Editorials and Perspectives: Analysis and Commentary
Chronic allograft nephropathy is understood to be a multifactorial process that involves synergistic and time-dependent effects of both immunologic and nonimmunologic factors (1). The characteristic structural abnormalities of glomerulosclerosis, tubulointerstitial fibrosis, and arteriosclerosis are similar to chronic nephron loss in native kidneys, suggesting that the factors responsible for the progression of chronic kidney disease may be generic (1). Apart from the dissection of the role of ischemia, the identification of other nonimmunologic factors underlying chronic allograft loss has received little attention.
The role of lipids in mediating the progression of chronic allograft loss is not well understood. Hyperlipidemia is a common feature in the renal transplantation population, but based on a small number of studies, statins do not appear to affect graft function (2). Nonesterified (or free) fatty acids (NEFAs) are the main building blocks of triglycerides, which consists of three fatty acids linked to a glycerol backbone. Structurally, NEFAs are carboxylic acids with long-chain hydrocarbon groups and may be classified into various categories (essential vs. nonessential; mono/polyunsaturated vs. saturated). NEFAs serve as a key metabolic fuel for the body and are released from adipose tissue in response to systemic hormones (glucagon, corticosteroids, adrenocorticotropic hormone, catecholamines) acting through hormone-sensitive lipase (present in the cytosol of adipocytes). Besides this, NEFAs are likely to have pathologic roles because they are increased in obesity, type 2 diabetes, and many other chronic inflammatory diseases (3). Moreover, certain types of NEFAs are precursors of bioactive eicosanoids, such as prostaglandin E2 (3), have antibacterial properties (4), and all probably act as secondary messengers capable of upregulating or downregulating proinflammatory transcription factor (nuclear factor-κB) and transcriptomes (tumor necrosis factor α interleukin 1β, interleukin 6, monocyte chemotactic protein 1), depending on the type of NEFA (5).
In this issue, Klooster et al. (6) started with a hypothesis that NEFAs have a detrimental role in chronic allograft dysfunction. Because 99.9% of NEFAs are albumin bound, the hypothesis was based on previous experimental data suggesting that the glomerular ultrafiltration of NEFA-bound albumin leads to luminal toxicity, promoting tubulointerstitial inflammation in experimental models of proteinuric renal disease. The results, however, were converse to the authors’ hypothesis and expectations. Using a longitudinal study design, they showed that posttransplantation serum levels of NEFAs (from appropriately collected samples and using a colorimetric assay that measured both “free” and albumin-bound NEFAs) are inversely correlated with better graft function in 461 renal transplant recipients with an average follow-up of 7.1 years (hazard ratio of 0.61 using multivariate analysis). These results were independent of body mass index, proteinuria, anti–human leukocyte antigen antibodies, and type of rejection. One of the main limitations of these data is that it is based on a single measurement of NEFA. NEFAs are a biomarker of negative energy balance, and levels can be highly variable and influenced by systemic hormones and nutritional status, limiting their routine use in clinical practice.
Nevertheless, further investigation of these intriguing observations is warranted. Perhaps the most vexing questions are what could be the mechanisms of graft protection and which type of NEFA is important. These questions have in part been addressed by a previous study (7) and interestingly mirror the data of Klooster et al. (6). In a carefully undertaken study, Baker et al. (7) reported an inverse relationship between pretransplantation serum levels of NEFA (for the omega-6 and omega-3 polyunsaturated families measured using high-performance liquid chromatography) and graft outcome in 130 nonconsecutive renal transplant recipients, and revealed that an inverse relationship was present for the n-6 family (arachidonic acid and γ-linoleic acid) but not for the n-3 family (α-linoleic, eicosapentaenoic, and docosahexaenoic). For arachidonic acid, the highest quartile was associated with an 80% reduction in graft failure. These data raise the hypothesis that the protective effects of NEFAs against graft loss may relate to the direct immunomodulatory effects of specific NEFAs (such as arachidonic acid) rather than the hypothesized nonspecific luminal nephrotoxicity of all NEFAs-coupled albumin involving glomerular ultrafiltration (6). Other potential mechanisms of the renoprotection include the possibility of the effects of NEFAs on either infection or on drug handling of immunosuppressants (6).
Clearly, there are many complexities to resolve. If indeed levels of NEFA are found to prevent graft loss, then what impact will this have on cardiovascular disease and posttransplantation diabetes, given that obesity and insulin resistance are positively correlated with NEFAs in renal transplant recipients (8)? Meanwhile, the task of understanding the role of common factors in the progression of chronic native and transplant kidney disease remains important.
1. Nankivell BJ, Kuypers DR. Diagnosis and prevention of chronic kidney allograft loss. Lancet 2011; 378: 1428.
2. Navaneethan SD, Perkovic V, Johnson DW, et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst Rev 2009; CD005019.
3. Wood LG, Scott HA, Garg ML, et al. Innate immune mechanisms linking non-esterified fatty acids and respiratory disease. Prog Lipid Res 2009; 48: 27.
4. Desbois AP, Smith VJ. Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential. Appl Microbiol Biotechnol 2010; 85: 1629.
5. Chang CF, Chau YP, Kung HN, et al. The lipopolysaccharide-induced pro-inflammatory response in RAW264.7 cells is attenuated by an unsaturated fatty acid–bovine serum albumin complex and enhanced by a saturated fatty acid–bovine serum albumin complex. Inflamm Res 2012; 61: 151.
6. Klooster A, Hofker HS, Navis G, et al. Nonesterified fatty acids and development of graft failure in renal transplant recipients. Transplantation 2013; 95: 1383.
7. Baker AC, de Mattos A, Watkins S, et al. Pretransplant free fatty acids (FFA) and allograft survival in renal transplantation. J Surg Res 2010; 164: 182.
8. Armstrong KA, Hiremagalur B, Haluska BA, et al. Free fatty acids are associated with obesity, insulin resistance, and atherosclerosis in renal transplant recipients. Transplantation 2005; 80: 937.