Urinary C‑X‑C motif chemokine 13 is a noninvasive biomarker of antibody‑mediated renal allograft rejection
- Authors:
- Published online on: June 22, 2018 https://doi.org/10.3892/mmr.2018.9211
- Pages: 2399-2406
Abstract
Introduction
Kidney transplantation has been established as the optimal renal replacement therapy for end-stage renal diseases, which surpasses dialysis treatment for the quality and quantity of life, as well as cost-effectiveness (1); however, rejection episodes and infection remain the major obstacles associated with kidney transplantation. Based on the increasing application of non-invasive monitoring technologies, the diagnosis of renal insufficiency during the early stages post-transplantation has progressed considerably in past decades; however, specific biomarkers for the noninvasive diagnosis/prognosis of acute rejection (AR), particularly antibody-mediated rejection (ABMR), are yet to be identified.
Chemokine (C-X-C motif) ligand 13 (CXCL13), otherwise known as B cell-attracting chemokine 1, is a small cytokine belonging to the CXC chemokine superfamily (2). As its name suggests, CXCL13 is selectively chemotactic for circulating B cells by interacting with chemokine receptor (CXCR)5 (3,4), a 7-transmembrane G-protein-coupled receptor expressed on the surface of mature B cells and a subset of memory cells (5,6). The gene for CXCL13 is located on human chromosome 4 in a cluster with other CXC chemokines (7), including interleukin-8 and interferon-inducible protein 10.
Recent studies suggest that the ligation of CXCR5 with CXCL13 may lead to an aberrant aggregation of B cells, which has been confirmed in rheumatoid arthritis, gastric lymphoma, and central nervous system lymphoma (8–11). Additionally, a notable colocalization of CXCL13 expression with CXCR5 and cluster of differentiation 20-positive B lymphocytes has also been detected in renal allografts undergoing rejection (12,13). In addition, our previous study revealed that CXCL13 expression levels are highly upregulated in the peripheral blood mononuclear cells of patients with AR (14).
The particular interaction between CXCL13 and B lymphocytes, as well as the significance of B cell infiltration in transplant rejection, may be detected noninvasively as an intragraft signature by measuring the levels of CXCL13 in urine samples. Furthermore, such an investigation may contribute to the monitoring of immune kinetics. To test this hypothesis, the urinary protein expression levels of CXCL13 were measured following renal transplantation in a total of 146 renal allograft recipients. The present study examined whether urinary CXCL13 may effectively identify AR, in particular ABMR. Secondly, whether the early elevation of urinary CXCL13 expression levels may serve as an indication of graft function was investigated.
Materials and methods
Study population and sample collection
The present study retrospectively reviewed 146 patients (aged 22–69 years old; 97 males and 49 females) who received a single kidney transplantation from donors who had succumbed to mortality between June 2006 and December 2009 at the Kidney Disease Center, the First Affiliated Hospital of College of Medicine of Zhejiang University (Hangzhou, China). Fresh first-morning urine specimens were routinely collected from the patients every 2 weeks during the first 2 months following transplantation. In addition, urine samples were collected from patients who had undergone transplantation and were scheduled for a biopsy with a serum creatinine (Scr) concentration ≥25% above baseline levels post-transplantation, and from patients who were to undergo a protocol needle biopsy with stable renal function within 2–3 months post-transplantation. Furthermore, urine samples were obtained from 36 patients with stable renal function and 21 patients with AR every day within the first week and at a one-week interval up to the first month post-transplantation. According to the mean urinary CXCL13/Cr levels (>2 pg/µmol Cr or <2 pg/µmol Cr) exhibited by patients within the first week post-transplantation, patients were separated into two groups: High CXCL13/Cr levels group (>2 pg/µmol Cr) and low CXCL13/Cr levels (<2 pg/µmol Cr) group. For these 57 patients, renal function at 3, 6 and 12 month time intervals post-transplantation were investigated. On the day of the biopsy, urinary samples were collected prior to biopsy collection. Furthermore, 40 healthy individuals were included as controls (aged 27–65 years old; 24 males and 16 females) that did not exhibit any signs of infection or malignant tumors. On the first day of recruitment, one urine sample was collected from each patient. All patients were assigned to a diagnostic category based on an aggregate of all available diagnostic data, including clinical and pathological manifestation as determined by histological analysis (15).
