Authors' Reply: Urinary Cytokines in BK Viruria

Abstract

We are writing in response to the letter by Dr. Vanchiere, commenting on our article “Urinary Proinflammatory Cytokine Response in Renal Transplant Recipients With Polyomavirus BK Viruria.” 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) were analyzed. Dr. Vanchiere questioned the normalized urine cytokine levels, the presence of JC virus and cytomegalovirus (CMV) in the urine samples, the cytokine levels in serial urine specimens, and the ethnicity of the transplant recipients and HCs in our study. He asked for additional or confirmatory data. Our data were obtained in transplant recipients with only low retention. Maximum urine and serum creatinine levels in the 65 transplant recipients were 220 and 2.4 mg/dL, respectively. A retrospective normalization of the urine cytokine levels, calculating urine cytokine/ urine creatinine ratios, confirmed the published results. BK-positive patients (n=32), and particularly BK-positive patients with high VL (n=16), showed higher sIL-1RA (P=0.08 and P=0.041, respectively), interleukin (IL)-3 (P=0.002 and P=0.016, respectively), IL-6 (P=0.02 and P=0.003, respectively), and sIL-6R (P=0.006 and P=0.001, respectively) urine cytokine/urine creatinine ratios than BK-negative patients (n=33). A second urine specimen, obtained 99±128 days (mean±SD) after the first sample, was available from 13 patients. BK VL remained high in four and decreased in three patients with initially high VL, four patients showed low BK VL in both urine samples, and two initially BK-negative patients developed a low BK VL subsequently. Normalized and not normalized sIL-1RA, IL-3, IL-6, and sIL-6R levels were similar in the 2 urine samples of the 11 consistently BK-positive patients (P>0.05), indicating the stability of increased urine cytokine levels in BK-positive patients. Unfortunately, stability of low cytokine levels in the urine of BK-negative patients could not be tested, because the necessary samples were not available. We tested 42 available urine samples of the first series retrospectively for the presence of JC virus and CMV. Four of the 42 samples contained JC virus, and two samples contained CMV. Of the four JC virus-positive samples, one was BK positive and three were BK negative; of the two CMV-positive specimens, one was BK positive and one was BK negative. Because of the low frequency of CMV and JC virus in BK-positive urine samples, we would not expect that the high urine cytokine levels in BK-positive patients were associated with active CMV or JC virus infection. Ethnicity did not affect our data, because all patients and HCs were whites. In summary, additional analyses confirmed the previous finding that strong BK virus replication was associated with the strong increases of particular cytokines and soluble cytokine receptors in the urine. The increase of cytokine and cytokine receptor levels in the urine of consistently BK-positive patients was stable and may be helpful for disease monitoring. Mahmoud Sadeghi1 Volker Daniel1 Paul Schnitzler2 Imad Lahdou1 Cord Naujokat1 Martin Zeier3 Gerhard Opelz1 1 Department of Transplantation Immunology University of Heidelberg Heidelberg, Germany 2 Department of Virology University of Heidelberg Heidelberg, Germany 3 Department of Nephrology University of Heidelberg Heidelberg, Germany