Risk of Prostate Cancer in Chronic Kidney Disease Patient: A Meta-Analysis using Observational Studies

ABSTRACT

Background:

Both clinical and experimental findings demonstrated a rise in prostate cancer in chronic renal illness. However, the clinical data associated with CKD was not looked at the context of prostate cancer. The study aims to investigate prostate cancer risk in CKD patients using clinical data via systemic review and meta-analysis.

Materials and Methods:

Using pertinent pairing keywords, I carried out a thorough exploration of PubMed/MEDLINE and Web of Science. The pooled HR with 95% CI of the considered clinical findings was estimated involving the general inverse variance outcome type. With RevMan 5.3, the total pooled estimate meta-analysis was evaluated utilizing the random effects model.

Results:

Total of six findings were considered for this analysis, with a total of 2,430,246 participants. The age and mean follow-up of the included patients and studies ranged from 55 to 67.4 years and 10.1 to 12 years, respectively. The meta-analysis showed no significant risk of prostate cancer among CKD patients (HR: 0.92; 95% CI: 0.60-1.41; P = 0.70). The results from subgroup analysis based on eGFR levels ranged ≥30-59 ml/min per 1.73 m² and also found no significant risk of prostate cancer among CKD patients (HR: 1.04; 95% CI: 0.92-1.18; P = 0.52). Here I did not report statistical heterogeneity found (Q = 0.56, I² = 0%, P = 0.87). As per the Newcastle-Ottawa scale, the included studies suggested good quality.

Conclusion:

The results suggest no significant risk of developing prostate cancer among CKD patients. Therefore, well-designed prospective cohort studies with stages of CKD and clear predefined prior history and causative factors are needed to support the present evidence strongly.

INTRODUCTION

The clinical and experimental findings have demonstrated a higher prevalence and occurrence of prostate cancer (PCa).[1] Male populations with different ancestries—African, Asian, Hispanic, and European—had varying incidence and mortality rates, suggesting that genetics plays a part.[2] On the other hand, disparities between patients of the same race and ethnicity residing in various nations raise the possibility that environmental factors are also at play.[3] Depending on the nation, there are different rates of prostate cancer cases and mortality, which are determined by the accessibility and availability of diagnostic and healthcare facilities as well as by recommendations for prostate cancer testing.[4,5] Over 55% of all fatalities from prostate cancer happen beyond the age of 65.[6] According to a comparison study by Sarabu et al. (2020), more end-stage renal disease (ESRD) patients had an advanced-stage prostate cancer diagnosis than those without ESRD.[7] Studies have demonstrated that the occurrence and prevalence of prostate cancer among kidney recipients older than 50 has significantly increased over the past ten years (13% to 21%).[8] The danger of developing prostate cancer has grown significantly due to its high incidence and mortality as more elderly patients receive kidney transplants and dialysis. Regular active treatment approaches for ESRD patients with prostate cancer, as well as concerns with prostate cancer-related prostate-specific antigen screening criteria, have also grown to be major points of contention.[9,10]

Both PCa and CKD share similar risks. factors and both conditions may trigger CKD with higher severe pathophysiology along with side effects. On the other hand, CKD may also increase one’s PCa probability with higher incidence. Hence both ailments’ common risk factors, which are often toxins, the two diseases may be related.[11] Cancer risk is increased in patients receiving renal replacement treatment for end-stage CKD who are receiving dialysis or transplants.[12,13] Few studies[14-16] reported on the likelihood of malignancy in CKD patients who were still in the early stages of the disease. Prior research found that patients with ESRD had an overall standardized incidence ratio for cancer risk that ranged from 0.9 to 1.5. Thyroid tumors, bladder, kidney, multiple myeloma, and virus-induced tumors were among the cancers for which ESRD patients had an increased risk.[17,18] The danger of prostate cancer being more common in people with chronic renal impairment is still mainly unknown. Kidney replacement considered as most promising approach to CKD management for people with chronic dialysis-dependent end-stage kidney disease.[19] Furthermore, the frequent kidney replacement performed for chronic renal disorders brought on by diabetic nephropathy and atherosclerosis are improving patients’ short- and medium-term results. Since localized prostate cancers account for the majority of prostate cancers that arise after renal transplantation, recipient cases are subjected to a wide range of therapeutics and surgical interventions in accordance with recommended protocols because there do not appear to be any specific guidelines for treating localized prostate cancer.