Patients classified in the AR group exhibited histological alterations following H&E and Periodic Acid-Schiff (PAS) staining. Immunohistochemical analysis was performed using the Cd4 stain. For H&E and PAS staining, renal tissues were fixed in a 4% formaldehyde solution for 48 h at 24°C and then embedded in paraffin. Sections (4 µm) were both stained using H&E stain at 24°C for 2 h and PAS stain at 24°C for 3 h. For IHC staining, paraffin embedded sections (4 µm), fixed in a 4% formaldehyde solution for 48 h at 24°C, and subsequently incubated for 30 min at 37°C with a polyclonal rabbit anti-human C4d antibody (cat. no. BI-RC4D; 1:50; Biomedica, Inc., Vienna, Austria). Following this, sections were blocked with 5% bovine serum albumin (cat. no. A1933; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) at 24°C for 30 min. Following three washes with PBS, sections were incubated for 30 min at 24°C with peroxidase AffiniPure goat anti-rabbit secondary antibodies (cat. no. 111-035-003; 1:4,000; Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA). Antibody detection was performed using a DAB Horseradish Peroxidase Color Development Kit (cat. no. GA042329; Gene Tech Co., Ltd., Hong Kong, China). Images of these stained sections were obtained using a light microscope (magnification, ×200 and ×400). Classification was performed using the Banff 97 criteria (16), while meeting the clinical criteria associated with renal dysfunction (Scr elevation of ≥25% above baseline within 6 months post-transplant); patients classified as stable renal transplant manifested as normal allograft function and no abnormal pathological findings (NO-AR) in the protocol biopsies performed 2–3 months following transplantation. Primary grafts were also received from deceased donors.
All patients provided written informed consent. All procedures performed in studies involving human participants were approved by the Ethics Committee of the First Affiliated Hospital of College of Medicine of Zhejiang University (Hangzhou, China) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards (Reference number: 2017–390).
In the present study, immunosuppressive agents were used as previously described (17,18). All patients received a regimen of three immunosuppressive drugs at the time of transplantation, comprising a calcineurin inhibitor (tacrolimus), prednisone and azathioprine or mycophenolate mofetil. Anti-rejection therapy following a clinical and biopsy-proven diagnosis of AR constituted a 3-day course of intravenous methylprednisolone (6–10 mg/kg per day, once a day). A lack of response to steroid treatment (graft function exhibited no improvement or worsened) was defined as steroid-resistant AR (SRAR). Histology was classified according to the Banff 97 classification (16,19) and was performed by two experienced renal pathologists in a blinded fashion.
Fresh urinary samples were collected and centrifuged for 10 min at 800 × g at 4°C, using a D-37520 Sorvall Legend RT centrifuge (Heraeus Holding GmbH, Hanau, Germany). The supernatant was frozen in 1 ml aliquots at −80°C. Urinary Cr and protein were detected in all samples.
ELISA: Quantification of CXCL13 in urine samples
The expression levels of CXCL13 were measured in urinary samples using a commercial human CXCL13 ELISA kit, according to the manufacturer's protocols (R&D Systems, Inc., Minneapolis, MN, USA, cat. no. DCX130). All samples were undiluted and analyzed in duplicate.
Statistical analysis
To eliminate the influence of renal function on urinary protein quantitation, all urinary CXCL13 levels were normalized to urine creatinine (Cr) in the present study. Summary statistics for normally distributed quantitative variables were expressed as the mean ± standard deviation. For non-normally distributed variables, we used the median and interquartile range (IQR). Differences in the continuous variables were judged using a Mann-Whitney U test or Kruskal-Wallis H test followed by Tukey's post hoc test. A conventional receiver operating characteristic (ROC) curve was conducted to determine the sensitivities and specificities for patients with and without AR. Youden's index, defined as sensitivity + specificity-1, was used to calculate the diagnostic threshold. All statistical analyses were performed using SPSS software package (version 23.0; IBM Corp., Armonk, NY, USA), and a two-sided P<0.05 was considered to indicate a statistically significant difference.
