Shedding some light on chronic inflammation

One of the most important concepts in nephrology is that of chronic systemic inflammation and its role in increased cardiovascular (CV) risk in patients with chronic kidney disease (CKD) and those on dialysis. Despite a significant research effort the precise drivers of this inflammation have remained difficult to pin down.

Recent work has implicated bacterial lipopolysaccharide (LPS or endotoxin), a glycolipid found in the outer membrane of gram negative bacteria, in this process. (The potency of LPS as a pro-inflammatory stimulus is detailed in this extraordinary case report from the NEJM archive)

Previous work in patients with congestive cardiac failure (reviewed here) has demonstrated that relative underperfusion of the gut results in leakage of LPS from the GI tract into the circulation. A group of UK investigators analogised this situation to the haemodynamic perturbations seen in haemodialysis sessions and used this as a starting point to investigate the concentration of circulating LPS in CKD patients.

They found that endotoxemia (i.e. circulating LPS concentrations) :

• tended to increase with worsening CKD stage

• showed a 6-fold increase in patients on dialysis

• tripled at the initiation of dialysis

Combining these findings with the fact that the study demonstrated correlations between LPS levels, the magnitude of hypotensive episodes during dialysis and dialysis-induced myocardial stunning, the authors concluded that haemodialysis associated circulatory stress leads to exposure to sustained endotoxemia. Importantly, they also found a significant association between this endotoxemia and reduced survival.

So should we be giving our most haemodynamically unstable dialysis patients antibiotic treatment, or selective gram negative gut decontamination or polymyxin B haemadsorption instead of dialysis? Well, my thought is that individually tailored dialysis prescriptions to reduce CV stress during dialysis sessions are likely to be a good start in reducing LPS translocation and potentially decreasing the sequelae of this. I also note that the same group have just published a paper suggesting that plain (and good) old aggressive anti-hypertensive therapy might be a good option too.