QJM Advance Access originally published online on January 9, 2008
QJM 2008 101(2):163-164; doi:10.1093/qjmed/hcm141
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Hyponatraemia due to renal proximal tubule dysfunction in a patient with adult-onset Still's disease
Sir,Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by spiking fever, evanescent rash and multiple organ involvements. Renal involvement has been, however, rarely reported in AOSD. We report an unusual occurrence of proximal tubular dysfunctions presenting with hyponatraemia in a patient with AOSD.
A 56-year-old Japanese man was admitted after 1 week of high-grade intermittent fever, arthralgias and myalgias. Physical examination revealed polyarthritis and pink-red rashes on the arms and trunk concomitant with a high spiking fever. Laboratory examination showed marked inflammatory signs and hyperferritinaemia (225 400 ng/ml; reference: 20–200). Our patients did not show any evidences of infections, malignancy, or rheumatic diseases; thus, we diagnosed him as having AOSD1 and started corticosteroids therapy [oral prednisolone (PSL) at 100 mg/day], resulting in prompt improvement of his symptoms.
During the hospitalization, the counts of peripheral leucocytes and platelets markedly decreased and the bone marrow aspiration revealed macrophages actively phagocytozing haematopoietic cells, indicating macrophage activating syndrome (MAS).2 Further, hyponatraemia (124 mEq/l) concomitantly developed. The working diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made, and fluid restriction was instituted. However, the fluid restriction worsened his symptoms (i.e. palpation, light-headedness, lethargy and postural hypotension). At this time, laboratory examination revealed mild renal dysfunction, no remarkable urinary abnormalities, hyponatraemia, hypouricaemia with high fractional excretion of uric acid (FEUA) and a low level of maximal tubular reabsorption of phosphorous per glomerular filtration rate (TmP/GFR) (Table 1). Further, the level of atrial natriuretic peptide (ANP), a marker of volume status, was suppressed (<10 pg/ml; reference: <40), indicating hypovolaemia. Therefore, our patient might have proximal tubular dysfunction resulting in salt-losing, rather than SIADH.3 Percutaneous renal biopsy was performed; however, no marked pathological changes (e.g. tubular necrosis or interstitial nephritis) were found. The PSL therapy gradually improved his clinical/laboratory abnormalities (Table 1); thus, he was discharged.
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We have described here a patient with AOSD who developed MAS and renal proximal tubular dysfunction. His renal biopsy showed no marked pathological changes and the clinical/laboratory abnormalities due to proximal tubular dysfunction (i.e. postural hypotension, hyponatraemia, hypouricaemia and low TmP/GFR) were paralleled with the disease activities of AOSD; thus, his proximal tubular function might be functionally disturbed. Our patient also showed the marked reduction of GFR. We speculated that this might be in part due to the tubulo-glomerular feedback caused by increased sodium chloride delivery to the macula densa (due to decreased reabsorption in the proximal tubular cells) resulting in afferent arteriolar constriction and a fall in GFR.
AOSD complicated with MAS is considered to be associated with the excess activation of T lymphocytes and macrophages, which leads to overproduction of various cytokines. In the present case, extremely high ferritin levels indicated the activation of macrophages and marked hypercytokinaemia was also observed when MAS had developed (Table 1). Sodium, phosphate and uric acid are mainly reabsorbed in the proximal renal tubular cells via the electrochemical gradient generated by basolateral sodium/potassium ATPase (Na/K ATPase). Pro-inflammatory cytokines have been shown to suppress proximal tubular transport in vitro via inhibition of Na/K ATPase mediated by the production of nitric oxide.4 Therefore, the marked hypercytokinaemia might be responsible for the development of proximal tubular dysfunction in our case. Hyponatraemia has been described as one of the strong laboratory discriminators in patients with MAS complicating systemic juvenile idiopathic arthritis.2 Further, a similar proximal tubular dysfunction has been reported for a 25-month-old girl with MAS complicating systemic juvenile idiopathic arthritis, who developed marked hyponatraemia, hypophosphataemia and hypouricaemia with a high serum level of TNF-
.5 The elevation of serum TNF- levels was not observed in the present case; however, the IL-6 level was markedly elevated and reduced with the PSL therapy (Table 1); thus, IL-6 might play an important role in the development of renal proximal tubular dysfunction in our case. Our study suggests the possibility of the occurrence of cytokine-induced renal proximal tubular dysfunction in patients with AOSD. Further clinical studies in a large number of patients are needed.
Department of Internal Medicine
Shiga University of Medical Science
Otsu, Shiga, 520-2192
Japan
email: toshiro{at}belle.shiga-med.ac.jp
Department of Medicine
Otsu Municipal Hospital
Otsu, Shiga 520-0804
Japan
References
1. Yamaguchi M, Ohta A, Tsunematsu T, Takei M, Tomita Y, Nishinarita S, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol (1992) 19:424–30.[Web of Science][Medline]
2. Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr (2005) 146:598–604.[CrossRef][Web of Science][Medline]
3. Maesaka JK, Miyazaki N, Palaia T, Fishbane S, Durham JHC. Renal salt wasting without cerebral disease: diagnostic value of urate determinations in hyponatremia. Kidney Int (2007) 71:822–6.[CrossRef][Web of Science][Medline]
4. Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm (2006) 3:5. [doi: 10.1186/1476-9255-3-5].[CrossRef]
5. Yamazawa K, Kodo K, Maeda J, Omori S, Hida M, Mori T, et al. Hyponatremia, hypophosphatemia, hypouricemia in a girl with macrophage activating syndrome. Pediatrics (2006) 118:2557–60.
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