Long-Term Outcomes of Pulmonary Resection for Lung Cancer Patients with Chronic Kidney Disease

Lung cancer is the leading cause of cancer-related death in the western world [1]. Pulmonary resection is the treatment modality with the best chance of curing early-stage lung cancer. As such, in recent decades, the life expectancy of these patients has been increasing, which in turn results in an increasing frequency of a wide range of morbidities such as cardiac and respiratory diseases [2, 3].

Chronic kidney disease (CKD) is a concept that includes all chronic kidney damage or dysfunction, regardless of the primary disease, and was proposed by the National Kidney Foundation in the USA in 2002. CKD is defined as a persistent decline in the renal function to a glomerular filtration rate (GFR) of <60 ml/min/1.73 m² or findings that suggest renal impairment for ≥3 months [4]. Several studies have reported that patients with CKD experience a high incidence of malignant tumors [5, 6]. Furthermore, comorbidity of CKD is associated with an increase in surgical complications and the surgical mortality rate, as well as a reduced overall survival (OS) in several malignancies [7‐11].

Whether or not CKD negatively affects the survival of patients with lung cancer remains controversial. There have been a few reports concerning patients with CKD who underwent medical treatment of lung cancer based on data from a national database [12]. However, to our knowledge, there have been no reports on the outcomes of lung cancer patients with CKD limited to surgical cases. In addition, the influence of CKD on the feasibility of surgery is also unclear, necessitating the clarification of the effects of CKD on patients who undergo surgery.

In the present study, we investigated the impact of CKD on the perioperative and long-term outcomes of pulmonary resection for lung cancer patients.

Staging was assessed according to the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology 7th edition [13]. CKD was defined according to the Clinical Practice Guideline book for the diagnosis and treatment of CKD, 2012, published by the Japanese Society of Nephrology [14]. The renal function was evaluated as the estimated eGFR, calculated as follows: eGFR (ml/min/1.73 m²) = 194 × serum creatinine (mg/dl)^−1.094 × age^−0.278 (if female ×0.739). CKD was defined as an eGFR <60 ml/min/1.73 m². The CKD stage was defined as stage 1 + 2 for an eGFR >60 ml/min/1.73 m², stage 3 for eGFR 30–60 ml/min/1.73 m², stage 4 for eGFR 15–30 ml/min/1.73 m², stage 5 for eGFR <15 ml/min/1.73 m². We used the eGFR basically from the first visit to our hospital up until the performance of lung cancer surgery without any intravenous hydration. As underlying comorbidities other than CKD, cardiovascular and cerebrovascular diseases, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), diabetes mellitus, and the use of steroid or immunosuppressive agents were also evaluated. The criteria used to determine COPD were based on the “Guidelines for the diagnosis and treatment of COPD, 3rd edition” presented by the Japanese Respiratory Society [15]. The length of the operation, intraoperative bleeding, and postoperative complications were also reviewed.

In the present study, we focused on CKD as a comorbidity in lung cancer patients who underwent pulmonary resection. We showed that patients with CKD had a higher frequency of COPD, cardiovascular disease (CVD), and radiological interstitial lung disease (ILD), and a notably lower pulmonary function, than those without CKD, resulting in their receiving limited pulmonary resection and a tendency to have a poor DFS. We also found that patients with CKD had a poorer OS than those without CKD. To our knowledge, this is the first study to evaluate the influence of the renal function on the clinical features and survival outcomes of patients who underwent lung cancer surgery.

The influence of CKD on the lung cancer survival has not been clarified. Few studies have evaluated the outcomes of lung cancer among patients with CKD, and the association between CKD and the prognosis of lung cancer is controversial [12, 18, 19]. In a retrospective study of 107 lung cancer patients with CKD, Patel et al. [18] reported that CKD did not have influence the clinical course or survival compared with non-CKD. However, some authors have conversely reported that CKD had a negative influence on the prognosis of lung cancer. Cenik et al. [19] found that the renal function might be inversely associated with the survival in 298 patients with stage IV non-small cell lung cancer (NSCLC). According to a nationwide Taiwan-based cohort study, CKD was independently associated with increased mortality in lung cancer patients [12]. The presence of CKD may limit the therapeutic options available to lung cancer patients, resulting in suboptimal management. However, no study has evaluated lung cancer patients with CKD limited to surgical cases. Therefore, to our knowledge, this is the first report that CKD has a negative influence on the OS in patients undergoing lung cancer surgery.

