Skip to main content

Prognostic significance of the albumin-to-globulin ratio for upper tract urothelial carcinoma

Abstract

Background

Although the albumin-to-globulin ratio (AGR) is a promising biomarker for various malignancies, few studies have investigated its prognostic significance for upper tract urothelial carcinoma (UTUC).

Methods

This retrospective study conformed to the REporting recommendations for tumour MARKer prognostic studies (REMARK) guideline. We reviewed 179 patients with UTUC who underwent radical nephroureterectomy at our institution between 2008 and 2018. Associations of preoperative clinicopathological factors, including the AGR, with cancer-specific survival (CSS) and overall survival (OS) were assessed. The Cox proportional hazards model was used for univariate and multivariable analyses. AGR was dichotomized as < 1.25 and ≥ 1.25, according to the most discriminatory cutoff determined from the receiver operating characteristic curve analysis.

Results

During a median follow-up of 34 months after surgery, 37 patients died from UTUC and 13 died of other causes. The preoperative AGR significantly correlated with pathological T stage, pathological N stage, and adjuvant chemotherapy. Multivariate analyses demonstrated that a decreased (< 1.25) preoperative AGR was an independent poor prognostic factor for both CSS (hazard ratio [HR] = 2.81, P <  0.01) and OS (HR = 2.09, P <  0.05).

Conclusions

Preoperative AGR < 1.25 might serve as a useful prognostic marker for patients with UTUC undergoing radical nephroureterectomy.

Peer Review reports

Background

Upper tract urothelial carcinoma (UTUC) is a relatively rare malignancy that accounts for 5–10% of urothelial carcinomas and generally has a poor prognosis [1, 2]. Radical nephroureterectomy with bladder cuff excision is the gold standard treatment for nonmetastatic UTUC [3], whereas up to 19% of patients with UTUC have metastasis upon initial presentation [4].

Clinicopathological factors [5,6,7,8,9,10,11,12,13,14,15] including laboratory markers [11,12,13,14,15] serve as prognostic markers for UTUC. In contrast, the significance of the albumin-to-globulin ratio (AGR), which serves as a useful biomarker for various malignancies [16,17,18,19,20,21,22,23,24,25,26], has not been fully investigated in UTUC [23,24,25,26]. Therefore, the present study assessed the significance of the association of preoperative AGR on oncological outcomes of patients with UTUC undergoing radical nephroureterectomy.

Methods

This retrospective study conformed to the REporting recommendations for tumour MARKer prognostic studies (REMARK) guideline [27] (Supplementary Table 1 shows the REMARK checklist of the present study). This study was approved by the internal institutional review board of Kyorin University School of Medicine (approval number: 1154).

Patients

We retrospectively reviewed 185 consecutive patients who underwent radical nephroureterectomy with curative intent at Kyorin University Hospital between 2008 and 2018. We excluded six patients because of pathological diagnoses of urothelial dysplasia (n = 3), renal cell carcinoma (n = 2), and squamous cell carcinoma (n = 1), which left 179 available for analysis.

Preoperative AGR

Routine preoperative blood tests including serum total protein and albumin levels (g/dl) were performed within 1 month before surgery. The AGR was calculated using the following formula: AGR = [albumin / (total protein – albumin)]. No patient had active infectious disorders during the blood tests.

Endpoints and follow-up

We assessed the associations of preoperative clinicopathological factors, including the AGR, with cancer-specific survival (CSS) and overall survival (OS). The follow-up period started on the day of surgery. Follow-up information was obtained as of October 2018.

Statistical analysis

Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value of the AGR. Sensitivity, specificity and area under the curve (AUC) were calculated using a 2 × 2 contingency table for different cutoff values of the AGR. The optimal cutoff value of the AGR was determined by maximization of the Youden’s index [Sensitivity − (1 − Specificity)]. Relations of the AGR to other variables were evaluated using the χ2 test or Spearman’s rank correlation coefficient. Survival curves were generated using the Kaplan–Meier method and compared using log-rank tests. The Cox proportional hazard regression model was used for univariate and multivariate analyses. All statistical analyses were performed using JMP Pro version 14.0.0 (SAS Institute, Cary, NC, USA). P <  0.05 was considered to indicate a significant difference.

