Annals of Clinical & Laboratory Science 38:210-214 (2008)
© 2008 Association of Clinical Scientists
Kidney Injury Molecule-1 Expression Identifies Proximal Tubular Injury in Urate Nephropathy
Manish Nepal1,
Glenn H. Bock2,
Azra M. Sehic2,
Michael F. Schultz3 and
Ping L. Zhang4
1 Departments of Internal Medicine, 2 Pediatric Nephrology, and 3 Adult Nephrology, Geisinger Medical Center, Danville, Pennsylvania, and 4 Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan
Address correspondence to Ping L. Zhang, M.D., Ph.D., Department of Anatomic Pathology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 48073-6769, USA; tel 248 898 9060; fax 248 898 8020; e-mail ping.zhang{at}beaumont.edu.
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Abstract
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Urate nephropathy in children is uncommon, occurring mostly in those who have undergone chemotherapy or radiotherapy. The characteristic obstruction of distal nephron tubules by uric acid precipitates is considered key to the subsequent parenchymal injury. Whether proximal tubular injury plays a role in urate nephropathy remains unclear. We report one case of acute urate nephropathy and one case of chronic urate nephropathy in two pediatric patients. In their renal biopsies, we demonstrate upregulation of kidney injury molecule-1 (KIM-1), a specific injury marker, in proximal tubular cells. This finding implicates a role for proximal tubular injury in urate nephropathy.
Keywords: urate nephropathy, kidney injury molecule-1 (KIM-1), hyperuricemia, acute renal failure
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Introduction
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Uric acid is the end product of purine metabolism in humans and thereby serves an important role in the elimination of the important sources of nitrogen from the body [1]. In contrast, with the exception of higher primates, most mammalian species have conserved an enzyme, urate oxidase, which mediates conversion of uric acid to allantoin, a relatively soluble and easily excreted substance. In humans, the lack of urate oxidase, the occurrence of hyperuricemic conditions, the urinary route of urate excretion, the low pH in the distal portion of the nephron, and the relatively low solubility of uric acid can result in crystallization of uric acid and its deposition in distal renal tubules and interstitium, with resultant tissue injury and, if extensive, impairment of renal function [1,2]. In children, acute urate nephropathy most often occurs in patients with leukemia and lymphoma as a result of rapid nucleoprotein turnover, especially during cytotoxic therapy [3]. Idiopathic urate nephropathy in children is very rare.
Kidney injury molecule-1 (KIM-1), a type I trans-membranous protein [4], is markedly upregulated in proximal tubules following renal ischemic or toxic injury in humans and experimental animals [5–8]. KIM-1 is a sensitive marker of early injury to proximal tubular cells [9]. Investigation of KIM-1 expression could clarify whether proximal tubular injury coexists with distal nephron damage in urate nephropathy. We report two pediatric cases of urate nephropathy of unknown etiology in which proximal tubular injury was identified using KIM-1 staining of renal biopsies.
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Case Reports
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Case 1.
A 12-yr-old girl had a few days’ history of nausea, vomiting, intermittent abdominal pain, and dysuria. No significant weight loss or fever was reported. She had intermittent abdominal pain a few months previously, at which time she was told that she had a urinary tract infection and was given an antibiotic. She had been advised to ingest ample fluids and she became asymptomatic after several days. She had no history of medical or surgical problems, of intake of other medications, or of allergy. Specifically, she did not have any history suggesting prior kidney disease. Her mother had systemic lupus erythematosis and her father had hypertension and gout. Two elder siblings had histories of hyperuricemia.
The patient’s initial evaluation in the Emergency Department revealed a blood pressure of 120/60 mm Hg with a pulse rate of 100/min and a respiratory rate of 14/min. Abdominal palpation showed mild guarding in the peri-umbilical area with bilateral costovertebral angle tenderness. At that time, her serum urea nitrogen concentration was 86 mg/dl, serum creatinine 3.2 mg/dl, and serum uric acid 23.1 mg/dl (normal range 1.5 – 7.0 mg/dl) (Table 1
). Ultrasonography of the kidneys showed no calculi or hydronephrosis. She was initially managed with iv fluids, total parenteral nutrition, and iv rasburicase, following which her uric acid level decreased rapidly to 1.1 mg/dl. Her serum creatinine level diminished to 1.9 mg/dl within two days and became normal within a week. The patient had slightly decreased activity of adenine phosphoribosyl transferase (3.06 nmol/hr/ blood spot (normal range = 3.20 to 6.90 nmol/hr/ blood spot). Uromodulin gene DNA analysis (a test for familial juvenile hyperuricemic nephropathy) was normal. Because of concern about possible small bowel malrotation, surgical exploration was performed with negative results, at which time a renal biopsy was obtained, although serum creatinine and uric acid levels were both normal by the time of the surgery (Table 1).