Results
Patients and baseline clinical and biopsy characteristics
A total of 146 patients who had both biopsy results and matched urine samples were analyzed in the present study, including 49 patients with biopsy-proved AR. Among the 49 patients with AR, 37 were diagnosed as acute cellular rejection (ACR), exhibiting significant infiltration of interstitial mononuclear cells, including >25% of parenchyma affected and moderate (>4 mononuclear cells/tubular cross section) to severe tubulitis (>10 mononuclear cells/tubular cross section); and 12 were diagnosed with ABMR, exhibiting microvascular inflammation or arteritis and positive C4d staining results (data not shown). Demographic information for the four histologically-defined groups is summarized in Table I, and no differences in the baseline characteristics were observed (P>0.05). The remaining 97 biopsy specimens revealed NO-AR patients (n=58) in the protocol biopsy, and dysfunction with no rejection (DNR, n=39), including acute tubular necrosis (ATN; n=10) and chronic allograft nephropathy (CAN; n=29) in the indication biopsy.
 | Table I.Baseline characteristics of transplant recipients, grouped according to histological results. |
Urinary CXCL13/Cr is a diagnostic biomarker of acute renal allograft rejection
As presented in Fig. 1, the CXCL13/Cr urinary levels were significantly different between the diagnostic groups (P<0.0001). Urinary CXCL13/Cr was notably low in NO-AR (median: 0.244; IQR, 0.164–0.562 pg/µmol Cr) and healthy control subjects (median: 0.275; IQR, 0.165–0.409 pg/µmol Cr) (P=0.772). Conversely, the levels of CXCL13/Cr in the urine were differentially elevated in patients with ATN (median: 2.46; IQR, 1.370–3.775 pg/µmol Cr; P<0.001), CAN (median: 0.706; IQR, 0.278–2.309 pg/µmol Cr) (P=0.01), and AR in particular (median: 2.438; IQR, 0.802–8.261 pg/µmol Cr); P<0.0001) compared with patients with NO-AR. It is important to note that the urinary CXCL13/Cr levels in patients with AR were significantly higher than that of patients with DNR (ATN + CAN; P=0.034).
A ROC curve analysis for CXCL13/Cr was conducted to assess its performance in the diagnosis of AR (Fig. 2), compared with the diagnosis of NO-AR. The results revealed that CXCL13/Cr yielded a good diagnostic power, with an area under the curve (AUC) of 0.818 [95% confidence interval (CI): 0.732–0.903]. At the cut point for optimizing the diagnostic effect, the sensitivity and the specificity reached 84 and 79%, respectively. In addition, the analysis was repeated while distinguishing AR from the DNR diagnosis, which yielded an AUC of 0.632 (95% CI: 0.516–0.748; P=0.034).
Urinary CXCL13/Cr level identifies ABMR
Among the 49 patients with AR, 37 were diagnosed as ACR and 12 were ABMR according to the antibody-mediated rejection criteria. As expected, the levels of urinary CXCL13/Cr in the patients with ABMR (median: 18.559; IQR: 5.206–35.281 pg/µmol Cr) were significantly higher than those with ACR (median: 1.237; IQR: 0.686–4.425 pg/µmol Cr) (Fig. 3).
A ROC curve was performed to determine the discriminatory capacity of CXCL13/Cr levels for ABMR. The results indicated that urinary CXCL13/Cr effectively distinguished ABMR from ACR with an AUC of 0.856 (95% CI: 0.701–1.0; Fig. 4).
Levels of urinary CXCL13/Cr are associated with the response to anti-rejection treatment and prognosis
The present study analyzed the association between CXCL13/Cr levels in the urine specimens obtained prior to biopsy with the response to anti-rejection therapy. As aforementioned, the AR recipients received anti-rejection treatment with high-dose methylprednisolone. There were 18 patients who demonstrated a positive response to anti-rejection treatment, and Cr declined to baseline levels following anti-rejection therapy (steroid-sensitive). Conversely, 31 recipients showed a poor response to anti-rejection treatment, in whom Cr did not recover to baseline levels and were maintained above 200 µmol/l following anti-rejection therapy (steroid-resistant). Additionally, 6 patients lost renal function and returned to dialysis after 3 months. Compared with patients with steroid-sensitive AR, urinary CXCL13/Cr levels were significantly higher in patients with SRAR (median: 5.55; IQR: 1.508–11.874; P<0.001), as presented in Fig. 5. Therefore, urinary CXCL13/Cr may also be used to detect steroid-resistant rejection among patients with AR. An ROC analysis was performed, which revealed that the CXCL13/Cr levels in the urine may be a moderately good predictor of a poor response to anti-rejection treatment, with an AUC of 0.810 (95% CI: 0.676–0.945). Based on the ROC curve (Fig. 5), a CXCL13/Cr value of 0.9 was associated with 90% sensitivity and 67% specificity for detecting a patient with steroid-resistant rejection; however, no significant discrepancy was observed between the recipients with allograft dysfunction and reversible acute rejection (P=0.259).