CKD is associated with other comorbid diseases. The present study showed that patients with CKD were older and with a higher incidence of smoking than those without CKD, and the frequencies of coexisting CVD, COPD, and ILD were also higher among patients with CKD than among those without it. Regarding accompanying disorders, the pulmonary function was notably lower in patients with CKD than in those without it, resulting in the CKD patients receiving limited pulmonary resection. An advanced age, smoking history, hypertension, and diabetes mellitus are well known to be important risk factors for CKD [20]. CKD has many characteristics in common with COPD, such as the dependence of the patient prognosis on CVD [21]. However, little is known regarding the association between ILD and CKD. We speculated that there were two points to note regarding the association between CKD and ILD. First, there are a number of systemic autoimmune diseases that are related to both CKD and ILD, including rheumatism, systemic lupus erythematosus, and MCTD. Second, there is an association between idiopathic pulmonary fibrosis (IPF) and CKD. A recent retrospective study on 124 patients with IPF and 61 patients with COPD as the control disease reported that CKD was highly prevalent among patients with IPF as well as COPD [22]. Recent epidemiologic studies have shown that patients with IPF have an increased risk of hypertension, diabetes mellitus, and CVD, which are closely associated with CKD [23]. In addition, IPF, COPD, and CKD share some common clinical risk factors, such as an advanced age and smoking history, suggesting a correlation among them. It is reported that smoking is associated with a higher relative risk of lung squamous cell carcinoma than of adenocarcinoma [24]. Moreover, several studies reported that the most frequently occurring lung cancer type in patients with IPF is squamous cell carcinoma [25, 26]. As a result of these factors related to CKD, the frequency of squamous cell carcinoma was higher in patients with CKD than in those without CKD.

To our knowledge, the present study was the first to analyze the association between CKD and postoperative complications of pulmonary resection. Several studies have reported that renal dysfunction increases the risk of anastomotic leakage following gastrointestinal surgery [7, 8]. Furthermore, the frequencies of postoperative cardiovascular events have been reported to also be higher in patients with CKD than in those without CKD. In contrast, CKD did not affect the rate of postoperative complications of lung cancer surgery as shown in the present study. Postoperative arrhythmia was the most common complication, regardless of the presence of CKD. The rates of bronchopleural fistula and prolonged air leakage were also similar between the two groups. Because the frequencies of coexisting COPD and ILD were higher in patients with CKD than in those without it, the lung tissues of CKD patients tended to be emphysematous. We proactively control air leakage using a free subcutaneous fat pad during surgery, which is effective in reducing the duration of air leakage and chest tube drainage [27]. These preventive procedures for air leakage are also considered effective in patients with CKD. However, pneumonia after pulmonary resection was more frequently observed in patients with CKD (n = 4, 7.3%) than in those without CKD (n = 8, 1.3%, p < 0.01). Several mechanisms potentially linking CKD and pneumonia have been proposed. Immune response deficiency is a common occurrence, and the humoral immune defense is often compromised in patients with CKD [28, 29]. In addition, the present study showed that comorbidity of hypertension, COPD, and CVD was associated with the occurrence of postoperative complications. Thoracic surgeons should be alert for postoperative complications when these patients undergo pulmonary resection.

Our main concern when treating patients with CKD was whether or not less invasive pulmonary resection and lymph node dissection performed due to their worse clinical characteristics affects the oncological outcome. Our findings that the DFS did not differ significantly between the two groups mean that our treatment strategy is reasonable and suggests that lymph node dissection may be lessened in the current lung cancer surgery strategy. Recently, several studies demonstrated that selective lymph node dissection is not inferior to standard systematic lymph node dissection in terms of the postoperative prognosis in lung cancer surgery [30, 31]. Furthermore, the pattern of recurrence between the two groups was similar in the present study. Thus, thoracic surgeons should carefully consider the level of lymph node dissection using an intraoperative frozen histological examination and lymph node sampling as much as possible in patients with CKD. However, the OS differed significantly between the two groups. It is speculated that patients with CKD were not physically fit to receive systemic chemotherapy, which subsequently reduced their OS. Of note, cytotoxic chemotherapy has renal toxicity and so was generally not introduced for patients with CKD. Regarding the treatment for recurrent disease, the proportion of patients who received supportive care was significantly higher in those with CKD than in those without CKD. However, our multivariate analysis showed that CKD was not significant, while age, sex, histology, postoperative complications, and pStage were independent prognostic factors for the survival in patients undergoing lung cancer surgery. The presumed reason for this is as follows: CKD group demonstrated a poor prognosis according to a univariate analysis because the CKD group was associated with poor prognostic factors in their background. As CKD alone was not an independent prognostic factor, the most suitable treatment for patients with CKD determined after taking clinical factors other than CKD into consideration might result in a survival outcome not inferior to that in patients without CKD. Based on our findings, selecting the appropriate extent of pulmonary resection and lymph node dissection while balancing radicality and surgical stress is important for treating patients with CKD.

Several limitations associated with the present study warrant mention. First, we had a small sample size and our data were necessarily derived from a single institution, limiting the power of our statistical findings. Second, because of the long duration of this study, the diagnostic modalities changed with the introduction of positron emission tomography. Advancements in radiologic examination techniques might therefore have affected the patient selection. Third, the classification of patients into CKD stages was based on the preoperative creatinine level without consideration of chronicity. Finally, the retrospective design introduces inevitable selection bias. Further studies are needed to achieve a more detailed conclusion.

In conclusion, we herein report for the first time that CKD is associated with a poor OS among patients who undergo lung cancer surgery. The suboptimal treatment choice for recurrent disease might explain this result in part. Because patients with CKD are limited in their choice of systemic treatment, surgery remains a mainstay for the treatment of lung cancer in this population. As patients with CKD tend to have a poor respiratory function, thoracic surgeons should carefully select the type of resection to achieve a balance between the therapeutic benefit and invasiveness in these patients.