Biopsies the “Imperfect Gold Standard” for Diagnosing Post-Transplant Rejection

By Karen Blum

WASHINGTON, DC -- Biopsies remain the gold standard for diagnosing post-transplant kidney disease but they are imperfect, a speaker said here during Kidney Week 2019. Emerging biomarkers may provide a complement to helping nephrologists diagnose and manage disease. The session entitled, "Needle Phobia: Kidney Transplant Biopsy Alternatives", included four speakers on the topic.

“Histology is required for a lot of diagnoses to provide prognostic information, so it is our gold standard because it’s what we have now to know what to do for management,” said Mei Lin Bissonnette, MD, PhD, FRCPC, director of the British Columbia Provincial Renal Pathology Laboratory and a clinical assistant professor at the University of British Columbia, in Vancouver.

Biopsies work well in providing essential information about whether the patient is suffering from T-cell mediated rejection or antibody-mediated rejection, diagnostic information about what type of infection may be occurring, and presence of disease recurrence or de novo disease, Bissonnette said. But they have some limitations. There can be many different etiologies that have similar or overlapping histologies, and biopsies are subject to sample variability since the volume taken for study is small compared to the overall graft size. Biopsies require specialized expertise to perform and interpret them. They also are invasive, with not every patient being a good candidate and pediatric patients requiring sedation to undergo the procedure.

Nephrologists do not look at biopsies in isolation, considering factors like serum creatinine and donor-specific antibodies, said Bissonnette. Emerging biomarkers measured in blood and urine that could help with management of kidney disease fall in several categories: diagnostic markers to help identify patients with disease; susceptibility/risk markers to predict which patients could develop disease; monitoring markers that measure the status or extent of disease; prognostic markers to indicate the likelihood of disease recurrence or progression, and predictive markers to specify which patients would be  most likely to respond to an intervention.

There’s a lot of value with adding newly developed biomarkers into practice, said Bissonnette, particularly as minimally invasive screening tests to replace protocol biopsies: “Blood and urine are much easier to obtain than tissue, and it can really be used to divide patients into low-risk and high-risk groups.” Biomarkers also can be helpful to refine diagnoses and to aid in definitions and reproducibility. However, she noted, more widespread adoption will require large validation studies, and there is a need to determine when and how frequently to run biomarkers, and when to treat once results are obtained.

Cell-free DNA (Cf-DNA), fragments of genomic DNA in body fluids that originate from cell death and injury, can be used as one noninvasive measure of organ transplant rejection, said Roy D. Bloom, MD, medical director of the kidney/pancreas transplant program at the Hospital of the University of Pennsylvania, in Philadelphia. A 2011 study1 found that Cf-DNA may provide a signal prior to biopsy and that it could decline after treating rejection. A 2017 study of Cf-DNA done by Bloom and colleagues2 found that the marker could discriminate active rejection from no-active rejection and it performed especially well in assessing antibody-mediated rejection.

Many knowledge gaps remain concerning the use of this test, he added, including the ideal testing frequency, how to combine it with other biomarkers and defining meaningful changes.

Additional talks during the session covered urinary chemokines and molecular biomarkers in the peripheral blood.
 


Resources

  1. Snyder TM, Khush KK, Valantine HA, Quake SA. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6229-34. doi: 10.1073/pnas.1013924108. Epub 2011 Mar 28.
  2. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-Free DNA and Active Rejection in Kidney Allografts. J Am Soc Nephrol. 2017 Jul;28(7):2221-2232. doi: 10.1681/ASN.2016091034. Epub 2017 Mar 9.
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WASHINGTON, DC -- Biopsies remain the gold standard for diagnosing post-transplant kidney disease but they are imperfect, a speaker said here during Kidney Week 2019. Emerging biomarkers may provide a complement to helping nephrologists diagnose and manage disease. The session entitled, "Needle Phobia: Kidney Transplant Biopsy Alternatives", included four speakers on the topic.

“Histology is required for a lot of diagnoses to provide prognostic information, so it is our gold standard because it’s what we have now to know what to do for management,” said Mei Lin Bissonnette, MD, PhD, FRCPC, director of the British Columbia Provincial Renal Pathology Laboratory and a clinical assistant professor at the University of British Columbia, in Vancouver.

Biopsies work well in providing essential information about whether the patient is suffering from T-cell mediated rejection or antibody-mediated rejection, diagnostic information about what type of infection may be occurring, and presence of disease recurrence or de novo disease, Bissonnette said. But they have some limitations. There can be many different etiologies that have similar or overlapping histologies, and biopsies are subject to sample variability since the volume taken for study is small compared to the overall graft size. Biopsies require specialized expertise to perform and interpret them. They also are invasive, with not every patient being a good candidate and pediatric patients requiring sedation to undergo the procedure.

Nephrologists do not look at biopsies in isolation, considering factors like serum creatinine and donor-specific antibodies, said Bissonnette. Emerging biomarkers measured in blood and urine that could help with management of kidney disease fall in several categories: diagnostic markers to help identify patients with disease; susceptibility/risk markers to predict which patients could develop disease; monitoring markers that measure the status or extent of disease; prognostic markers to indicate the likelihood of disease recurrence or progression, and predictive markers to specify which patients would be  most likely to respond to an intervention.

There’s a lot of value with adding newly developed biomarkers into practice, said Bissonnette, particularly as minimally invasive screening tests to replace protocol biopsies: “Blood and urine are much easier to obtain than tissue, and it can really be used to divide patients into low-risk and high-risk groups.” Biomarkers also can be helpful to refine diagnoses and to aid in definitions and reproducibility. However, she noted, more widespread adoption will require large validation studies, and there is a need to determine when and how frequently to run biomarkers, and when to treat once results are obtained.

Cell-free DNA (Cf-DNA), fragments of genomic DNA in body fluids that originate from cell death and injury, can be used as one noninvasive measure of organ transplant rejection, said Roy D. Bloom, MD, medical director of the kidney/pancreas transplant program at the Hospital of the University of Pennsylvania, in Philadelphia. A 2011 study1 found that Cf-DNA may provide a signal prior to biopsy and that it could decline after treating rejection. A 2017 study of Cf-DNA done by Bloom and colleagues2 found that the marker could discriminate active rejection from no-active rejection and it performed especially well in assessing antibody-mediated rejection.

Many knowledge gaps remain concerning the use of this test, he added, including the ideal testing frequency, how to combine it with other biomarkers and defining meaningful changes.

Additional talks during the session covered urinary chemokines and molecular biomarkers in the peripheral blood.
 


Resources

  1. Snyder TM, Khush KK, Valantine HA, Quake SA. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6229-34. doi: 10.1073/pnas.1013924108. Epub 2011 Mar 28.
  2. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-Free DNA and Active Rejection in Kidney Allografts. J Am Soc Nephrol. 2017 Jul;28(7):2221-2232. doi: 10.1681/ASN.2016091034. Epub 2017 Mar 9.
Date:
Thursday, November 7, 2019