Adult Idiopathic Renal Fanconi Syndrome: A Case Report

Dae Jin Park; Ki-Seok Jang; Gheun-Ho Kim

doi:10.5049/EBP.2018.16.2.19

Abstract

Renal Fanconi syndrome (RFS) is caused by generalized proximal tubular dysfunction and can be divided into hereditary and acquired form. Adult-onset RFS is usually associated with drug toxicity or systemic disorders, and modern molecular genetics may explain the etiology of previous idiopathic cases of RFS. Here, we report the case of a 52-year-old woman with RFS whose etiology could not be identified. She presented with features of phosphaturia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis. Her family history was unremarkable, and previous medications were nonspecific. Her bone mineral density was compatible with osteoporosis, serum intact parathyroid hormone level was mildly elevated, and 25(OH) vitamin D level was insufficient. Her blood urea nitrogen and serum creatinine levels were 8.4 and 1.19 mg/dL, respectively (estimated glomerular filtration rate, 53 mL/min/1.73 m²). Percutaneous renal biopsy was performed but revealed no specific renal pathology, including mitochondrial morphology. No mutation was detected in EHHADH gene. We propose the possibility of involvement of other genes or molecules in this case of adult RFS.

Introduction

Fanconi syndrome is caused by generalized proximal tubular dysfunction and manifested by phosphaturia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis (RTA). It is associated with systemic features in many cases1), and its renal-limited form is called renal Fanconi syndrome (RFS).

The etiology of RFS includes inherited and acquired disorders, and RFS diagnosed in adults is most commonly associated with drug toxicity2). However, idiopathic adult-onset RFS has been reported3). With the advances in molecular genetics, three genetic forms of RFS have been identified, namely Fanconi renotubular syndrome (FRTS) types 1–31). Previously, these were considered idiopathic disorders.

Although the underlying gene is yet to be identified, FRTS1 is inherited in an autosomal dominant fashion and associated with progressive chronic kidney disease (CKD)4). FRTS2 is characterized by phosphate wasting and rickets, and caused by a mutation in SLC34A1, encoding the phosphate transporter NaPi-IIa5). It has so far been described only in two siblings6) and may not be a true RFS in those cases because RTA was not present7).

On the other hand, FRTS3 is the prototype of RFS characterized by no kidney failure1). Its autosomal dominant inheritance was described in a five-generation family8), and the heterozygous missense mutation in the EHHADH gene was identified9). However, possibilities remain that other genes and molecules are involved in the pathogenesis of RFS or FRTS. Furthermore, adult idiopathic cases or spontaneous mutations in RFS are elusive. Here, we report the case of a 52-year-old woman with RFS whose etiology could not be identified.

Case Report

A 52-year-old woman was admitted to our hospital for further evaluation of kidney disease. She was previously healthy except for an incidentally found osteoporosis during the previous year's checkup. Her bone mineral density was aggravated at that year's follow-up, so she visited a local hospital, where she was diagnosed as having Fanconi syndrome. The following amionoacids were elevated in the 24-h urine collection: taurine, aspartic acid, threonine, serine, asparagine, glutamine, glycine, alanine, citrulline, α-aminobutyric acid, valine, cysteine, isoleucine, leucine, tyrosine, phenylalanine, ornithine, lysine, l-methylhistidine, histidine, and arginine. Her family history was unremarkable. In the previous last year, she took some herbal medicine as a lipid-lowering agent for approximately 1 year. She was unmarried and did missionary work in foreign countries. She complained of no urinary symptoms.

Her blood pressure was 100/60 mmHg, and physical examination results were normal. Urinalysis revealed the following: specific gravity of 1.024, pH 7.0, albumin +, glucose ++, RBC 20-29/HPF, and WBC 0-2/HPF. The following laboratory values were obtained: serum calcium, 8.9 mg/dL; phosphorus, 1.9 mg/dL; uric acid, 0.8 mg/dL; magnesium, 2.8 mg/dL; cholesterol, 202 mg/dL; protein, 6.9 g/dL; albumin, 4.2 g/dL; BUN, 8.4 mg/dL; creatinine, 1.19 mg/dL; glucose, 104 mg/dL; and HbA1c, 4.7%. Her estimated glomerular filtration rate (eGFR) was 53 mL/min/1.73m², calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The following values were obtained in 24-hour urine monitoring: protein, 2935 mg; albumin, 153 mg; sodium, 142 mmol; potassium, 59 mmol; chloride, 132 mmol; calcium, 428 mg; magnesium, 83.5 mg; uric acid, 455 mg; glucose, 20797 mg; and creatinine, 1.0 g. The urine β2- microglobulin level was >20,000 µg/L.

