Inflammaging and Transplantation Is Important: Now What?

Advancing age, frailty, and sarcopenia are associated with an inflammatory phenotype, and individuals expressing proinflammation possess a lesser ability to withstand the stresses of surgical interventions, cancer, and vascular disease.1 In this issue of Transplantation, Lorenz et al2 from the Mayo Clinic report a linkage between the magnitude of the pretransplant (serum) inflammatory phenotype and an increasing likelihood of death with a functioning (DWF) graft after kidney transplantation (KT). Nine inflammatory biomarkers were measured from stored pretransplant serum samples of 1595 kidney recipients. Recipients demonstrating a greater inflammatory milieu were observed to have a higher incidence of DWF (predominantly due to neoplasia and infection). Growth/differentiation factor-15 (GDF-15, member of the transforming growth factor-β superfamily) was the biomarker with the greatest association, but interleukin-6 (IL-6) and monokine induced by gamma (MIG or chemokine ligand 9 [CXCL9]) were also significant. DWF was experienced by 21.2% of all kidney recipients during the observation period (mean 7.5 ± 3.9 y). Of those experiencing DWF, <5% occurred during the first posttransplant year, 27.5% within years 1 to 5, and 68% >5 y after transplantation. This report has a peculiar KT population; almost 90% of the KT recipients received live donated kidneys and most were White. The most frequently recognized reasons for DWF were those associated with immunosenescence, neoplasia, and infection. "Unknown" was the most prevalent reason, and almost 90% of them occurred >5 y after KT. Patients within the upper quartiles of GDF-15, IL-6, and MIG/CXCL9 had a 10-y risk of DWF approaching 50%. However, these biomarkers and the stimuli are also likely diverse, and identifying a single causative predisposition would be difficult. GDF-15 is part of the transforming growth factor-β superfamily response to tissue injury, IL-6 is a ubiquitous proinflammatory cytokine, and MIG/CXCL9 is a chemoattractant for a variety of immune cells. The transplant clinician should become familiar with an "inflammaging" approach to the stratification of kidney candidates. However, what actions should result from this information is much less clear. Will the increased risk of DWF ever exceed the transplant survival benefit provided by KT and make transplant an undesirable treatment? It is unlikely, but a differential in survival with and without a transplant needs to be addressed. With substantial mortality in living donor recipients, one must query whether recipients of deceased kidneys might do significantly worse. A more practical question is whether the risk associated with the pretransplant inflammatory state can be reduced with pretransplant therapy. In a separate report, the Mayo aging group (however, only Nathan LeBrasseur coauthored both articles) observed that gene expression of proinflammatory, senescence-associated secretory phenotype was decreased and older adult participants self-reported an increased sense of well-being and quality of life after undergoing a 12-wk structured exercise program.3 Is the proinflammatory state of end-stage renal disease susceptible to clinical and environmental modifications and will any pretransplant interventions alter the untoward posttransplant outcomes for at-risk kidney candidates? GDF-15 elevation is quickly and significantly reduced in ESRD patients after successful KT. Connelly et al4 found elevated GDF-15 in pretransplant and continuously dialyzed patients (4684 versus 5509 pg/mL, pretransplant versus dialysis, respectively). Within 3 mo of KT, GDF-15 reduction in those with a functioning KT was significant (1867 pg/mL) versus continued elevation (5630 pg/mL) in those with continued dialysis and remained such for a year. Although KT recipients had a slightly elevated GFD-15 compared with "normal" levels (<1200 pg/mL), KT was associated with a markedly lower GFD-15. Jehn et al5 also noted serum a GDP-15 reduction after successful KT and an inverse relationship between eGFR and GDF-15; those with lesser amounts of estimated glomerular filtration rate (eGFR) had higher GDF-15 levels. Additionally, those transplant recipients with >1000 pg/mL posttransplant tended to have an accelerated eGFR loss than those with GDF-15 <1000 pg/mL. One must query whether the recipients in the Mayo Report received a sufficient reduction to reduce circulating inflammatory mediators and possible adverse clinical effects. The increasing literature associating the inflammatory phenotype with adverse clinical outcomes should be incorporated into management strategies for KT recipients. However, exactly how "inflammaging" fits into either clinical risk/benefit assessment (informed consent) or therapeutic approaches to candidates and recipients remains uncertain (immunomodulation or post-KT surveillance) is unknown. This report provides yet another bit of support that "inflammaging" transplant candidates/recipients can identify people at risk. Elevated inflammatory biomarkers in kidney candidates portend a higher risk for undesired outcomes after transplantation (DWF). This article supports that candidates with upper quartile GDF-15, IL-6, and MIG/CXCL9 were predisposed to the immunosenescence-like complications of DWF from neoplasia and infection after becoming KT recipients. However, their DWF did not occur early after the transplant, rather almost 70% occurred >5 years after a successful KT when they should have had the benefit of prolonged GDF-15 reduction. The authors mention multiple proposed therapies to modify the inflammatory phenotype, but none of those were likely to be as effective in reducing the inflammatory profile as a functioning KT with sufficient (e)GFR. If GDF-15 elevations do have a causal relationship with DWF and persistent immunosenescence, one must ask whether these recipients received sufficient renal function to change the proinflammatory profile? If GDF-15 reduction was persistent until DWF occurred (suggested by stable renal function) or whether eGFR deteriorated post-KT and the proinflammatory profile returned over time, it implies different mechanisms of immunosenescence. Of course, it is feasible that the pretransplant proinflammatory state may be an epiphenomenon of an associated but different process that predisposes to DWF. The observation that high GDF-15, IL-6, and MIG/CXCL9 identify a population of future kidney recipients at risk of DWF identifies a real problem that needs a proposed solution. However, without a working hypothesis/mechanism for the delayed risk for DWF from immunosenescence-like events, the modulation of change in post-KT care is speculative. Confirmation that this observation is similar in a more diverse KT population is necessary. However, as it is likely reproducible, the transplant community needs to understand, why so that DWF can be addressed.