The renal biopsy showed normal glomerular morphology. There were scattered foci of distal tubular obstruction by intratubular crystal deposits that were cytokeratin-7 positive and consistent with urate precipitates (Fig. 1A). The biopsy was stained by an immunohistochemical method [7] using monoclonal AKG7 antibody against KIM-1. This antibody was kindly provided by Dr. Joseph V. Bonventre, Renal Division, Brigham and Women’s Hospital, Boston, MA. Proximal tubules adjacent to obstructed distal tubules showed mild dilatation and stained mildly positive for KIM-1, indicating proximal tubular injury (Fig. 1B). Blood vessels were not remarkable and there was no significantly interstitial fibrosis or tubular atrophy. Immuno-fluorescent stains for immnunoglobulins, complement (C3 and C4), and light chains were all negative. Electron microscopic examination of glomeruli was unremarkable.
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Fig. 1. Urate nephropathy. In case 1, crystal deposits (arrow) were present in the distal nephron tubules (1A, hematoxylin and eosin stains). Adjacent proximal tubules showed mild positivity for kidney injury molecule-1 (KIM-1) along the luminal surface (1B, white arrow, immunohistochemistry with anti-KIM-1 antibody; black arrow, crystal deposits). In case 2, urate deposits (arrow) obstructed distal nephron tubules with surrounding inflammation (1C, hematoxylin and eosin stains). In the cortex, dilated proximal tubules were moderately stained for KIM-1 along the luminal surface (1D, white arrow, immunohistochemistry with anti-KIM-1 antibody) (1A-1D, original magnification x 400).
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The patient was discharged from the hospital with normal renal function and serum uric acid level. She was advised to consume a normal diet and she was seen periodically. Her serum uric acid level and renal function tests remained normal during subsequent visits (Table 1
).
Case 2.
A 15-yr-old boy developed painless lymph node enlargement in his neck. He denied weight loss, fever, chills, night sweats, or swellings in other parts of the body. He was prescribed amoxicillin for a week with no improvement. Since he had had Epstein Barr virus infection, he underwent an excisional submandibular lymph node biopsy, which revealed a pleomorphic adenoma. He did not have any history of other medical or surgical diseases, including kidney disease, but he had a strong family history of gout. He had no history of consumption of alcohol or illicit drugs. In the course of his evaluation, his serum creatinine concentration was found to be 2.2 mg/dl and his serum uric acid concentration was 10.5 mg/dl (Table 1). Urinalysis was negative for blood or cell casts, but showed mild proteinuria. His urine concentration of uric acid was 21.2 mg/dl. Renal ultrasonography showed a small right kidney with mildly increased echogenicity. Because of his age and elevated serum creatinine level, he was prescribed allopurinol and potassium citrate.
A renal biopsy showed unremarkable glomeruli. Collecting ducts in the renal medulla were obstructed by uric acid deposits (Fig. 1C). Mild chronic interstitial nephritis including lymphocytes and a few eosinophils was evident in the medulla. In the renal cortex, proximal tubular cells showed dilated lumina with diminished brush borders and moderately positive staining of KIM-1 along the luminal membranes (Fig. 1D). Mild interstitial fibrosis was noted in the renal cortex. Vessels were not remarkable. Epstein-Barr virus staining by in situ hybridization was negative. The patient’s serum uric acid level became normal with medical therapy but his serum creatinine has remained between 1.8 and 2.1 mg/dl. At 7 mo after the biopsy, he had an acute episode of deterioration of renal function with dehydration (Table 1). During allopurinol therapy, his serum uric acid level was 7.5 mg/dl. When allopurinol therapy was discontinued for a short period of time, his serum uric acid level increased to 10 to 11 mg/dl.
