Abatacept in B7-1 Positive Proteinuric Kidney Disease

Transcription

1 correspondence practicing orthopedic surgeons, in which mechanical symptoms were not even included owing to the presumption that they would be unanimously considered a definite surgical indication. As noted by Jevsevar et al., the AAOS shares this stance. 1 However, compelling evidence is lacking to support the assumption that mechanical symptoms are caused by degenerative meniscal tears or that they can be alleviated by arthroscopic partial meniscectomy in these patients. Krych et al. state that subchondral edema and chondromalacia could affect the outcome of arthroscopic partial meniscectomy. Although this is possible, to our knowledge, no conclusive evidence exists to support such assumptions in this particular patient population. Reliable testing of hypotheses like these would require that criteria for these potential prognostic factors first be accepted and validated. In response to Lattermann et al.: we emphasize that FIDELITY was designed as an efficacy (proof-of-concept) trial with the intention of recruiting not typical patients undergoing arthroscopic partial meniscectomy but rather patients most likely to have a good response (those with a medial meniscal tear but no osteoarthritis). This also explains the lengthy recruitment period despite the participation of five high-volume centers. Although the study design has been elaborated in detail previously, 2 we briefly note that an efficacy trial assesses whether an intervention here, arthroscopic partial meniscectomy can theoretically work under the best circumstances. If the results are negative, this suggests that it is not necessary to assess effectiveness in less optimal, routine settings. 3 With respect to the concern that lavage was not an appropriate control, the existing high-quality evidence is unambiguous: tidal irrigation 4 and arthroscopic lavage 5 have failed to provide a benefit over sham procedures (sham irrigation and skin incisions, respectively) in randomized trials involving patients with osteoarthritis. The AAOS seems to endorse this view. 1 Teppo L.N. Järvinen, M.D., Ph.D. Helsinki University Central Hospital Helsinki, Finland teppo.jarvinen@helsinki.fi Raine Sihvonen, M.D. Hatanpää City Hospital Tampere, Finland Antti Malmivaara, M.D., Ph.D. National Institute for Health and Welfare Helsinki, Finland Since publication of their article, the authors report no further potential conflict of interest. 1. Jevsevar DS, Brown GA, Jones DL, et al. The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition. J Bone Joint Surg Am 2013;95: Sihvonen R, Paavola M, Malmivaara A, Jarvinen TL. Finnish Degenerative Meniscal Lesion Study (FIDELITY): a protocol for a randomised, placebo surgery controlled trial on the efficacy of arthroscopic partial meniscectomy for patients with degenerative meniscus injury with a novel RCT within-a-cohort study design. BMJ Open 2013;3(3):pii:e Haynes B. Can it work? Does it work? Is it worth it? The testing of healthcare interventions is evolving. BMJ 1999;319: Bradley JD, Heilman DK, Katz BP, Gsell P, Wallick JE, Brandt KD. Tidal irrigation as treatment for knee osteoarthritis: a shamcontrolled, randomized, double-blinded evaluation. Arthritis Rheum 2002;46: Moseley JB, O Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002;347:81-8. DOI: /NEJMc Abatacept in B7-1 Positive Proteinuric Kidney Disease To the Editor: In their Brief Report, Yu et al. (Dec. 19 issue) 1 describe the use of abatacept, an inhibitor of the T-cell costimulatory molecule B7-1, in inducing remission in five patients with focal segmental glomerulosclerosis (FSGS) resistant to rituximab and glucocorticoids (one patient with primary FSGS and four with recurrent FSGS after transplantation). The rationale for using abatacept was that B7-1 is induced in podocytes in primary and recurrent FSGS as well as in patients with membranous nephropathy. In an attempt to reproduce their findings with the same antibodies, we found no B7-1 signal in samples obtained from patients with recurrent FSGS after transplantation and strong staining in samples obtained from patients with membranous nephropathy, results almost identical to those reported by Yu et al. However, sec- n engl j med 370;13 nejm.org march 27,

