In this study, we examined the possible immune-mediated mechanisms in cardiorenal syndrome (CRS) type 1 pathogenesis. We enrolled 40 patients with acute heart failure (AHF), 11 patients with CRS type 1 and 15 controls. Plasma from the different groups was incubated with monocytes; subsequently, cell apoptosis was evaluated by DNA fragmentation, caspase activity and cytofluorometric assay. Cytokine quantification in plasma and supernatant was performed by ELISA. Monocytes treated with CRS type 1 plasma showed significantly higher apoptosis compared with those treated with AHF and the controls (p < 0.05). Caspase-3 (CRS type 1: 2.20 ng/ml, IQR 2.06-2.33; AHF: 1.48 ng/ml, IQR 1.31-1.56; controls: 0.71 ng/ml, IQR 0.67-0.81) and caspase-8 levels (CRS type 1: 1.49 ng/ml, IQR 1.42-1.57; AHF: 0.94 ng/ml, IQR 0.84-0.98; controls: 0.56 ng/ml, IQR 0.51-0.58) in cells incubated with plasma from these patients demonstrated a significantly higher concentration. We observed a strong upregulation of plasma IL-6 and IL-18 in CRS type 1 compared with AHF and the controls (p < 0.05). Interestingly, we observed a similar concentration of TNF-α in CRS type 1 and AHF. In CRS type 1 patients, IL-6 (52.13 ng/ml, IQR 47.29-66.83) and IL-18 levels (197.75 ng/ml, IQR 120.80-265.49) in supernatant were significantly higher than in AHF patients (IL-6: 28.79 ng/ml, IQR 19.90-36.10; IL-18: 21.98 ng/ml, IQR 15.98-29.85) and controls (IL-6: 5.02 ng/ml, IQR 4.56-6.44; IL-18: 7.91 ng/ml, IQR 5.57-10.62). These findings suggest the presence of a defective regulation of monocyte apoptosis in CRS type 1 patients and the involvement of an immune-mediated mechanism in the pathophysiology of this syndrome.

Keywords:
Cardiorenal syndrome, Acute heart failure, Apoptosis, Immune-mediated mechanism, Monocytes, Inflammation
1.
Ledoux P: Cardiorenal syndrome (in French). Avenir Med 1951;48:149-153.
2.
Molls RR, Rabb H: Limiting deleterious cross-talk between failing organs. Crit Care Med 2004;32:2358-2359.
3.
Ronco C, Haapio M, House AA, Anavekar N, Bellomo R: Cardiorenal syndrome. J Am Coll Cardiol 2008;52:1527-1539.
4.
Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House AA, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P: Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31:703-711.
5.
Haase M, Müller C, Damman K, Murray PT, Kellum JA, Ronco C, McCullough PA: Pathogenesis of cardiorenal syndrome type 1 in acute decompensated heart failure: workgroup statements from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 2013;182:99-116.
6.
Ronco C, Cicoira M, McCullough PA: Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure. J Am Coll Cardiol 2012;60:1031-1042.
7.
Virzì GM, Clementi A, Brocca A, de Cal M, Vescovo G, Granata A, Ronco C: The hemodynamic and nonhemodynamic crosstalk in cardiorenal syndrome type 1. Cardiorenal Med 2014;4:103-112.
8.
Cruz DN: Cardiorenal syndrome in critical care: the acute cardiorenal and renocardiac syndromes. Adv Chronic Kidney Dis 2013;20:56-66.
9.
Metra M, Nodari S, Parrinello G, Bordonali T, Bugatti S, Danesi R, Fontanella B, Lombardi C, Milani P, Verzura G, Cotter G, Dittrich H, Massie BM, Dei Cas L: Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance. Eur J Heart Fail 2008;10:188-195.
10.
Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, Yancy CW, Califf RM, Stevenson LW, Hill JA: Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol 2008;51:1268-1274.
11.
Forman DE, Butler J, Wang Y, Abraham WT, O'Connor CM, Gottlieb SS, Loh E, Massie BM, Rich MW, Stevenson LW, Young JB, Krumholz HM: Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004;43:61-67.
12.
Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA: Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 2004;65:1357-1365.
13.
Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP: Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209-216.
14.
Newsome BB, Warnock DG, McClellan WM, Herzog CA, Kiefe CI, Eggers PW, Allison JJ: Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med 2008;168:609-616.
15.
Liang KV, Williams AW, Greene EL, Redfield MM: Acute decompensated heart failure and the cardiorenal syndrome. Crit Care Med 2008;36(1 suppl):S75-S88.
16.
Virzì GM, de Cal M, Cruz DN, Bolin C, Vescovo G, Ronco C: Type 1 cardiorenal syndrome and its possible pathophysiological mechanisms (in Italian). G Ital Nefrol 2012;29:690-698.
17.
Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
18.
Sundström C, Nilsson K: Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer 1976;17:565-577.
19.
Akcay A, Nguyen Q, Edelstein CL: Mediators of inflammation in acute kidney injury. Mediators Inflamm 2009;2009:137072.
20.
Lee DW, Faubel S, Edelstein CL: Cytokines in acute kidney injury (AKI). Clin Nephrol 2011;76:165-173.
21.
Goh CY, Vizzì G, de Cal M, Ronco C: Cardiorenal syndrome: a complex series of combined heart/kidney disorders. Contrib Nephrol 2011;174:33-45.
22.
Charakida M, Halcox JP: Tumor necrosis factor-α in heart failure: more questions than answers (in Spanish). Rev Esp Cardiol 2005;58:470-472.
23.
Rordorf R, Savastano S, Sanzo A, Spazzolini C, De Amici M, Camporotondo R, Ghio S, Vicentini A, Petracci B, De Regibus V, Taravelli E, Landolina M, Schwartz PJ: Tumor necrosis factor-α predicts response to cardiac resynchronization therapy in patients with chronic heart failure. Circ J 2014;78:2232-2239.
24.
Virzi G, Day S, de Cal M, Vescovo G, Ronco C: Heart-kidney crosstalk and role of humoral signaling in critical illness. Crit Care 2014;18:201.
25.
Virzì GM, Torregrossa R, Cruz DN, Chionh CY, de Cal M, Soni SS, Dominici M, Vescovo G, Rosner MH, Ronco C: Cardiorenal syndrome type 1 may be immunologically mediated: a pilot evaluation of monocyte apoptosis. Cardiorenal Med 2012;2:33-42.
26.
Dounousi E, Koliousi E, Papagianni A, Ioannou K, Zikou X, Katopodis K, Kelesidis A, Tsakiris D, Siamopoulos KC: Mononuclear leukocyte apoptosis and inflammatory markers in patients with chronic kidney disease. Am J Nephrol 2012;36:531-536.
27.
Bordoni V, Piroddi M, Galli F, de Cal M, Bonello M, Dimitri P, Salvatori G, Ranishta R, Levin N, Tetta C, Ronco C: Oxidant and carbonyl stress-related apoptosis in end-stage kidney disease: impact of membrane flux. Blood Purif 2006;24:149-156.
28.
de Cal M, Cruz DN, Corradi V, Nalesso F, Polanco N, Lentini P, Brendolan A, Tetta C, Ronco C: HLA-DR expression and apoptosis: a cross-sectional controlled study in hemodialysis and peritoneal dialysis patients. Blood Purif 2008;26:249-254.
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2015
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