Glomerular Hyperfiltration and Cancer: A Nationwide Population-Based Study

A lot of medical conditions influence the development of cancer, which is the leading cause of death worldwide regardless of race or geography. Kidney dysfunction has been reported to be associated with the development of certain kinds of cancer (1–3). Interestingly, previous studies have shown that both glomerular hyperfiltration and a decline in the glomerular filtration rate (GFR) are associated with cancer (4, 5). These studies focused on hyperfiltration at the time of the diagnosis of cancer, and it has been suggested that the tumor burden or hypermetabolic status of the host may trigger hyperfiltration. However, no large cohort study has investigated the association between hyperfiltration and the development of cancer.

Glomerular hyperfiltration is defined as an increased GFR in response to medical or nonmedical conditions. In the healthy population, increased protein loading is a well-known inducer of glomerular hyperfiltration (6). In addition, obesity and pregnancy lead to nonpathognomonic glomerular hyperfiltration with increased renal plasma flow (7, 8). On the contrary, some medical conditions, such as diabetes, focal segmental glomerular sclerosis, and autosomal dominant polycystic kidney disease, have also been reported to induce glomerular hyperfiltration related to glomerular hypertension, which is affected by various factors. Unlike these physiologic or relatively benign responses, glomerular hyperfiltration has been reported to be associated with an increased risk for all-cause mortality, even after adjusting for risk factors such as age, sex, and body mass index (BMI; ref. 9).

Given its high mortality rate, glomerular hyperfiltration may have a relationship with the development of cancer in the same manner as a significant relevance between the deterioration of renal function and cancer. Herein, we aimed to evaluate the association between glomerular hyperfiltration and the development of cancer. Moreover, we aimed to identify the specific cancer sites associated with glomerular hyperfiltration.

We included subjects who underwent national health screenings between January 2012 and December 2013. We included subjects ages 18 years old and over who had available isotope dilution mass spectrometry (IDMS) creatinine results with an estimated GFR (eGFR) ≥60 mL/min/1.73 m². Subjects with a history of cancer within 3 years before the health screening or during the inclusion period were excluded. In addition, subjects with a history of renal replacement therapy, such as dialysis and transplantation, were excluded. The study population was dichotomized using the eGFR categorized by sex and age decile; subjects with eGFR ≥ the 95th percentile were classified as the glomerular hyperfiltration group (9, 10), and the others were considered to be the non-glomerular hyperfiltration group.

All included data were obtained from the Korean National Health Insurance Service (NHIS) and the Health Insurance Review and Assessment Service (HIRA) databases. Korea has national insurance, which supports the whole nation. Individuals aged 40 years or older have the opportunity to undergo charge-free health screenings biannually, and the examination rate in 2011 was reported over 70% (11, 12). In addition, the five most frequently developed cancers (stomach, liver, colon, breast, and cervix) are specially screened for by the national cancer screening service program (Supplementary Table S1). The diagnostic information was coded according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) with the diagnosis date. We obtained information including demographic variables and laboratory results at the time of the health screening from the NHIS database (11, 13). In addition, health care utilization information, diagnosis, medical procedures, prescription records, and medical costs were recruited from the HIRA database (14).

We collected baseline data such as age, sex, income status, history of smoking, history of alcohol consumption, and anthropometric data including height, weight, waist and hip circumferences, and blood pressure. Recommended physical activity was defined as 30 minutes of moderate exercise for more than five times a week, or 20 minutes of vigorous activity for more than three times a week. Laboratory variables consisting of the serum creatinine, serum glucose, and lipid profile were included in the analysis. The serum creatinine (sCr) was measured by the IDMS method, and we calculated the eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation: 141 × minimum (sCr/κ, 1)^α × maximum (sCr/κ, 1)^−1.209 × 0.993^Age × 1.018 [if female], κ = 0.7 (females) or 0.9 (males), α = −0.329 (females) or −0.411 (males). We obtained the diagnostic information for site-specific cancer according to body systems and organs based on the ICD-10 codes (Supplementary Table S2).

We assessed the relative risk for the development of cancer for subjects with glomerular hyperfiltration compared with those without. Cancer was restricted to solid organ tumors, and it was separately analyzed by each organ system. In addition, we performed multivariate Cox analysis to evaluate the impact of glomerular hyperfiltration on the development of cancer.