2 The new england journal of medicine Figure 1. Kidney-Biopsy Specimens Analyzed for the Detection of B7-1 with the Use of Two Secondary Antibodies. Shown are frozen sections of kidney obtained from patients with focal segmental glomerulosclerosis (FSGS) (left column), membranous nephropathy (MN) (middle column), or the uninvolved portion of kidney collected from a tumor nephrectomy sample (CTR) (right column). Sections were incubated with goat antihuman B7-1 or medium alone (as indicated by a minus sign), followed by either donkey antigoat secondary antibody (Alexa Fluor 488, Invitrogen) (Panel A) or rabbit antigoat secondary antibody (Jackson ImmunoResearch) (Panel B). tions that were treated with secondary antibody alone had exactly the same staining (Fig. 1), which suggests that the authors finding (as seen in Fig. S9H in the Supplementary Appendix, available with the full text of the article by Yu et al.) is probably an artifact, at least in the sample of membranous nephropathy. This is not surprising, since in membranous nephropathy, reactivity 1262 n engl j med 370;13 nejm.org march 27, 2014

3 correspondence of the secondary antibody with the IgG deposited in glomeruli often leads to false positive results. A different appropriately human IgG-adsorbed secondary antibody gave us no signal in FSGS and mild or absent staining in membranous nephropathy (Fig. 1). Thus, with the use of the appropriate reagents, B7-1 does not appear to be induced in FSGS and membranous nephropathy, so the antiproteinuric action of abatacept, if confirmed, may not be the result of an effect on podocyte B7-1. Ariela Benigni, Ph.D. Elena Gagliardini, Ph.D. Giuseppe Remuzzi, M.D. Istituto di Ricerche Farmacologiche Mario Negri Bergamo, Italy giuseppe.remuzzi@marionegri.it No potential conflict of interest relevant to this letter was reported. 1. Yu C-C, Fornoni A, Weins A, et al. Abatacept in B7-1 positive proteinuric kidney disease. N Engl J Med 2013;369: DOI: /NEJMc To the Editor: Yu et al. suggest a new pathway for drug action in patients with primary and recurrent FSGS. The authors report successful responses to abatacept on the basis of in vitro findings that the expression of B7-1 in podocytes resulted in the deactivation of β1-integrin and subsequent cellular injury. 1 We would like to share data with respect to five patients with FSGS after transplantation who did not have a response to plasmapheresis and rituximab and who subsequently received B7-1 blockers. The patients did not have positive therapeutic responses, despite positive podocyte B7-1 expression in their respective kidney-biopsy specimens (Table 1, and Table S1 in the Supplementary Appendix). The responses to abatacept in patients with recurrent FSGS who also received concurrent plasmapheresis, rituximab, and other immunosuppressive agents will require additional confirmation in prospective trials to study the role of B7-1 in FSGS. Nada Alachkar, M.D. Naima Carter-Monroe, M.D. Johns Hopkins University School of Medicine Baltimore, MD nalachk1@jhmi.edu Jochen Reiser, M.D., Ph.D. Rush University Medical Center Chicago, IL Dr. Reiser reports holding pending or issued patents on novel kidney-protective therapies with the possibility of royalties. No other potential conflict of interest relevant to this letter was reported. 1. Reiser J, von Gersdorff G, Loos M, et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 2004;113: DOI: /NEJMc The authors reply: We agree with Benigni and colleagues that donkey-derived secondary antibodies can react nonspecifically with human IgG, thereby masking specific B7-1 staining in immune complex mediated glomerulopathies. This problem can be avoided by using preabsorbed rabbit secondary antibodies (Fig. 1A). Using human tonsil B lymphocytes as a positive control and a nephrectomy specimen as a negative control, we confirmed specific podocyte B7-1 staining in a new series of native renal-biopsy specimens, including staining in specimens obtained from two of five patients with primary FSGS, from two of five patients with minimal change disease, and from two of four patients with membranous nephropathy (Fig. 1B). Benigni and colleagues report two patients with B7-1 negative recurrent FSGS but no positive control; since only a subgroup of patients with proteinuric kidney diseases are B7-1 positive, this is not unexpected, but care must be taken in the interpretation of negative B7-1 staining in the absence of positive controls. The key characteristics of all the patients presented by Alachkar and colleagues suggest that the correspondents have been misled in their conclusions by the comparisons they chose. In the absence of controls, B7-1 staining, as shown in their patients, is not a meaningful diagnostic procedure. Patients 1, 2, and 3 have results that are inconsistent with recurrent or newly diagnosed primary FSGS in the allograft but rather support a secondary cause, a situation in which we reported little to no relevance for B7-1. In Patient 1, the underlying native kidney disease is unknown. Specific B7-1 staining above background fluorescence is absent. Therefore, judgment regarding treatment outcomes with abatacept is not meaningful. In Patient 2, underlying native kidney disease is lupus nephritis, not FSGS, so comparisons with our results are not meaningful. In Patients 2 and 3, proteinuria at the time of diagnosis is well below the ne- n engl j med 370;13 nejm.org march 27,

