Recent studies show that elevated Creatinine levels are a late indicator of damage done to a graft. In fact, subclinical acute rejection (silent rejection) is prevalent in 25% of patients histology and characterized as borderline in 80% of these cases1. Until recently, studies have ignored the prevalence of borderline rejection in protocol biopsies that could be a leading cause for renal failure. 

What is "silent" Subclinical Acute rejection?

Subclinical Acute Rejection, also referred to as "silent" rejection or "inflammation", is when a patient has a stable serum creatinine (within normal range for the patient) but without renal deterioration. It is further classified as:

  • Mononuclear cell infiltration of renal tubules without renal dysfunction
  • All types of rejection/grades (including borderline)

What is Clinical Acute Rejection?

Clinical Acute Rejection is the consequence of an immune response to the graft once significant damage has occurred. Some signs and symptoms of Clinical Acute Rejection are elevated serum creatinine, decreased urine output, proteinuria.

Some causes of acute kidney injury are:

  • Allograft rejection
  • Drug induced injury (tacrolimus)
  • Dehydration
  • Blood loss or decreased flow
  • Infection (UTI, sepsis)
  • Recurrent renal disease (FSGS)

Subclinical acute rejection is not easily detected and is caused by mononuclear cell infiltration of renal tubules without renal dysfunction. While clinical acute rejection is detected once enough damage to the kidney has occurred. Timely detection of subclinical acute rejection and intervention can lead to better long-term graft outcome.

Other than risky biopsies, TruGraf is the only alternative to rule out "silent" rejection in stable kidney patients.

 

* Am J Transplant 2010; 10(9): 2066–73; Am J Transplant 2010; 10: 324–330

DeKAF Study*: Impact of Inflammation

IATR associated with death censored graft failure
figure 2
figure 1
Patients with biopsy for new onset late graft dysfunction
  • n=337, time from transplant to biopsy: 7.1±5.9 years
  • High frequency of inflammation (iatr) in areas of fibrosis/atrophy (69%)

The Right Test for Your Protocol

No protocol is a one-size-fits-all and monitoring assays are no exception. That's why understanding what test is right for your patient is crucial. Below is a comparison of TruGraf vs dd-cfDNA and their utility.

What is TruGraf?

TruGraf® is a non-invasive blood test validated to rule out "silent" subclinical acute rejection in stable kidney transplant recipients.

  • Measures state of the immune system: immune quiescence vs. inflammation (rejection)
  • Kidney transplant patients with STABLE renal function
  • Rule out subclinical rejection in setting of stable renal function (high NPV test)
  • RNA microarray technology
  • Pattern of gene expression levels observed is compared to GEP of reference population using complex algorithm

What is dd-cfDNA?

Donor-derived cell-free DNA (dd-cfDNA) is an non-invasive assay that monitors clinical acute rejection in transplant recipients.

  • Measures allograft cell injury (not specific to rejection)
  • Kidney transplant patients with clinical kidney allograft injury and suspected rejection
  • Rule out acute rejection in setting of acute renal dysfunction (high NPV test)
  • DNA sequencing test to identify, quantify, and measure dd-cfDNA as a fraction of all cfDNA utilizing SNPs

Downstream Impact of Subclinical Rejection

normal kidney-01

Normal Kidney Biopsy

borderline t cell-01

Borderline T Cell Mediated Rejection

ia_tcell_mediated-01

Banff IA Acute T Cell Mediated Rejection

aute ib_rejection-01

Banff IB Acute T Cell Mediated Rejection

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What Clinicians Are Asking

Can dd-cfDNA rule out "silent" rejection in stable patients?

dd-cfDNA assays do not rule out silent rejection in patients with stable renal function.

Study: J Am Soc Nephrol 20; 28: 2221–2232

  • Active rejection defined as TCMR Banff IB or greater or acute/chronic AMR
  • Median dd-cfDNA value for Banff 1A was same (0.2%) as no rejection group (0.3%)
  • Subclinical acute rejection includes borderline (80%) and Banff 1A, which are almost all negative with dd-cfDNA
  • Patients with dd-cfDNA <1% can be ruled out for active rejection (> Banff 1A) (NPV 84%)
  • Bromberg et al (JALM 2017) reported that 96% of patients with stable renal function have dd-cfDNA <1%, when prevalence of subclinical rejection is ~25%
Can dd-cfDNA rule out patients with borderline rejection?

The use of dd-cfDNA may complement the Banff classification and risk stratify patients with borderline/TCMR 1A identified on biopsy

But it's only useful AFTER a biopsy, and not for surveillance.

Study: doi: 10.1111/AJT.15822

Can dd-cfDNA distinguish subclinical rejection?

Despite published data, dd-cfDNA can’t distinguish STA (stable) from BL (borderline), and 80% of subclinical rejection cases are BL.

The data provided either can’t be classified as “subclinical” by definition or there's a lack of data on renal function and therefore impossible to draw conclusions from the data set.

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