The kidney proximal tubule is the first part of the nephron after the filtering glomerulus and performs the bulk of reabsorption of filtered solutes. Proximal tubular cells are highly adapted to this task and express numerous sodium-coupled transporters. They also express two large receptors called megalin and cubilin, which bind filtered low mol wt proteins and albumin, and internalize them via receptor-mediated endocytosis to prevent urinary losses (1). Numerous genetic and acquired insults can affect the proximal tubule, which depending on their severity, can lead to a spectrum of clinical presentations. Milder insults typically cause asymptomatic increases in urinary low mol wt protein excretion (so-called “tubular proteinuria”). More severe insults induce a partial or global breakdown in the transport of solutes that are predominantly or exclusively reabsorbed in the proximal tubule: namely, glucose, phosphate, bicarbonate, urate, and amino acids. This clinical scenario is known as Fanconi syndrome after Guido Fanconi, a Swiss pediatrician working in Zurich, who first described it in children with cystinosis. Systemic depletion of phosphate can result in bone demineralization, which is the most serious complication of Fanconi syndrome and manifests clinically as rickets or osteomalacia. Finally, patients with sudden and harsh proximal tubular insults—such as ischemia or sepsis—typically present with rapid increases in serum creatinine and oliguria, a clinical scenario now known as AKI and what used to be described as “acute tubular necrosis.” In this article, we describe a patient with a drug-induced functional defect in the proximal tubule to illustrate the typical clinical features.
A 22-year-old man was referred to the nephrology outpatient clinic because of worsening kidney function over several months. He had a history of hereditary anemia requiring recurrent lifelong blood transfusions, which had led to complications associated with iron overload. Therefore, he received regular iron chelation therapy, which had been switched from deferoxamine to deferasirox a few months previously. On presentation, he had evidence of a moderate defect in kidney excretory function, with an eGFR of 52 ml/min per 1.73 m2. Other blood tests revealed evidence of hypophosphatemia (2.29 mg/dL [normal range, 2.69–4.50]) and metabolic acidosis (20 mmol/L [normal range, 22–29]), and alkaline phosphatase was elevated at 244 IU/L (normal <140). Urine protein/creatinine excretion was markedly increased at 124 mg/mmol (1240 mg/g), but urinary albumin excretion was only mildly abnormal. A dual-energy x-ray absorptiometry scan revealed decreased bone mineral density.
The clinical picture of moderately impaired kidney excretory function, hypophosphatemia, metabolic acidosis, and predominantly nonalbumin proteinuria was consistent with a functional defect in the proximal tubule and a diagnosis of Fanconi syndrome. In this case, the temporal association between the onset of kidney disease and starting deferasirox meant that toxicity from this drug was the most likely cause, and bone demineralization probably occurred secondary to phosphate depletion. Deposition of iron in tubules might also play a role in the development of CKD in patients with systemic iron overload.
Causes of Fanconi Syndrome
There are many recognized etiologies of Fanconi syndrome, which can be classified in different ways. Genetic causes typically present in childhood, and they include cystinosis, mitochondrial cytopathies, and various inborn errors of metabolism (2). In contrast, Fanconi syndrome presenting in adults is usually secondary to acquired proximal tubular insults, such as light-chain disease and drug toxicity (3,4). Although the pathogenesis of Fanconi syndrome is not very well understood, broadly speaking most insults are thought to primarily target either the endolysosomal system or mitochondria (Figure 1). The proximal tubule has a highly developed endolysosomal system, which is responsible not only for the endocytosis of filtered proteins but also, for the trafficking and recycling of membrane transporters. Some specific hereditary forms of Fanconi syndrome, such as Dent disease and Lowe syndrome, occur due to mutations in proteins (CLC-5 and OCRL, respectively) that have important roles in endolysosomal function (5).
Proximal tubule cells are densely packed with mitochondria, which are required to produce sufficient ATP to drive solute transport. The importance of mitochondrial function in the proximal tubule is demonstrated by the fact that Fanconi syndrome is the most frequent kidney manifestation in children with mitochondrial cytopathies (6) and also, by the recent discovery that genetic mutations affecting mitochondria cause autosomal dominant hereditary forms of Fanconi syndrome (7,8). The proximal tubule is particularly vulnerable to mitochondrial insults, because it lacks the enzymes necessary to generate ATP via anaerobic glycolysis (9).
Along with the liver, the proximal tubule represents a major excretory pathway from the body for xenobiotics. Proximal tubule cells express numerous organic ion transporters, and they can take up drugs from the bloodstream and secrete them into urine. Unfortunately, a number of clinically used therapies are toxic to proximal tubular cells and can cause Fanconi syndrome (3,4). Examples of such drugs include gentamycin, vancomycin, ifosfamide, cisplatin, and tenofovir. In most cases, the exact mechanisms of toxicity are not well understood, but mitochondrial abnormalities are often noted in kidney biopsies (4), suggesting that these organelles are major targets. The reasons why only a subset of patients taking any particular drug seems to develop toxicity are also unclear, but might relate to underlying pharmacogenomic factors (e.g., genetic polymorphisms in drug transporters). A variety of environmental toxins—including cadmium and aristolochic acid—can also cause Fanconi syndrome.