Results

Patients’ baseline characteristics are summarized in Table 1. The median follow-up was 34 months (interquartile range [IQR], 17–63) months. Thirty-seven patients died from UTUC and 13 died of other causes. ROC curve analysis identified 1.25 as the most discriminatory cutoff value of AGR by maximization of the Youden’s index [Sensitivity − (1 − Specificity)] for both endpoints of CSS and OS (Fig. 1).

Table 1 Patient characteristics (n = 179)
Fig. 1
figure1

ROC curve analyses for (a) CSS and (b) OS. The optimal cutoff value of AGR was estimated as < 1.25 by maximizing the Youden’s index [Sensitivity − (1 − Specificity)] for both endpoints of CSS and OS. Abbreviations: AGR = albumin-to-globulin ratio; CSS = cancer-specific survival; OS = overall survival; ROC = receiver operating characteristic

χ2 test revealed pathological T stage (≥T3, P <  0.01), pathological N stage (N1–3, P <  0.01), and adjuvant chemotherapy (yes, P <  0.05) to be significantly associated with AGR < 1.25, while the other variables (sex, surgical technique, tumor location, tumor grade and previous or synchronous bladder cancer) were not. Spearman’s rank correlation coefficient showed a weakly significant negative correlation between age at surgery and the AGR (ρ = − 0.25, P <  0.01).

Kaplan–Meier curves with log-rank tests showed significant associations of preoperative AGR < 1.25 with shorter CSS (Fig. 2) and OS (Fig. 3). Multivariate Cox proportional hazard regression analyses identified preoperative AGR < 1.25 as an independent poor prognostic factor for both CSS (hazard ratio [HR] = 2.81, P <  0.01) (Table 2) and OS (HR = 2.09, P <  0.05; Table 3).

Fig. 2
figure2

Kaplan–Meier curves depicting CSS in patients with AGR < 1.25 versus ≥1.25 (P < 0.01, log-rank test). Abbreviations: AGR = albumin-to-globulin ratio; CSS = cancer-specific survival

Fig. 3
figure3

Kaplan–Meier curves depicting OS a in patients with AGR < 1.25 versus ≥1.25 (P < 0.01, log-rank test). Abbreviations: AGR = albumin-to-globulin ratio; OS = overall survival

Table 2 Univariate and multivariate Cox proportional hazard regression analyses of CSS
Table 3 Univariate and multivariate Cox proportional hazard regression analyses of OS

Discussion

The present study demonstrates that a decreased (< 1.25) preoperative AGR was an independent indicator of poor prognosis for CSS and OS of patients with UTUC treated with radical nephroureterectomy.

Clinicopathological factors that serve as prognostic factors for UTUC [5,6,7,8,9,10,11,12,13,14,15] include sex [5], age [6], tumor size [7, 8], ureteral involvement [9], and body mass index [10], as well as laboratory markers [11,12,13,14,15] such as the neutrophil-to-lymphocyte ratio [11, 12], albumin [13], hemoglobin [14], and the prognostic nutritional index [15]. On the other hand, the AGR has been reported as a useful biomarker in various malignancies [16,17,18,19,20,21,22,23,24,25,26], including urological cancers [20,21,22,23,24,25,26]. However, the significance of the AGR as a prognostic marker for UTUC has not been fully investigated [23,24,25,26]. For example, a study of a Chinese cohort of 187 operable patients with UTUC [23] demonstrated that AGR < 1.45 is an independent risk factor for poorer CSS and OS. Another study of a Chinese cohort of 620 patients with UTUC treated with radical nephroureterectomy found that AGR < 1.45 is an independent predictor of adverse pathologic features, recurrence-free survival, CSS, and OS [24]. Similarly, analysis of a Japanese cohort of 124 patients with UTUC undergoing radical nephroureterectomy identified AGR < 1.40 as an independent prognostic factor for recurrence-free survival, CSS, and OS [25]. Finally, another Japanese study comprising 105 patients with UTUC undergoing radical nephroureterectomy reported that AGR < 1.24 was an independent predictor for both worse disease-free and overall survivals [26]. Our results are consistent with those of these previous reports and add further evidence in this field.

