Editorial Comment: Fanconi Syndrome and Tenofovir-Understanding Proximal Tubular Function

June 1, 2007

Although it bears his name, Guido Fanconi only defined the “syndrome” after it was first described by Lignac in 1924.1 Fanconi described children with rickets, glucosuria, and growth retardation.1 Fanconi syndrome now includes multiple disorders, with the common pathologic mechanism of proximal tubular dysfunction. This syndrome is a rare disorder, making it conspicuous when it does occur. Most cases in children are linked to inherited disorders, while those in adults are usually acquired, most commonly from multiple myeloma2 (due to immunoglobulin light chains in the urine) or drug-related toxicity.1 Recently, much attention has been paid to the occurrence of Fanconi syndrome as a result of exposure to the NRTI class of antiretroviral agents.3-5 In HIV-infected persons, Fanconi syndrome was initially associated with adefovir nephrotoxicity.3 Therefore, when the closely structurally related NRTI tenofovir was introduced, there was concern about a risk of nephrotoxicity similar to that of adefovir. Although no nephrotoxic events were reported in clinical trials,6,7 subsequent use in clinical practice revealed tenofovir-associated renal side effects. A recent review by Sax and colleagues8 details the renal effects of this agent, which include acute renal failure from acute tubular necrosis and isolated Fanconi syndrome. Although most of the case reports of acute renal failure in HIV-infected patients exposed to tenofovir have been described with Fanconi syndrome,9 this is possibly a result of publication bias. Because Fanconi syndrome was a well-recognized feature of tenofovir’s predecessor adefovir3 and because the syndrome is otherwise relatively rare, tenofovir was generally easy to identify as the culprit. The presence of Fanconi syndrome certainly confirms a diagnosis of tenofovir-induced injury. However, when acute renal failure is present without Fanconi syndrome, tenofovir still needs to be considered as the cause. The findings of the case reported by Brim and colleagues10 can be best appreciated through an understanding of proximal tubular function. Proximal tubular epithelial cells are the workhorses of the nephron; they have the highly important role of reabsorbing the electrolytes and small molecules that are filtered at the glomerulus. For example, the proximal tubule reabsorbs almost all of the 0.5 kg of filtered sodium daily-the equivalent amount of sodium in 2.5 pounds of table salt. This function is dependent on the cells’ ability to generate large amounts of energy through a very rich concentration of mitochondria. It is not surprising that small defects in energy generation could result in significant wasting of substances. Indeed, Fanconi syndrome is an instance of this. One of the most important energy-requiring steps is the action of the adenosine triphosphate (ATP)–requiring basolateral (blood side) sodium-potassium (Na+-K+) pump. Through the function of sodium-potassium ion exchange, the epithelial cell maintains very low intracellular sodium concentration. This provides a gradient for sodium to move into cells from the lumen through various apical transporters. Sodium reabsorption driven by the gradient is coupled with reabsorption of phosphate, glucose, and amino acids and, with excretion of hydrogen ions (H+), allows bicarbonate reabsorption. If the Na+-K+ pump does not function adequately, as occurs with proximal tubular mitochondrial dysfunction, the sodium gradient is reduced, and there is a loss of the cotransported phosphate, glucose, amino acids, and bicarbonate in the urine. The result is a proximal renal tubular acidosis (usually hypokalemic) with hypophosphatemia, glucosuria, and aminoaciduria (ie, Fanconi syndrome). Hypouricemia has also been seen, although its genesis is not understood.1 The occurrence of Fanconi syndrome with mitochondrial disorders is well described. Based on evidence of mitochondrial defects in the proximal tubule with adefovir toxicity,11,12 one proposed theory is that the structurally related tenofovir may cause Fanconi syndrome by similarly affecting mitochondrial function in the proximal tubule. Tenofovir secretion and accumulation in proximal tubule epithelial cells is detailed in the above-mentioned review by Sax and colleagues.8 Important to note is that not all the features of Fanconi syndrome need to be present simultaneously, and the presence of a partial syndrome is not uncommon. Certainly, any appearance of glucosuria in patients without diabetes suggests the presence of Fanconi syndrome. Hypophosphatemia may take longer to evolve with ample bone stores providing a reservoir for repletion. It is the loss of phosphate through this mechanism that will result in osteomalacia, as described in the Case Report presented by Brim and colleagues.10 The role of tenofovir in isolated hypophosphatemia is unclear. Hypophosphatemia has not been attributed to tenofovir in major trials. Two retrospective studies have evaluated hypophosphatemia in tenofovir-treated patients.13,14 Buchacz and colleagues13 reported phosphate blood levels less than 2.4 mg/dL (normal 3.0 to 4.5) in 15.1% and 6.7% of patients treated with and without tenofovir, respectively. In another study, hypophosphatemia (phosphate level less than 2.5 mg/dL) developed in 30.7% of patients who received tenofovir, compared with 22.1% who did not receive tenofovir.14 These differences did not reach statistical significance in either study. Not surprisingly, an elevated level of urinary 2-microglobulin, a small protein usually reabsorbed by the proximal tubule, was noted in the case reported by Brim and associates.10 How­ever, even in the absence of overt kidney dysfunction, recent studies have described high levels of 2-microglobulin associated with tenofovir treatment.15,16 This implies a possible subclinical tubular defect, but the clinical significance of this has yet to be established. Although not common, the presence of Fanconi-like features in a patient treated with tenofovir should be highly suggestive of a drug-related effect. Consideration should be given to drug discontinuation, regardless of the degree of renal impairment. In addition to frequent monitoring of kidney function by estimating glomerular filtration rates, those taking tenofovir should be assessed at the same time for proximal tubular dysfunction, by obtaining serum levels for phosphate and bicarbonate and urinary glucose and protein levels. While it is not always the case with associated renal failure, tenofovir-related tubular effects are revers­ible, and an early diagnosis will avoid complications, such as those seen in the case reported by Brim and colleagues.