Initial safety studies with deferasirox (marketed as Exjade) revealed that it frequently caused small rises in serum creatinine (10). Numerous reports have subsequently appeared in the literature describing patients with proximal tubular dysfunction and Fanconi syndrome caused by deferasirox (11), leading to the inclusion of boxed warnings on prescribing information (10). The mechanism of toxicity remains to be elucidated. Iron is crucial for mitochondrial metabolism, and some evidence of mitochondrial toxicity induced by deferasirox has been reported from in vitro studies. However, it is important to note that other iron chelators have been used for decades without causing Fanconi syndrome, raising the possibility that deferasirox may have deleterious off-target effects independent of iron chelation.
Diagnosis of Fanconi Syndrome
The extent to which patients with Fanconi syndrome require investigation depends on the nature of the insult and the certainty of the diagnosis. Screening tests for proximal tubular dysfunction include measurement of proteinuria, dipstick testing for nondiabetic glycosuria, and assessment of kidney phosphate handling. Because urinary albumin excretion largely reflects glomerular dysfunction, this is not a sensitive test (12). Elevated urinary excretion of urinary low mol wt proteins, such as retinol binding protein and β-2-microglobulin, is the most sensitive marker of proximal tubular dysfunction and can provide a quantitative readout of the severity of the defect (12). However, the long-term clinical significance of isolated tubular proteinuria is unclear. Spot urine protein-to-creatinine ratio is a reasonable alternative if low mol wt proteins cannot be measured, and a discrepancy between this and urinary albumin excretion should raise the likelihood of tubular proteinuria.
Glycosuria in the absence of hyperglycemia is a classic sign of proximal tubular dysfunction, but because of the large uptake capacity of glucose in the proximal tubule, this is typically quite a late sign. Serum phosphate level normally rises with loss of GFR, and therefore, the finding of hypophosphatemia should alert to the possibility of a functional defect in the proximal tubule. Tubular handling of phosphate (fractional excretion or tubular maximal reabsorption/GFR) can be calculated from paired serum and urine measurements of phosphate and creatinine. Because phosphate depletion and bone demineralization are the most serious sequelae of Fanconi syndrome, fractional excretion or tubular maximal reabsorption/GFR also has particular clinical relevance. Patients with Fanconi syndrome often have metabolic acidosis due to bicarbonate wasting, but this is usually mild, provided that urinary acidification by the distal tubule remains intact. Serum urate may also be low due to increased fractional excretion.
Serum creatinine is sometimes raised in patients with Fanconi syndrome, which may reflect either genuine decreases in GFR and/or impairment of proximal tubular creatinine secretion. However, serum creatinine is not a sensitive test for proximal tubular dysfunction and can be within the normal range in Fanconi syndrome. There are no specific imaging studies for Fanconi syndrome, although decreased solute uptake can be demonstrated with some routinely used radio-labeled tracers, such as dimercaptosuccinic acid. In patients with sustained phosphate wasting, measurements of bone density are important and useful to check for evidence of demineralization. Kidney biopsy is not routinely performed in patients with Fanconi syndrome unless there is significant doubt about the diagnosis or etiology.
Management of Fanconi Syndrome
The most important tenet of patient management is to stop or reverse the underlying cause of proximal tubular dysfunction if at all possible. In the case of drug-induced Fanconi syndrome, most patients show gradual improvements in kidney function over time after stopping the offending agent due to the well known regenerative capacity of the proximal tubule. However, function does not always return to pretreatment levels. In some cases, patients are taking nephrotoxic drugs for serious life-threatening conditions, such as HIV or cancer. In these situations, the decision whether to stop therapy can be far from straightforward and often requires a multidisciplinary discussion, including with the patient. Ultimately, treatment decisions are usually guided by the nature of the disease-requiring treatment, the severity and rate of change of proximal tubular dysfunction, and the availability of alternative therapies. Decreasing the drug dosage rather than stopping it completely can be an effective strategy in some patients.
Most other causes of Fanconi syndrome do not have any specific associated therapies, and therefore, management is largely supportive and consists of regular monitoring and replacement of deficient substances to prevent complications. Phosphate supplements can be given but are limited in their effectiveness by poor compliance and side effects. Vitamin D levels should be checked and supplemented if low to promote and restore bone mineralization. Because vitamin D is hydroxylated in the proximal tubule, some patients with proximal tubular dysfunction may require its active form.
In the patient described, deferasirox was stopped, and he was switched back to the older injectable iron chelator deferoxamine, which has a better kidney safety profile. Over the following months, kidney function slowly improved, and his eGFR increased to approximately 80 ml/min per 1.73 m2. Serum phosphate and bicarbonate returned to within their normal ranges, and alkaline phosphatase decreased markedly to 175 IU/L. Urine protein-to-creatinine ratio also reduced substantially to 11 mg/mmol (110 mg/g), well within the normal range (<45 mg/mmol).
Dr. Unwin is an employee of AstraZeneca. Dr. Hall has nothing to disclose.
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