The association between pre-transplant C-reactive protein and chronic allograft nephropathy in renal transplant recipients highlights the importance of atherogenesis in this disease

Jeffrey C. Fink MD, MS

Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore. USA

Jfink@medicine.umaryland.edu

Chronic allograft nephropathy (CAN), also known as chronic rejection, has been a major cause of allograft failure in renal transplant recipients ranking only second after death with a functioning allograft . Despite major improvements in short term allograft survival rates, CAN continues to limit transplant survival in a large portion of this population [1,2]. Several pathogenic factors, are likely to contribute to the development of CAN and these can be divided into alloantigen-dependent and alloantigen-independent processes[3].

The primary alloantigen-dependent event associated with CAN is acute rejection, which is a strong risk factor for development of CAN and accelerated allograft loss [4]. Several allogenic-independent factors have been invoked as important in the development of CAN such as chronic exposure to calcineurin inhibitors, diminished nephron dose at transplant, and preservation injury [3]. One factor that is likely to be important in the development of CAN is artherosclerosis, which is likely to contribute to the transplant vasculopathy of CAN [5,6].

In renal transplantation, accerelerated atherogenesis is considered to be an important risk factor for transplant vasculopathy for several reasons[7]. Many of the pathologic vascular characteristics of CAN are analogous to those seen in systemic vascular atherosclerotic lesions with macrophages and lymphocytes along with lipoprotein deposits[8,9]. The vasculopathy found in the CAN of renal transplant patients is strikingly similar to the coronary vascular lesions found in the chronic rejection of cardiac transplant patients [6,10]. Furthermore, hyperlipidemia appears to be a risk factor for development of CAN in renal transplant recipients [11,12].

Observational studies have demonstrated an association between inflammation, as reflected by elevations of CRP and sICAM-1, and subsequent development of clinically significant CVD in both the general population and patients with ESRD [13-17]. The interaction between inflammation and atherosclerosis hypothesized as the putative process leading to CVD in the general population may also induce the manifestations of ASCVD in the renal transplantation population, which includes CAN. ASCVD is likely to be an important factor in premature allograft loss in renal transplant patients both by contributing to the pathogenesis of CAN and leading to death from CVD. Therefore, it is quite possible that pre-transplant elevations of inflammatory markers are associated with CAN after renal transplantation.

To demonstrate this association between the inflammatory marker, CRP and CAN, a case-control study was conducted comparing pre-transplant CRP concentrations in transplant recipients with confirmed CAN to CRP levels in a stable control group [18]. The controls were renal transplant patients who received their allograft during the same period as the cases with stable renal function and no need for a transplant biopsy for allograft dysfunction. The results are shown in Fig 1.

The findings demonstrate that those transplant patients who went on to develop CAN had significantly higher pre-transplant CRP levels than those patients who remained stable after transplant. The higher pre-transplant CRP levels in the CAN versus stable patients was also demonstrated in the subgroup who did not experience acute rejection and those who received a living transplant. A similar trend was shown in the cadaveric transplant subgroup.

The association between CRP and CAN underscores the likelihood of a common pathogenesis between atherogenesis and CAN in renal transplantation. The results suggest that pre-transplant inflammatory markers can be used to stratify individuals into risk groups for CAN and would allow providers to customize immunosuppressive regimens to minimize the likelihood of this outcome. This association also emphasizes the critical importance of intervening on several modifiable cardiovascular risk factors such as smoking, hyperlipidemia, hypertension and glucose intolerance, which lead to the ASCVD in the transplant population.

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