Rapidly progressive renal failure associated with successful pharmacotherapy for obesity

Sir, We thank Drs Calo and Davis for highlighting their interesting studies. We were, in fact, aware of these studies and have used them as background in grant applications in the broader context. Our paper was not intended to be a review of the literature, since this area, we believe, is still evolving. It is always a subjective decision which references to include or not in any given publication. We felt it unnecessary to include the works cited by Drs Calo and Davis, for obvious reasons. It should be apparent that our emphasis was on the modulatory role of transforming growth factor-b (TGF-b) on renal tissue gene expression in the setting of tacrolimusinduced nephrotoxicity, in an experimental rodent model of renal transplantation. In contrast, the studies by Calo and Davis evaluated the modulation by angiotensin converting enzyme (ACE) inhibitor treatment on Cyclosporin and tacrolimus-induced hypertension in human renal transplant models but in peripheral monocytes. In this case, the emphasis for their studies was on non-renal tissue. Due to this and the emphasis on nitric oxide in the setting of hypertension, it is clear that the focus was on the potential interaction of inflammatory cells and endothelial/vascular disease. Since we did not evaluate these issues, we could not credibly comment on them. Our studies were clearly addressing issues of immunosuppression-induced nephrotoxicity as evidenced by renal dysfunction and histological changes. These indices were not end-points of the studies by Calo et al. Calo specifically indicated in their paper that patients had normal kidney function. To illustrate this difference in focus, no published papers by Calo and colleagues could be found using various criteria of literature search on PubMED (e.g. tacrolimus, nephrotoxicity, transforming growth factor; NADPH oxidase, tacrolimus, kidney; NADPH oxidase, tacrolimus). So, it is clear that we are talking about two different facets of calcineurin inhibitorinduced side-effects. We would also like to reiterate the comments explained in our ‘Discussion’, that our findings of absence of gp expression (i.e. phagocytic cells) together with the up-regulation of NOX-1 (i.e. a non-phagocytic NADPH oxidase) clearly distinguishes our findings from those of hypertension-induced oxidative stress. It should be noted that Calo et al. dealt solely with issues of monocyte NAPDH oxidase subunit expression in the context of hypertension. This is clearly a separate issue and we did not specifically analyze gene expression in peripheral monocyte fractions. More significantly, the overall goals of the studies by Calo et al., vs our study, are entirely different. The focus of our published [1–5] and ongoing studies is to understand the mechanism of immunosuppression-associated nephrotoxicity in organ transplantation. Our paper published in NDT was designed to understand the direct relationship of TGF-b and oxidative stress in tacrolimus-associated nephrotoxicity in a rat renal transplantation. sults uniquely emphasize the fact that the inhibition of TGF-b by a neutralizing antibody ameliorates nephrotoxicity but prolongs graft survival. This is completely different to the published studies of Calo et al. involving hypertension in renal transplantation. Furthermore, we are confident that Calo et al. are also aware of the fact that nephrotoxicity is the single most common limiting factor in achieving long-term graft survival in any type of organ transplantation. We wish Dr Calo and Davis had, instead, commended us on our unique and meaningful study, which we feel is a step forward in designing a newer therapeutic strategy to achieve nephrotoxicity-free immunosuppression in organ transplantation. Also, we are positive that Calo et al. will agree that the coherent ‘Discussion’, linking results and conclusions, is important for a successful publication and our intention was to cite references which were relevant to TGF-b, oxidative stress, immunosuppression and nephrotoxicity. We sincerely hope that the concerns of Calo et al. are answered. Furthermore, we hope that their elegant published studies will find an appropriate place in our forthcoming related publications.