Fractional excretions of calcium, phosphorus, magnesium, and uric acid were 3.4%, 43.1%, 2.2%, and 63.4%, respectively. The serum intact parathyroid hormone (PTH) level was 74.5 pg/mL, and the 25(OH) vitamin D level was 20.4 ng/mL. Her bone mineral density was compatible with osteoporosis. Bone scintigraphy revealed old multiple rib fractures and diffusely increased whole-body bone uptake, which are suggestive of metabolic bone disease.

The serum concentrations of sodium, potassium, chloride, and total CO₂ were 139, 3.6, 114, and 19.0 mmol/L, respectively. Arterial blood gas analysis revealed the following values: pH, 7.30; PaCO₂, 34.8 mmHg; PaO₂, 118 mmHg; and HCO₃⁻, 16.6 mmol/L. The urine sodium, potassium, chloride, and creatinine concentrations were 63 mmol/L, 21 mmol/L, 80 mmol/L, and 40 mg/dL, respectively. The fractional excretion of bicarbonate was elevated from 0.8% (at urine pH 6.8) to 15.3% (at urine pH 7.53) in response to the intravenous sodium bicarbonate infusion. The urine-blood PCO₂ gradient reached 53mmHg.

Percutaneous renal biopsy was performed but did not reveal any specific renal pathology (Fig. 1). Glomerular and tubulointerstitial architectures were normal, and the mitochondrial ultrastructure was unremarkable. In addition, immunostaining for the Na/K-ATPase α1 subunit was intact along the basolateral membrane of the proximal tubule. We performed a mutation analysis and detected no mutation in the EHHADH gene. She was discharged with a prescription of NaHCO₃ and calcitriol.

Discussion

We present an adult case of RFS in which no etiology could be identified. The patient was 52 years old when she was diagnosed, and osteoporosis was the only manifestation associated with her RFS. She had typical features of generalized proximal tubular dysfunction, and proximal RTA was demonstrated by the bicarbonate loading test.

As expected, metabolic bone disease was the predominant feature in this case. Vitamin D insufficiency, and renal wasting of phosphorus and calcium were linked to osteoporosis and increased intact PTH level. Calcitriol was administered but not bisphosphates because of several reports of zoledronate-induced RFS10 11 12).

Drug-induced nephrotoxicity would be the most probable cause of adult-onset RFS3). In our case, a certain herbal medicine taken for lipid lowering could be the culprit of the RFS because aristolochic acid-associated nephropathy was reported to be associated with RFS13). However, the renal tissues and ultrastructure revealed no pathology. We believe that she took natural remedies only.

Systemic diseases such as monoclonal gammopathy and legionella pneumonia were reported to be complicated by RFS14 15). These possibilities were excluded using our clinical and laboratory examinations.

Then, genetic causes of RFS can be suspected. Our case was compatible with isolated RFS because it was not accompanied by systemic disorders1). However, previously known FRTS types 1, 2, and 3 were unlikely because of the lack of information on family history and evidence of rickets. In particular, the diagnosis of FRTS3 was excluded by performing a mutation analysis of the EHHADH gene.

We also tested whether the basolateral expression of Na/K-ATPase was deficient in the proximal tubule because it acts as the primary drive for solute transport along the nephron16). However, we found no abnormality of the Na/K-ATPase α1 subunit immunoreactivity. Finally, we suggest the possibility of spontaneous mutation of previously unknown genes involving the ion transport in the proximal tubule. Whole-exome sequencing might be useful for identifying another RFS-related mutation in our patient.

Acknowledgment

We thank Prof. Hae Il Cheong at Seoul National University for the mutation analysis of the EHHADH gene.

Notes

^{Conflict of interest} The authors declare no relevant financial interests.

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