Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy.
BACKGROUND
Serum cytokines are increased in patients with acute kidney injury (AKI) and predict increased mortality. It is widely assumed that increased renal production of cytokines is the source of increased serum cytokines; the role of extra-renal cytokine production and impaired renal cytokine clearance is less well studied. We hypothesized that cytokine production in AKI was mononuclear phagocyte dependent, independent of production by the kidneys, and that serum cytokine clearance would be impaired in AKI.


METHODS
Bilateral nephrectomy was used as a model of AKI to assess cytokine production independent of kidney cytokine production. Mononuclear phagocytes were depleted utilizing intravenous (IV) administration of liposome-encapsulated clodronate (LEC). Twenty-three serum cytokines were determined utilizing a multiplex cytokine kit. Proteins for cytokines were determined in the spleen and liver by enzyme-linked immunosorbent assay. Recombinant cytokines were injected by IV into mice with bilateral nephrectomy to determine the effect of absent kidney function on serum cytokine clearance.


RESULTS
Serum interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), IL-10, IL-1β, monocyte chemotactic protein 1 (MCP-1), IL-5 and eotaxin were increased in the serum of mice after bilateral nephrectomy and were reduced with LEC. Serum IL-12p40 and regulated upon activation, normal T-cell expressed, and secreted (RANTES) were increased after bilateral nephrectomy and were further increased with LEC. Spleen IL-6, CXCL1, IL-10 and IL-1β and liver IL-6 and IL-10 were increased after bilateral nephrectomy. After IV injection, IL-6, CXCL1, IL-10 and IL-1β had a prolonged serum cytokine appearance in mice with bilateral nephrectomy versus sham operation.


CONCLUSIONS
Increased mononuclear phagocyte production and impaired renal clearance contribute to serum cytokine accumulation in AKI, independent of kidney injury. The effect of AKI on cytokine production and clearance may contribute to the increased mortality of patients with AKI.
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO, USA. Ana.AndresHernando@ucdenver.edu
Ana
A
Andres-Hernando
Belda
B
Dursun
Christopher
C
Altmann
Nilesh
N
Ahuja
Zhibin
Z
He
Rhea
R
Bhargava
Charles E
CE
Edelstein
Alkesh
A
Jani
Thomas S
TS
Hoke
Christina
C
Klein
Sarah
S
Faubel
D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy
D016207:Cytokines