Cytomegalovirus‐Induced Arterial Intimal Fibrosis in the Kidney Transplant

Arteriosclerosis is defined by thickening or hardening of the arterial walls. In kidneys, arteriosclerosis is characterized by fibrosis and hyperplasia of the intimal layer of the arterial wall. Arterial intimal fibrosis of newonset is a pattern associated with antibody-mediated rejection (ABMR) and the presence of donor-specific antibodies (DSAs), as noted in the most recent Banff Classification of allograft pathology [1, 2]. In heart transplant recipients, arteriosclerosis in the form of coronary artery atherosclerosis has been attributed to cytomegalovirus (CMV) infections [3-5]. The link between CMV and arteriosclerosis in kidney transplant recipients remains poorly described. A 56-year-old male with kidney failure received his second kidney transplant in 2024. The cause of his kidney failure was unknown as he never underwent biopsy of his native kidneys and had unremarkable glomerulonephritis serology before initiating hemodialysis. His first kidney transplant came from a livingrelated donor and failed after 21 years due to presumed allograft nephropathy. Both his first and second kidney transplants were performed with the goal of improving his long-term survival and quality of life (as compared to staying on dialysis). His second kidney transplant came from a 50-year-old deceased donor (neurologically determined death), had a preoperative cold ischemia time of 24 hours, and was HLA- and ABO-compatible with the recipient. The recipient was CMV IgG-negative and the donor was CMV IgG-positive. He received 4.2 mg/kg of antithymocyte globulin for induction and was treated with tacrolimus, mycophenolate mofetil, and prednisone. An implantation biopsy (Biopsy 1) was unremarkable, with no significant inflammation and minimal glomerular and parenchymal scarring (Figure 1). He was maintained on valganciclovir 450 mg twice weekly (900 mg daily dose adjusted for Cockcroft-Gault calculated creatinine clearance of 9 mL/min) for CMV prophylaxis. A kidney biopsy performed approximately four months post-transplant for graft dysfunction (Biopsy 2, Figure 1) showed multiple arteries with severe, circumferential intimal fibrosis, without evidence of intimal arteritis, thrombosis, or vessel wall necrosis. There were minimal-mild chronic changes (6/31 or 19% globally sclerotic glomeruli, less than 10% interstitial fibrosis and tubular atrophy) without microvascular inflammation, tubulitis, interstitial inflammation, or C4d staining to suggest acute rejection (Figure 1). Cell-free DNA testing was not performed. This initially raised concern for antibody-medicated rejection; however, there were no other features to support this diagnosis. Further history revealed that the patient had been experiencing acute watery diarrhea, prompting testing for serum CMV viral load, which was 54,026 IU/mL. Of note, the patient was not being serially evaluated for CMV viremia before this diagnosis (which is standard practice in our program for patients being treated with CMV prophylaxis). Further, prior to developing the CMV infection, the prophylactic dose of valganciclovir was not modified for his increasing renal allograft function, suggesting that underdosing of the valganciclovir may have allowed for breakthrough infection. Drug resistance testing was not performed. There was no evidence of bone marrow suppression, hepatitis, pneumonitis, or retinitis from the CMV infection. Further review of systems did not reveal uncontrolled hypertension, supratherapeutic tacrolimus trough levels, thrombotic microangiopathy, or de novo autoimmune disease as a cause of the allograft vasculopathy [6, 7]. Given the known association of CMV with vasculopathy in cardiac allografts [3-5], we considered CMV infection as a potential unifying diagnosis. Thus, the biopsy was re-examined using CMV immunohistochemical staining and deeper levels were assessed; this revealed rare but definitive positive nuclear staining for CMV immunohistochemistry. Rare endothelial cell intranuclear inclusions were detected on deeper levels, consistent with CMV infection (Figure 2). The patient was subsequently treated with a dose reduction of mycophenolate mofetil and an increase of valganciclovir dose from prophylaxis (900 mg daily dose adjusted for creatinine clearance of 28 mL/min, or 450 mg every other day) to treatment (450 mg daily). After 2.5 months of CMV treatment, the CMV viral load was undetectable and the patient had seroconverted. A repeat transplant kidney biopsy performed 3 months after CMV treatment (Biopsy 3) showed persistent severe arterial intimal fibrosis, without evidence of CMV infection (Figure 1). To the best of our knowledge, this report is the first to show temporal progression in the histology with the course of CMV infection by including the results of an implantation biopsy, indication biopsy, and biopsy following CMV treatment. Two previous reports have linked arteriosclerosis with CMV in the renal allograft and both involved protocol biopsies rather than indication biopsies, and did not show temporal changes with treatment like in our report [8, 9]. CMV infection of the tubules, vessels, and other renal tissue may result in the development of arterial intimal fibrosis [10]. CMV infection may also lead to systemic inflammation that ultimately induces arteriosclerosis. Among renal transplant recipients, CMV infections have been associated with atherosclerotic events and transplant renal artery stenosis [10]. The pathogenesis of CMV vasculopathy is thought to be related to CMV-mediated pro-inflammatory pathways and consequential endothelial damage [10]. CMV-induced intimal fibrosis of new-onset in the renal allograft is similar to — but distinct from — CMV-related cardiac allograft arteriosclerosis, which typically involves atherosclerosis [3-5]. Our case underscores the importance of effective communication between nephrologists, infectious disease physicians, and pathologists. Without suspicion of CMV from the clinicians, the vascular changes in this case may have been misattributed to ABMR by the pathologist. Specifically, this pattern of intimal fibrosis of new-onset should trigger a discussion between clinicians and pathologists about infectious triggers (such as CMV). The index of suspicion for CMV infection should be high for pathologists, as these findings can be very subtle and potentially missed without cues from the clinical team. The authors have nothing to report. No ethical approval was required for this report. Formal consent was obtained from the patient to share his de-identified data for this case report. The authors declare no conflicts of interest. The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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