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Investigational methods in the diagnosis of acute renal allograft rejection

W James Chon, MD, FACP
Daniel C Brennan, MD, FACP
Section Editor
Barbara Murphy, MB, BAO, BCh, FRCPI
Deputy Editor
Alice M Sheridan, MD


The introduction of potent immunosuppressive drugs in the past three decades has led to a dramatic reduction in the incidence of acute rejection in kidney transplant recipients. At the present time, renal allograft biopsy with conventional histologic evaluation remains the gold standard for diagnosing acute rejection among patients with a deterioration in kidney function, as detected by measuring serum creatinine levels. However, the lack of additional markers of rejection makes it difficult to optimize anti-rejection therapy for transplant recipients.

The evaluation of methods other than conventional renal biopsy and/or measurement of the serum creatinine to help diagnosis acute kidney rejection has been the focus of a large number of investigators. This topic review will discuss some of the methods undergoing investigation for the diagnosis of acute rejection. The clinical diagnosis of rejection is discussed separately. (See "Clinical manifestations and diagnosis of acute renal allograft rejection".)


Measuring the levels of urinary or circulating proteins and cytokines, circulating soluble interleukin-2 (IL-2) receptor, the urinary concentration of soluble adhesion molecules, or cellular activation with urinary flow cytometry may be helpful in diagnosing acute allograft rejection [1-9]. As examples:

A study of 367 unique human peripheral blood samples and their matched renal allograft biopsy specimens (including 115 from patients with acute rejection, 180 stable patients, and 72 with other causes of graft injury) showed that quantitative polymerase chain reaction (PCR) analysis of a five-gene set (genes involved in T/B-cell activation and leukocyte trafficking: DUSP1, PBEF1, PSEN1, MAPK9, and NKTR) was able to discriminate acute rejection from all other non-acute rejection phenotypes with 91 percent sensitivity and 90 percent specificity [10].

Urinary expression of a three-gene signature that included CD3ε mRNA, interferon-inducible protein 10 (IP-10) and 18S rRNA discriminated acute rejection from no rejection among transplant recipients in a multicenter study [11]. Forty three urine samples were compared with matched biopsies (38 indication and 5 surveillance from 34 patients) that showed acute rejection. One-hundred sixty-three urine samples were compared with 163 biopsies (107 indication and 56 surveillance) that did not show rejection and with 1501 urinary samples from 201 patients who did not undergo biopsy.

Urinary concentrations of mRNA for CD3ε, perforin, granzyme B, IP-10, and 18s RNA were higher in patients with acute rejection compared with those without rejection. Receiving operator characteristic (ROC) analysis of a selected parsimonious three-gene model including CD3ε mRNA, IP-10, and 18S rRNA demonstrated an area under the curve (AUC) of 0.85 (95% CI 0.78-0.91), which had a sensitivity and specificity of 79 and 78 percent, respectively.

In an external validation set derived from 24 separate biopsy samples that showed acute rejection and 47 biopsy samples randomly selected from transplant recipients enrolled in a separate clinical trial, ROC analysis yielded an AUC of 0.74 (95% CI 0.61-0.86), which was not different from the AUC used to construct the original model. In the validation set, the three-gene signature had a sensitivity and specificity of 71 and 72 percent, respectively.

This molecular signature could also distinguish between acute cellular and antibody-mediated rejection and could identify patients who had received IL-2 receptor antibodies versus those who had received T-cell depleting antibodies for induction.

The three-gene signature profile, however, was also elevated in urine samples from patients with BK virus infection [12].


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Literature review current through: Sep 2016. | This topic last updated: Mar 4, 2014.
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