Although it bears his name, Guido Fanconi only defined the “syndrome” after it was first described by Lignac in 1924.1 Fanconi described children with rickets, glucosuria, and growth retardation.1 Fanconi syndrome now includes multiple disorders, with the common pathologic mechanism of proximal tubular dysfunction. This syndrome is a rare disorder, making it conspicuous when it does occur.

Most cases in children are linked to inherited disorders, while those in adults are usually acquired, most commonly from multiple myeloma2 (due to immunoglobulin light chains in the urine) or drug-related toxicity.1 Recently, much attention has been paid to the occurrence of Fanconi syndrome as a result of exposure to the NRTI class of antiretroviral agents.3-5

In HIV-infected persons, Fanconi syndrome was initially associated with adefovir nephrotoxicity.3 Therefore, when the closely structurally related NRTI tenofovir was introduced, there was concern about a risk of nephrotoxicity similar to that of adefovir. Although no nephrotoxic events were reported in clinical trials,6,7 subsequent use in clinical practice revealed tenofovir-associated renal side effects. A recent review by Sax and colleagues8 details the renal effects of this agent, which include acute renal failure from acute tubular necrosis and isolated Fanconi syndrome.

Although most of the case reports of acute renal failure in HIV-infected patients exposed to tenofovir have been described with Fanconi syndrome,9 this is possibly a result of publication bias. Because Fanconi syndrome was a well-recognized feature of tenofovir’s predecessor adefovir3 and because the syndrome is otherwise relatively rare, tenofovir was generally easy to identify as the culprit. The presence of Fanconi syndrome certainly confirms a diagnosis of tenofovir-induced injury. However, when acute renal failure is present without Fanconi syndrome, tenofovir still needs to be considered as the cause.

The findings of the case reported by Brim and colleagues10 can be best appreciated through an understanding of proximal tubular function. Proximal tubular epithelial cells are the workhorses of the nephron; they have the highly important role of reabsorbing the electrolytes and small molecules that are filtered at the glomerulus. For example, the proximal tubule reabsorbs almost all of the 0.5 kg of filtered sodium daily-the equivalent amount of sodium in 2.5 pounds of table salt.

This function is dependent on the cells’ ability to generate large amounts of energy through a very rich concentration of mitochondria. It is not surprising that small defects in energy generation could result in significant wasting of substances. Indeed, Fanconi syndrome is an instance of this.

One of the most important energy-requiring steps is the action of the adenosine triphosphate (ATP)–requiring basolateral (blood side) sodium-potassium (Na+-K+) pump. Through the function of sodium-potassium ion exchange, the epithelial cell maintains very low intracellular sodium concentration. This provides a gradient for sodium to move into cells from the lumen through various apical transporters. Sodium reabsorption driven by the gradient is coupled with reabsorption of phosphate, glucose, and amino acids and, with excretion of hydrogen ions (H+), allows bicarbonate reabsorption.

If the Na+-K+ pump does not function adequately, as occurs with proximal tubular mitochondrial dysfunction, the sodium gradient is reduced, and there is a loss of the cotransported phosphate, glucose, amino acids, and bicarbonate in the urine. The result is a proximal renal tubular acidosis (usually hypokalemic) with hypophosphatemia, glucosuria, and aminoaciduria (ie, Fanconi syndrome). Hypouricemia has also been seen, although its genesis is not understood.1

The occurrence of Fanconi syndrome with mitochondrial disorders is well described. Based on evidence of mitochondrial defects in the proximal tubule with adefovir toxicity,11,12 one proposed theory is that the structurally related tenofovir may cause Fanconi syndrome by similarly affecting mitochondrial function in the proximal tubule. Tenofovir secretion and accumulation in proximal tubule epithelial cells is detailed in the above-mentioned review by Sax and colleagues.8