It is crucial to refer these patients to urological cancer care centers with surgeons skilled in both oncological and transplant surgery because the concurrent use of immune suppressants and the location of the renal graft in the pelvic cavity make treating localized prostate cancer after kidney transplantation more challenging.[19,20] In contrast, a different study found that immune suppression following kidney transplantation demonstrates a detrimental effect on the onset or progression of prostate tumors.[21] Therefore, it is uncertain whether prostate cancer is a concern following renal donation. Prostate cancer is a disorder that may be tackled with diagnosis and regular monitoring, making post-transplant malignancies one of the prevailing reasons for death in these individuals. Previously, a meta-analysis using individual patient data was conducted to assess the overall cancer risk in CKD patients.[16] Studies presenting the pooled estimation of the risk of prostate cancer among CKD patients are, nevertheless, scarce. Additionally, knowledge of the disease risk for prostate cancer would be crucial for decision-making about insurance and the measurement and screening of the disease burden. Hence, a thorough literature search and meta-analysis were performed to determine the estimated pooled prostate cancer probability in CKD patients. Patients with early-stage renal disease have a higher chance of developing cancer, according to previous studies, but it is unclear how less severe CKD will affect this risk. Prostate cancer is the leading form of malignancy in males across the globe and is associated with several risk factors including chronic renal disease. The rationale of the present study is to examine the association of CKD with prostate cancer.

MATERIALS AND METHODS

Current systematic literature review and meta-analysis associated with included studied Items for Systematic Reviews and Meta-analyses (PRISMA) standard.[22]

Data sources and search strategy

A thorough search method was used to look through two databases, including Web of Science and the Medical Literature Analysis and Retrieval System Online (MEDLINE), to find all qualifying research written in the English language between the beginning and the first of January 2022. Prostate cancer, renal insufficiency, chronic kidney failure, prostate neoplasm, prostate carcinoma, and prostate tumors were among the keywords or Medical Subject Headings (Mesh) used in the search queries. The references of the included studies and earlier reviews were also reviewed for other pertinent papers, as were manual Google Scholar searches. Here in the present study search of the literature search was not subject to time restrictions. For the sake of this analysis, only English was used.

Selection of studies and screening of data

Studies and observations were typically regarded as appropriate if they satisfied the following criteria: studies examining the prostate tumor risk in CKD and ESRD; studies utilizing observational study designs (cross-sectional, cohort, nested case-control, or case-control); reported unadjusted or adjusted estimates of the association between exposure and outcome (hazard ratio (HR), odds ratio (OR), or risk ratio (RR), and the corresponding 95% confidence interval (CI), or sufficient raw data to allow their calculation; (d) published studies that were fully searchable. The following exclusion criteria were applied: Studies evaluating the incidence ratio or standardized incidence ratio (SIR), studies conducted in languages other than English, studies analyzing the risk of prostate cancer in kidney or renal replacement patients, and studies with insufficient data or no complete information reported were also disqualified from the analysis. The third author was consulted to discuss any disagreements until an agreement was reached on every point. First author’s name, publication year, nation, study design, data source, population, sample size, age (in years), gender, race, and length of follow-up, as well as the unadjusted and fully adjusted HR or OR or RR and their respective 95% confidence intervals, were all collected as part of the study information.

Quality assessment

Two writers separately examined the methodological value of all included studies considering the Newcastle-Ottawa Scale (NOS), which was suggested by the Cochrane Non-Randomized Studies Methods Working Group.[23] The evaluation instrument is graded on three scales: selection (up to four stars), comparability (up to two stars), and exposure/outcome (maximum of three stars). Consequently, the scale is graded using a nine-point system (stars). An evaluation of the studies’ internal (systematic error) and external validity was conducted to make sure they weren’t swayed by their own conclusions. The requirements for changing NOS to Agency for Healthcare Research and Quality (AHRQ) standards establish three quality levels: good, fair, and poor. High-quality studies are those that receive 6 or more stars.[24] The consensus was used to settle any conflicts.

Data analysis

The adjusted impact investigate prostate cancer risk (HR, OR, or RR) and related 95% CI were taken. Standard errors (SE) were calculated using the following formula: [log (95%CI, higher limit)-log (95%CI, lower limit)]/3.92.[25] A natural log scale was used for all studies. A meta-analysis of cumulative pooled estimates was assessed using the random-effects model. In this analysis, the presence of study heterogeneity was assessed using the Cochran chi-square (2) and quantified using the I² (0-100%) and tau-square (2), with the values provided in the text. When I² values were above 75%, significant heterogeneity was expected. The pooled HR with% CI of the included studies was estimated using the general inverse variance outcome type. I performed the Begg and Egger test to look at potential publication bias when three or more papers were included in the primary analysis, and I made funnel plots to show likely asymmetry.[26] RevMan 5.3 (Review Manager 5.3; Nordic Cochrane Centre, Cochrane Collaboration, 2014) and R software, version 3.3.2 (R Foundation for Statistical Computing, Vienna, Austria), utilizing the packages “meta”[27] were used for all of the statistical analysis. When 0.05, all P values were deemed statistically significant.

