Does adipose tissue have a key role in inflammation in CKD?

Authors

  • C. Zoccali,

    1. From the Nephrology, Dialysis and Transplantation Unit, and CNR-IBIM, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria, Italy
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  • F. Mallamaci

    1. From the Nephrology, Dialysis and Transplantation Unit, and CNR-IBIM, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria, Italy
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Dr. Carmine Zoccali, CNR-IBIM Nephrology and Dialysis Unit, Via Vallone, Petrara 89124, Reggio Calabria, Italy.
(e-mail: carmine.zoccali@tin.it).

Advanced renal insufficiency, also termed end-stage renal disease (ESRD) kidney failure or stage 5 chronic kidney disease (CKD), has long been considered as a prototypical condition of protein–energy wasting, and the dialysis patient has often been portrayed as a Caravaggio’s Saint Jerome. This perception reflected a dominant phenotype in the dialysis population from the 1970s to the 1990s. Though still frequent, this phenotype has been gradually replaced by the overweight and obese phenotype [1]. By 2002, according to the United States Renal Data System (USRDS), the prevalence of obesity in patients with ESRD in the USA had reached more than 25% [2]. Cross-sectional analyses performed in 2005 in the USRDS database showed that only 17.6% of American dialysis patients had a body mass index (BMI) below 22.5 (i.e. the threshold below which protein–energy wasting is likely), whereas the majority were either overweight (28%), obese (25%) or severely obese (7%) (H. Kramer, personal communication) (Fig. 1).

Figure 1.

Distribution of body mass index in the USRDS database in 2005. Data were kindly provided by Dr. Holly Kramer (personal communication).

As in other chronic diseases such as heart failure or coronary heart disease, BMI is inversely associated with survival in ESRD. Thus, at first sight, the obesity epidemic in patients with ESRD might not appear to be of great concern. However, a high BMI per se cannot be considered as a protective factor for two reasons. First, because ‘obese sarcopenia’ (i.e. a high body mass in the face of protein–energy wasting) underlies a high risk of death in patients with ESRD [3]. Second, because recent studies have shown that abdominal obesity as measured by waist circumference [4] or by the conicity index [5] is directly associated with the risk of death in this population. As in proportional terms visceral fat represents a higher fraction of body mass in patients with ESRD than in individuals without CKD, the negative effect of excessive visceral fat in ESRD might be even greater than that in the general population. Although of major aetiological and prognostic interest, investigation of the biological relevance of fat excess and of fat compartmentalization (subcutaneous vs visceral fat) has been limited in patients with renal insufficiency. A pro-inflammatory profile associated with excessive adiposity has been described in patients with CKD [5], but there is little evidence to support a causal role of fat excess in inflammation and in metabolic disturbances in this population.

In this issue of the Journal of Internal Medicine, Witasp et al. [6] report a case–control study comparing the gene expression of 21 cytokines in abdominal subcutaneous adipose tissue in 37 predialysis stage 5 CKD patients and in a small group (n = 9) of age- and sex-matched individuals with no evidence of CKD. Genes were selected on the basis of a credible ‘a priori’ and included a large series of pro-inflammatory adipokines, insulin-signalling molecules, glucose transporters and proteins involved in generation of reactive oxygen species (ROS). Abdominal subcutaneous fat in patients with CKD exhibited a threefold increase in the expression of interleukin (IL)-6 gene associated with a similar upregulation (2.5-fold) of suppressor of cytokine signalling-3 gene expression and a downregulation of leptin and the oxidative stress genes uncoupling protein (UCP)-2 and cytochrome b-245, alpha polypeptide (CYBA), compared to controls. Although differences between patients and control subjects were insensitive to adjustment for BMI, adjustment for diabetes and background cardiovascular involvement substantially attenuated these differences so that only UCP2 and CYBA (both downregulated) maintained statistical significance in fully adjusted analyses. Witasp et al. point out the problems of multivariate analysis when applied to test for aetiology and conclude that CKD per se rather than associated comorbidities determines the observed differences in the expression of inflammation genes between patients with stage 5 CKD and controls.

Overall, this study is the best attempt so far to provide a biological insight at the cellular level (adipose tissue) with regard to an issue that has hitherto been explored mainly by relating circulating levels of biomarkers of inflammation and oxidative stress and anthropometric measurements. In this commentary, I will first focus on the most robust data, i.e. those concerning downregulation of two key proteins implicated in oxidative stress (UCP2 and CYBA), and then discuss inflammation and pro-inflammatory mechanism(s).