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5 correspondence phrotic range, which is very different from the status of our patients. In contrast to our approach, all their patients were treated either many weeks or many months after the onset of proteinuria, which precludes comparisons with our results. n engl j med 370;13 nejm.org march 27,

6 The new england journal of medicine Figure 1 (previous page). Podocyte B7-1 Detection in Human Kidney-Biopsy Specimens. Panel A shows a comparison of kidney-biopsy specimens that have been stained for B7-1 with the use of donkey or rabbit secondary antibodies. All specimens were obtained from patients who were described in our study. Although no significant difference is detected in a B7-1 negative control case (acute tubular necrosis [ATN]), a sample of membranous nephropathy (MN) shows intense nonspecific background staining of IgG in coarse granular immune deposits with the donkey secondary antibody (at left), which masks the specific, granular B7-1 staining that is revealed with the rabbit secondary antibody (at right). Panel B shows representative images of a previously unpublished series of kidney-biopsy specimens that have been stained for B7-1 and rabbit secondary antibody (B7-1) or for rabbit secondary antibody alone (control). Human tonsil, serving as a positive control, shows specific membrane staining for B7-1 in lymphocytes, whereas the control sample shows background fluorescence. A tumor nephrectomy specimen (tumor Nx), which serves as a negative control, shows no specific B7-1 staining. A subset of biopsy specimens from patients with FSGS, minimal change disease (MCD), or MN show positive (+) granular B7-1 staining that follows the glomerular basement membranes, whereas other samples from patients with these diseases are negative ( ) for B7-1. The focal, coarse background staining probably represents nonspecific autofluorescence in erythrocytes. The most fundamental difference between the findings of Alachkar et al. and our experience with abatacept is that Patients 2 through 5 in their study received belatacept. The therapeutic protocols for belatacept are very different from those for abatacept. As compared with abatacept, belatacept has markedly enhanced affinity for B7-2 (also called CD86). 1 Since podocytes do not express B7-2, and abatacept favors the inhibition of B7-1, 1 the distinct differences between abatacept and belatacept informed our choice to use abatacept for the treatment of podocyte B7-1 positive proteinuric kidney disease. We agree that prospective trials are necessary to further evaluate abatacept therapy in patients with B7-1 positive proteinuric kidney disease, and indeed such efforts are under way. Anna Greka, M.D., Ph.D. Massachusetts General Hospital Boston, MA Astrid Weins, M.D., Ph.D. Brigham and Women s Hospital Boston, MA Peter Mundel, M.D. Massachusetts General Hospital Boston, MA mundel.peter@mgh.harvard.edu Since publication of their article, Drs. Greka and Mundel report anticipated fees from BMS for the planning of a clinical trial, and Dr. Weins reports participation in negotiations with BMS to initiate a clinical trial. No further potential conflict of interest relevant to this letter was reported. This letter was updated on December 22, 2014, at NEJM.org. 1. Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy 2011;31: DOI: /NEJMc Endotracheal Extubation To the Editor: It is well known that intravenous lidocaine can suppress coughing due to tracheal intubation. 1 But the statement in the Videos in Clinical Medicine review by Ortega et al. (Jan. 16 issue) 2 that local anesthetic agents in general can be used to treat coughing may lead to the false assumption that this is correct for all local anesthetic agents. The intravenous administration of local anesthetic agents other than lidocaine to prevent coughing may lead to life-threatening central nervous system and cardiac toxicity and should be definitely avoided. 3 Figure 1 of the Videos in Clinical Medicine review showed an oxygen mask, which allows a patient to breathe oxygen-enriched air but is not a device to provide mechanical ventilation. It would have been useful to reference modern video-based intubating devices 4 as a step in the management of the difficult airway before cricothyroidotomy. Alexander Avidan, M.D. Hadassah Hebrew University Medical Center Jerusalem, Israel alex@avidan.co.il No potential conflict of interest relevant to this letter was reported. 1. Yukioka H, Yoshimoto N, Nishimura K, Fujimori M. Intravenous lidocaine as a suppressant of coughing during tracheal intubation. Anesth Analg 1985;64: Ortega R, Connor C, Rodriguez G, Spencer C. Videos in clinical medicine: endotracheal extubation. N Engl J Med 2014; 370(3):e4. 3. Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity: 1266 n engl j med 370;13 nejm.org march 27, 2014