Protocol Renal Allograft Biopsies and the Design of Clinical Trials Aimed to Prevent or Treat Chronic Allograft Nephropathy1

Serón, Daniel; Moreso, Francesc; Ramón., José; Hueso, Miguel; Condom, Enric; Fulladosa, Xavier; Bover, Jordi; Gil-Vernet, S.; Castelao, Alberto Martínez; Alsina, J; Grinyó, Josep M.

doi:10.1097/00007890-200005150-00019

Cited by 101 publications

(64 citation statements)

References 26 publications

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“…Interstitial fibrosis and tubular atrophy that are detected as early as 3 to 6 mo posttransplantation in well-functioning transplants are correlates of later allograft dysfunction and loss (9,19,27,35,41). Similarly, increased chronic scores reported with the CADI system at 1 yr (40) or 2 yr (39) have been correlated with graft losses at 3 and 6 yr, respectively.…”

Section: Significance Of Interstitial Fibrosis and Tubular Atrophy Inmentioning

confidence: 95%

“…The detection of interstitial fibrosis and tubular atrophy remains a useful end point for clinical trials (42), and quantitative methods of interstitial fibrosis assessment likely will improve on its predictive value (32-34). Finally, secondary prevention trials that enter patients with interstitial fibrosis should markedly reduce the number of patients required to detect a change in the rate of graft loss (33,40,41).…”

Section: Significance Of Interstitial Fibrosis and Tubular Atrophy Inmentioning

confidence: 99%

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Protocol Transplant Biopsies

Rush¹

2006

Clinical Journal of the American Society of Nephrology

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Section: Significance Of Interstitial Fibrosis and Tubular Atrophy Inmentioning

confidence: 95%

Section: Significance Of Interstitial Fibrosis and Tubular Atrophy Inmentioning

confidence: 99%

Protocol Transplant Biopsies

Rush¹

2006

Clinical Journal of the American Society of Nephrology

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“…Evidence suggests that the first few months after transplantation are critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of chronic allograft damage that have yet to become clinically apparent. In particular, early protocol biopsies have shown that the presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival (16). Furthermore, serial protocol biopsies have shown that both interstitial and vascular chronic damage rapidly increase during the first 6 mo after transplantation, then slowly thereafter (17).…”

Section: Diagnosis Of Can By Protocol Biopsymentioning

confidence: 99%

“…Serón et al (16) estimated the minimum sample size of a clinical trial using the presence/absence of CAN in a protocol biopsy at 3 mo posttransplantation as the primary efficacy variable. Power calculations suggested that approximately 300 patients in each of the treatment and placebo groups would be necessary to detect a 50% reduction in the incidence of CAN at 3 mo.…”

Section: Use Of Protocol Biopsies In Clinical Trials Designed To Prevmentioning

confidence: 99%

Protocol Transplant Biopsies

Wilkinson

2006

Clinical Journal of the American Society of Nephrology

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Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment. Although the benefit of this approach has yet to be evaluated in large, multicenter, prospective trials, numerous studies suggest that implementation of protocol biopsies may improve long-term graft function. In particular, a number of reports suggest that detection of chronic allograft nephropathy in early protocol biopsies is predictive of subsequent graft function and loss and that early treatment may have a dramatic effect on the outcome of the graft. Protocol biopsies also have the potential to be of great value in high-risk patients, such as those with delayed graft function, by allowing for early intervention for acute rejection. Furthermore, the procedure seems to be relatively straightforward and safe. Nevertheless, paucity of data has meant that clear proof of a benefit of early treatment of subclinical rejection and chronic allograft nephropathy detected by protocol biopsy is lacking. Moreover, the optimal timing of protocol biopsies and reliable methods to quantify the histologic changes observed in biopsy specimens have yet to be determined. This review discusses the pros and cons of protocol biopsies and considers the place of this procedure in the routine treatment of kidney transplant patients.

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“…At the molecular level, no differences were found in the extent of protein deposition of TGF-␤ and interstitial collagens, as well as cortical mRNA levels of TGF-␤ and collagens ␣1(I) and ␣1(III) (20). The histologic features of CAN, although most often mild, may occur early after renal transplantation, with a reported prevalence up to 40% in surveillance biopsies performed as early as 3 mo after transplantation (21,22). Treatment of SAR in 1-, 2-, or 3-mo protocol biopsies support the clinical relevance of early detection and treatment of SAR (9).…”

mentioning

confidence: 99%

Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function

Scholten

Rowshani²,

Cremers³

et al. 2006

Journal of the American Society of Nephrology

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Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased-and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve-controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (r ‫؍‬ ؊0.26; P ‫؍‬ 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.

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Protocol Renal Allograft Biopsies and the Design of Clinical Trials Aimed to Prevent or Treat Chronic Allograft Nephropathy1

Abstract: Protocol biopsies may allow a reduction of sample size and especially the time of follow-up in a trial aimed to prevent CAN.

Cited by 101 publications

References 26 publications

Protocol Transplant Biopsies

Protocol Transplant Biopsies

Protocol Transplant Biopsies

Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function

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