patients’ underlying risk factors for TDF-related nephrotoxicity. The optimal monitoring strategy for proximal tubular dysfunction in patients receiving TDF may be variable and remains to be defined.

The 2016 WHO HIV guidelines recommended baseline creatinine testing for all patients starting TDF. ² The guidelines particularly advise monitoring renal function in patients with risks of TDF toxicity, including underlying kidney disease, age more than 50 years, low body weight (<50 kg), untreated hypertension, and diabetes. Patients with impaired eGFR at baseline (<50 mL/min) should not initiate TDF. ²

The 2015 WHO hepatitis B guidelines also recommend a careful assessment of renal function before TDF treatment initiation, including serum creatinine, eGFR, and urinalysis for proteinuria and glucosuria. ⁶ For individuals with normal renal function, a suggested minimum monitoring package could include annual urine dipstick testing and creatinine measurement for eGFR. Closer monitoring was recommended for persons with preexisting renal dysfunction and persons at high risk of renal toxicity. ⁶

As well as monitoring creatinine (eGFR) every 3 to 12 months, the 2015 European AIDS Clinical Society guidelines recommend checking the bone profile (calcium, phosphate, and ALP) every 6 to 12 months for all patients on TDF. ⁷

Treatment of TDF-related renal dysfunction and phosphate and bicarbonate loss requires discontinuation of TDF. ¹ Although some degree of renal tubular damage may be permanent, renal function tends to gradually improve after discontinuing TDF. For patients with osteomalacia, as in the case we presented above, supplementing with phosphate and vitamin D can assist with bone healing and remineralization.

In recent clinical trials, tenofovir alafenamide (TAF), a prodrug of TDF, has been demonstrated to be as efficacious as TDF for HIV treatment but less likely to influence renal function. ⁸ It is expected that the use of TAF will carry a lower risk of renal tubular dysfunction.

Conclusion

Tenofovir disoproxil fumarate–related renal toxicity may be underdiagnosed, especially in patients with other risk factors for renal injury. If unrecognized and allowed to progress, phosphate loss in the urine can lead to osteomalacia, bone pains, and weakness, which can be disabling and associated with deformity and fracture. ^3,4 Monitoring and clinical suspicion are needed for early recognition.

It is important to note that TDF-related proximal renal tubular dysfunction can occur even in the setting of serum creatinine in the normal range; a normal serum creatinine does not rule out TDF-related nephrotoxicity.

The optimal monitoring strategy of patients on TDF depends on individual risk factors and available resources. As our case presentation illustrates, existing laboratory capacity in some areas is inadequate to meet the needs of all patients. Although urine dipsticks provide an additional inexpensive measure for monitoring, increased laboratory capacity is required for monitoring and diagnosis of TDF-related toxicity.