The association between a low AGR and poor outcome of patients with cancer requires further research. However, the available data show that poor nutritional status or hypoalbuminemia is a negative prognostic factor for certain malignancies [13, 15, 16]. Chronic inflammation involving serum globulins plays a crucial role in tumor proliferation, immune evasion, and metastasis. These serum globulins secreted by tumor-related cells reportedly promote tumor development, immunosuppression, and metastasis [16]. A low AGR may thus reflect the degree of poor nutritional status (hypoalbuminemia) and tumor progression (hyperglobulinemia) in a more sensitive manner than either measure alone and may therefore serve as a highly significant prognostic biomarker. Based on a similar concept as AGR (i.e. use of a ratio), several systemic inflammatory markers, such as the neutrophil-to-lymphocyte ratio [11, 12, 28], platelet-to-lymphocyte ratio [28], and lymphocyte-to-monocyte ratio [28], have been established and well-investigated in the field of oncology, including urothelial carcinoma.

The major limitations of this study are its retrospective, single-institutional design and the limited number of patients. Further studies with larger populations are needed to confirm our results.

Conclusions

Given the significant prognostic associations of the AGR with CSS and OS, AGRs are easy to determine in routine clinical practice, and a preoperative AGR < 1.25 might serve as a useful prognostic biomarker of patients with UTUC treated with radical nephroureterectomy.

Availability of data and materials

Because of ethical restrictions, the raw data underlying this study are available from the corresponding author upon reasonable request.

Abbreviations

AGR:

Albumin-to-globulin ratio

AUC:

Area under the curve

CSS:

Cancer-specific survival

IQR:

Interquartile range

OS:

Overall survival

ROC:

Receiver operating characteristic

UTUC:

Upper tract urothelial carcinoma

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  2. 2.

    Munoz J, Ellison L. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol. 2000;164:1523–5.

    CAS  Article  Google Scholar 

  3. 3.

    Margulis V, Shariat SF, Matin SF, Kamat AM, Zigeuner R, Kikuchi E, Lotan Y, Weizer A, Raman JD. Wood CG; upper tract Urothelial carcinoma collaboration. The upper tract Urothelial carcinoma collaboration. Outcomes of radical nephroureterectomy: a series from the upper tract Urothelial carcinoma collaboration. Cancer. 2009;115:1224–33.

    Article  Google Scholar 

  4. 4.

    Akaza H, Koiso K, Niijima T. Clinical evaluation of urothelial tumors of the renal pelvis and ureter based on a new classification system. Cancer. 1987;59:1369–75.

    CAS  Article  Google Scholar 

  5. 5.

    Fernández MI, Shariat SF, Margulis V, Bolenz C, Montorsi F, Suardi N, Remzi M, Wood CG, Roscigno M, Kikuchi E, Oya M, Zigeuner R, Langner C, Weizer A, Lotan Y, Koppie TM, Raman JD, Karakiewicz P, Bensalah K, Schultz M, Bernier P. Evidence-based sex-related outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: results of large multicenter study. Urology. 2009;73:142–6.

    Article  Google Scholar 

  6. 6.

    Kobayashi H, Kikuchi E, Tanaka N, Shirotake S, Miyazaki Y, Ide H, Obata J, Hoshino K, Matsumoto K, Kaneko G, Hagiwara M, Kosaka T, Oyama M, Nakajima Y, Oya M. Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy. Jpn J Clin Oncol. 2016;46:554–9.

    Article  Google Scholar 

  7. 7.

    Shibing Y, Liangren L, Qiang W, Hong L, Turun S, Junhao L, Lu Y, Zhengyong Y, Yonghao J, Guangqing F, Yunxiang L, Dehong C. Impact of tumour size on prognosis of upper urinary tract urothelial carcinoma after radical nephroureterectomy: a multi-institutional analysis of 795 cases. BJU Int. 2016;118:902–10.

    Article  Google Scholar 

  8. 8.