UCP2 is a member of the mitochondrial UCP family. Like other UCPs, it serves to uncouple oxidative phosphorylation from ATP synthesis, a phenomenon associated with energy dissipation. The main action of UCPs is anion transport from the inner to the outer mitochondrial membrane coupled with transfer of protons in the reverse direction. UCP2 activity appears to be important in patients undergoing peritoneal dialysis because individuals homozygous for the del/del polymorphism of the UCP2 gene display a higher risk of total and truncal fat accumulation during the first year of dialysis [7]. UCP2 inhibition in adipocytes in vitro not only increases production of ROS but also impairs insulin-stimulated glucose uptake and suppresses insulin signal transduction, via hyperactivation of c-Jun N-terminal kinase, and the accompanying serine phosphorylation of insulin receptor substrate-1 [8]. These clinical and biological data clearly suggest that UCP2 may have a role in insulin resistance and in the metabolic response to chronic exposure to glucose overload in peritoneal dialysis patients. Therefore, the UCP2 pathway, which is a complex pathway encompassing oxidative stress and regulation of glucose metabolism, rather than primary alterations in insulin-signalling genes and glucose transporters (all of which are unaltered in the study by Witasp et al.), appears to be at cross-road of fat-dependent alterations in insulin sensitivity in patients with advanced CKD.

Cytochrome b is composed of a light chain (α) and a heavy chain (β). The α subunit is a primary component of the microbicidal oxidase system of phagocytes. Of note, the corresponding gene (CYBA) encodes the p22phox subunit of the mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex, which is a major pro-oxidant system in various cell types. The relevance of this gene in microbicidal activity is highlighted by the fact that mutations in CYBA determine autosomal recessive chronic granulomatous disease, a severe disease characterized by severe infections [9]. The prototypical cell of the innate immunity system, the macrophage, shows similarities to the adipocyte [10]; it expresses gene products typical of the adipocyte, such as the cytoplasmic fatty-acid-binding protein adipocyte lipid-binding protein 2 and peroxisome proliferator-activated receptor gamma. Furthermore, like adipocytes, macrophages have lipid-storage capabilities, and preadipocytes may differentiate into fully functional macrophages. It is important to note that in obese patients, these two cell types, the macrophage and the adipocyte, co-localize in adipose tissue forming an integrated system that is involved in the innate immune response and in metabolic regulation. Thus, the reduced expression of CYBA in the adipose tissue of patients with stage 5 CKD may be part of a systemic disorder of the reticulo-histiocitary system. If confirmed in parallel studies in circulating macrophages, CYBA downregulation in CKD might have an important role in the high rate of infection and death secondary to infection in this population.

Uraemia induces complex changes in the innate and adaptive immune responses through impaired endocytosis, amplification of IL-12p70 production, and proliferation of allogenic T-cells [11] and the proportion of circulating monocytes that actively synthesise IL-6 [12]. Given the biological homologies between cells of the monocyte lineage and the adipocyte, the 3-fold increase in the expression of IL-6 levels observed by Witasp et al. is consistent with previous data on circulating monocytes in haemodialysis patients. However, because of the potential confounding effect of diabetes and concomitant atherosclerotic complications, this finding should be interpreted with caution. IL-6 levels are elevated in insulin-resistant states, such as obesity and type-2 diabetes, and high concentrations of insulin specifically stimulate IL-6 synthesis in adipocytes in vitro [13]. The low BMI in patients with stage 5 CKD is another relevant confounder with regard to the interpretation of high IL-6 expression in adipocytes in these patients. Indeed, a low BMI may entail protein–energy wasting, a condition that is a strong stimulus for IL-6 synthesis, as is the case in patients with heart or liver failure. Statistical adjustment for BMI may not eliminate potential confounding because both protein–energy wasting and excess weight/obesity are associated with high IL-6 expression. Thus, further studies in patients with CKD perfectly matched for subcutaneous fat mass or BMI are still needed to confirm the intriguing observations made in this study. In the only study in female haemodialysis patients reported to date, no difference in IL-6 gene expression was noted between patients and healthy subjects [14]. Subcutaneous fat and visceral fat represent substantially different compartments of fat mass with regard to their relationship with metabolic risk factors. Studies including the evaluation of visceral fat should be performed to complete the characterization of the association between adipose tissue and inflammation in CKD.

In conclusion, the rising epidemic of CKD attributable to excess weight/obesity and the high prevalence of obesity in the dialysis population demand specific studies to determine the health implications of fat excess in patients with CKD. The intriguing observations by Witasp et al. suggest that downregulation of two oxidative stress proteins, UCP2 and CYBA, may have an important role in insulin resistance and in alterations in innate immunity and the response to infectious agents in patients with CKD. Further studies are needed to ascertain whether uraemia amplifies adipocyte production of IL-6, a cytokine unanimously recognized as critical in inflammation in patients with CKD.

Conflict of interest statement

No conflict of interest was declared.

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