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Discussion
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Urate nephropathy, when seen in children, is usually associated with chemotherapy or radio-therapy for malignancy. Genetic defects in purine metabolism and certain medications can also predispose to precipitation of uric acid in the kidneys [1,9,10]. In our two pediatric cases, the first patient developed acute urate nephropathy. Because of her slightly low activity of adenine phosphoribosyl transferase in blood, and the family history of gout and hyperuricemia, we suspected a genetic defect of purine metabolism with overproduction of uric acid. Low activity of adenine phosphoribosyl transferase may reduce production of adenylic acid, an inhibitor of aminophosphoribosyl transferase (APT). Since APT promotes metabolism of 5-phosphoribosyl-1-pyrophosphate (the up-stream product of uric acid), diminished APT activity impairs purine salvage and increases nucleic acid degradation and uric acid production. The patient’s renal function recovered quickly after her hyperuricemia was normalized. The second patient presented with chronic urate nephropathy with renal interstitial nephritis and fibrosis with urate crystal deposition. Despite normalization of the patient’s serum uric acid level by drug treatment, his serum creatinine level remained high, supporting the chronic nature of his kidney disease. His serum uric acid level increased when allopurinol therapy was temporally withdrawn. Several eosinophils were evident in the renal medulla, raising a possibility of drug reaction, but no drug was identified. His strong family history of gout led us to suspect a defect in his purine metabolism as well. Another possibility is that an underlying chronic renal insufficiency (possibly secondary to another cause) resulted in defective uric acid excretion and uric acid accumulation.
The finding of KIM-1 in proximal tubules in these two cases is notable. In the first case, proximal tubular damage appeared at an early stage since only mild dilation was evident in the proximal tubules. Mildly positive staining of KIM-1 was noted in 20% of proximal tubules, indicating active injury to proximal tubular cells, although her serum creatinine had returned to a normal level by the time of the renal biopsy. The second case showed prominent dilatation of proximal tubules with epithelial flattening and diminished brush borders. KIM-1 staining was moderately positive along the luminal surface of proximal tubules, indicating active tubular injury. KIM-1 is not expressed in normal renal parenchyma but is specifically upregulated only in injured proximal tubules [8,11], although the definite role of this biomarker in the tubular injury remains unknown. Generally, the expression of KIM-1 is significantly correlated with serum creatinine levels [11]. Furthermore, urinary excretion of the KIM-1 ectodomain is present when there is acute kidney injury [7]. In the current two cases, we found that KIM-1 expression was useful in establishing proximal tubular injury in the clinical-pathologic process.
Deficiency of uricase in humans, combined with relatively inefficient clearance of uric acid from the body, results in exceptionally higher serum levels of uric acid when compared to most other mammals [1,12]. Humans, therefore, have a tendency toward uric acid crystallization, whereby even modest alterations in uric acid homeostasis may cause hyperuricemia, gout, and renal failure [1]. In addition to the obstructive effects of uric acid crystallization in distal nephron tubules, several other factors can contribute to acute kidney injury, including renal vasoconstriction, pro-inflammatory mediators, and the antiangiogenic and pro-oxidative properties of uric acid [12–14]. The upregulated KIM-1 expression in proximal tubules in our two cases indicates that the injured proximal tubules could significantly contribute to the renal dysfunction in acute and chronic urate nephropathy. Proximal tubules are known to have bi-directional functions during excretion of uric acid, ie, reabsorbing uric acid from lumen to circulation and secreting uric acid into the lumen. Because of the high pH in proximal tubules, uric acid does not precipitate in this segment of tubules under hyperuricemic conditions. The proximal tubular injury most likely resulted from obstruction associated with the multifactorial insults noted previously. In addition, accumulated uric acid in proximal tubules may possibly exert direct toxic effects on tubular epithelial cells, thereby contributing to the pathological process.
In summary, we describe two pediatric patients with urate nephropathy, one acute and one chronic. Upregulated KIM-1 expression in their proximal renal tubules highlighted the potential contribution of injured proximal tubules to the renal dysfunction associated with urate nephropathy.
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Abstract
Introduction
