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Department of Infection, Immunity and Inflammation, University of Leicester School of Medicine, Leicester, UK
Address correspondence to: Dr. Nigel J. Brunskill, Department of Infection, Immunity and Inflammation, University of Leicester School of Medicine, Medical Sciences Building, University Road, Leicester, UK. Phone: +44-0-116-2588043; Fax: +44-0-116-2584764; E-mail: njb18{at}le.ac.uk
Progressive renal disease in the presence of proteinuria is characterized by an infiltration of inflammatory cells into the renal interstitium associated with incremental atrophy of tubular structures and replacement of the tubulointerstitium by fibrous scar. This process is commonly known as proteinuric nephropathy, a term intended to distinguish this pathology from that of the initial glomerular or other renal injury responsible for its initiation. The pathophysiological processes underlying the development of proteinuric nephropathy have been extensively studied. As a result, a variety of general antiproteinuric strategies, supported by high-level evidence, have been introduced into clinical practice designed to slow the progression of a diverse range of primary renal diseases linked only by the commonality of proteinuria (1). Their widespread introduction into the clinic over the last 10 yr or so has been widely embraced and can be considered a spectacular success. Enthusiasm for these new treatments is also greatly encouraged by observations that for the first time, in some patients at least, regression of renal fibrosis may be possible (2). Indeed, their development vindicates the current scientific approach to medical research where intensive and careful investigation at the bench and in animals eventually translates into meaningful therapeutic interventions at the bedside.
So, given the progress in this field in the recent past, do we need to do more? The answer of course is yes, for two important reasons. First, the daily experience of most practicing nephrologists is that even after the institution of maximal antiproteinuric treatment in the majority of patients, some proteinuria still persists and progression of renal disease still occurs, albeit at a reduced rate. Second, the nephrology community is just beginning to appreciate the alarming scale of undetected proteinuria and chronic kidney disease in our populations, and the potentially burgeoning numbers of patients with end-stage renal disease in the future (3).
Fortunately, additional targets for therapeutic intervention are clearly evident. Considerable experimental data indicates that the interaction of proximal tubular cells with proteinuric tubular fluid results in their production of pro-inflammatory mediators via activation of the transcription factor NF
B (4). Mononuclear cells, predominantly macrophages and T lymphocytes, heavily infiltrate the interstitium of proteinuric kidneys. It is generally believed that these cells are key mediators of scarring and fibrosis and that the degree of infiltration is directly proportional to the prevailing level of proteinuria encountered by the proximal tubular cells (5,6). Work performed in proteinuric animals 15 yr ago indicates that if these cells are depleted using whole body irradiation, or their recruitment to the kidney is paralyzed by essential fatty acid deficiency, then a salutary effect on renal function is observed (7). Although such maneuvers will never be applicable to human disease, these infiltrating inflammatory cells are enticing candidates for further pharmacologic manipulation.
Anti-inflammatory approaches employing glucocorticoids have already been tested. Generally, however, steroids have proved ineffective in the treatment of nonimmunologically mediated renal disease and progressive renal impairment. In animals and humans with proteinuria, steroids are associated with accentuated glomerular and systemic hypertension and increased urinary protein excretion (8,9). Furthermore, in contrast to other cell types, NFB activation in tubular epithelial cells is not blocked by steroids (10). Therefore, while steroid therapy may have a place in the treatment of some forms of immunologically mediated glomerulonephritis, until now efforts to control interstitial inflammation in proteinuria with steroids, and other immunosuppressive agents, have been disappointing.
In the current issue of JASN, however, Bonegio et al. present an exciting new angle on the use of immunosuppressive agents in proteinuric nephropathy (11). Using a model of passive Heymann nephritis accelerated by severe renal mass reduction, the authors have characterized a new model of proteinuric nephropathy associated with tubulointerstitial inflammation and fibrosis, but lacking substantial glomerular inflammation or glomerulosclerosis. Most importantly, proteinuria, tubulointerstitial inflammation, cortical fibrosis, renal expression of pro-inflammatory and profibrotic genes, and glomerular hypertrophy were substantially ameliorated by the administration of rapamycin. Effectively, rapamycin alone was able to halt progression of disease.
Several cell types are likely to be involved in this protective effect of rapamycin. The immunosuppressive function of rapamycin is derived from its ability to block clonal expansion of stimulated T cells by inhibition of mTOR (mammalian target of rapamcyin), a central controller of cell growth. Clearly, therefore, inhibition of injury mediated by infiltrating T cells in the proteinuric kidney may be crucial to the protective effect of rapamycin. However, recent evidence suggests that rapamycin also blocks proliferation of renal epithelial cells in response to proteinuria (12,13). Proliferation of proximal tubular epithelial cells has been observed in both proteinuric animals and nephrotic patients (14,15), and is proposed to represent a factor favoring progression of renal disease. Thus rapamycin may also act beneficially at this level.
Most nephrologists are likely to be familiar with rapamycin in the context of immunosuppressive therapy in renal transplantation. Some may worry about potential side effects of this potent drug if proposed for nontransplant indications. The results of Bonegio et al. (11), however, indicate that rapamycin may exert its beneficial effects in proteinuric nephropathy at doses considerably lower than those required for the prevention of transplant rejection. Clearly, rapamycin therefore holds promise as a future addition to our antiproteinuric armamentarium. There is, however, a note of caution. Significant inhibition of renal compensatory hypertrophy was seen in the study of Bonegio et al. (11), and in other studies of unilateral nephrectomy in mice (16). The significance of this observation is unclear at present and may possibly be beneficial or detrimental in terms of preservation of renal function. More studies of rapamycin are required, particularly in models of nephropathy associated with declining glomuerular filtration rate. Nonetheless, the ongoing process of scientific scrutiny previously applied to other antiproteinuric medications may eventually result in low-dose rapamycin accompanying angiotensin-converting enzyme inhibitors, and the like, on our prescription charts for proteinuric patients.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
References
This article has been cited by other articles:
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  S. Kramer, Y. Wang-Rosenke, V. Scholl, E. Binder, T. Loof, D. Khadzhynov, H. Kawachi, F. Shimizu, F. Diekmann, K. Budde, et al. Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat Am J Physiol Renal Physiol, February 1, 2008; 294(2): F440 - F449. [Abstract] [Full Text] [PDF]
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 G. K. Rangan and J. D. Coombes Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2175 - 2182. [Abstract] [Full Text] [PDF]
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