Objectives: Because of recent developments in immunosuppressive therapy, renal transplant outcomes have improved. Although reports on the association between immunosuppressive therapy and malignant disease are available, the results are controversial. The neutrophil-to-lymphocyte ratio has been reported as an easy tumor marker for predicting the prognoses of some solid tumors. In the present study, we examined changes in neutrophil-to-lymphocyte ratio after renal transplant and discussed cases in which malignant disease developed after renal transplant.
Materials and Methods: Our study included 137 patients who underwent renal
transplant between August 2001 and September 2015. Four of these patients (2.9%)
developed malignant disease. The neutrophil-to-lymphocyte ratio was calculated
based on the numbers of neutrophils and lymphocytes in the complete blood count
and evaluated before and at 1, 3, 6, and 12 months and at 3 years after renal
Results: The neutrophil-to-lymphocyte ratio was markedly high at 1 week and 1 month after renal transplant and gradually decreased until it became stable at 3 months posttransplant. In patients with malignant disease, there was a gradual increase in the neutrophil-to-Iymphocyte ratio after renal transplant.
Conclusions: We observed dramatic differences in the neutrophil-to-lymphocyte ratio at 1 and 3 months after renal transplant. The neutrophil-to-lymphocyte ratio of patients with malignant disease after renal transplant continued to increase.
Key words : Immunosuppressants, Kidney transplantation, Malignant disease
Outcomes after renal transplant have been improving due to developments in immunosuppressive therapy. Calcineurin inhibitors (CNI), mycophenolate mofetil (MMF), methylprednisolone, and basiliximab are now used as standard immunosuppressive treatments. Although immunosuppressive drugs are needed to protect the transplanted kidney, the increased risk of lifestyle-related diseases and malignant diseases remains a matter of concern.
Although many reports have suggested an association between immunosuppressive therapy and malignant disease, the results remain controversial.1-3 For example, cyclosporine and tacrolimus have been reported to be associated with the development of cancer.4 On the other hand, MMF has been reported to have an indirect antitumor effect.
The use of neutrophil-to-lymphocyte ratio (NLR) has been reported as an easily measurable tumor marker that predicts the prognosis in some solid malignant tumors.5,6 Patients with higher NLR show poorer prognosis. It is possible that lower lymphocyte levels are associated with cancer development. In the present study, we examined NLR changes after renal transplant and analyzed cases in which malignant disease developed after renal transplant.
Materials and Methods
The Institutional Review Board of Yokohama City University Hospital approved this study. Our analysis included 137 patients who underwent renal transplant between August 2001 and September 2015. Malignant disease developed in 4 of these patients (2.9%). The NLR was calculated from the numbers of neutrophils and lymphocytes in the complete blood count. The NLR was evaluated before and at 1 month, 3 months, 6 months, 12 months, and 3 years after renal transplant.
Immunosuppression protocols used to prevent rejection in transplanted organs vary by institution. At our center, the standard regimen includes CNIs, MMF, and methylprednisolone. Immunosuppressive levels are affected by absorbance and metabolism, which differ according to the individual. Therapeutic drug monitoring is performed to monitor the concentration of immunosuppressive agents, and the dose is adjusted as necessary.7 The immunosuppression protocol is adjusted as follows after transplant. Mycophenolate mofetil is introduced at a dose 1500 mg/day for a 50-kg adult (approximately 1000 mg/m2/d). If the patient has an adverse reaction or the trough concentration is high, then the dose of MMF is reduced to 1250 mg/day. Calcineurin inhibitors are controlled to maintain a trough concentration of 10 to 12 ng/mL until 2 weeks after renal transplant and then administered at 5 ng/mL for 1 year after transplant. Thereafter, the trough concentration is set to 3 ng/mL and adjusted in the event of CNI toxicities. High-dose methylprednisolone is introduced during the perioperative period and reduced at a dose of 4 mg/day within 4 months after surgery. If a patient has a primary disease that requires steroid therapy to be maintained, such as systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated glomerulonephritis, or immunoglobulin A glomerulonephritis, methylprednisolone is continued.