To compare the baseline characteristics, we used Student t tests and Kruskal–Wallis test for continuous variables. Chi-square tests were used for categorical variables. The continuous and categorical variables are expressed as the means and SDs and numbers and percentages, respectively. Two-sided P values were derived by setting the significance level at 0.05. We performed multivariable Cox regression analysis to estimate hazard ratio (HR) and 95% confidence intervals (CI) for associations with the risk of the development of cancer. To reflect the impact of age on the development of cancer, we used the age time-scale in the Cox analysis (15). We performed an analysis with three different models, and the covariates for adjusting were sex, income, smoking status, BMI, alcohol consumption, physical activity, total cholesterol, eGFR, and comorbidities, including hypertension and diabetes. These statistical analyses were performed using SAS 9.4 (SAS Institute).

This study was approved by the institutional review board of Seoul National University Hospital (E-1801-027-913). We acquired approval from the relevant government organization to use the data from the NHIS and HIRA databases (NHIS 2018-1-138). The study was conducted in accordance with the principles of the Declaration of Helsinki.

This study was performed with 2,251,032 subjects who underwent national health screenings between January 2012 and December 2013. After excluding subjects younger than 18 years old (n = 1,170), those who had previously diagnosed malignancies (n = 198,525) or ESRD (n = 1,760), those who lacked sCr values (n = 15,863), and those with eGFRs less than 60 mL/min/1.73 m² (n = 80,591), 1,953,123 subjects were finally included in the study (Fig. 1).

Among 1,953,123 subjects, 100,009 subjects were classified in the glomerular hyperfiltration group. A comparison of the baseline characteristics between the subjects with glomerular hyperfiltration and those without is shown in Table 1. The glomerular hyperfiltration group had a greater proportion of smokers, heavy drinkers, and subjects with underweight, smaller waist circumference, and lower-income status in compared with the group without glomerular hyperfiltration. In addition, the glomerular hyperfiltration group had a more favorable lipid profile and a significantly greater proportion of subjects with a history of diabetes than those without glomerular hyperfiltration. The median follow-up duration was 60.6 (IQR = 53.1–65.5) and 60.5 (IQR = 52.3–65.4) months in the glomerular hyperfiltration and those without groups, respectively.

In the eight GFR categories, the pattern of the risk of cancer differed according to organ (Fig. 2). The incidence rates of cancer and adjusted hazard ratio (aHR) for the development of cancer in the subjects with glomerular hyperfiltration compared with those in the non-glomerular hyperfiltration group are shown in Table 2. The overall risk for the development of cancer was significantly higher in subjects with glomerular hyperfiltration than those without even after adjusting for sex, income, smoking status, and BMI (aHR = 1.08; 95% CI, 1.04–1.13; P < 0.001).

Among the eight different site-specific disease categories, the risk for cancer involving digestive organs was significantly higher in the subjects with glomerular hyperfiltration than those without. With regard to the specific digestive organs, the highest levels of risk were for liver or intrahepatic cancer when adjusted for sex, income, smoking, and BMI (aHR = 1.35; 95% CI, 1.14–1.59; P < 0.001). There were significantly increased risks for stomach cancer (aHR = 1.22; 95% CI, 1.09–1.37; P < 0.001) and colorectal cancer (aHR = 1.16; 95% CI, 1.00–1.34; P = 0.048). When we additionally adjusted for sex, income, smoking status, drinking habitual, BMI, physical activity, total cholesterol, eGFR, and underlying disease such as hypertension and diabetes, stomach cancer was the only organ which significantly affected by glomerular hyperfiltration (aHR = 1.14; 95% CI, 1.01–1.29; P = 0.036; Table 2).

Although respiratory and intrathoracic organ (HR = 1.18; 95% CI, 1.03–1.36; P = 0.021), and lung (HR = 1.19; 95% CI, 1.02–1.38; P = 0.023) were at significantly increased risk of developing cancer in the subjects with glomerular hyperfiltration compared with those without it, the statistical significance was attenuated after adjusted in models 2 and 3.

In this study, using a nationwide population-based database, we found that glomerular hyperfiltration is associated with the development of cancer. Among all site-specific classifications, cancer of the digestive organs was closely related to glomerular hyperfiltration.

Protein loading leads to an increased GFR, and the capacity for increased GFR is regarded as the renal functional reserve (16–18). Some conditions, including pregnancy, obesity, and diabetes, consume the renal functional reserve and lead to glomerular hyperfiltration. Eventually, glomerular hyperfiltration, combined with subclinical kidney disease or risk factors for CKD, might lead to the development of overt CKD (19, 20). Apart from the aspect of kidney function, it has also been reported that increased GFR is associated with increased all-cause mortality and negative cardiovascular outcomes (9, 21, 22). Thus, glomerular hyperfiltration would be considered a potential risk factor for negative clinical outcomes.

