Serum Copeptin, NLPR3, and suPAR Levels among Patients with Autosomal-Dominant Polycystic Kidney Disease with and without Impaired Renal Function

Abstract

<b><i>Background:</i></b> The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function. <b><i>Methods:</i></b> This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m<sup>2</sup>; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m<sup>2</sup>; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques. <b><i>Results:</i></b> Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], <i>p</i> = 0.042; 2.42 [1.96], <i>p</i> < 0.001; and 313.78 [178.85], <i>p</i> = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; <i>p</i> < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (<i>p</i> < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels. <b><i>Conclusions:</i></b> This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.

Involvement of Inflammasome Components in Kidney Disease

“…In addition, IL-1β gene expression in the whole blood of ADPKD patients was associated with hypertension [ 327 ]. This is in line with a study suggesting an association between serum NLRP3 protein concentration and endothelial dysfunction in ADPKD [ 328 ].…”

Copeptin in autosomal dominant polycystic kidney disease: real-world experiences from a large prospective cohort study

“…Existing information on copeptin in patients with ADPKD comes mostly from a post hoc analysis of the interventional TEMPO 3:4 trial [ 10 ], and all studies from a real-world setting are too small to be considered conclusive and do not provide a homogenous picture [ 16–20 , 24 ]. However, real-world data are necessary because copeptin values are expected to vary depending on factors such as sampling technique.…”

“…These different findings may be explained by differences in kidney function between ADPKD cohorts and the retrospective use of data from the healthy cohort in the present study. Beyond this, no uniform picture emerges from the published literature: while some studies found significantly higher copeptin levels in patients with ADPKD compared with healthy controls [ 16 ], others found only non-significant tendencies to higher copeptin levels at baseline [ 25 ] or no significant differences at all [ 24 ]. Usually, gender-specific comparisons between ADPKD and healthy individuals were not conducted [ 16 , 24 , 25 ].…”

“…Therefore copeptin, which is part of the same precursor molecule and is released in an equimolar amount, is commonly determined as a surrogate [ 14 ]. Initial small, single-center studies pointed towards an association of plasma copeptin levels with ADPKD disease severity [ 15 , 16 ] and disease progression [ 17–19 ]. More recently, in a large post hoc analysis of the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial copeptin levels were associated with kidney function loss, TKV increase and effectiveness of tolvaptan therapy [ 10 ].…”

suPAR to Risk-Stratify Patients With Malaria

“…Dysregulated host endothelial activation is a key pathophysiological feature in P. falciparum infection (2). uPAR and suPAR have previously been linked with endothelial dysfunction (33)(34)(35). uPAR is expressed on endothelial cells and upregulated during endothelial activation (36,37).…”