Avinash Rao Ullur, MD, DNB
Clinical Fellow in Adult Nephrology
University of Toronto
NSMC Intern 2021
Rushing through the dialysis unit can leave little time to consider issues other than electrolytes, volume status, anemia, and bone mineral metabolism. However, it’s the missed opportunities that consistently make me stop and think “what if”?
“Hi there, how are you doing today?” Rushing to finish rounds in the dialysis unit, I glanced at Mrs. Pinto.
“I have a lot of issues, doctor. Alas, nothing is curable!” grinned the 65-year-old woman, with dull eyes conveying her pain.
She had been on hemodialysis for the last 7 years and was recently diagnosed with metastatic breast cancer when evaluated for significant weight loss and anorexia.
I returned to my office, pondering.
There are many unknowns in cancer screening for patients with kidney failure. What are the benefits? What are the risks? Does it substantially change life expectancy? Are the tests available to screen the malignancies valid in patients with kidney failure on dialysis?
‘Yes’.. I mumbled, now making a decision to dive into the literature and see if any data existed.. I wondered ‘how many of these patients with malignancies would have remained undiagnosed until today?’ Nevertheless, it was the time for me to get enlightened.
What is the risk of cancer in patients with kidney failure?
Overall, malignancy is a rare cause of death in patients with kidney failure and the incidence varies with age, dialysis vintage, and co-morbidities. Moreover, patients on hemodialysis and peritoneal dialysis have a similar incidence of malignancy. People aged more than 60 years have higher cancer incidence (except for Taiwanese population, where younger individuals have higher cancer incidence) and lower malignancy rates have been seen in patients with diabetes as many of them succumb to cardiovascular causes. Patients with kidney failure are exposed to a variety of malignancy associated risk factors throughout their life (Table 1).
Table 1. Contributors to malignancy risk in patients with kidney failure
| Contributors | Examples |
| Age | >60 years old (Except for Asians) |
| Native kidney disease | Analgesic nephropathy, Balkan nephropathy |
| Treatment | Cyclophosphamide |
| Viral infections | Hepatitis B, Hepatitis C |
| Dialysis vintage | Acquired cystic kidney disease |
A review of this topic in AJKD reports the standardized incidence rates of cancer in patients with kidney failure on dialysis (Table 2). It is noted that kidney cancer has a standardized incidence rate of 4.03, thus indicating kidney cancer is four times more common to occur in the hemodialysis population compared to the general population. Although patients treated with maintenance dialysis have increased risk of kidney cancer, an ideal screening test has not been determined.
Table 2. Standardized Incidence rates of cancer in hemodialysis patients
| Cancer type | Standard Incidence Rate |
| All types | 1.42 |
| Kidney/Renal pelvis | 4.03 |
| Bladder | 1.57 |
| Breast (female) | 1.42 |
| Non-Hodgkin lymphoma | 1.37 |
| Lung | 1.28 |
| Colon/Rectum | 1.27 |
| Pancreas | 1.08 |
| Prostate | 1.06 |
Characteristics of the potential cancer screening tests which can be considered for patients with kidney failure.
Before opting for a screening test, one should consider the following:
- What are the disease characteristics?
- What are the characteristics of the screening test to be opted?
- What are the patient characteristics for which these tests are applicable?
Following figure summarizes these queries:
Table 3. Optimal characteristic of screening tests for cancer.
| Disease characteristics | Diagnostic test characteristics | Patient Characteristics |
| Associated with substantial morbidity and mortality | Able to effectively detect disease in asymptomatic phase | Prevalence of the disease is high enough to warrant screening |
| Not a rare disease | Highly sensitive and specific | Screening test has been studies in the patient population of interest |
| Natural history and biology is well understood | Test is safe | Trials of therapy show efficacy in the patient of interest at earliest stages of detection |
| Associated with asymptomatic phase that can be detected effectively | Has a reasonable costs associated with testing and testing strategy | False-positive screening tests do not result in unacceptable harm or costs |
| There is an effective treatment of asymptomatic disease | Acceptable to patient population | Mortality benefit of screening is meaningful |
What are the key points I should be aware of before ordering cancer screening tests in patients with kidney failure?
1) Efficacy of malignancy screening tools in patients with kidney failure:
- Unfortunately, there are no studies validating the sensitivity, specificity, positive or negative predictive value of the different cancer screening tests.