    Su X, Fang D, Li X, Xiong G, Zhang L, Hao H, Gong Y, Zhang Z, Zhou L. The influence of tumor size on oncologic outcomes for patients with upper tract Urothelial carcinoma after radical Nephroureterectomy. Biomed Res Int. 2016;2016:4368943.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Waseda Y, Saito K, Ishioka J, Matsuoka Y, Numao N, Fujii Y, Sakai Y, Koga F, Okuno T, Arisawa C, Kamata S, Nagahama K, Masuda H, Yonese J, Kageyama Y, Noro A, Tsujii T, Morimoto S, Gotoh S, Kihara K. Ureteral involvement is associated with poor prognosis in upper urinary tract Urothelial carcinoma patients treated by Nephroureterectomy: a multicenter database study. Eur Urol Focus. 2016;2:296–302.

    Article  Google Scholar 

  10. 10.

    Dabi Y, El Mrini M, Duquesnes I, Delongchamps NB, Sibony M, Zerbib M, Xylinas E. Impact of body mass index on the oncological outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. World J Urol. 2018;36:65–71.

    Article  Google Scholar 

  11. 11.

    Azuma T, Matayoshi Y, Odani K, Sato Y, Sato Y, Nagase Y, Oshi M. Preoperative neutrophil-lymphocyte ratio as an independent prognostic marker for patients with upper urinary tract urothelial carcinoma. Clin Genitourin Cancer. 2013;11:337–41.

    Article  Google Scholar 

  12. 12.

    Vartolomei MD, Kimura S, Ferro M, Vartolomei L, Foerster B, Abufaraj M, Shariat SF. Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients. World J Urol. 2018;36:1019–29.

    CAS  Article  Google Scholar 

  13. 13.

    Ku JH, Kim M, Choi WS, Kwak C, Kim HH. Preoperative serum albumin as a prognostic factor in patients with upper urinary tract urothelial carcinoma. Int Braz J Urol. 2014;40:753–62.

    Article  Google Scholar 

  14. 14.

    Yeh HC, Chien TM, Wu WJ, Li CC, Li WM, Ke HL, Chou YH, Wang CJ, Huang SP, Li CF, Liang PI, Huang CN. Is preoperative anemia a risk factor for upper tract urothelial carcinoma following radical nephroureterectomy? Urol Oncol. 2016;34:337.e1–9.

    Article  Google Scholar 

  15. 15.

    Huang J, Yuan Y, Wang Y, Chen Y, Kong W, Xue W, Chen H, Zhang J, Huang Y. Preoperative prognostic nutritional index is a significant predictor of survival in patients with localized upper tract urothelial carcinoma after radical nephroureterectomy. Urol Oncol. 2017;35:671.e1–9.

    Article  Google Scholar 

  16. 16.

    He J, Pan H, Liang W, Xiao D, Chen X, Guo M, He J. Prognostic effect of albumin-to-globulin ratio in patients with solid tumors: a systematic review and meta-analysis. J Cancer. 2017;8:4002–10.

    Article  Google Scholar 

  17. 17.

    Azab BN, Bhatt VR, Vonfrolio S, Bachir R, Rubinshteyn V, Alkaied H, Habeshy A, Patel J, Picon AI, Bloom SW. Value of the pretreatment albumin to globulin ratio in predicting long-term mortality in breast cancer patients. Am J Surg. 2013;206:764–70.

    CAS  Article  Google Scholar 

  18. 18.

    Shibutani M, Maeda K, Nagahara H, Ohtani H, Iseki Y, Ikeya T, Sugano K, Hirakawa K. The pretreatment albumin to globulin ratio predicts chemotherapeutic outcomes in patients with unresectable metastatic colorectal cancer. BMC Cancer. 2015;15:347.

    Article  Google Scholar 

  19. 19.

    Yoshino Y, Taguchi A, Shimizuguchi T, Nakajima Y, Takao M, Kashiyama T, Furusawa A, Kino N, Yasugi T. A low albumin to globulin ratio with a high serum globulin level is a prognostic marker for poor survival in cervical cancer patients treated with radiation based therapy. Int J Gynecol Cancer. 2019;29:17–22.

    Article  Google Scholar 

  20. 20.

    Liu J, Dai Y, Zhou F, Long Z, Li Y, Liu B, Xie D, Tang J, Tan J, Yao K, Zhang Y, Tang Y, He L. The prognostic role of preoperative serum albumin/globulin ratio in patients with bladder urothelial carcinoma undergoing radical cystectomy. Urol Oncol. 2016;34:484.e1–8.

