Cardiovascular Disease in Kidney Transplant Recipients

Leave No Stone Unturned

Steven Van Laecke; Daniel Abramowicz


Nephrol Dial Transplant. 2019;34(5):727-730. 

In This Article

Immunity and Cardiovascular Disease: Myth or Reality in KTRs

An underemphasized element in the pathophysiology of CVD in KTRs is the role of immunity.[16] This knowledge gap translates into its absence in most review articles about CVD in KTRs. Nevertheless, the role of inflammation in coronary artery disease has been recognized for quite some time. In the general population, a meta-analysis of prospective observational studies demonstrated an incremental risk of coronary artery disease with increasing concentrations of pro-inflammatory cytokines independent of classical risk factors.[17] Also in KTRs, genotypes associated with increased tumour necrosis factor-α (TNF-α) production were associated with a greater risk of CVD.[18] This concept has gained new attention after the publication of the Canakinumab Antiinflammatory Thrombosis Outcome Study, which demonstrated a cardioprotective effect of a monoclonal interleukin-1 (IL-1) inhibitor with canakinumab versus placebo in patients with previous myocardial infarction and high-sensitivity C-reactive protein (hs-CRP) concentrations >2 mg/L.[19] In a recently published post hoc analysis among subjects with CKD, the findings remained robust and were most pronounced in subjects with a better response to anti-inflammatory treatment.[20] A meta-analysis of observational studies in study populations with no confounding comorbidities, such as kidney dysfunction, demonstrated that immunosuppressive drugs such as methotrexate are associated with fewer cardiovascular events.[21] Both interventional and observational data demonstrated that TNF-α blockade decreases cardiovascular morbidity in patients with rheumatoid arthritis or psoriasis.[22,23] However, the recent Cardiovascular Inflammation Reduction Trial in patients with stable atherosclerosis and type 2 diabetes or metabolic syndrome did not demonstrate a beneficial effect of low-dose methotrexate versus placebo on cardiovascular events nor on concentrations of IL-1β, IL-6 or hs-CRP.[24] However, exposed patients had very low hs-CRP concentrations, suggesting that a persistent pro-inflammatory response is a prerequisite to observe beneficial effects from cytokine-targeted treatment. The pipeline certainly is not empty here. Ongoing trials in the general population aim at demonstrating a potential beneficial role of colchicine, a microtubule inhibitor with some NACHT, LRR and pyrin domains-containing protein 3 (NLRP3)-inhibiting effects, in atherosclerotic vascular disease. This should not surprise us completely, as it was already alleged in the writings of Arab physicians back in the 11th century.[25]

Apart from some interventional studies evaluating different immunosuppressive regimens with regard to surrogate cardiovascular outcomes, such as left ventricular hypertrophy or vascular stiffness, the individual effects of separate drugs on the cardiovascular status of KTRs remain largely elusive. Immunosuppressive drugs such as tacrolimus decrease the production of the potentially atherogenic pro-inflammatory cytokines IL-1β and TNF-α from monocytes, T lymphocytes and/or peripheral blood mononuclear cells.[26] However, these theoretically beneficial effects could be entirely offset by negative effects on classical metabolic risk factors, including dyslipidaemia and PTDM. Along this line, the beneficial role of statins in KTRs could be interpreted not only by their lipid-lowering properties, but also in light of their well-recognized anti-inflammatory effects. This paradigm shift could alter our approach of KTRs with the rather common 'apparent treatment-resistant hypertension' (ATRH).[27] In a subanalysis of the Chronic Renal Insufficiency Cohort, increased concentrations of pro-inflammatory cytokines IL-6 and TNF-α were independently associated with the development of ATRH.[28] Provided these cytokines, which activate endothelial cells, are not solely the markers but also play a causal role in ATRH, it is tempting to hypothesize that immunosuppressive drugs may have opposing effects on blood pressure control in KTRs. In numerous animal models, anti-inflammatory treatment decreases blood pressure.[29] Moreover, in humans with psoriasis and rheumatoid arthritis, mycophenolate mofetil decreased blood pressure in parallel with a decrease in urinary TNF-α concentration.[30] Other immunosuppressive drugs such as corticosteroids and calcineurin inhibitors definitely contribute to the development or persistence of hypertension due to intrinsic effects on salt handling and vascular tone.

Anyway, atherosclerotic inflammation is not a single-pathway issue. Recent data have indicated a role of cholesterol crystals and western diet in activating the NLRP3 inflammasome, with involvement of both innate and adaptive immunity.[31] IL-1β seems to be the key messenger generated by NLRP3 following its activation.[31] An emerging role for anti-atherogenic regulatory T cells has also been proposed following many experimental and clinical studies that suggest the potential of cellular therapy as a treatment modality to combat CVD.[32] Of note, the exploration of regulatory T cells in KTRs is still confined to the exploration of protolerogenic effects.

Of particular interest for KTRs is the robust dose-dependent association between human leucocyte antigen (HLA) sensitization and major adverse cardiac events as well as cardiovascular mortality.[33,34] We also observed an independent association between the presence of HLA class II antibodies at the time of kidney transplantation and the future development of CVD and mortality (Van Laecke et al. unpublished observation). We can speculate that their presence is a marker of a pro-inflammatory phenotype with altered lymphocytic distribution and overexpression of interferon-γ, which has a proven role in destabilization of vulnerable atherosclerosis plaques.

Also, the role of cytomegalovirus (CMV) in the pathophysiology of CVD merits further investigation. CMV induces immunological alterations, including cellular senescence of T lymphocytes, and contributes to ongoing low-grade inflammation and endothelial dysfunction, which can explain the higher incidence of cardiovascular events in KTRs with post-transplant CMV replication.[16] Furthermore, CMV prophylaxis decreases the incidence of cardiovascular death in KTRs.[35] Possibly the incorporation of new markers will improve risk stratification of KTRs and result in therapeutic applications (for instance, CMV vaccination) and well-targeted anti-inflammatory treatment that could decrease CVD and mortality.