A Case of Drug-Induced Proximal Tubular Dysfunction

Kidney Case Conference: Attending Rounds

Andrew M. Hall1,2 and Robert J. Unwin3,4 CJASN 14: 1384–1387, 2019. doi: https://doi.org/10.2215/CJN.01430219

Introduction hypophosphatemia (2.29 mg/dL [normal range, 2.69– 1 The kidney proximal tubule is the firstpartofthe 4.50]) and metabolic acidosis (20 mmol/L [normal range, Institute of Anatomy, nephron after the filtering glomerulus and performs – University of Zurich, 22 29]), and alkaline phosphatase was elevated at Zurich, Switzerland; fi , 2 the bulk of reabsorption of ltered solutes. Proximal 244 IU/L (normal 140). Urine protein/creatinine Department of tubular cells are highly adapted to this task and express excretion was markedly increased at 124 mg/mmol Nephrology, numerous sodium-coupled transporters. They also (1240 mg/g), but urinary albumin excretion was only University Hospital express two large receptors called megalin and cubilin, mildly abnormal. A dual-energy x-ray absorptiometry Zurich, Zurich, fi Switzerland; which bind ltered low mol wt proteins and albumin, scan revealed decreased bone mineral density. 3Department of Renal and internalize them via receptor-mediated endocyto- The clinical picture of moderately impaired kidney Medicine, University sis to prevent urinary losses (1). Numerous genetic and excretory function, hypophosphatemia, metabolic ac- College London, London, United acquired insults can affect the proximal tubule, which idosis, and predominantly nonalbumin proteinuria 4 depending on their severity, can lead to a spectrum Kingdom; and CVRM was consistent with a functional defect in the proximal Biopharmaceuticals of clinical presentations. Milder insults typically cause tubule and a diagnosis of Fanconi syndrome. In this R&D, AstraZeneca, asymptomatic increases in urinary low mol wt protein case, the temporal association between the onset of Gothenburg, Sweden excretion (so-called “tubular proteinuria”). More se- kidney disease and starting deferasirox meant that vere insults induce a partial or global breakdown toxicity from this drug was the most likely cause, and Correspondence: in the transport of solutes that are predominantly or bone demineralization probably occurred secondary Dr. Andrew M. Hall, exclusively reabsorbed in the proximal tubule: namely, Institute of Anatomy, to phosphate depletion. Deposition of iron in tubules University of Zurich, glucose, phosphate, bicarbonate, urate, and amino acids. might also play a role in the development of CKD in Winterthurerstrasse This clinical scenario is known as Fanconi syndrome patients with systemic iron overload. 190, 8057 Zurich, after Guido Fanconi, a Swiss pediatrician working in Switzerland. Email: Zurich, who first described it in children with cysti- [email protected] nosis. Systemic depletion of phosphate can result in Causes of Fanconi Syndrome bone demineralization, which is the most serious com- There are many recognized etiologies of Fanconi fi plication of Fanconi syndrome and manifests clini- syndrome, which can be classi ed in different ways. cally as rickets or osteomalacia. Finally, patients with Genetic causes typically present in childhood, and sudden and harsh proximal tubular insults—such they include cystinosis, mitochondrial cytopathies, and as ischemia or sepsis—typically present with rapid various inborn errors of metabolism (2). In contrast, increases in serum creatinine and oliguria, a clinical Fanconi syndrome presenting in adults is usually scenario now known as AKI and what used to be secondary to acquired proximal tubular insults, such described as “acute tubular necrosis.” In this article, as light-chain disease and drug toxicity (3,4). Although we describe a patient with a drug-induced functional the pathogenesis of Fanconi syndrome is not very well defect in the proximal tubule to illustrate the typical understood, broadly speaking most insults are thought clinical features. to primarily target either the endolysosomal system or mitochondria (Figure 1). The proximal tubule has a highly developed endolysosomal system, which is Clinical Patient responsible not only for the endocytosis of filtered A 22-year-old man was referred to the nephrology proteins but also, for the trafficking and recycling outpatient clinic because of worsening kidney function of membrane transporters. Some specific hereditary over several months. He had a history of hereditary forms of Fanconi syndrome, such as Dent disease and anemia requiring recurrent lifelong blood transfusions, Lowe syndrome, occur due to mutations in proteins which had led to complications associated with iron (CLC-5 and OCRL, respectively) that have important overload. Therefore, he received regular iron chelation roles in endolysosomal function (5). therapy, which had been switched from deferoxamine Proximal tubule cells are densely packed with mito- to deferasirox a few months previously. On presenta- chondria, which are required to produce sufficient ATP tion, he had evidence of a moderate defect in kidney to drive solute transport. The importance of mitochon- excretory function, with an eGFR of 52 ml/min per drial function in the proximal tubule is demonstrated 1.73 m2. Other blood tests revealed evidence of by the fact that Fanconi syndrome is the most frequent