Post-transplantation urinary CXCL13/Cr levels are associated with restricted graft outcome
Urine samples were obtained from 36 patients with stable renal function and 21 patients with AR every day within the first week and at a one-week interval up to the first month post-transplantation. These samples were additionally used to investigate whether elevated CXCL13/Cr levels in the urine within the first month post-transplantation were predictive of graft function after 3, 6 and 12 months. The 57 patients were divided into two groups according to the individual mean urinary CXCL13/Cr levels within the first month post-transplantation; 2 pg/µmol Cr was defined as the cutoff value. With an exception of 12 months, the 3 and 6-month estimated glomerular filtration rates were significantly lower in patients with high CXCL13/Cr levels (>2 pg/µmol Cr) compared with in patients with low CXCL13/Cr levels (<2 pg/µmol Cr; Fig. 6). In addition, whether elevated levels of urinary CXCL13/Cr during the first month post-transplantation were associated with poor graft function independent of AR was investigated in the present study. Urinary CXCL13/Cr levels of the patients in the group without any signs of clinical rejection were analyzed separately. The results of the analysis indicated that there was no significant difference in the graft function between patients with high urinary CXCL13/Cr and the other patients throughout the entire first year (data not shown).
Discussion
The accurate and timely detection of transplant rejection and effective therapy are essential for the long-term survival of kidney transplant patients. Measurement of Scr following kidney transplantation is one of the most widely used methods of monitoring renal allograft function; however, the elevation of Scr is a relatively late event of intragraft injury (20).
Some publications have revealed that distinct alterations occur in the levels of certain proteins in the urine obtained from transplant patients during AR, which are notably pronounced compared with alterations in Scr. For example, Hu et al (21) reported that CXCL9 and CXCL10 are associated with acute renal injury, by screening urine samples for 23 types of chemokines and cytokines. Matz et al (20) further demonstrated that CXCL-10 expression in the urine may be used to identify patients with ongoing AR episodes several days prior to a biopsy based on increasing Scr levels. In addition, data from a multicenter observational Clinical Trials in Organ Transplantation Protocol-01 (CTOT-01) (22) revealed that CXCL9 protein levels possess a strong predictive value for noninvasively diagnosing T cell-mediated rejection (TCMR). In addition, Ho et al (23) recently reported that elevated urinary matrix metalloproteinase-7 may be used to detect underlying renal allograft inflammation and injury, which may improve the overall diagnostic performance of urinary CXCL10 for distinguishing normal histology from subclinical and clinical injury.
ABMR has gradually become a major problem and is now considered to be the main cause of long-term allograft dysfunction compared with TCMR (24); however, few studies have succeeded in identifying specific biomarkers for the diagnosis and noninvasive serial monitoring of ABMR. Thus, ABMR is often underdiagnosed in clinical research and routine clinical practice. It was reported in the CTOT-01 study (22) that only two ABMRs and four mixed rejections were diagnosed among 150 indication biopsies.
Using quantitative polymerase chain reaction, we previously reported that CXCL13 expression levels are significantly elevated in the peripheral blood mononuclear cells of transplant rejection patients, which are also associated with a poor response to anti-rejection therapy (14). Furthermore, an expression analysis of biopsy specimens indicated that the intrarenal CXCL13 mRNA expression levels were 27-fold higher in transplants with B-cell clusters, compared with in rejecting allografts without B-cell aggregation. Collectively, these results suggest a potential role for CXCL13 in AR, particularly in ABMR (13).