Median (range) age of patients without malignant disease after renal transplant was 54 years (range, 12-70 y). Median age of patients with malignant disease after renal transplant was 53 years (range, 41-73 y). None of the patients showed infections at time of pretransplant blood tests. The types of malignancies that developed in patients included breast cancer, ovarian cancer, gastric cancer, and prostate cancer. Characteristics of patients with malignant diseases after renal transplant are shown in Table 1.
Neutrophil-to-lymphocyte ratio and patient outcomes
Figure 1 shows the sequence of changes in the NLR after transplant. We observed that NLR was markedly high at 1 month after renal transplant and gradually decreased until it became stable at 3 months after transplant (Figure 1). In patients who died of malignant diseases (patients 1, 2, and 3), NLR increased continuously after renal transplant (Figure 2, Table 2).
Recent innovations in powerful immunosuppressive agents have contributed to a longer organ rejection-free period. On the other hand, the incidence of malignant disease after renal transplant has been increasing.8 Hoshida and associates9 reported that the standardized incidence rate of cancer after renal transplant in Japan is 2.78. With regard to types of cancer, rates of skin cancer and malignant lymphoma development are higher in renal transplant patients than in patients who have not had renal transplant. In Japan, the rates of renal cancer and digestive organ cancer development are high.9-11 The reported risk factors for malignant diseases after organ transplant include age, CNI use, and preoperative dialysis.2,12
The use of tumor markers for cancer screening can help to diagnose cancer at an early stage. The NLR, which is determined based on the complete blood count, can be easily calculated during clinical examination. Previous studies have shown that inflammation is associated with the development and progression of cancer. Some authors have revealed that NLR is an independent prognosticator in various solid tumors, including renal cell carcinoma, bladder urothelial carcinoma, and prostate cancer.13-16 Based on these findings, the use of NLR to detect malignant disease could be useful.
In our study, NLR was markedly increased at 1 week and 1 month after renal transplant and then gradually decreased until it became stable. This phenomenon was affected by postoperative steroid therapy. Steroids suppress interleukin 2 development and result in a decrease in the number of T-cell lymphocytes. Steroids also have a negative effect on macrophages and then suppress the immunosuppressive effect by inhibiting both interleukin 1 and interleukin 6. Steroids induce neutrophil production in peripheral blood, which contributes to the elevation of the NLR. On the other hand, immunosuppressive drugs other than steroids have a lymphocyte-reducing effect, which contributes to the elevation of NLR. Although immunosuppressive agents have some influence, their long-term effects on NLR remain unknown.
The NLR results of patients who died during our follow-up period continued to increase during follow-up. These results suggest that observing NLR in renal transplant patients could help to detect malignant disease.
In conclusion, our study revealed that there were dramatic changes in the NLR within 3 months after renal transplant. Furthermore, the NLR values of patients who developed malignant disease posttransplant continued to increase during follow-up.
Volume : 16
Issue : 5
Pages : 546 - 549
DOI : 10.6002/ect.2017.0098
From the 1Department of Urology, Yokohama City University Graduate School of
Medicine, Yokohama, Japan; and the 2Departments of Urology and Renal
Transplantation, Yokohama City University Medical Center, Yokohama, Japan
Acknowledgements: The present study was supported by grants from KAKENHI (16K20152) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors declare no conflicts of interest in association with the present study. Due to ethical restrictions, raw data are available from the corresponding author upon request. *Mari Ohtaka and Takashi Kawahara contributed equally to this work.
Corresponding author: Takashi Kawahara, Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 2320024, Japan
Phone: +81 45 261 5656
Figure 1. Changes in Neutrophil-to-Lymphocyte Ratio (NLR) After Renal Transplant (Patients With Malignant Disease Were Excluded)
Figure 2. Changes in Neutrophil-to-Lymphocyte Ratio (NLR) After Renal Transplant (RTx) in Patients Who Developed Malignant Disease
Table 1. Characteristics of Patients With Malignant Diseases After Renal Transplant
Table 2. Neutrophil-to-Lymphocyte Ratio Before and After Renal Transplant in Patients Who Developed Malignant Disease