RESULTS

Literature search and study inclusion

Figure 1 displays the PRISMA diagram that condenses the complex procedures of screening clinical findings. Database search yielded a total of 746 possibly pertinent records, of which 740 studies remained after the duplicates were removed. After reviewing the title and abstract, 685 papers were disqualified because they failed to satisfy the inclusion and exclusion requirements. After being assessed for eligibility, 50 of the remaining 55 full-text papers were deemed ineligible. Only six research,[14,16,28-31] were included for qualitative synthesis and one extra study was eliminated because there was no uniform estimation of the risk of prostate cancer and CKD. Five studies,[30-36] were eligible for the quantitative data synthesis in this analysis.

Figure 1.

PRISMA flow chart for study selection and screening

Study characteristics and quality assessment

The features of the findings that were considered are listed in Table 1. Cohort studies are made up of each. The six investigations were two from the USA[14,29] and one each from Australia,[16] Korea,[30] Sweden,[31] Taiwan,[29] and Australia. The studies that were taken into consideration had sample sizes that ranged from 1629 to 1,190,538. In this investigation, a total of 2,430,246 samples were used [Table 1]. The included patients’ and studies’ mean follow-up varied from 10.1 to 12 years and 55 to 67.4 years, respectively. With the exception of one research,[31] which showed a mean (SD) of 87 ml/min per 1.73 m², all included studies revealed eGFR in the range. The range of the serum creatinine level was 40-1502.8 mmol/L. The most frequently addressed confounding variables. are found to be age, sex, socioeconomic status, and comorbidities. A comprehensive list of research features can be found in Table 2. All studies scored between 7 and 9 on the Newcastle-Ottawa scale, with exception of one finding that received an 8, indicating the high caliber of the included studies [Supplementary Table S1].

Table 1.

Characteristics of the included studies

Author, year	Study design	Country	Data source	Population	Sample size (n)	Age (years)	Gender, n (%)	Race, n (%)	Follow up (years)	eGFR (mmol/min per 1.73 m2)	Serum creatinine concentration (mmol/L)
Taneja, 2007	Cohort study	USA	SEER-Medicare database	ESRD	16,29	At diagnosis, Mean: 67.4	Male: 935 Female: 694	White: 808 Black: 510 Other: 311	NR	NR	NR
Wong, 2009	Prospective cohort study	Australia	CCR	CKD	36,54	Mean: 65.8	Male: 1295 Female: 1752	NR	Mean: 10.1	Range: 113-14.5	Range: 40-375
Liang, 2011	Retrospective cohort study	Taiwan	National Health Insurance system	ESRD	43,634	Range: <40-≥70	Male: 20,677 Female: 22,957	NR	Mean: 12	NR	NR
Lowrance, 2014	Retrospective cohort study	USA	US Census-block data	ESRD	1,190,538	Median: 55	Male: 5,59,552 Female: 6,30,985	White: 6,90,512 Black: 81,194 Native American: 17,977 Asian: 1,30,959 Other, multiple, or unknown race: 2,67,275	Median: 5.3	Range: <30-150	NR
Park, 2019	Cohort study	Korea	National health insurance database	CKD	471,758	Median: 64	Male: 243,137	NR	Median: 4.77	Range: 55-70	Range: 88.4-123.7
Xu, 2019	Cohort study	Sweden	Regional and national administrative databases	CKD	71,9033	Mean: 60	Male: 336,997 Female: 382,036	White: 71,9033	Median: 5	Range: <30-≥ 150	Range: 44.2-1502.8

eGFR=Estimated glomerular filtration rate, SEER=Surveillance, Epidemiology, and End Results, ESRD=End stage renal disease, NR=Not reported, CCR=Central cancer registry, CKD=Chronic kidney disease

Table 2.