The present study reported that transplant patients with AR episodes exhibited significantly increased urinary CXCL13 protein expression compared with patients with stable renal function, ATN, as well as CAN. It is important to note that the CXCL13 expression levels of almost all healthy controls were near the lowest threshold of detection. In addition, among patients with AR, the severity was associated with the CXCL13 levels in the urine, which may be explained by the existence of a positive feedback mechanism between CXCL13 and its receptor, CXCR5 (25). Additionally, higher CXCL13 levels in the urine of patients with ABMR were observed, compared with in patients with ACR. Therefore, the present study conducted an ROC curve to test the discriminatory power of CXCL13 for ABMR. The results revealed that AUC reached up to 0.856, with a cut point of 8.26 pg/µmol creatinine. These findings were consistent with the results of Steinmetz et al (13) and our previous study (14), which generated a convincing conclusion that the detection of urinary CXCL13 levels may provide a good basis for the clinical diagnosis of AR and more importantly, distinguish it from other patterns of rejection.
The prognostic attributes of CXCL13 expression for AR, particularly ABMR, were further analyzed by conducting kinetic observations of CXCL13 protein levels in urinary specimens obtained from a subset of transplant patients. The present study revealed that the 3 and 6-month renal function of patients with high levels of CXCL13/Cr post-transplantation was decreased compared with patients exhibiting low CXCL13/Cr levels; however, no variations were observed when analysis was limited to patients without AR. These data revealed an association between enhanced CXCL13 expression in the urine during the first month and intragraft immune activation, which may result in AR and subsequent compromised graft function.
The possible origin of CXCL13 has been investigated in previous studies. In murine secondary lymphoid organs, CXCL13 is primarily produced by stromal cells resident in B cell follicles, comprising follicular dendritic cells and marginal reticular cells (26,27). Conversely, germinal-center follicular helper T (Tfh) cells may be potent producers of CXCL13 in humans (28,29). The early induction of CXCL13 in the graft may be the result of tissue injury and innate immune activation leads to the infiltration of inflammatory cells (such as Tfh cells), which initiates the secretion of various chemokines, including CXCL13. The release of CXCL13 may further increase the recruitment of activated leukocytes to the graft in a self-sustaining positive feedback loop thereafter.
The primary strength of this assay is its non-invasiveness, which provides the opportunity for frequent, serial immune monitoring. Compared with blood biomarkers, urine markers have several advantages, including the non-invasive nature of sample collection and few interfering proteins. Thus, this assay can be performed in clinical practice to instruct clinical decision-making with respect to the requirement for a biopsy (separating patients into those that should undergo an immediate biopsy from those that may be followed-up and even taper their immunosuppressive therapy). Furthermore, this test may be used to predict patient responses to anti-rejection therapy.
The present study was associated with several limitations: Firstly, the clinical-pathological classification of all patients relied on an allograft histological examination, which may have been subject to sampling error. Secondly, this was a retrospective analysis and there was a lack of data on peritubular capillaritis, and donor-specific antibody status, to regroup all patients according to the updated Banff criteria (30). Thus, it is possible that mixed rejection phenotypes may have contaminated the ACR groups; however, the relatively small in the quantity of ABMR patients suggests that if the ACR group was contaminated with mixed rejection, the differences in urinary CXCL13 levels between ACR and ABMR patients may have been underestimated in the present study. Finally, the cohort size of the present study was small, and these results will require validation in larger prospective cohorts.
In conclusion, in addition to confirming the feasibility of using urinary CXCL13 protein levels for the noninvasive diagnosis of AR, the results of the present study demonstrated that urinary CXCL13/Cr levels were highly associated with ABMR, which may serve to distinguish ABMR from ACR. Furthermore, patients with heightened urinary CXCL13/Cr were associated with a poor response to steroid treatment and restricted short-term graft function. Finally, the present study suggested that monitoring the expression of CXCL13 protein in the urine of renal transplant recipients may have contributed to early individualized rectifications of immunosuppressive therapy and therefore, lowered the incidence of severe graft damage.
Acknowledgements
The authors would like to thank the pathologists from the Kidney Disease Immunology Laboratory, the First Affiliated Hospital of Zhejiang University (Hangzhou, China).
Funding
The present study was supported by grants from the Medical and Health Technology Development Program in Zhejiang (grant no. 2014KYA057) and the Foundation of Zhejiang Provincial Natural Science Foundation of China (grant no. LQ16H050003).
Availability of data and materials
The original datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contribution
JC and DC designed the study. CW and WP performed sample collection. ZJ and DC performed sample collection, and acquired and analyzed the data. DC and ZJ contributed to the writing and editing of the manuscript.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were approved by the Ethics Committee of the First Affiliated Hospital of College of Medicine of Zhejiang University (Hangzhou, China). All patients provided written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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