- Decision making becomes difficult when a screening test turns out positive in patients with kidney failure. For example, mammography to screen breast cancer in women with kidney failure could lead to a false positive result if significant vascular calcification is present.
- Plasma concentrations of tumor markers are unreliable for screening malignancies in patients with kidney failure. Most tumor markers {eg. cancer antigen 125 (CA 125), carbohydrate antigen 1909 (CA 19-9), carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) antigen, neuron specific enolase (NSE)} are present in high plasma concentrations because these are high molecular glycoproteins accumulate due to kidney failure and are not removed in dialysis. Unlike prostate specific antigen (PSA), which may be a valid screening test for prostate cancer in patients with kidney failure, the free PSA and free/total PSA ratios are unreliable, because of higher molecular weight and less clearance.
- The lower incidence of lung cancer in patients with kidney failure argues against its screening in these individuals.
2) Cost of screening: As the average survival of patients with kidney failure is considerably affected by mortality rates from non-malignancy causes, cost-effectiveness should be considered as an important point.
3) Benefit versus risk: The benefits of screening tests including improvement in quality of life by reducing the pain, anxiety and disability should supersede over the risks like potential exposure to radiation and complications from individual procedures (eg. colonoscopy). Adding to this, “Choosing Wisely” initiative by American Board of Internal Medicine Foundation and Consumer Reports argues against screening for cancers in patients on dialysis with limited life expectancy of less than 5 years and without signs and symptoms.
Is cancer screening really necessary in patients with kidney failure?
Chertow et al performed a cost effective analysis of hypothetical cancer screening programs in the population with kidney failure and compared this to the general population employing declining exponential approximation of life expectancy. The net gain in life expectancy from a typical cancer screening program was calculated to be 5 days or less. The costs per unit of survival benefit provided by cancer screening were 1.6–19.3 times higher in patients with kidney failure compared to the general population depending on age, gender and race. Again, a cost-effective analysis of breast cancer screening in Australian women on dialysis therapy using deterministic Markov model found only 0.1% absolute reduction in breast cancer mortality with a net gain in life expectancy of 1.3 days.
However, there is consensus that patients undergoing kidney transplant evaluation requires screening for malignancies as the transplanted patients will have improved survival and the immunosuppressants pose risk for development of cancer. The KDIGO clinical practice guideline on the evaluation and management of candidates for kidney transplantation recommends the following.
- 11.1.1: We recommend candidates undergo routine cancer screening, as per local guidelines for the general population (1D).
- 11.1.1.1: We suggest chest imaging prior to transplantation in all candidates (2C).
- 11.1.1.2: We suggest chest CT for current or former heavy tobacco users (≥ 30 pack-years) as per local guidelines, and chest radiograph for other candidates (2C).
- 11.1.2: Screen candidates at increased risk for renal cell carcinoma (eg ≥ 3 years dialysis, family history of renal cancer, acquired cystic disease or analgesic nephropathy) with ultrasonography (Not Graded).
- 11.1.3: We suggest cystoscopy to screen for bladder carcinoma in candidates at increased risk, such as those with high-level exposure to cyclophosphamide or heavy smoking (≥ 30 pack-years) (2D).
- 11.1.4: We recommend screening for hepatocellular carcinoma in candidates with cirrhosis prior to transplantation using techniques (eg, ultrasound, α-fetoprotein) and frequency as per local guidelines (1C).
- 11.1.5: We recommend screening for bowel cancer in candidates with inflammatory bowel disease as per local guidelines (1C).
Are there any guidelines to guide screening in patients with kidney failure?
Yes, based on the available literature, the American Cancer Society has suggested recommendations which need to be individualized considering the expected survival, risk factors, and transplant candidacy (Fig 1). As mentioned above, although the risk of renal cell carcinoma (RCC) is high in patients with kidney failure, the absolute incidence is low and there is no optimal method of screening suggested.
Figure 1. Suggested cancer screening algorithm in the maintenance dialysis patients.
In summary, there needs to be an individualistic risk-benefit approach in screening for cancers in patients with kidney failure. Interestingly, older patients who have kidney failure and receive dialysis are more likely to be screened for malignancies by primary care providers, at odds with the Choosing Wisely campaign. Further research is needed to better understand the validity of the screening tools in patients with kidney failure. An individualized approach with shared decision making is important.
Reviewed by Matthew Sparks, MD, S. Sudha Mannemuddhu, MD, Dhwanil Patel, MD, Anju Yadav, MD, Nayan Arora, MD
