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

Neutrophil Gelatinase Associated Lipocalin Is an Early and Accurate Biomarker of Graft Function and Tissue Regeneration in Kidney Transplantation from Extended Criteria Donors

<div><p>Background</p><p>Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from extended criteria donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD.</p><p>Methods</p><p>We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction.</p><p>Results</p><p>Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. <i>In vitro</i>, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio).</p><p>Conclusions</p><p>NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury.</p></div

Evaluation of serum creatinine (sCr in A) and plasma NGAL (pNGAL in B) in the first 4 consecutive days after KT in non-DGF patients (n = 36).

<p>NGAL significantly decreased starting from day 2 to day 4 after KT reaching a value near to normal levels (100 ng/ml). Each value of pNGAL was significantly lower in comparison to the previous day (*p<0.05). By contrast, sCr remained stable or even increased (p>0.05).</p

TEC functional assays after hypoxia or Tac.

<p>(A) Analysis of TEC polarity assessed by trans-epithelial electrical resistance (TEER) in different experimental conditions. Hypoxia and Tac (20 ng/ml) significantly decreased TEER (*p<0.05). NGAL (500 ng/ml) significantly increased TEER in both hypoxia- (#p<0.05) and Tac-treated (§p<0.05) TEC. (B) Analysis of uptake of FITC-conjugated albumin by TEC in different experimental conditions. Hypoxia and Tac (20 ng/ml) significantly decreased albumin uptake (*p<0.05). NGAL (500 ng/ml) significantly increased albumin uptake in both hypoxia- (#p<0.05) and Tac-treated (§p<0.05) TEC. (C-D) FACS analysis of the tight junction molecule ZO-1 (C) and of the endocytic receptor megalin (D) in TEC cultured in different experimental conditions. Hypoxia and Tac significantly decreased ZO-1 and megalin expression. NGAL (500 ng/ml) up-regulated ZO-1 and megalin in both hypoxia- and Tac-treated TEC. Kolomogorov Smirnov statistical analysis was performed in three different experiments with similar results.</p

<i>In vitro</i> analysis of NGAL expression and release by human tubular epithelial cells (TEC) in different experimental conditions.

<p>Relative quantification analysis (A) of NGAL mRNA expression in TEC evaluated by qRT-PCR; mRNA expression of 3 different experiments was normalized for both GAPDH (black columns) and Beta-Actin (white columns) after calculating housekeeping gene variation (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129279#sec006" target="_blank">methods</a>). Hypoxia and 20 ng/ml Tacrolimus (Tac) significantly increased NGAL mRNA expression when compared to basal culture condition (Control, *p<0.001, #p<0.001). FACS (B) and immunofluorescence (B inserts) analysis confirmed Hypoxia- and Tac-induced NGAL production. For FACS, Kolmogorov-Smirnov statistical analysis was performed; control isotype antibody is represented by white plots, NGAL staining by black plots. For immunofluorescence analysis, nuclei were counterstained with 1μg/ml propidium iodide, original magnification was x200. (C) ELISA analysis of NGAL released from TEC. Hypoxia and Tacrolimus (Tac) significantly increased NGAL release in TEC supernatants (*p<0.01).</p

Evaluation of plasma NGAL levels before and after Tacrolimus (Tac) introduction.

<p>NGAL was significantly higher after Tac administration (post-Tac) than before drug introduction (pre-Tac) (*p<0.001, n = 50).</p

Evaluation of plasma NGAL levels at day 1 after KT in patients subdivided on the basis of graft function (DGF: Delayed Graft Function; SGF: Slow Graft Function; IGF: Immediate Graft Function).

<p>(A) NGAL was significantly higher in DGF (662.7 ±97.2 ng/ml, n = 14) vs. non-DGF patients (SGF + IGF: 379.7±139.7 ng/ml, n = 36; #p<0.00001). A statistical significance was also observed comparing DGF vs SGF (444.1±149.5 ng/ml, n = 19; *p<0.001) or IGF (307.8±101.8 ng/ml, n = 17; $p<0.00001) and SGF vs IGF (§p<0.01). NGAL levels of KT from living donors (LD) were used as control. (B) The Area Under the ROC curve (AUC) of NGAL as biomarker of DGF at day 1 post-KT was 0.94.</p

Number of KT performed (white bars) and relative DGF incidence (expressed as % of total KT in black bars) from 2002 to 2012 in KT from ECD (A) or non-ECD (B).

<p>DGF incidence in KT from ECD was significantly higher than in KT from non-ECD (p<0.0001). ECD: extended criteria donors; DGF: delayed graft function; KT: kidney transplantation.</p

Comparison between DGF and non-DGF groups.

<p>Analysis of clinical variables related to donors, recipients and transplant procedures in the study group of KT from ECD (n = 50) subdivided between patients with DGF (n = 13) and non-DGF (n = 37). No significant differences between DGF and non-DGF group were observed. eGFR: estimated glomerular filtration rate; BMI: body mass index; DGF: delayed graft function; HLA MM: HLA-mismatches; KT: kidney transplant; N-DGF: not delayed graft function; PRA: panel reactive antibodies; pto: 24h proteinuria; sCr: serum creatinine; SD: standard deviation. The p values were calculated by t-student test for continues variables, by χ² test for other variables</p><p>*variable “dialysis duration” has not a normal distribution, thus the “p-value” was calculated with Mann-Whitney test.</p><p>Comparison between DGF and non-DGF groups.</p