Abstract
Deposition of uric acid in the kidney can lead to progressive tubulointerstitial injury with granuloma formation. We hypothesized that uric acid crystal deposition may induce granuloma formation by stimulating local expression of macrophage migration inhibitory factor (MIF), which is a known mediator of delayed type hypersensitivity (DTH). A model of acute uric acid nephropathy was induced in rats by the administration of oxonic acid (an inhibitor of uricase), together with uric acid supplements. MIF expression and local cellular response were examined by in situ hybridization and immunohistochemistry. Kidney tissue examined at 35 days posttreatment showed widespread tubulointerstitial damage with intratubular uric acid crystal deposition and granuloma formation. Tubules within the areas of granuloma showed a six-fold increase in MIF mRNA, compared with uninvolved areas by in situ hybridization. Moreover, the areas of increased MIF mRNA expression correlated with sites of dense accumulation of macrophages and T cells, and these cells were activated when assessed by the expression of interleukin-2R (IL-2R) and (MHC) class II. Interestingly, cytoplasmic staining for MIF protein in the uric acid (UA) crystal-associated granulomatous lesions was reduced, indicating a rapid MIF secretion by damaged tubules and macrophages secondary to uric acid crystal stimulation. This was confirmed by the demonstration of a marked increase in urinary MIF protein by Western blot analysis. Control rats fed either a normal diet or only oxonic acid had no discernible evidence of renal disease by routine light microscopy and minimal tubular expression of MIF mRNA and protein. These data suggest that intrarenal granulomas in urate nephropathy may be the consequence of a crystal induced DTH reaction mediated by MIF.
Highlights
Patients with hyperuricemia are at risk for developing both acute and chronic renal disease.An acute urate nephropathy has been described in the setting where massive urate overproduction leads to marked hyperuricosuria with intratubular crystal formation and acute renal failure
Urinary uric acid excretion was increased markedly in the UA group from days 7–35, and this parameter peaked at day 14 (Fig. 1B)
The infiltrating macrophages and T cells within the granuloma were activated with high expression of major histocompatibility complex (MHC) class II and IL-2R (Figs. 5D, 5E and 6D, 6F). It has been known for many years that patients with longstanding gout may develop severe tubulointerstitial disease in which intrarenal medullary urate crystal deposition is prominent
Summary
Patients with hyperuricemia are at risk for developing both acute and chronic renal disease.An acute urate nephropathy has been described in the setting where massive urate overproduction leads to marked hyperuricosuria with intratubular crystal formation and acute renal failure. Patients with longstanding hyperuricemia may develop modest renal insufficiency, in which the renal lesion is that of chronic tubulointerstitial disease, often with urate crystal deposition in the outer medulla. These crystals are usually localized within collecting ducts and/or in the interstitium, and are often surrounded by a granulomatous reaction containing leukocytes and giant cells [3,4,5]. Cytoplasmic staining for MIF protein in the uric acid (UA) crystalassociated granulomatous lesions was reduced, indicating a rapid MIF secretion by damaged tubules and macrophages secondary to uric acid crystal stimulation This was confirmed by the demonstration of a marked increase in urinary MIF protein by Western blot analysis.
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