Figure 1. | Four cellular mechanisms by which drugs can cause proximal tubular dysfunction and Fanconi syndrome. Filtered solutes (S), such as 1 amino acids, phosphate, and glucose, are cotransported across the proximal tubular apical membrane with Na , whereas low mol wt proteins (LMWPs) are taken by receptor-mediated endocytosis into endosomes and ultimately lysosomes (L) for degradation. A number of toxic drugs (X) canrapidlyaccumulateintoproximaltubularcellsfromthebloodstreamviabasolateralorganicanion/cationtransportersandcausefunctionaldefects insolutetransport,leadingtourinarywasting(Fanconisyndrome).Potentialpathogenicmechanismsinclude(1)impairedendocytosisandrecyclingof receptors/transporters to the membrane; (2) abnormal lysosomal function; (3) oxidative stress and depletion of antioxidant defenses, such as 1 1 glutathione (GSH); and (4) mitochondrial toxicity and inhibition of ATP production, leading to decreased basolateral Na /K -ATPase activity. kidney manifestation in children with mitochondrial cyto- transporters). A variety of environmental toxins—including pathies (6) and also, by the recent discovery that genetic cadmium and aristolochic acid—can also cause Fanconi mutations affecting mitochondria cause autosomal dom- syndrome. inant hereditary forms of Fanconi syndrome (7,8). The Initial safety studies with deferasirox (marketed as Exjade) proximal tubule is particularly vulnerable to mitochondrial revealed that it frequently caused small rises in serum creat- insults, because it lacks the enzymes necessary to generate inine (10). Numerous reports have subsequently appeared ATP via anaerobic glycolysis (9). in the literature describing patients with proximal tubular Along with the liver, the proximal tubule represents a dysfunction and Fanconi syndrome caused by deferasirox major excretory pathway from the body for xenobiotics. (11), leading to the inclusion of boxed warnings on pre- Proximal tubule cells express numerous organic ion trans- scribing information (10). The mechanism of toxicity remains porters, and they can take up drugs from the bloodstream to be elucidated. Iron is crucial for mitochondrial metabolism, and secrete them into urine. Unfortunately, a number of and some evidence of mitochondrial toxicity induced by clinically used therapies are toxic to proximal tubular cells deferasirox has been reported from in vitro studies. and can cause Fanconi syndrome (3,4). Examples of such However, it is important to note that other iron chelators drugs include gentamycin, vancomycin, ifosfamide, cisplatin, have been used for decades without causing Fanconi syn- and tenofovir. In most cases, the exact mechanisms of toxicity drome, raising the possibility that deferasirox may have are not well understood, but mitochondrial abnormalities deleterious off-target effects independent of iron chelation. 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 toxic- Diagnosis of Fanconi Syndrome ity are also unclear, but might relate to underlying phar- The extent to which patients with Fanconi syndrome macogenomic factors (e.g., genetic polymorphisms in drug require investigation depends on the nature of the insult 1386 CJASN