Important to note is that not all the features of Fanconi syndrome need to be present simultaneously, and the presence of a partial syndrome is not uncommon. Certainly, any appearance of glucosuria in patients without diabetes suggests the presence of Fanconi syndrome. Hypophosphatemia may take longer to evolve with ample bone stores providing a reservoir for repletion. It is the loss of phosphate through this mechanism that will result in osteomalacia, as described in the Case Report presented by Brim and colleagues.10

The role of tenofovir in isolated hypophosphatemia is unclear. Hypophosphatemia has not been attributed to tenofovir in major trials. Two retrospective studies have evaluated hypophosphatemia in tenofovir-treated patients.13,14 Buchacz and colleagues13 reported phosphate blood levels less than 2.4 mg/dL (normal 3.0 to 4.5) in 15.1% and 6.7% of patients treated with and without tenofovir, respectively.

In another study, hypophosphatemia (phosphate level less than 2.5 mg/dL) developed in 30.7% of patients who received tenofovir, compared with 22.1% who did not receive tenofovir.14 These differences did not reach statistical significance in either study.

Not surprisingly, an elevated level of urinary 2-microglobulin, a small protein usually reabsorbed by the proximal tubule, was noted in the case reported by Brim and associates.10 How­ever, even in the absence of overt kidney dysfunction, recent studies have described high levels of 2-microglobulin associated with tenofovir treatment.15,16 This implies a possible subclinical tubular defect, but the clinical significance of this has yet to be established.

Although not common, the presence of Fanconi-like features in a patient treated with tenofovir should be highly suggestive of a drug-related effect. Consideration should be given to drug discontinuation, regardless of the degree of renal impairment.

In addition to frequent monitoring of kidney function by estimating glomerular filtration rates, those taking tenofovir should be assessed at the same time for proximal tubular dysfunction, by obtaining serum levels for phosphate and bicarbonate and urinary glucose and protein levels. While it is not always the case with associated renal failure, tenofovir-related tubular effects are revers­ible, and an early diagnosis will avoid complications, such as those seen in the case reported by Brim and colleagues.

Derek M. Fine, MD
Assistant Professor
Department of Medicine, Division of Nephrology
Johns Hopkins University School of Medicine
Baltimore

Dr Fine reports having received honoraria and consultant fees from GlaxoSmithKline. No other potential conflict of interest relevant to the commentary was reported.

References:

References


1.

Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Drug-induced Fanconi’s syndrome.

Am J Kidney Dis

. 2003;41:292-309.

2.

Batuman V. Proximal tubular injury in myeloma.

Contrib Nephrol

. 2007;153: 87-104.

3.

Fisher EJ, Chaloner K, Cohn DL, et al. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial.

AIDS

. 2001;15:1695-1700.

4.

Rifkin BS, Perazella MA. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure.

Am J Med

. 2004;117:282-284.

5.

Vandercam B, Moreau M, Goffin E, et al. Cidofovir-induced end-stage renal failure.

Clin Infect Dis

. 1999;29:948-949.

6.

Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efa­virenz vs zidovudine, lamivudine, and efavirenz for HIV.

N Engl J Med

. 2006; 354:251-260.

7.

Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial.

JAMA

. 2004;292:191-201.

8.

Sax PE, Gallant JE, Klotman PE. Renal safety of tenofovir disoproxil fumarate.

AIDS Reader

. 2007;17:90-92, 99-104, C3.

9.

Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions.

Clin Infect Dis

. 2006;42:283-290.

10.

Brim NM, Cu-Uvin S, Hu SL, O’Bell JW. Bone disease and pathologic fractures in a patient with tenofovir-induced Fanconi syndrome.

AIDS Reader

. 2007;17:322-C3.

11.

Tanji N, Tanji K, Kambham N, et al. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion.

Hum Pathol

. 2001;32:734-740.

12.

Bendele RA, Richardson FC. Adefovir nephrotoxicity and mitochondrial DNA depletion.

Hum Pathol

. 2002;33:574.

13.

Buchacz K, Brooks JT, Tong T, et al. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy.

HIV Med

. 2006; 7:451-456.

14.

Day SL, Leake Date HA, Bannister A, et al. Serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice.

J Acquir Immune Defic Syndr

. 2005; 38:301-304.

15.

Gatanaga H, Tachikawa N, Kikuchi Y, et al. Urinary beta2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate.

AIDS Res Hum Retroviruses

. 2006;22:744-748.

16.

Kinai E, Hanabusa H. Renal tubular toxicity associated with tenofovir assessed using urine-beta 2 microglobulin, percentage of tubular reabsorption of phosphate and alkaline phosphatase levels.

AIDS

. 2005;19:2031-2033.