Comprehensive results summary of included studies

Author, year	Study design	Measure of risk	Result of estimates	Confounding variables	Results/conclusion
Taneja, 2007	Cohort study	RR (95% CI)	1.87 (1.05, 3.33)	Marital status, socioeconomic status, and comorbidity	Prostate cancers were significantly more likely to be diagnosed at a later stage of end-stage renal disease (ESRD).
Wong, 2009	Prospective cohort study	HR (95% CI)	0.97 (0.34, 9.15)	Age, smoking status, degree of sun-related skin damage, and diastolic blood pressure	The risk for lung and urinary tract cancers but not prostate was higher among men with chronic kidney disease (CKD). Moderate CKD (stage 3) may be an independent risk factor for the development of cancer among older men but not women, and the effect of CKD on risk may vary for different types of cancer.
Liang, 2011	Retrospective cohort study	HR (95% CI)	0.65 (0.43, 0.97)	Age, sex and sociodemographic	The ESRD to have a lower risk to get lung, prostate and esophageal cancer.
Lowrance, 2014	Retrospective cohort study	HR (95% CI)	eGFR (ml/min per 1.73 m2), range 90-150: 0.76 (0.71, 0.81) 45-59: 1.02 (0.98, 1.06) 30-44: 0.98 (0.91, 1.06) <30: 1.02 (0.89, 1.18)	Age, sex, race, socioeconomic, status, smoking status, body mass index (BMI), health care use, comorbid conditions (heart failure, hypertension, diabetes mellitus, coronary heart disease, chronic lung disease, and chronic liver disease)	Lower glomerular filtration rate (GFR) level was an independent risk factor for incident renal and urothelial cancer but not prostate, colorectal, lung, breast, or all cancers.
Park, 2019	Cohort study	HR (95% CI)	CKD Stage based on (dipstick albuminuria or eGFR level) 1 (≥ 90): 0.708 (0.541-0.926) 2 (< 90 and ≥60): 0.887 (0.758-1.039) 3 (< 60 and ≥30): 1.101 (1.034-1.172) 4 or 5 (<30): 0.689 (0.507-0.936)	Age, sex, socioeconomic status, smoking, BMI and history of hypertension, diabetes mellitus	The risk of digestive, respiratory, thyroid, and prostate malignancy demonstrated a non-linear association with CKD stage, with stage 1 or stage 4/5 CKD without dialysis demonstrating relatively lower risk.
Xu, 2019	Cohort study	HR (95% CI)	eGFR (ml/min per 1.73 m2), range <30: 0.87 (0.64, 1.19) 30-59: 1.04 (0.95, 1.15) 60-89: 1.08 (1.03, 1.15) >105: 0.94 (0.82, 1.09)	Age, sex, and comorbidities	Modestly higher cancer risk in individuals with mild to severe CKD driven primarily by skin and urogenital cancers. Lower eGFR strata were significantly associated with higher risk of skin, urogenital, prostate, and hematologic cancers.

RR=Risk ratio; HR=Hazard ratio, ESRD=End stage renal disease, CKD=Chronic kidney disease, eGFR=Estimated glomerular filtration rate, BMI=Body mass index

Supplementary Table S1.

Quality assessment of included studies using Newcastle-Ottawa Scale

Author year	Title	Study design	Selection (Maximum 4 stars)	Comparability (Maximum 2 stars)	Outcome (Maximum 3 stars)	Total score (Maximum 9 stars)	Quality of the study
Taneja 2007	Comparison of Stage at Diagnosis of Cancer in Patients Who Are on Dialysis versus the General Population	Cohort	****	*	**	7	Good
Wong 2009	Association of CKD and Cancer Risk in Older People	Cohort	****	**	**	8	Good
Liang 2011	The Association Between Malignancy and End-stage Renal Disease in Taiwan	Cohort	****	*	**	7	Good
Lowrance 2014	CKD and the Risk of Incident Cancer	Retrospective cohort	****	*	**	7	Good
Park 2019	Risk of cancer in pre-dialysis chronic kidney disease: A nationwide population-based study with a matched control group	Cohort	****	*	**	7	Good
Xu 2019	Estimated Glomerular Filtration Rate and the Risk of Cancer	Cohort	****	*	**	7	Good

CKD=Chronic kidney disease

CKDs cases and prostate cancer risk

According to the meta-findings, analysis patients with CKD have a negligible chance of developing prostate cancer (HR: 0.92; 95% CI: 0.60-1.41; P = 0.70; Figure 2a and b). There were no publication biases or small-study effects, and the funnel plot’s shape was symmetrical throughout (Egger’s test: P = 0.18). (Q = 0.56, I² = 0%, P = 0.97) No statistical heterogeneity was discovered. A subgroup analysis based on stages and eGFR levels (ml/min per 1.73 m2) was also attempted. I was only able to evaluate the subgroup analysis for eGFR values between 30 and 59 ml/min per 1.73 m². A substantial risk of prostate cancer was not discovered among CKD patients, according to the analysis’s findings (HR: 1.04; 95% CI: 0.92-1.18; P = 0.52). Additionally, no statistical heterogeneity was discovered by subgroup analysis (Q = 0.27, I² = 0%, P = 0.87).

