The irbesartan group had greater than 30% reduction in proteinuria, compared with 6% for amlodipine and 10% for placebo. cells of renal or extrarenal origin may also have a role. This review describes recent advances in our understanding of the mechanisms and mediators underlying renal tissue repair ultimately responsible for regression of renal injury. Historical view Progression to end-stage renal disease (ESRD) is common in chronic nephropathies, independent of the initial insult. Since 1830, disorders of the kidney with albuminuria and changes of blood chemistry were defined as Brights disease (1, 2). In his 1931 book (2), Thomas Addis indicated that study of the urine could be advantageous to the categorization of structural disease in the kidneys. By 1939, Addis (3) introduced the idea of osmotic work and calculated how this work would vary with the amount of protein in the diet. An important implication of those studies was that dietary protein restriction could be of help for patients with renal impairment. Meanwhile, in 1932 Alfred Chanutin and Eugene Ferris (4) observed that removal of three quarters of the total renal mass in the rat led to a slowly progressive deterioration in the function of the remaining nephrons, with progressive azotemia and glomerulosclerosis. The glomerular lesions of the remnant kidney were associated with abnormal glomerular permeability and proteinuria. At that time, proteinuria was considered a marker of the extent of glomerular damage, despite the fact that Franz Volhard and Theodor Fahr in 1914 (5) and Wilhelm von Mollendorf and Philipp Stohr in 1924 (6) had already found that renal damage was related to exuberant protein excretion in the urine. In 1954 Jean Oliver and colleagues (7) recognized protein droplets in the cytoplasm of tubular cells. They suggested that such findings were possibly the result of impairment in the process of reabsorption of plasma proteins normally carried out by the renal tubule and proposed that proteinuria could lead to structural and functional nephron damage. Robert Platt, during the second of the two Lumleian Lectures delivered to the Royal College of Physicians of London (8), reported that the functional disturbances known to occur in human renal disease are precisely those which occur in animal experiments as a result of reduction in the amount of functioning renal substance, that is, loss of nephrons. Rats from which 80% of the renal tissue has been removed had hypertrophy of the remaining nephrons, as they take in a volume of work which they would never be called up to perform in normal kidney. This was interpreted as a possible adaptation to overcome the handicap imposed by the loss of nephrons. Shimamura and Morrison (9) found hyalinization of the glomerular structure after partial five-sixths nephrectomy in animals. In the late 1960s Brenner had access to a unique strain of rat with glomeruli on the cortical surface and developed a new micropuncture technique (10). By such means, Brenner and coworkers clarified the pathophysiology of renal adaptation to nephron loss. KC01 They found that after removal of renal mass, arteriolar resistance lowers and plasma flow increases in remnant glomeruli (11). The tone of afferent arterioles drops by a greater degree than that of efferent ones, which increases glomerular capillary hydraulic pressure, leading to more filtrate formed per nephron. These changes serve to enhance the filtration capacity of the remaining nephron units, minimizing the functional consequences of nephron loss, but are ultimately detrimental (12). Brenner also found (13) that therapies that attenuate such adaptive changes limit GFR decline and structural damage (14). A possible link between glomerular hypertension and proteinuria was not established formally at that time; nevertheless, Cameron had already found that patients with nephrotic syndrome did progress more rapidly than those who had never been nephrotic (15, 16). This was in harmony with previous findings KC01 by KC01 Habib (17) that in focal and segmental glomerulosclerosis those patients who had their proteinuria lowered by corticosteroids did not develop renal failure. In 1986, studies in rats (18) renewed the old idea that urinary proteins may have intrinsic renal toxicity and contribute to the progression Mouse monoclonal to ERBB3 of damage. Later, Eddy and Michael (19), in an experimental model of nephrosis, found that proteinuria correlated with increased numbers of interstitial cell infiltrates. Excessive proteinuria was also induced in rats by intraperitoneal injections of albumin (20, 21) or by transplanting a pituitary tumor (22). In both models proteinuria was followed by tubular damage and interstitial inflammation of macrophages and T lymphocytes. The.