    CAS  Article  Google Scholar 

  21. 21.

    Niwa N, Matsumoto K, Ide H, Nagata H, Oya M. Prognostic value of pretreatment albumin-to-globulin ratio in patients with non-muscle-invasive bladder Cancer. Clin Genitourin Cancer. 2018;16:e655–61.

    Article  Google Scholar 

  22. 22.

    Koparal MY, Polat F, Çetin S, Bulut EC, Sözen TS. Prognostic role of preoperative albumin to globulin ratio in predicting survival of clear cell renal cell carcinoma. Int Braz J Urol. 2018;44:933–46.

    Article  Google Scholar 

  23. 23.

    Zhang B, Yu W, Zhou LQ, He ZS, Shen C, He Q, Li J, Liu LB, Wang C, Chen XY, Fan Y, Hu S, Zhang L, Han WK, Jin J. Prognostic significance of preoperative albumin-globulin ratio in patients with upper tract Urothelial carcinoma. PLoS One. 2015;10:e0144961.

    Article  Google Scholar 

  24. 24.

    Xu H, Tan P, Ai J, Huang Y, Lin T, Yang L, Wei Q. Prognostic impact of preoperative albumin-globulin ratio on oncologic outcomes in upper tract Urothelial carcinoma treated with radical Nephroureterectomy. Clin Genitourin Cancer. 2018;16:e1059–68.

    Article  Google Scholar 

  25. 25.

    Otsuka M, Kamasako T, Uemura T, Takeshita N, Shinozaki T, Kobayashi M, Komaru A, Fukasawa S. Prognostic role of the preoperative serum albumin : globulin ratio after radical nephroureterectomy for upper tract urothelial carcinoma. Int J Urol. 2018;25:871–8.

    CAS  Article  Google Scholar 

  26. 26.

    Fukushima H, Kobayashi M, Kawano K, Morimoto S. Prognostic value of albumin/globulin ratio in patients with upper tract Urothelial carcinoma patients treated with radical Nephroureterectomy. Anticancer Res. 2018;38:2329–34.

    CAS  PubMed  Google Scholar 

  27. 27.

    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer. 2005;41:1690–6.

    Article  Google Scholar 

  28. 28.

    Cantiello F, Russo GI, Vartolomei MD, ARA F, Terracciano D, Musi G, Lucarelli G, Di Stasi SM, Hurle R, Serretta V, Busetto GM, Scafuro C, Perdonà S, Borghesi M, Schiavina R, Cioffi A, De Berardinis E, Almeida GL, Bove P, Lima E, Ucciero G, Matei DV, Crisan N, Verze P, Battaglia M, Guazzoni G, Autorino R, Morgia G, Damiano R, de Cobelli O, Mirone V, Shariat SF, Ferro M. Systemic Inflammatory Markers and Oncologic Outcomes in Patients with High-risk Non-muscle-invasive Urothelial Bladder Cancer. Eur Urol Oncol. 2018;1:403–10.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Dr. Alla Bradley from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.

Funding

None.

Author information

Affiliations

Authors

Contributions

SO and ST contributed to the conception, study design, analysis, interpretation of data, and drafted the first manuscript. SM, RM, MS, NN, KM, YN, TY, MK, and MT contributed to acquisition of data. TO, EH, and HF supervised the study, helped to draft the manuscript, and were involved in revising it critically for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Satoru Taguchi.

Ethics declarations

Ethics approval and consent to participate

The present study was approved by the internal institutional review board of Kyorin University School of Medicine (approval number: 1154). This was a retrospective study, and additional informed consent was not required by the board.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Additional file 1:

Table S1. The REporting recommendations for tumour MARKer prognostic studies (REMARK) checklist of the present study (based on the original guideline [27]).

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Omura, S., Taguchi, S., Miyagawa, S. et al. Prognostic significance of the albumin-to-globulin ratio for upper tract urothelial carcinoma. BMC Urol 20, 133 (2020). https://doi.org/10.1186/s12894-020-00700-8

Download citation

Keywords

  • AGR
  • Albumin-to-globulin ratio
  • Biomarker
  • Radical nephroureterectomy
  • REMARK
  • Upper tract urothelial carcinoma
\