Targeting Immunity in End-Stage Renal Disease

Background: Despite the stable incidence of end-stage renal disease (ESRD), it continues to be associated with an unacceptably high cardiovascular risk. Summary: ESRD is characterized by enhanced oxidative stress and severe inflammation, which boost cardiovascular risk, thus increasing cardiovascular-associated mortality rate. While substantial effort has been made in the technological innovation of dialytic techniques, few significant advances have been made to reduce inflammation in patients with ESRD. Indeed, this contrasts with the extensive scientific breakthroughs made in the basic field of science in targeting inflammation. There is thus a pressing need for clinical trials to test the effect of reducing inflammation in patients with ESRD. Here, we will revisit the negative effect of ESRD on inflammation and explore the impact of enhanced inflammation on cardiovascular outcomes and survival in patients with ESRD. Finally, we will discuss the need for clinical trials that target inflammation in ESRD, as well as weigh potential disadvantages and offer novel innovative approaches. Key Message: We will try to understand why the issue of inflammation has not been successfully addressed thus far in patients with ESRD, while at the same time weighing the potential disadvantages and offering novel innovative approaches for targeting inflammation in patients with ESRD

Associations between depressive symptoms and disease progression in older patients with chronic kidney disease: results of the EQUAL study

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease; however, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (>= 65 years; estimated glomerular filtration rate <= 20 mL/min/1.73 m(2)) were included from a European multicentre prospective cohort between 2012 and 2019. Depressive symptoms were measured by the five-item Mental Health Inventory (cut-off <= 70; 0-100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73 m(2)/month. A total of 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (P = 0.08). Unlike women, men with depressive symptoms had an increased mortality rate compared with those without symptoms [adjusted hazard ratio 1.41 (95% confidence interval 1.03-1.93)]. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, or with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men

Low Plasma Lecithin: Cholesterol Acyltransferase (LCAT) Concentration Predicts Chronic Kidney Disease

Low high-density lipoprotein-cholesterol (HDL-c) is the most remarkable lipid trait both in mild-to-moderate chronic kidney disease (CKD) patients as well as in advanced renal disease stages, and we have previously shown that reduced lecithin:cholesterol acyltransferase (LCAT) concentration is a major determinant of the low HDL phenotype. In the present study, we test the hypothesis that reduced LCAT concentration in CKD contributes to the progression of renal damage. The study includes two cohorts of subjects selected from the PLIC study: a cohort of 164 patients with CKD (NefroPLIC cohort) and a cohort of 164 subjects selected from the PLIC participants with a basal estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 (PLIC cohort). When the NefroPLIC patients were categorized according to the LCAT concentration, patients in the 1st tertile showed the highest event rate at follow-up with an event hazard ratio significantly higher compared to the 3rd LCAT tertile. Moreover, in the PLIC cohort, subjects in the 1st LCAT tertile showed a significantly faster impairment of kidney function compared to subjects in the 3rd LCAT tertile. Serum from subjects in the 1st LCAT tertile promoted a higher reactive oxygen species (ROS) production in renal cells compared to serum from subjects in the third LCAT tertile, and this effect was contrasted by pre-incubation with recombinant human LCAT (rhLCAT). The present study shows that reduced plasma LCAT concentration predicts CKD progression over time in patients with renal dysfunction, and, even more striking, it predicts the impairment of kidney function in the general population

Cox regression for the decline of renal function including -374 T/A RAGE.

<p>Cox regression. Table shows that –374 A RAGE genotype, together with albuminuria, LDL cholesterol, HDL cholesterol and BMI are significantly associated with the decline of renal function. –374 A allele for RAGE, albuminuria and LDL cholesterol are predictor of CKD progression, while HDL cholesterol and BMI are inversely associated with renal function decline.</p

Cox regression for the decline of renal function including the levels of the soluble form of RAGE.

<p>Cox regression. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060089#pone-0060089-t003" target="_blank">Table 3b</a> shows that replacing sRAGE rather than –374 A RAGE genotype in the same model showed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060089#pone-0060089-t003" target="_blank">table 3a</a>, only albuminuria, and HDL cholesterol are significantly associated with the decline of renal function.</p

Renal survival of wild-type, heterozygous and homozygous patients for the A allele.

<p>The figure shows that T/A and A/A subjects present a faster decline of renal function than T/T patients. The main end point of the analysis was an increase of serum creatinine over 50% or the beginning of chronic dialysis. Figure shows a total of 40 events: 6 in T/T subjects, 26 in T/A subjects and 8 in A/A subjects.</p

Prevalence of medications according to genotypes.

<p>Medications: no differences have been found between patients carrying –374 T/T, T/A and A/A genotypes in terms of antihypertensive or antidiabetic therapy. A Pearson Chi square test was used, keeping a significant difference for p values <0.05.</p

Renal survival of patients carrying –374 T/T and the A allele.

<p>The figure shows that the subjects carrying the A allele present a faster decline of renal function than wild type patients. The main endpoint of the analysis was an increase of serum creatinine over 50% or the beginning of chronic dialysis. The figure shows a total of 40 events: 6 in T/T subjects, 34 in subjects carrying the A allele.</p