Figure 2.

(a) Forest plot for overall risk of prostate cancer (b) Forest plot for risk of prostate cancer based on eGFR level 30-59

DISCUSSION

A thorough literature review and meta-analysis were used to determine the burden of prostate cancer in CKD cases. The summary of the studies’ results revealed that having CKD was not significantly linked with a patient’s chance of developing a prostate tumor. The study’s conclusions are in line with those of an earlier meta-analysis that used 32,057 participants’ individual patient data. Therefore, it was clear that patients with impaired renal function do not involve with a higher risk of developing cancer.[16] Some real-world investigations have revealed elevated risks of different malignancies, including prostate cancer, in people with ESRD renal disorders well before would use a renal transplant like dialysis and kidney transplantation. Apparently, the risk of cancer is mainly unknown whether or not there was a considerable risk of prostate cancer.[14,32-34] Our subgroup analysis also revealed that CKD cases did not have a noticeably greater risk of prostate cancer based on eGFR values of 30-59 ml/min per 1.73 m². This result is in line with a previous observational study that found reduced eGFR levels could be a danger element for the emergence of renal and urothelial carcinoma but not prostate, colorectal, lung, breast, or any other type of tumor.[14]

Obesity-related CKD patients have been shown to produce more pro-inflammatory cytokines.[35] Chronic inflammation is now understood as a key contributing cause of a number of tumors. Immune mediators causing inflammation can result in neoplasia by bringing about pro-neoplastic mutations, adaptive responses, apoptosis resistance, and environmental alterations including angiogenesis stimulation.[36] According to a preclinical investigation, advanced CKD could cause gut mucosal degradation in mice, and this change in CKD may hasten the development of colonic malignancy.[37] Following organ donation, immunosuppressive medications are linked to an increase in the risk of developing different malignancies.[38,39] Additionally, cancers such as genitourinary cancer, of which prostate cancer was the most prevalent, are more common among transplant recipients. Among the cases gone for transplantation, a 5-year incidence of cancer was reported at 4.4%, according to a systematic analysis that summarized the available data. However, associations differ according to age and the organ that was transplanted.[40] It is yet unknown, though, whether men who have renal transplants actually have a higher chance of developing prostate cancer.

Study Limitations

This is a basal comprehensive evaluation of the published scientific data and meta-analysis to evaluate the body of research involving prostate cancer risk in CKD cases. Furthermore, our investigation did not discover any degree of heterogeneities among the studies that were included. Nevertheless, our research has several limitations. This study started off with a tiny sample size. Second, patients who received kidney transplants and underwent prostate cancer screening were excluded from the study. Finally, subgroup analysis based on phases and severity was tried; however, only three of the included studies met the requirements for this type of analysis. Furthermore, due to a paucity of information in each included study and a gap in the systematic data given, I was unable to characterize CKD in terms of etiology, past history of the disease, and racial/ethnic disparities.

Evidence-based implications

The results of this study will enable us to correlate the epidemiological and disease burden of prostate tumors in CKD cases. advising medical professionals and informed decision-makers to ensure cancer screening in CKD cases, who receive dialysis along with kidney transplants, would help prevent this double challenge.

CONCLUSION

The study’s findings imply that CKD patients had a negligible probability of developing prostate cancer. Despite this, there is a wealth of information in the literature that links prostate cancer to other variables that may have an impact on outcomes. A few studies lacked details on the phases, severity, and other aspects of CKD. The current data must therefore be substantially supported by well-designed prospective cohort studies including stages of CKD, clear predefined prior histories, and causal variables.

Abbreviations; Chronic renal diseases (CKD), estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), hazard ratio (HR), odds ratio (OR), or risk ratio (RR), confidence interval (CI), standardized incidence ratio (SIR), Newcastle-Ottawa Scale (NOS), Agency for Healthcare Research and Quality (AHRQ), Standard errors (SE).

Financial support and sponsorship

Nil.

Conflicts of interest

The author declares that this publication is free of conflicting interests.