As the first study to evaluate the prognostic value of serum α-HBDH in UTUC patients after RNU, the present study proposed that preoperative serum α-HBDH value was an independent biomarker for predicting survival outcomes by retrospectively analyzing 544 UTUC patients who underwent RNU in Southwest China. Moreover, we built a nomogram based on α-HBDH and 5 other variables, and verified the predictive accuracy of the nomogram to further evaluate the predictive value of α-HBDH.

α-HBDH, which plays a role in catalyzing the oxidation of α-hydroxybutyrate to α-ketobutyric acid, is one of the enzymes that contributes to the formation of the myocardial enzyme spectrum and reflects hemolysis and heart injury when the level increases [13, 14]. The increase in α-HBDH in serum was not only the result of myocardial injury, but also associated with the damage to the renal and hematologic systems, which reflected the abnormity of multiple systems and might be a predictive factor for adverse prognosis of patients with systemic disease, such as viral infection and malignant carcinomas.

In 2021, Liu et al. reported their findings that the in-hospital mortality and disease severity of patients infected by SARS‐Cov‐2 were significantly associated with the α-HBDH level [15, 16]. However, such findings were confounded by the coexisting factors (age, white blood cell count, IL‐6, D‐dimer, LDH, lymphocyte count, and albumin levels), and further research about the specific mechanism is needed. In the present study, age, albumin level and LDH were also included. Although UTUC patients in the α-HBDH-high group had advanced age and lower albumin levels, these two factors did not have a significant impact on oncological outcomes. Our data showed that α-HBDH, which is an isoenzyme of LDH and could represent LDH1 and LDH2, has a similar or parallel expression with LDH in serum [17]. However, further Cox analysis indicated that there was a significant association between the serum α-HBDH value and CSS in the whole group and even localized UTUC, while such an association was not found for LDH. Interestingly, a study, conducted by our center, investigated the effect of LDH on the prognosis of UTUC and found that the LDH-high group did not reach a significant difference in metastasis-free survival with the comparison of LDH-low group [8]. The different cutoff values of LDH might be the reasons for such a difference. More future studies are needed to validate the conclusion and further explore the relationship by combining LDH and α-HBDH.

Previous studies on α-HBDH have mostly focused on myocardial infarction, atherothrombotic and liver injury and only a few on cancers [14, 18, 19]. The phenomena concerning the elevation of serum α-HBDH in malignant carcinomas have been observed in several specific cancers. In children, the simultaneous presence of high α-HBDH values with musculoskeletal symptoms suggests the necessity of screening for the occult tumors, such as acute lymphocytic leukemia, lymphoma, neuroblastoma and so on [9]. After comparing 51 cases of testicular germ tell tumors with 40 healthy controls, Khanolkar et al. proposed that serum LDH and α-HBDH could both be used as tumor markers in the diagnosis of testicular germ cell tumors as well as prognostic indicators in monitoring therapy. Moreover, α-HBDH was more specific in monitoring therapy than serum LDH [10]. Recently, Yuan et al. launched a study on the prognostic value of α-HBDH in lung cancer patients, and found that α-HBDH was an independent risk factor for CSS and that the sensitivity of α-HBDH was higher than that of LDH [11]. Although the cutoff value of α-HBDH in our study (158 U/L) was different from that in Yuan’s study (220 U/L), we divided the included patients at a ratio of nearly 1:3. Moreover, benefitting from a relatively larger sample size, in the present study, we further performed subgroup analysis by pathological tumor stage and found a more precise conclusion, which might represent precise applicability. Therefore, the application of α-HBDH for oncological outcome prediction is only in its infancy, and whether the ability of α-HBDH to predict survival is effective for other tumors remains to be witnessed.

In addition to the tumor size, stage and grade which are level C evidence recommended by the EAU guidelines, another independent risk factor, that cannot be ignored, for CSS is the lymph node status [2]. In our study, patients with LNM tended to be associated with worse CSS, which was consistent with a systematic review [20]. However, there were several adverse conditions that might affect the conclusion. In our center, lymphadenectomy was not performed routinely (72.3% patients were not staged with a lymph node dissection in our study) and only for patients with abnormal examination about lymph nodes preoperatively or palpable lymph nodes intraoperatively, which meant that the positive rate of lymph nodes might be overestimated. What’s more, we regarded patients who were lymph node-negative and unevaluated as the negative group, which would reduce the proportion of patients in the lymph node-positive group and thus render the inauthentic effect of node-positivity on prognosis.

In the present study, albumin was not an independent risk factor for CSS. Hypoalbuminemia was previously proven to be strongly associated with cancer patients’ worsened OS and PFS, but the clinical practice of the single factor was limited because it could be easily affected by liver function, fluid volume and systemic inflammation [21,22,23]. This might be the reason for the results in our study. Recently, based on the level of albumin, the novel nutrition assessment tools, named the Prognostic Nutrition Index (PNI) and Naples prognostic score (NPS), have gained increasing popularity in predicting the prognosis of patients with different cancers [24, 25]. Data from our center showed that NPS and PNI were easy and effective tools in predicting OS in UTUC patients especially in locally advanced patients, which emphasized the importance of the nutrition status of patients with malignant carcinomas and advocated paying more attention to managing nutrition status throughout cancer treatment.

Nonetheless, our study had some limitations. First, it was performed in a retrospective, single-center designed study, which might lead to selection bias and be different from other studies’ findings. Second, the cutoff value of α-HBDH came from X-Tile software, which was different from that in other studies. The applicability of the conclusion is limited. Third, the information about comorbidities of UTUC patients before or at the time of RNU was not recorded, and coexisting disease, such as myocardial infarction, atherothrombotic and liver injury, might affect the α-HBDH level and further impact the conclusion. We are conducting a prospective, multicenter study with more improved baseline data to address these limitations.