Experimental chronic kidney disease by dietary adenine overload: initial tubular injury, mechanism of granuloma formation and prevention of fibrosis

Abstract

Despite the undeniable advances verified in the last twenty years, the mechanisms involved in the progression of chronic kidney disease (CKD) to the stage of advanced renal insufficiency are still far from being fully understood. It is known, however, that the tubulointerstitial fibrosis constitutes a final common pathway for a series of processes that cause CKD. Some of these originate in the glomeruli and propagate to the renal interstitium. In other cases, however, the process begins and progresses in the interstitium itself - so-called chronic interstitial nephritides (CIN) - leading to the destruction of tubules and, in more advanced phases, of glomeruli as well. Therefore, the study of interstitial nephritis, especially during its initial phases, when the causative mechanisms are still operative and can be more easily identified, is of great interest, making it possible, on the other hand, to design and test therapeutic maneuvers to halt progression of the disease.The need to better understand the pathogenesis of CIN has led to the development of a number of experimental models, seeking to mimic these processes. Dietary adenine overload is a model that closely resembles human CIN, its pathogenesis and the attending functional impairment. Although the nephrotoxic effect of adenine has been known for over a century, its use in Experimental Nephrology has been limited. Only in 1986 a fairly consistent model was developed, which however aroused little interest in the two decades that followed. In recent years, this model has attracted attention because of its peculiar features: besides causing intense inflammation and fibrosis of the renal interstitium, excess adenine promotes hypertension, bone disorders and vascular calcification. The mechanisms that lead from crystal precipitation to CIN remain largely unclear. Equally uncertain are the possible beneficial effects of anti-inflammatory drugs such as mycophenolate mofetil (non-steroidal anti-inflammatory drugs are contraindicated in patients with advanced CKD).The objectives of this study are: 1) To analyze the sequence of phenomena causing renal damage from excess adenine, from early stages - formation of insoluble crystals in the tubular lumen - to more advanced phases, when formation of granulomas and renal interstitial fibrosis take place, 2) analyze the behavior of the chronic nephropathy - its possible regression or, conversely, its progression - once the original stimulus - excess adenine - has been removed, 3) investigate the effects of treatment with two compounds known to exert anti-inflammatory activity: a) Mycophenolate mofetil (MMF), a drug that inhibits the proliferation of lymphocytes and b) pyrrolidine dithiocarbamate (PDTC), a compound that inhibits the NF-ºB, system and hence is expected to detain the intracellular propagation of the stimulus initiated by crystal precipitation. (AU)