To our knowledge, this is the first prospective study to evaluate the change in myocardial native T1 after renal transplantation. We demonstrated that native T1 significantly decreased 6 months after transplantation.
Use of non-immunosuppressive drugs
The inhibition of the renin-angiotensin-aldosterone system, induced by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), reduces myocardial fibrosis, regardless of its hypotensive action [
28]. In addition, the selective AT1 angiotensin II antagonist prevents myocyte hypertrophy and interstitial fibrosis [
29]. Most patients use ARBs or ACEIs during the dialysis period. In the early postoperative period after transplantation, however, these medications are frequently discontinued since they impair renal graft function, perpetuate anemia, and leads to hyperkalemia. In the present study, 6 months after transplantation, the use of ARBs/ACEIs decreased significantly; thus, the use of these medications was not the main factor to the improvement in native T1 after transplantation. Additionally there was no correlation between using ACEIs/ARBs and change in native T1 (data not shown).
Clinical and biochemical parameters
We found that at 6 months after renal transplantation, heart rate and systolic and diastolic blood pressures decreased significantly. This finding probably resulted from inactivation of the sympathetic system and the renin-angiotensin-aldosterone system after transplantation. Both systems, when activated, stimulate intracellular signaling pathways, with consequent increase in protein synthesis in myocytes and fibroblasts leading to cellular hypertrophy and fibrosis [
30]. Other effects are the activation of growth factors, activation of metalloproteinases, hemodynamic overload by vasoconstriction and water retention, increase in oxidative stress, and direct cytotoxic effect, leading to cell death due to necrosis or apoptosis [
31‐
33]. Blockade of these systems plays an important role in preventing or attenuating the developmental process for replacement fibrosis.
CMR
In the CMR evaluation, considering ventricular function, volume and mass, we did not find differences at 6 months, similar to Patel [
34] and Prasad et al. [
35]. Patel performed the first study to serially evaluate the LVs of patients who have undergone kidney transplantation using CMR. Prasad results showed a result deriving from an adjustment of LV parameters using a gender-specific method.
In contrast, improved CMR derived LV parameters have been demonstrated in children within 6 months after transplantation [
36], indicating that gender adjustment assumes particular importance in adults. The pediatric patients also had a short time on dialysis (median = 6 months), perhaps explaining lower abnormalities in cardiac structure and function. Additionally, different CMR technology, distinct reference populations and diverse study design might be the reason for this discrepancy.
In a different way from the ventricular function and mass, the native T1 was significantly reduced 6 months after renal transplantation. The native T1 time is a sensitive marker of myocardial fibrosis [
19,
37‐
39] and we associated the decrease of native T1 with the reduction of reactive fibrosis after renal transplantation. Reactive fibrosis is secondary to neurohumoral activation that was triggered by the cellular mediators angiotensin II, aldosterone and endothelin I, [
40‐
42] which stimulate the myofibroblasts to increase the production and deposition of collagen in the ECM. At this time, no cardiomyocyte necrosis is detected and the fibrosis can be discontinued. Thus, renal transplantation has the potential to inhibit this neurohumoral activation by improving volume overload and pressure control and thereby contribute to the regression of reactive fibrosis and prevent the progression to irreversible replacement fibrosis.
To date, no prior studies have evaluated native T1 in renal transplant recipients. Using 3 T CMR and measuring T1 times in the midventricular septum, Rutherford and Graham-Brown et al. found lower native T1 values in hemodialysis patients than the baseline values of the present study [
20,
38]. An explanation for these differences may be that in the present study the mean dialysis time was longer (38 months) than that in Rutherford and Grahan-Brown’s studies (5 and 21 months, respectively) [
20,
38]. There is still no standardization of native T1 values for the normal population that can differentiate between disease states and normality [
43,
44], although Weingärtner et al., using a protocol similar to that of the present study (MOLLI with 3 T CMR) in 20 healthy subjects, found a native T1 of 1183 ± 47 ms [
44]. We also observed that T1 values after 6 months of transplantation was not similar to normal healthy population. One explanation is that it would take a longer time to achieve values similar to those in a healthy population. Finally, it is likely that transplantation may not be able to fully reverse the myocardial fibrosis.
The discrepancies between ventricular mass/function and fibrosis in the present study are related to the specificity of the method. Thus, the studies that demonstrated a reduction of ventricular mass in post-transplant were performed using transthoracic echocardiography, which may be influenced by volume overload [
45]. Furthermore, echocardiography assumes an approximately cubic LV shape when calculating the LV mass index [
46]. On the other hand, the myocardial fibrosis in patients with advanced CKD [
4] is better accessed by CMR, using the native T1 measurement [
38,
39]. Thus, native T1 may be better correlated to morphological abnormalities in the myocardium of chronic renal patients [
11,
20].
In order to explore hidden patterns in the data, we performed a cluster analysis, and a group showed no improvement of native T1. The main finding of this group was the greater rate of diabetes. Previous studies have demonstrated that high glucose concentrations can lead to pathological changes in the myocardium, including the accumulation of ECM proteins. Mechanisms responsible for these alterations may include overproduction, decreased degradation, and / or chemical modifications of ECM proteins [
47]. Consequently, in diabetic patients the transplantation cannot interrupt these mechanisms that can explain the lack of decrease in native T1. In addition to diabetes, another characteristic of this cluster group is the greater baseline LV mass index. Patients with higher LV mass index also did not reach a decrease in T1 and myocardial fibrosis, possibly because these patients achieved such a striking change in cardiac structure that it became unlikely to be reversed.
Study limitations
Although native T1 time has demonstrated a positive correlation with biopsy-proven fibrosis in diseases with pressure overload [
21], we could not perform histological confirmation in this study. Thus, in the absence of confirmatory biopsy, a direct inference between native T1 and myocardial fibrosis is not allowed. Another limitation was the baseline CMR at the time of transplantation. Although performing the pre-transplant CMR would be more appropriate, this is not possible with deceased donors due to long waiting list times. Then, we performed the first CMR as close to the transplant surgery as possible. Native T1 is more stable than blood T1 for variations in hematocrit and heart rate [
48]. Furthermore, we conduced additional analyzes controlled for these factors and the results of native T1 were not affected by these confounders (Additional file
5). Although of sensitivity analysis, the decrease of hematocrit in the postoperative period may interfere with the analysis of native T1 resulting in lower T1 values. Additional studies with longer observation time are needed to evaluate the sequential changes of native T1 and parameters of left ventricular mass and function. However, this work is the first to evaluate the myocardium of renal transplant patients using native T1 time. The images were performed in the same apparatus, with the same magnetic field (3 T), and all the patients underwent the same imaging protocol and analyzed by a single blinded observer.
In conclusion, myocardial native T1 decreased significantly 6 months after renal transplantation. Patients that do not achieve a significant decrease in native T1 include those with diabetes and those with highest baseline LV mass index. The measurement of native T1 time by CMR may be considered an appropriate complementary method to evaluate myocardial fibrosis in renal transplant patients without using contrast.