Serum Amyloid A Protein: Not a Relevant Marker for Recognition of Cardiac Allograft Rejection (2004)

Acute rejection is one of the most common causes of death after heart transplantation. To diagnose acute rejection, endomyocardial biopsy (EMB) is still recommended in spite of the risk of complications. Finding a noninvasive method to reduce EMB is a challenge. Serum amyloid A (SAA) protein is synthesized in response to cytokines released by activated monocytes and macrophages. Some authors suggest that elevation of SAA may correlate with acute renal, liver, and cardiac allograft rejection (1–3), but these studies included few patients and biopsies. These findings prompted us to assess the value of SAA as a noninvasive marker of acute rejection in a large cohort of cardiac transplant patients. A prospective study of 219 consecutive EMBs in 33 cardiac transplant patients was conducted. To decrease the impact of surgical trauma on SAA concentration, we measured SAA in peripheral blood after the 10th postoperative day in a longitudinal study over the first 6 postoperative months. SAA samples were obtained before each biopsy, performed weekly until the 3rd month, then monthly. SAA was quantified by immunonephelometry. If the biopsy was greater or equal to grade 2, according to the ISHLT classification (4), anti-rejection treatment was initiated (methylprednisolone for 3 consecutive days). Significant acute rejection was detected in 26 of the 219 EMBs. Viral, bacterial and fungal infections were diagnosed on the basis of positive blood culture or serological tests. Direct antigen detection was used to screen for cytomegalovirus infection on the day of biopsy. Of 219 EMBs, 65 were done during periods of infection. SAA level correlated well with time after transplantation (Pearson’s r = 0.28; P= 0.00), with a progressive decrease between the 10th and 180th postoperative days. Mean SAA concentration did not differ significantly between rejection and no rejection (80.2 ± 148 mg/l vs. 95.0 ± 160 mg/l; P= 0.637). In contrast, mean SAA levels were significantly higher during infection than in its absence (133.9 ± 197 mg/l vs. 60.0 ± 118 mg/l; P= 0.001). We repeated the analysis according to the type of infection (bacterial or viral). SAA seemed more linked to bacterial infection than to viral infection. During 41 periods of bacterial infection, SAA levels were significantly higher than in the absence of infection (175.5 ± 232 mg/l vs. 61.0 ± 114 mg/l; P= 0.000). During 21 periods of viral infection, there was no significant difference in SAA between infection and its absence (102.1 ± 136 mg/l vs. 79.8 ± 151 mg/l; P= 0.517). To eliminate the confounding effects of infection, the same analysis was repeated after excluding simultaneous acute rejection and infection (n = 10). The remaining 209 serum samples were divided into 3 groups: Group 0: stable condition (no rejection, no infection) Group 1: acute rejection (greater or equal to grade 2 without infection) Group 2: infection without acute rejection The results were unchanged, with significantly higher SAA levels in group 2 (Figure 1).FIGURE 1.: Mean values of serum amyloid A (SAA) in three different situations after excluding simultaneous acute rejection and infection. SAA levels were significantly elevated during periods of infection without rejection. Means were compared using one-way ANOVA followed by Tukey’s multiple comparison.Overall, we found SAA to be an inadequate predictor of acute rejection in cardiac allograft. Emmanuelle Vermes Matthias Kirsch Titi Farrokhi Daniel Loisance Department of Cardiac Surgery Henri Mondor Hospital Créteil, France Pascale Fanen Régine Zimmermann Department of Biochemistry Henri Mondor Hospital Créteil, France