A relationship between dietary pattern and the development of cancer has been reported, especially cancer of the digestive organs. Salty food is linked to an increased risk of stomach cancer (23–25). The consumption of processed meat is commonly related to the development of stomach cancer as well, even though the risk may be different according to the cooking method, region, and patient race (23, 26, 27). Moreover, the consumption of red meat is also a well-known risk factor for colorectal cancer (28, 29). Meanwhile, protein loading is a well-known associate factor leading the glomerular hyperfiltration (30). Taken together with previous studies, we suggest that the increased risk for stomach and colorectal cancer in the population with glomerular hyperfiltration might be related to the effect of a high protein diet or unhealthy protein sources.

Unlike malignancies of the gastrointestinal organs, those of liver and intrahepatic malignancies were not significantly associated with glomerular hyperfiltration after adjusting for various risk factors, such as smoking status; drinking habitual; BMI; serologic markers, including glucose and total cholesterol; and a history of hypertension and diabetes. Interestingly, the relative risk for hepatocellular carcinoma depends on the type of meat consumed, unlike the risk for stomach and colon cancer. Poultry and fish are protein-rich foods, but the consumption of these foods decreases the risk for hepatocellular carcinoma when compared with the consumption of red meat (31). Thus, these inconsistent relationships between diet and malignancies could neutralize the effect of glomerular hyperfiltration.

It has been evaluated that red meat and white meat affect the development of cancer differently. Red meat and processed meat have been widely identified as risk factors for the development of cancer, especially gastrointestinal cancer (27, 29, 32). Moreover, although the mechanisms have not been fully evaluated, recent studies have made an effort to evaluate the role of heme in the negative effect of red meat (33, 34). In contrast, a diet rich in white meat is considered to be favorable for various cancer, including those in the lung, breast, and liver (31, 35–37). The risk for the malignancies involving the liver or lung was significantly decreased in individuals consuming a diet rich in white meat or fish (36, 38). In addition, no association has been found between the type of meat consumed and the development of several types of cancer, such as breast and prostate cancers (39, 40).

To date, diverse reports have suggested a relationship between the types of meat consumed and the development of cancer, but the relationship remains controversial. Diet could be affected by region, race, and culture. In addition, glomerular hyperfiltration associated with protein loading is not limited to individuals who consume red meat. Nevertheless, the stomach and colon are the organs most affected by diet, so the results of this study combined with results from previous studies (23–27), could suggest a link between glomerular hyperfiltration and cancer mediated by a diet.

This study covered approximately 2 million Korean people with normal renal function. The information used in the analysis was formally collected, robust epidemiological data, including baseline characteristics, laboratory data, diagnostic information, and income status. To the best of our knowledge, this is the first report to reveal the relationship between glomerular hyperfiltration and the development of cancer.

However, there are several limitations of this study to be considered. First, the cohort was composed of individuals of a single nationality, and cancer prevalence is affected by nationality (41, 42). Second, the population with glomerular hyperfiltration had a small number of events for some cancers, so it was difficult to evaluate the significance of those associations. Third, there were no data pertaining to diet and nutritional status except BMI and laboratory results. Even though we adjusted for variables that affect glomerular hyperfiltration, it was difficult to show causality because of the lack of specific diet information. Finally, we did not censor the death in the Cox-regression analysis. The number of deaths was less than 1% in the study populations during the study period. Therefore, the future study that considers the death information with a more extended follow-up period would help propose the relationship between glomerular hyperfiltration and the development of cancer and death. In addition, to evaluate the pathophysiologic relationship, further studies need to be performed with more specific data, including dietary information.

In conclusion, glomerular hyperfiltration could be a sign representing the presence of risk for the development of cancer, especially cancers involving the digestive organs. An inappropriately high GFR is no longer an indicator of good kidney function; however, it can be used as an indicator of the need for further evaluation to achieve better health outcomes.

No potential conflicts of interest were disclosed.

Y. Kim: Conceptualization, funding acquisition, and writing–original draft. S. Lee: Data curation and investigation. Y. Lee: Data curation and investigation. M.W. Kang: Data curation and investigation. Sehoon Park: Data curation and investigation. Sanghyun Park: Data curation, software, and formal analysis. K. Han: Data curation, software, and formal analysis. J.H. Paek: Methodology, writing–review and editing. W.Y. Park: Methodology, writing–review and editing. K. Jin: Methodology, writing–review and editing. S. Han: Methodology, writing–review and editing. S.S. Han: Supervision, writing–review and editing. H. Lee: Supervision, writing–review and editing. J.P. Lee: Supervision, writing–review and editing. K.W. Joo: Supervision, writing–review and editing. C.S. Lim: Supervision, writing–review and editing. Y.S. Kim: Supervision, writing–review and editing. D.K. Kim: Conceptualization, supervision, project administration, writing–review and editing.

The present research has been conducted by the Research Grant of Kidney Institute, Keimyung University in 2019 (Y. Kim).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.