Urinary proinflammatory cytokine response in renal transplant recipients with polyomavirus BK viruria.
BACKGROUND
Polyomavirus BK (BKV) has emerged as an important complication after kidney transplantation. BKV-associated nephropathy develops in approximately 5% to 8% of renal transplant recipients, and its prognosis is poor. The relationship between urine cytokines and BK viruria in kidney recipients has not been defined.


METHODS
We compared posttransplant urine cytokine levels of 65 renal transplant outpatients with (BK-positive) or without BK viruria (BK-negative, n=33), low- (n=16) or high-level (n=16) BK viral load (VL), and 24 healthy controls (HCs). Soluble interleukin-1 receptor antagonist (sIL-1RA), interleukin (IL)-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, IL-17, transforming growth factor-beta2, interferon-gamma, and tumor necrosis factor-alpha levels were determined using commercially available ELISA kits.


RESULTS
BK-positive patients showed higher urine IL-3 (P=0.006), sIL-6R (P=0.010), IL-6 (P=0.020), and sIL-1RA (P=0.050) than BK-negative patients. Compared with HCs, BK-negative patients had lower urine sIL-1RA (P=0.003), sIL-6R (P=0.001), and IL-17 (P<0.001), whereas BK-positive patients had higher urine IL-3 (P=0.004) and IL-6 (P=0.001) and lower IL-17 (P<0.001), suggesting cytokine suppression by immunosuppression and upregulation by BK-infection. Urine sIL-6R (P=0.003) and IL-6 (P=0.010) were higher in patients with high VL than in patients with low VL. Additionally, patients with high VL showed higher urine IL-6 (P=0.001), sIL-6R (P=0.001), sIL-1RA (P=0.016), and IL-3 (P=0.047) than BK-negative patients, and higher urine IL-6 (P<0.001) and lower IL-17 (P<0.001) than HCs.


CONCLUSIONS
BK-positive renal transplant recipients, especially those with high VL, showed strong inflammatory cytokine responses with increases of urine sIL-1RA, IL-3, IL-6, and sIL-6R. Our data suggest that monocyte- and Th-2-induced cytokines are involved in the pathogenesis of BKV-associated nephropathy.
Sadeghi
Mahmoud
M
Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany. mahmoud.sadeghi@med.uni-heidelberg.de
Daniel
Volker
V
Schnitzler
Paul
P
Lahdou
Imad
I
Naujokat
Cord
C
Zeier
Martin
M
Opelz
Gerhard
G
D000957:Antigens, Viral, Tumor / Q000235:genetics; D001739:BK Virus / Q000235:genetics / Q000302:isolation & purification; D016207:Cytokines / Q000652:urine*; D004359:Drug Therapy, Combination; D016679:Genome, Viral; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation / Q000652:urine; D007377:Interleukin-3 / Q000652:urine; D015850:Interleukin-6 / Q000652:urine; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology; D016133:Polymerase Chain Reaction; D027601:Polyomavirus Infections / Q000150:complications* / Q000652:urine; D019562:Viral Load
D000957:Antigens, Viral, Tumor; D016207:Cytokines; D007166:Immunosuppressive Agents; D007377:Interleukin-3; D015850:Interleukin-6