Insulin Resistance, the Metabolic Syndrome and Renal Failure Is There a Special Problem for Patients Treated with Peritoneal Dialysis?
Insulin resistance and the metabolic syndrome (MeS or syndrome X) are common in patients with chronic kidney disease (CKD).1–3 Moreover, the presence of MeS is an independent predictor of subsequent development of CKD, and MeS in patients with CKD predicts subsequent cardiovascular events and cardiovascular mortality, as is the case in the general population.4–8
In a recent analysis of the Atherosclerosis Risk in Communities Study in a total population of 10,096 non-diabetic subjects, the relative risk of developing CKD within a nine-year follow-up was 1.43 (95% confidence interval (CI): 1.18–1.73) for patients with MeS, and the increase in risk of CKD correlated with the number of components of the MeS and with increasing insulin resistance (assessed by homeostasis model assessment insulin resistance (HOMA-IR)).4
Data from the Third National Health and Nutrition Examination (NHANES III) showed a prevalence of MeS of 18.8% in patients with normal glomerular filtration rate (GFR: >90ml/min/1.73m2), 21% in patients with mild renal impairment (GFR: 45–89ml/min/1.73m2) and 33% in moderate CKD (GFR: 36–38ml/min/1.73m2).1 Insulin resistance detected by various means, including impaired glucose tolerance, HOMA-IR and the euglycaemic hyperinsulinaemic glucose clamp (EGC) has been identified in approximately 30% of patients treated with haemodialysis (HD) or peritoneal dialysis (PD).9,10
The cause of insulin resistance in CKD is almost certainly multifactorial. Initiation of dialysis treatment, whether by HD or PD, improves but does not normalise insulin sensitivity as measured by the EGC, suggesting that insulin resistance might be caused by a retained uraemic toxin.9,10 Protein carbamylation, increased in uraemia via the ureaisocyanate pathway, has also been suggested as a possible cause of insulin resistance.11 Other possible mechanisms include uraemic metabolic acidosis and disorders of intracellular ionic homeostasis.12,13
In the past decade, many avenues of research have implicated inflammation and central adiposity in the aetiology of MeS.14,15 Visceral adipose tissue is a potent source of pro-inflammatory cytokines, and inflammatory cytokines – e.g. tumour necrosis factor alpha (TNF-α) – reduce tissue sensitivity to insulin. Chronic low-grade inflammation as detected by minimally elevated c-reactive protein (CRP, >3mg/litre) is common in patients with CKD and dialysis patients and, as with the general population, inflammation independently predicts cardiovascular events and mortality in renal patients.16–19 Interestingly, the number of components of MeS correlates in CKD with CRP at all levels of renal function.1 It is not yet clear whether inflammation and MeS are independent or interdependent risk factors for cardiovascular disease in CKD. Due to the fact that elucidation of the nature of any link between inflammation and MeS would be critical to appropriate management, this should be the subject of further study.
Recent research has also identified major disturbances of the endocrine functions of adipose tissue and of insulin–glycaemia–lipidaemia homeostasis in patients with renal failure.20 Patients with CKD have hyperleptinaemia and hyperadiponectinaemia with paradoxical energy–nutrition balance. It is debatable whether hyperleptinaemia is the major cause of the anorexia frequently observed in patients with advanced CKD, but the evidence increasingly points in that direction.21 Although CKD is associated with hyperadiponectinaemia, the cardiovascular protective effects of adiponectin seem to be intact in that lower levels of adiponectin increase the risk of cardiovascular events in CKD.7
On-going research is likely to provide further insight into the complex and multisystem disorders of energy–nutrition homeostasis in CKD and provide direction for appropriate therapeutic intervention.