Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

Abstract

SummaryBackground and objectives Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of AD-PKD.Design, setting, participants, & measurements We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of Ͼ60 ml/min per 1.73 m 2 ; 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m 2 ; 42 normotensive subjects with ADPKD and eGFR of Ͼ60 ml/min per 1.73 m 2 ; and 50 healthy controls. We assayed serum C-reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F 2␣ (8-epi-PGF2␣ ) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance. ResultsThe hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of Ͼ60, and hypertensive ADPKD with eGFR of Ͼ60. The normotensive ADPKD eGFR Ͼ60, hypertensive ADPKD eGFR Ͼ60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF 2␣ and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships. ConclusionsInflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation.

Pravastatin Therapy and Biomarker Changes in Children and Young Adults with Autosomal Dominant Polycystic Kidney Disease

“…We and others have shown that adult patients with ADPKD have elevated levels of cardiovascular disease risk and oxidative stress markers compared with healthy individuals (11)(12)(13)(14)(15) (Figure 1). These as well as inflammatory bioactive lipid mediators were elevated early in the disease and were associated with the increase in total kidney volume (TKV) and decline in renal function (14,16,17) (Figure 1).…”

“…On the basis of this knowledge, we aimed to investigate whether the markers of endothelial dysfunction, inflammation, and oxidative stress identified in previous studies (11,(13)(14)(15)(16) (Figure 1) change in response to pravastatin therapy. This would qualify their use for monitoring of ADPKD disease progression and therapy efficacy.…”

Predictors of Autosomal Dominant Polycystic Kidney Disease Progression

“…90 In comparison, oxidative stress was apparent even in patients with ADPKD with normotension versus healthy subjects and likely precedes the appearance of hypertension, which may account for the increased levels of angiogenic growth factors described in young patients with ADPKD. Several other serum and laboratory factors have been associated with various aspects of ADPKD severity, including serum uric acid, HDL, fibroblast growth factor-23, collagenderived peptides, NGAL, IL-8, and TNFa.…”

Relationship between fibroblast growth factor and arrhythmogenesis in normotensive patients with polycystic kidney disease

“…A wide range of factors that end up with structural myocardial disease are responsible for this adverse outcome. A variety of subclinical organ damage markers such as LVH, increased carotid intimamedia thickness, endothelial dysfunction, microalbuminuria, decreased coronary flow velocity reserve and low-grade systemic inflammation, and chronic oxidative stress have been reported in several studies of patients with ADPKD with wellpreserved renal function [26,27]. Functional data supporting a role of FGF-23 in vascular biology is derived from Klotho null mice, which carry no functional FGF-23 activity due to lack of coreceptors [28].…”