and the certainty of the diagnosis. Screening tests for proximal straightforward and often requires a multidisciplinary dis- tubular dysfunction include measurement of proteinuria, cussion, including with the patient. Ultimately, treatment dipstick testing for nondiabetic glycosuria, and assessment decisions are usually guided by the nature of the disease- of kidney phosphate handling. Because urinary albumin requiring treatment, the severity and rate of change of excretion largely reflects glomerular dysfunction, this is proximal tubular dysfunction, and the availability of alter- not a sensitive test (12). Elevated urinary excretion of urinary native therapies. Decreasing the drug dosage rather than low mol wt proteins, such as retinol binding protein and stopping it completely can be an effective strategy in some b-2-microglobulin, is the most sensitive marker of proximal patients. tubular dysfunction and can provide a quantitative readout Most other causes of Fanconi syndrome do not have any of the severity of the defect (12). However, the long-term specific associated therapies, and therefore, management is clinical significance of isolated tubular proteinuria is un- largely supportive and consists of regular monitoring and clear. Spot urine protein-to-creatinine ratio is a reasonable replacementofdeficient substances to prevent complica- alternative if low mol wt proteins cannot be measured, and a tions. Phosphate supplements can be given but are limited discrepancy between this and urinary albumin excretion in their effectiveness by poor compliance and side effects. should raise the likelihood of tubular proteinuria. Vitamin D levels should be checked and supplemented if Glycosuria in the absence of hyperglycemia is a classic low to promote and restore bone mineralization. Because sign of proximal tubular dysfunction, but because of the vitamin D is hydroxylated in the proximal tubule, some large uptake capacity of glucose in the proximal tubule, patients with proximal tubular dysfunction may require its this is typically quite a late sign. Serum phosphate level active form. 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 han- Clinical Course dling of phosphate (fractional excretion or tubular max- In the patient described, deferasirox was stopped, and imal reabsorption/GFR) can be calculated from paired he was switched back to the older injectable iron chelator fi serum and urine measurements of phosphate and creat- deferoxamine, which has a better kidney safety pro le. inine. Because phosphate depletion and bone demineral- Over the following months, kidney function slowly improved, ization are the most serious sequelae of Fanconi syndrome, and his eGFR increased to approximately 80 ml/min per 2 fractional excretion or tubular maximal reabsorption/GFR 1.73 m . Serum phosphate and bicarbonate returned to also has particular clinical relevance. Patients with Fanconi within their normal ranges, and alkaline phosphatase de- syndrome often have metabolic acidosis due to bicarbonate creased markedly to 175 IU/L. Urine protein-to-creatinine wasting, but this is usually mild, provided that urinary ratio also reduced substantially to 11 mg/mmol (110 mg/g), , acidification by the distal tubule remains intact. Serum well within the normal range ( 45 mg/mmol). urate may also be low due to increased fractional excretion. Serum creatinine is sometimes raised in patients with Disclosures Fanconi syndrome, which may reflect either genuine de- Dr. Unwin is an employee of AstraZeneca. Dr. Hall has nothing creases in GFR and/or impairment of proximal tubular to disclose. creatinine secretion. However, serum creatinine is not a sensitive test for proximal tubular dysfunction and can References be within the normal range in Fanconi syndrome. There 1. Christensen EI, Birn H, Storm T, Weyer K, Nielsen R: Endocytic are no specific imaging studies for Fanconi syndrome, receptors in the renal proximal tubule. Physiology (Bethesda) although decreased solute uptake can be demonstrated 27: 223–236, 2012 2. Bockenhauer D and Kleta R: Approach to the patient with renal with some routinely used radio-labeled tracers, such as Fanconi syndrome, glycosuria, or aminoaciduria. In: Oxford dimercaptosuccinic acid. 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In some cases, patients Bernardini I, Krasnewich DM, Arcos-Burgos M, Izumi Y, Nonoguchi H, Jia Y, Reddy JK, Ilyas M, Unwin RJ, Gahl WA, are taking nephrotoxic drugs for serious life-threatening Warth R, Kleta R: Mistargeting of peroxisomal EHHADH conditions, such as HIV or cancer. In these situations, and inherited renal Fanconi’s syndrome. NEnglJMed370: the decision whether to stop therapy can be far from 129–138, 2014 CJASN 14: 1384–1387, September, 2019 Proximal Tubular Disorders, Hall et al. 1387

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